selective glycosity inhibitors and their uses

专利摘要:
SELECTIVE GLYCOSITY INHIBITORS AND USE OF THE SAME. The invention provides compounds with marked permeability to selectively inhibit glycosidases, compounds of the compounds and pharmaceutical compositions including the compounds or compounds of the compounds. The invention also provides methods of treating diseases and disorders related to O-GIcNAcase deficiency or overexpression, O-GIcNAc accumulation or deficiency.
公开号:BR112013033098B1
申请号:R112013033098-8
申请日:2012-06-27
公开日:2020-10-20
发明作者:Tong-Shuang Li；Ernest J. Mceachern；David J. Vocadlo；Yuanxi Zhou；Yongbao Zhu；Harold G. Selnick
申请人:Alectos Therapeutics Inc；Merck Sharp & Dohme Corp.；
IPC主号:

专利说明:

FIELD OF THE INVENTION
[1] This application relates to compounds that selectively inhibit glycosidases and uses thereof. BACKGROUND OF THE INVENTION
[2] A wide range of cellular proteins, both nuclear and cytoplasmic, are modified post-translation by the addition of the monosaccharide 2-acetamido-2-deoxy-β-D-glucopyranoside (β-N-acetylglucosamine) which is fixed via a bond O-glycosidics1. This modification is generally referred to as O-linked N-acetylglucosamine or 0-GlcNAc. The enzyme responsible for the post-translational binding of β-N-acetylglucosamine (GlcNAc) to specific serine and threonine residues of numerous nucleocytoplasmic proteins is 0-GlcNAc transferase (OGTp-3. A second enzyme known as 2-acetamido-2- glycoprotein deoxy-β-D-glucopyrananosidase (O-GlcNAcase) D 'removes this post-translational modification to release proteins making the 0-GlcNAc modification a dynamic cycle occurring several times during the life of a protein8.
[3] Proteins modified by 0-GlcNAc regulate a wide range of vital cellular functions, including, for example, transcription9-18, proteosomal degradation13 and cell signaling14. O-GlcNAc is also found in many structural proteins. For example, it has also been found in several cytoskeletal proteins, including neurofilament proteins 12'ly, synapsins1'2Ü, synapsin-specific clathrin protein AP-37, and ankyrin G14. The modification by O-GlcNAc was found to be abundant in the brain11,22. It, too, has been found in proteins clearly implicated in the etiology of several diseases including Alzheimer's disease (AD) and cancer.
[4] For example, it is well established that AD and several related tauopathies including Down's syndrome, Pick's disease, Niemann-Pick disease type C, 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 patients with AD, however, tau becomes hyperphosphorylated, deregulating its normal functions, forming PHFs and finally aggregating to form NFTs. Six isoforms of tau are found in the human brain. All six isoforms of tau are found in NFTs, and all are markedly hyperphosphorylated2j, ~ 4. Tau in healthy brain tissue contains only 2 or 3 phosphate groups, whereas those found in the brains of patients with AD contain, on average, 8 phosphate groups25,26. A clear parallel between the levels of NFT in the brains of patients with AD and the severity of dementia strongly supports a key role for tau dysfunction in AD27-29. The precise causes of this hyperphosphorylation of tau remain elusive. Thus, a considerable effort was devoted to: a) elucidating the molecular physiological basis of the hyperphosphorylation of tau30; and b) identify strategies that could limit the hyperphosphorylation of tau in the hope that it could stop, or even reverse, the progression of Alzheimer's disease31-34. To date, several lines of evidence suggest that the positive regulation of several kinases could be involved in the hyperphosphorylation of tau21'35'36, although, very recently, an alternative basis for this hyperphosphorylation has been advanced21.
[5] In particular, it has been shown that the levels of tau phosphate are regulated by the levels of O-GlcNAc in tau. The presence of O-GlcNAc in tau has stimulated studies that correlate the levels of O-GlcNAc with the levels of phosphorylation of tau. Interest in this field is based on the observation that the modification of O-GlcNAc has been found to occur in many proteins in amino acid residues that are also known to be phosphorylated37-32. Consistent with this observation, it has been found that increases in phosphorylation levels result in decreased 0-GlcNAc levels and, conversely, increased 0-GlcNAc levels are correlated with decreased phosphorylation levels40. This reciprocal relationship between 0-GlcNAc and phosphorylation was called the "Yin-Yang hypothesis" 41 and acquired a strong biochemical support for the discovery that the OGT4 enzyme forms a functional complex with phosphatases that act to remove phosphate groups from proteins42. Like phosphorylation, 0-GlcNAc is a dynamic modification that can be removed and re-installed several times during the lifetime of a protein. Suggestively, the gene encoding 0-GlcNAcase was mapped to a chromosomal locus that is linked to AD7'43. Hyperphosphorylated Tau in human brains with AD had markedly lower levels of 0-GlcNAc than are found in healthy human brains21. Levels of soluble tau protein 0-GlcNAc from human brains affected with AD have been shown to be markedly lower than those in healthy brains21. In addition, PHF from diseased brains has been suggested to be completely lacking any 0-GlcNAc modification whatever it may be21. The molecular basis of this hypoglycosylation of tau is not known, although it may originate from increased kinase activity and / or dysfunction of one of the enzymes involved in the processing of O-GlcNAc. In support of this latter consideration, both in PC-12 neuron cells and in sections of mouse brain tissue, a non-selective inhibitor of N-acetylglucosamidase was used to increase levels of O-GlcNAc in tau, where it was observed that phosphorylation levels have decreased21. The implication of these collective results is that by maintaining healthy levels of O-GlcNAc in AD patients, as by inhibiting the action of O-GlcNAcase, it would be possible to block tau hyperphosphorylation and all the associated effects of tau hyperphosphorylation, including the formation of NFTs and downstream effects. However, because the proper functioning of β-hexosaminidases is critical, any potential therapeutic intervention for the treatment of AD that blocks the action of 0-GlcNAcase would need to avoid concomitant inhibition of both hexosaminidases A and B.
[6] Neurons do not store glucose, so the brain depends on glucose supplied by the blood to maintain its essential metabolic functions. Notably, it has been shown that, within the brain, glucose absorption and metabolism decrease with aging44. Within the brains of patients with AD, marked decreases in glucose use occur and are considered to be a potential cause of neurodegeneration45. The basis for this decreased supply of glucose in the brain with AD46-48 is thought to stem from decreased glucose transport49'5u, impaired insulin signaling 51'5 ", and decreased blood flow53.
[7] In light of this impaired glucose metabolism, it should be noted that of all the glucose entering the cells, 2-5% is diverted to the hexosamine Biosynthetic pathway, thus regulating the cell concentrations of the final product of this pathway, uridine diphosphate -N-acetylglucosamine (UDP-GlcNAc) 54. UDP-GlcNAc is a substrate for the nucleocytoplasmic enzyme O-GlcNAc transferase (OGT) 2-5, which acts to add translationally GlcNAc powders to specific serine and threonine residues of numerous nucleocytoplasmic proteins. OGT recognizes many of its substrates55,56 and binding partners42,57 through its tetratricopeptide repeat (TPR) domains 58,59. As described above, O-GlcNAcase6'7 removes this post-translational modification to release proteins making the O-GlcNAc modification a dynamic cycle occurring several times during the lifetime of a protein8. O-GlcNAc has been found in several proteins at known phosphorylation sites10,38,39,60, including tau and neurofilaments61. In addition, OGT shows unusual kinetic behavior making it perfectly sensitive to concentrations of intracellular substrate UDP-GlcNAc and thus the supply of glucose4-.
[8] Consistent with the known properties of the hexosamine Biosynthetic pathway, the enzymatic properties of OGT, and the reciprocal relationship between 0-GlcNAc and phosphorylation, it has been shown that decreased glucose availability in the brain leads to a hyperphosphorylation of tau45. Thus, the gradual impairment of glucose transport and metabolism, whatever its cause, leads to decreased 0-GlcNAc and hyperphosphorylation of tau (and other proteins). Thus, the inhibition of O-GlcNAcase should compensate for the age-related impairment of glucose metabolism within the brains of healthy individuals as well as patients suffering from AD or related neurodegenerative diseases.
[9] These results suggest that a malfunction in the mechanisms regulating the levels of tau 0-GlcNAc may be vitally important in the formation of NFTs and associated neurodegeneration. Good support for blocking hyperphosphorylation of tau as a therapeutically usable intervention62 has emerged from recent studies showing that when transgenic mice harboring human tau are treated with kinase inhibitors, they do not develop typical motor defects34 and, in another case33, show decreased levels of insoluble tau. These studies provide a clear link between decreased levels of phosphorylation of tau and the alleviation of AD-like behavioral symptoms in a murine model of this disease. In fact, pharmacological modulation of tau hyperphosphorylation is widely recognized as a valid therapeutic strategy for the treatment of AD and other neurodegenerative disorders63.
[10] Small O-GlcNAcase inhibitor molecules, to limit hyperphosphorylation of tau, have been considered for the treatment of AD and related tauopathies12'4. Specifically, the O-GlcNAcase inhibitor tiamet-G has been implicated in reducing tau phosphorylation in PC-12 cells cultured in pathologically relevant sites64. In addition, oral administration of tiamet-G to healthy Sprague-Dawley rats has been implicated in reduced phosphorylation of tau in Thr231, Ser396 and Ser422 in both the cortex and hippocampus of the rat64.
[11] There is also consistent evidence indicating that increased levels of O-GlcNAc protein modification provide protection against the pathogenic effects of stress on heart tissue, including stress caused by ischemia, hemorrhage, hypervolemic shock, and calcium paradox. For example, activation of the hexosamine Biosynthetic (BPH) pathway by administration of glucosamine has been shown to have a protective effect in animal models of ischemia / reperfusion, 6j “'1 trauma hemorrhage, 72'74 hypervolemic shock,' ° and paradox of calcium.75''7 In addition, strong evidence indicates that these cardioprotective effects are mediated by high levels of 0-GlcNAc protein modification. 65,66, 68, / 1,73,76_'9 There is also evidence that modification by 0-GlcNAc plays a role in a variety of neurodegenerative diseases, including Parkinson's and Huntington's disease.77
[12] Humans have three genes encoding enzymes that cleave terminal β-N-acetyl-glucosamine residues from glycoconjugates. The first of these encodes 0-GlcNAcase. O-GlcNAcase is a member of the 84 glycoside hydrolases family that includes enzymes from organisms as diverse as prokaryotic pathogens for humans (for the classification of glycoside hydrolases families see Coutinho, PM and Henrissat, B. (1999) Carbohydrate-Active Enzymes Server at URL: http://afmb.cnrs-mrs.fr/CAZY/.81'82) O-GlcNAcase acts to hydrolyze 0-GlcNAc outside residues of post-translation modified proteins and serine and threonine. 1,6'7'83 '84 Consistent with the presence of 0-GlcNAc in 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 has probably been isolated before, 18'19 some 20 years elapsed before its biochemical role in acting to cleave O-GlcNAc from protein serine and threonine residues is understood .6 More recently, O-GlcNAcase has been cloned, 7 partially characterized / 0 and suggested to have an additional activity like a histone acetyl transferase. However, very little is known about the catalytic mechanism of this enzyme.
[13] The other two genes, HEXA and HEXB, encode enzymes catalyzing the hydrolytic dividing of terminal β-N-acetylglucosamine residues from glycoconjugates. The HEXA and HEXB gene products predominantly yield two dimeric isozymes, hexosaminidase A and hexosaminidase B, respectively. Hexosaminidase A (αβ), a heterodimeric isozyme, is composed of an a- subunit and a β ~ subunit. Hexosaminidase B (ββ), a homodimeric isozyme, is composed of two β-subunits. The two subunits, α- and β-, have a high level of sequence identity. Both of these enzymes are classified as members of the 20 family of glycoside hydrolases and are normally located within lysosomes. The correct functioning of these lysosomal β-hexosaminidases is critical for human development, a fact that is underlined by tragic genetic diseases, such as Tay-Sach and Sandhoff diseases, which originate from a dysfunction in, respectively, hexosaminidase A and hexosaminidase B. bb These enzymatic deficiencies cause an accumulation of glycolipids and glycoconjugates in lysosomes resulting in neurological damage and deformation. The deleterious effects of ganglioside accumulation at the organism level have not yet been discovered. 89
[14] As a result of the biological importance of these β-N-acetyl-glucosaminidases, small molecules inhibiting glycosidases90-93 have received great attention94, both as a tool to elucidate the role of these enzymes in biological processes and in the development of potential therapeutic applications . Controlling glycosidase function using small molecules offers several advantages over genetic "knockout" studies including the ability to quickly vary doses or withdraw treatment altogether.
[15] However, a major challenge in the development of inhibitors to block the function of mammalian glycosidases, including O-GlcNAcase, is the large number of functionally related enzymes present in higher eukaryotic tissues. Thus, the use of non-selective inhibitors in the study of the cellular and physiological role of a particular enzyme is complicated due to the complex phenotypes that arise from the concomitant inhibition of these functionally related enzymes. In the case of β-N-acetylglucosaminidases, many compounds that act to block the function of O-GlcNAcase are non-specific and act in a potent way to inhibit lysosomal β-hexosaminidases.
[16] Few of the best-characterized β-N-acetyl-glucosaminidases inhibitors that have been used in studies of post-translational modification of O-GlcNAc within both cells and tissues are streptozotocin (STZ), 2'-methyl-aD -glucopyran- [2,1-d] -Δ2'-thiazoline (NAG-thiazoline) and 0- (2-acetamido-2-deoxy-D-glucopyranosylidene) amino N-phenylcarbamate (PUGNAc) .14,95-98
[17] STZ has long been used as a diabetogenic compound because it has a particularly damaging effect on islet β cells.99 STZ exerts its cytotoxic effects through both the alkylation of cellular DNA99'100 as well as the generation of species of radical including nitrous oxide.101 The resulting DNA strand promotes the activation of poly (ADP-ribose) polymerase (PARP) 102 with the general effect of depleting NAD + cell levels and ultimately leading to cell death. 103,104 Other researchers have proposed, on the contrary, that the toxicity of STZ is a consequence of the irreversible inhibition of O-GlcNAcase, which is highly expressed within the β cells of the islets. 95,105 This hypothesis, however, was called into question by two independent research groups. 10d'107 Because cellular levels of O-GlcNAc in proteins increase in response to many forms of cellular stress105, it seems possible that STZ results in increased levels of O-GlcNAc modification in proteins by inducing cellular stress rather than through any specific and direct action on 0- GlcNAcase. In fact, Hanover and colleagues have demonstrated that STZ functions as a poor and sometimes selective inhibitor of 0-GlcNAcaselu9 and although it has been proposed by others that STZ acts to irreversibly inhibit 0-GlcNAcase, 110 there is no clear demonstration in this way. of action. More recently, it has been shown that STZ does not irreversibly inhibit O-GlcNAcase.111
[18] NAG-thiazoline has been found to be a potent inhibitor of family 20 of hexosaminidases, 93,112 and more recently, family 84 of 0-GlcNAcases.111 Despite its potency, an inconvenience of using NAG-thiazoline in a complex biological context is that it lacks selectivity and thus disrupts multiple cellular processes.
[19] PUGNAc is another compound that suffers from the same problem of lack of selectivity, although it has enjoyed use as an inhibitor of both human O-GlcNAcase5,113 and the 20 family of human β-hexosaminidases114. This molecule, developed by Vasella and collaborators, was found to be a potent competitive inhibitor of β-N-acetyl-glucosaminidases from Canavalia ensiformis, Mucor rouxii, and bovine kidney β-hexosaminidase.91 It has been shown that the administration of PUGNAc in a rat model of trauma hemorrhage decreases circulating levels of pro-inflammatory cytokines TNF-a and IL-6.115 It has also been shown that administration of PUGNAc in a model based on lymphocyte activation cells decreases the production of IL-cytokine 2.116 Subsequent studies have indicated that PUGNAc can be used in an animal model to reduce the extent of myocardial infarction after occlusions of the left coronary artery.117 Of particular significance is the fact that the elevation of 0-GlcNAc levels by administration of PUGNAc, a 0-GlcNAcase inhibitor, in a mouse model of trauma hemorrhage improves cardiac function.115,118 In addition, elevated levels of 0-GlcNAc per treatment with PUGNAc in a ischemia / reperfusion damage cell model using neonatal rat ventricular myocytes improved cell viability and reduced necrosis and apoptosis compared to untreated cells 119.
[20] More recently, it has been suggested that the selective O-GlcNAcase inhibitor NButGT exhibits protective activity in cell-based models of ischemia / reperfusion and cell stresses, including oxidative stress.120 This study suggests the use of O-GlcNAcase inhibitors for raise the levels of the O-GlcNAc protein and thus avoid the pathogenic effects of stress on cardiac tissue.
[21] International patent applications PCT / CA2006 / 000300, filed on March 1, 2006, published under No. WO 2006/092049 on September 8, 2006; PCT / CA2007 / 001554, filed on August 31, 2007, published under No. WO 2008/025170 on March 6, 2008; PCT / CA2009 / 001087, filed on July 31, 2009, published under WO No. 2010/012106 on February 4, 2010; PCT / CA2009 / 001088, filed on July 31, 2009, published under WO 2010/012107 on February 4, 2010; PCT / CA2009 / 001302, filed on September 16, 2009, published under WO 2010/037207 on April 8, 2010; PCT / CA2011 / 000548, filed on May 10, 2011, published under WO No. 2011/140640 on November 17, 2011; PCT / CA / 2011/001241, filed on November 8, 2011, published under WO 2012/061927 on May 18, 2012; and PCT / US2011 / 059668, filed on November 8, 2011, published under WO 2012/064680 on May 18, 2012, describe selective O-GlcNAcase inhibitors. SUMMARY OF THE INVENTION
[22] The invention provides, in part, compounds for compounds, uses of the compounds and prodrugs, pharmaceutical compositions including the compounds or compounds of the prodrugs, and methods of treating diseases and disorders related to deficiency or overexpression of O-GlcNAcase, and / or accumulation or deficiency of 0-GlcNAc.
[23] In one aspect, the invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
wherein R1 and R ~ can independently be H or F; R3 can be OR and R can be H, or R "can be H and R can be OR5; each R5 can be independently H or Cx-g acyl; R6 can be H, F, or OR5; R can be selected from the group consisting of: H, F, C1-2 alkyl, C2_2 alkenyl, C2_6 alkynyl, each excluding hydrogen and F optionally substituted from one to the maximum number of substituents with one or more fluorine or OH; R8 may be selected from the group consisting of: C2_2 alkyl, C2-8 alkenyl, C2_2 alkynyl, C3-g cycloalkyl, aryl and heteroaryl, optionally substituted from one to the maximum number of substituents with one or more fluorine or OH; or R7 and R8 and the carbon atom to which they are attached can come together to form vinyl; and each R9 can be independently selected from the group consisting of: H, C1-6 alkyl, C3-S alkenyl, C3_6 alkynyl, and Ci-S alkoxy, where Ci-6 alkyl, C3- and alkenyl, C3-6 alkynyl, or Ci-6 alkoxy can be optionally substituted from one to the maximum number of substituents with one or more of fluorine, OH, or methyl, or the two R9 groups can be connected together with the nitrogen atom to which they are attached to form a ring, said ring, optionally, independently substituted from one to the maximum number of substituents with one or more of fluorine, OH, or methyl; where when R6 is OR5, then R7 is different from F.
[24] In alternative embodiments, the invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
or C1-6 acyl; R6 can be H, F, or 0R5; R7 can be selected from the group consisting of: H, F, C1-8 alkyl, C2_8 alkenyl, C2_8 alkynyl, each excluding hydrogen and optionally substituted from one to the maximum number of substituents with one or more of fluorine or OH; R8 can be selected from the group consisting of: C1-8 alkyl, C2_8 alkenyl, C2_8 alkynyl, C3_6 cycloalkyl, aryl and heteroaryl, optionally substituted from one to the maximum number of substituents with one or more of fluorine or OH; or R7 and R8 and the carbon atom to which they are attached can come together to form vinyl; and each R9 can be independently selected from the group consisting of: H, C1-6 alkyl, C3-6 alkenyl, C3_6 alkynyl, and C1-6 alkoxy, where C1-6 alkyl, C3_6 alkenyl, C3_6 alkynyl, or Ci -6 alkoxy can be optionally substituted from one to the maximum number of substituents with one or more of fluorine, OH, or methyl, or the two R9 groups can be connected together with the nitrogen atom to which they are attached to form a ring, said ring, optionally independently substituted from one to the maximum number of substituents with one or more of fluorine, OH, or methyl; where when R6 is OR5, then R7 is different from F.
[25] In alternative embodiments, the invention provides a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof:
where R1 can be H and R2 can be F, or R1 can be F and R ~ can be H; each R5 can be, independently, H or Ci-e acyl; R6 can be H, F, or OR5; R7 can be selected from the group consisting of: H, F, C1-8 alkyl, C2-s alkenyl, C2-8 alkynyl, each excluding hydrogen and F optionally substituted from one to the maximum number of substituents with one or more fluorine or OH; R8 can be selected from the group consisting of: C2-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3_e cycloalkyl, aryl and heteroaryl, optionally substituted from one to the maximum number of substituents with one or more than fluorine or OH; or R7 and R8 and the carbon atom to which they are attached can come together to form vinyl; and each R9 can be independently selected from the group consisting of: H, C1-6 alkyl, C3-6 alkenyl, C3_s alkynyl, and C1-6 alkoxy, wherein C1-6 alkyl, C3_s alkenyl, C3-3 alkynyl, or C2-6 alkoxy can optionally be substituted from one to the maximum number of substituents with one or more of fluorine, OH, or methyl, or the two R9 groups can be connected together with the nitrogen atom to which they are attached to forming a ring, said ring optionally independently substituted from one to the maximum number of substituents with one or more of fluorine, OH, or methyl; where when R6 is OR5, then R7 is different from F.
[26] In alternative embodiments, the invention provides a compound of Formula (lb) or a pharmaceutically acceptable salt thereof:
wherein R1 and R2 can independently be H or F; each R5 can be, independently, H or C1-6 acyl; R8 can be selected from the group consisting of: C1-3 alkyl, C2_8 alkenyl, C2-s alkynyl, C3_6 cycloalkyl, aryl and heteroaryl, optionally substituted from one to the maximum number of substituents with one or more fluorine or OH; and each R9 can be independently selected from the group consisting of: H, C2-6 alkyl, C3_6 alkenyl, C3_6 alkynyl, and C1-6 alkoxy, where C1-6 alkyl, C3_6 alkenyl, C3_6 alkynyl, or C2- 6 alkoxy can optionally be substituted from one to the maximum number of substituents with one or more of fluorine, OH, or methyl, or the two R9 groups can be connected together with the nitrogen atom to which they are attached to form a ring, said ring, optionally independently substituted from one to the maximum number of substituents with one or more of fluorine, OH, or methyl.
[27] In alternative embodiments, the invention provides a compound of Formula (Ic) or a pharmaceutically acceptable salt thereof:
wherein each R5 can independently be H or C1-6 acyl; Rb can be selected from the group consisting of: C1-8 alkyl, C2_8 alkenyl, C2_8 alkynyl, C3-6 cycloalkyl, aryl and heteroaryl, optionally substituted from one to the maximum number of substituents with one or more fluorine or OH; and each R9 can be independently selected from the group consisting of: H, C1-6 alkyl, C3_6 alkenyl, C3_6 alkynyl, and C1-S alkoxy, wherein C1-6 alkyl, C3_6 alkenyl, C3_6 alkynyl, or C2- s alkoxy can optionally be substituted from one to the maximum number of substituents with one or more of fluorine, OH, or methyl, or the two R9 groups can be connected together with the nitrogen atom to which they are attached to form a ring, said ring, optionally independently substituted from one to the maximum number of substituents with one or more of fluorine, OH, or methyl.
[28] In alternative embodiments, the invention provides a compound of Formula (Id) or a pharmaceutically acceptable salt thereof:
wherein each R5 can independently be H or C1-6 acyl; R6 can be H, F, or OR5; R7 can be selected from the group consisting of: H, F, C1-3 alkyl, C2_8 alkenyl, C2-S alkynyl, each excluding hydrogen and optionally substituted from one to the maximum number of substituents with one or more than fluorine or OH; R8 can be selected from the group consisting of: C1-alkyl, C2_alkenyl, C2_6 alkynyl, C3-s cycloalkyl, aryl and heteroaryl, optionally substituted from one to the maximum number of substituents with one or more fluorine or OH; or R and R ':' and the carbon atom to which they are attached can join to form vinyl; and each R9 can be independently selected from the group consisting of: H, C1-6 alkyl, C3_alkenyl, C3_and alkynyl, and C1-6 alkoxy, where Cx-g alkyl, C3_6 alkenyl, C3_6 alkynyl, or Ci- 6 alkoxy can optionally be substituted from one to the maximum number of substituents with one or more of fluorine, OH, or methyl, or the two R9 groups can be connected together with the nitrogen atom to which they are attached to form a ring, said ring, optionally independently substituted from one to the maximum number of substituents with one or more of fluorine, OH, or methyl; where when R6 is OR5, then R 'is different from F.
[29] In alternative embodiments, the invention provides a compound of Formula (le) or a pharmaceutically acceptable salt thereof:
wherein each R5 can independently be H or C1-6 acyl; R6 can be H, F, or OR5; R7 can be selected from the group consisting of: H, F, C1-8 alkyl, C2-8 alkenyl, C2-3 alkynyl, each excluding hydrogen and F optionally substituted from one to the maximum number of substituents with one or more fluorine or OH; R8 can be selected from the group consisting of: C1-8 alkyl, C2- $ alkenyl, C2-s alkynyl, C3_e cycloalkyl, aryl and heteroaryl, optionally substituted from one to the maximum number of substituents with one or more of fluorine or OH; or R7 and R8 and the carbon atom to which they are attached can come together to form vinyl; and each R9 can be independently selected from the group consisting of: H, C1-6 alkyl, C3_6 alkenyl, C3_6 alkynyl, and C1-6 alkoxy, wherein C1-6 alkyl, C3_6 alkenyl, C3_6 alkynyl, or Ci- 6 alkoxy can optionally be substituted from one to the maximum number of substituents with one or more of fluorine, OH, or methyl, or the two R9 groups can be connected together with the nitrogen atom to which they are attached to form a ring, said ring, optionally independently substituted from one to the maximum number of substituents with one or more of fluorine, OH, or methyl; where when R6 is OR ”', then R is different from F.
[30] In alternative embodiments, the invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
wherein R1 and R2 can independently be H or F; RJ can be OR5 and R4 can be H, or R3 can be H and R4 can be OR5; each R5 can be, independently, H or acyl; RD can be H, F, or OR5; R7 can be selected from the group consisting of: H, F, C1-8 alkyl, C2_8 alkenyl, C2_8 alkynyl, each excluding hydrogen optionally substituted from one to the maximum number of substituents with fluorine and OH; R8 can be selected from the group consisting of: C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-s cycloalkyl, aryl and heteroaryl, optionally substituted from one to the maximum number of fluorine substituents and OH; and each R9 can be independently selected from the group consisting of: H, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, or C1-6 alkoxy; and two R9 groups can be connected together with the nitrogen atom to which they are attached to form a ring; where when R6 is OR5, then R7 is different from F.
[31] In alternative modalities, the compound can be a prodrug; the compound can selectively inhibit a 0-glycoprotein 2-acetamido-2-deoxy-β-D-glucopyranidasidase (0-GlcNAcase); the compound can selectively bind an O-GlcNAcase (for example, a mammalian O-GlcNAcase); the compound can selectively inhibit the dividing of 2-acetamido-2-deoxy-β-D-glucopyranoside (0-GlcNAc); the compound may not substantially inhibit a mammalian β-hexosaminidase.
[32] In alternative embodiments, a compound according to Formula (I), Formula (Ia), Formula (lb), Formula (Ic), Formula (Id), or Formula (le) may have a marked permeability.
[33] In alternative aspects, the invention provides a pharmaceutical composition including a compound according to the invention, in combination with a pharmaceutically acceptable carrier.
[34] In alternative aspects, the invention provides methods of selectively inhibiting an O-GlcNAcase, or of inhibiting an O-GlcNAcase in an individual in need of it, or of increasing the level of O-GlcNAc, or of treating a disease neurodegenerative, tauopathy, cancer or stress, in an individual in need of it, by administering to the individual an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
wherein R1 and R2 can independently be H or F; R2 can be OR5 and R4 can be H, or R2 can be H and R4 can be OR5; each R5 can be, independently, H or C1-6 acyl; R6 can be H, F, or OR5; R7 can be selected from the group consisting of: H, F, C1-8 alkyl, C2_8 alkenyl, C2_8 alkynyl, each excluding hydrogen and optionally substituted from one to the maximum number of substituents with one or more of fluorine or OH; R8 can be selected from the group consisting of: C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3_6 cycloalkyl, aryl and heteroaryl, optionally substituted from one to the maximum number of substituents with one or more of fluorine or OH; or R7 and R8 and the carbon atom to which they are attached can come together to form vinyl; and each R9 can be independently selected from the group consisting of: H, C1-6 alkyl, C3_6 alkenyl, C3_6 alkynyl, and C1-6 alkoxy, wherein C1-6 alkyl, C3-alkenyl, C3_6 alkynyl, or C1-6 alkoxy can optionally be substituted from one to the maximum number of substituents with one or more of fluorine, OH, or methyl, or the two R9 groups can be connected together with the nitrogen atom to which they are attached to forming a ring, said ring, optionally independently substituted from one to the maximum number of substituents with one or more of fluorine, OH, or methyl; where when R6 is OR5, then R7 is different from F. The condition may be Alzheimer's disease, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), argyrophilic grain dementia, Bluit's disease, corticobasal degeneration (CBD), pugilistic dementia, diffuse neurofibrillary tangles with calcification, Down syndrome, British familial dementia, Danish familial dementia, fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Gerstmann-Straussler-Scheinker disease, parkinsonism guadeloupe disease, Hallevorden-Spatz disease (neurodegeneration with type 1 brain iron accumulation), multiple system atrophy, myotonic dystrophy, Niemann-Pick disease (type C), Pallido-ponto-nigral degeneration, Guam parkinsonism-dementia complex , Pick's disease (PiD), post-encepfalltic parkinsonism (PEP), prion diseases (including Creutzfeldt-Jakob disease (CJD), variant of Creutzfeldt-Jakob disease (vCJD), insomnia fatal familial, and kuru), progressive supercortical gliosis, progressive supranuclear palsy (PSP), Richardson's syndrome, subacute sclerosing panencephalitis, tangle only dementia, Huntington's disease, Parkinson's disease, schizophrenia, mild cognitive impairment (MCI), neuropathy (including peripheral neuropathy, autonomic neuropathy, neuritis, and diabetic neuropathy), or glaucoma. The stress can be a cardiac disorder, for example, ischemia; bleeding; hypovolemic shock; myocardial infarction; an interventional cardiology procedure; cardiac bypass surgery; fibrinolytic therapy; angioplasty; and stent placement.
[35] In alternative aspects, the invention provides a method of treating a condition mediated by 0-GlcNAcase that excludes a neurodegenerative disease, tauopathy, cancer or stress, in an individual in need of it, by administering to the individual an amount efficacy of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
wherein R1 and R2 can independently be H or F; R ~ can be OR5 and R4 can be H, or R5 can be H and R4 can be OR5; each R5 can be, independently, H or C1-6 acyl; R6 can be H, F, or OR; R can be selected from the group consisting of: H, F, C1-8 alkyl, C2_8 alkenyl, C2_8 alkynyl, each excluding hydrogen and F optionally substituted from one to the maximum number of substituents with one or more fluorine or OH; R8 can be selected from the group consisting of: C2-8 alkyl, C2-8 alkenyl, C2_8 alkynyl, C3-6 cycloalkyl, aryl and heteroaryl, optionally substituted from one to the maximum number of substituents with one or more of fluorine or OH; or R and R8 and the carbon atom to which they are attached can come together to form vinyl; and each R2 can 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, wherein C 1-6 alkyl, C 3-6 alkenyl, C 3- alkynyl, or C 1-6 alkyl. 6 alkoxy can optionally be substituted from up to a maximum number of substituents with one or more of fluorine, OH, or methyl, or the two R9 groups can be connected together with the nitrogen atom to which they are attached to form a ring said ring optionally independently substituted from one to the maximum number of substituents with one or more of fluorine, OH, or methyl; where when R6 is OR5, then R7 is different from F. In some modalities, the condition may be of inflammatory or allergic diseases, such as asthma, allergic rhinitis, lung hypersensitivity diseases, hypersensitivity pneumonitis, eosinophilic pneumonia, delayed type hypersensitivity , atherosclerosis, interstitial lung disease (ILD), (for example, idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity response, allergy to drugs, allergy to insect bites, autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Guillain-Barré syndrome, systemic lupus erythematosus, myasthenia gravis, autoimmune glomerulonephritis, thyroid glandulitis immune, graft rejection, including allograft rejection, graft-versus-host disease, inflammatory bowel disease, such as Crohn'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, (for example, necrotizing, cutaneous and hypersensitivity vasculitis); eosinophilic kernel, and eosinophilic fasciitis; graft rejection, in particular but not limited to, solid organ transplants, such as heart, lung, liver, kidney; and pancreas transplants (for example, allografts from the kidney, and lung); epilepsy, pain, fibromyalgia; stroke, for example, neuroprotection after a stroke.
[36] In alternative modalities, R1 and R3 can be, independently, H or F; R3 can be OR5 and R4 can be H, or R3 can be H and R4 can be OR5; each R5 can be, independently, H or C1-6 acyl; R6 can be H, F, or OR5; R7 can be selected from the group consisting of: H, F, C1-8 alkyl, C2_2 alkenyl, C2_6 alkynyl, each excluding hydrogen and optionally substituted from one to the maximum number of substituents with one or more fluorine or OH; R5 can be selected from the group consisting of: C2-2 alkyl, C2_2 alkenyl, C2_8 alkynyl, C3-6 cycloalkyl, aryl and heteroaryl, optionally substituted from one to the maximum number of substituents with one or more fluorine or OH; or R 'and R5 and the carbon atom to which they are attached can join to form vinyl; Each R9 can be independently selected from the group consisting of: H, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and C2-6 alkoxy, where C1-6 alkyl, C3-6 alkenyl, C3 -6 alkynyl, or C1-6 alkoxy can optionally be substituted from one to the maximum number of substituents with one or more fluorine, OH, or methyl, or the two R9 groups can be connected together with the nitrogen atom to the which they are attached to form a ring, said ring, optionally independently substituted from one to the maximum number of substituents with one or more of fluorine, OH, or methyl; where when R ”is OR5, then R7 is different from F. Administration can increase the level of O-GlcNAc in the individual. The individual may be a human.
[37] In alternative aspects, the invention provides the use of a compound of an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
wherein R and R can independently be H or F; R "can be OR5 and R4 can be H, or R5 can be H and R4 can be OR5; each R5 can independently be H or C1-6 acyl; R" can be H, F, or OR5; R7 can be selected from the group consisting of: H, F, C2-8 alkyl, C2_8 alkenyl, C2_8 alkynyl, each excluding hydrogen and optionally substituted from one to the maximum number of substituents with one or more fluorine or OH; R4 can be selected from the group consisting of: C2-8 alkyl, C2-8 alkenyl, C2_8 alkynyl, C3-6 cycloalkyl, aryl and heteroaryl, optionally substituted from one to the maximum number of substituents with one or more fluorine or OH; or R7 and R8 and the carbon atom to which they are attached can bond to form vinyl; and each R9 can be independently selected from the group consisting of: H, C2-6 alkyl, C8-S alkenyl, C2-s alkynyl, and C2-6 alkoxy, where C1-8 alkyl, C3-6 alkenyl, C3-6 alkynyl, or C1-6 alkoxy can be optionally substituted partly go from one to the maximum number of substituents with one or more fluorine, OH, or methyl, or the two R9 groups can be connected together with the nitrogen atom to which they are attached to form a ring, said ring, optionally, independently substituted from one to the maximum number of substituents with one or more of fluorine, OH, or methyl; where when R6 is OR5, then R7 is different from F in the preparation of a drug. The medication may be to selectively inhibit an O-GlcNAcase, to increase the level of O-GlcNAc, to treat a condition modulated by an O-GlcNAcase, to treat a neurodegenerative disease, a tauopathy, a cancer, or stress.
[38] In alternative aspects, the invention provides a method for screening for a selective inhibitor of a 0-GlcNAcase, by a) contacting a first sample with a test compound; b) contact of a second sample with a compound of Formula (I)
wherein R1 and R "may independently be H or F; R3 may be OR" and R4 may be H, or R3 may be H and R4 may each R ° may independently be H or Ci-S acyl; R "can be H, F, or OR5; R7 can be selected from the group consisting of: H, F, C1-8 alkyl, C2-8 alkenyl, C2-2 alkynyl, each excluding hydrogen and F optionally substituted from from one to the maximum number of substituents with one or more fluorine or OH; R8 can be selected from the group consisting of: C1-6 alkyl, C2-8 alkenyl, Cb-s alkynyl, C3-e cycloalkyl, aryl and heteroaryl, optionally substituted from one to the maximum number of substituents with one or more of fluorine or OH; or R7 and R8 and the carbon atom to which they are attached can be joined to form vinyl; and each R9 can be independently selected from the group consisting of: H, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and C1- g alkoxy, wherein C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl C1-6 alkoxy can be optionally substituted from one to the maximum number of substituents with one or more of fluorine, OH, or methyl, or the two R9 groups can be connected together with the nitrogen atom to which they are attached to form a ring, said ring, optionally independently substituted from one to the maximum number of substituents with one or more of fluorine, OH, or methyl; where when R6 is OR5, then R7 is different from F; c) determine the level of inhibition of 0-GlcNAcase in the first and second samples, where the test compound is a selective inhibitor of an O-GlcNAcase if the test compound exhibits the same or greater inhibition of 0-GlcNAcase when compared to the compound of Formula (I)
[39] This summary of the invention does not necessarily describe all features of the invention. DETAILED DESCRIPTION
[40] The invention provides, in part, new compounds that are capable of inhibiting an O-glycoprotein 2-acetamido-2-deoxy-β-D-glucopyranidasidase (O-GlcNAcase). In some embodiments, O-GlcNAcase is a mammalian O-GlcNAcase, like a rat, mouse or human O-GlcNAcase.
[41] In some embodiments, one or more of the compounds according to the invention exhibit marked 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 (for example, PAMPA test); Appropriate techniques for measuring effective permeability (Peff) or apparent permeability (Papp) 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 marked permeability when tested in one or more of these tests to determine Peff or Papp. In some embodiments, a compound that exhibits marked permeability exhibits greater oral absorption. In some embodiments, a compound that exhibits marked permeability exhibits greater penetration into the brain when administered in vivo. In some embodiments, a compound that exhibits marked permeability achieves higher concentrations in the brain when administered in vivo. In some embodiments, a compound that exhibits marked permeability exhibits a higher brain / plasma concentration ratio when administered in vivo. In some embodiments, "marked permeability" means an increase in Pθff or Papp measured by any value between 10% and 100%, or by any integer value between 10% and 100%, for example, 10%, 20%, 30 %, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or above 100%, or an increase by 1 time, 2 times, or 3 times, or more, when compared to an appropriate reference compound, described in, for example, WO 2006/092049 or WO 2008/025170. An appropriate reference compound can be, for example, (3aR, 5R, 6S, 7R, 7aR) -5- (hydroxymethyl) -2-propyl-5, 6, 7,7a-tetrahydro-3aH-pyran [3,2 -d] thiazole-6,7-diol, or (3aR, 5R, 6S, 7R, 7aR) -2- (ethylamino) -5- (hydroxymethyl) -5,6,7,7a- tetrahydro-3aH-pyran [ 3,2-d] thiazole-6,7-diol, or (3aR, 5R, 6S, 7R, 7aR) -2- (dimethylamino) -5- (hydroxymethyl) - 5,6,7, 7a-tetrahydro-3aH -pyran [3,2-d] thiazole-6,7-diol. In some embodiments, "enhanced permeability" means a measurable Papp value (i.e., a value greater than zero) in the test described below for the determination of Papp in LLC-PK1 cells. In some embodiments, "enhanced permeability" means a Papp value greater than 2 x 10 "b cm / s in the test described below for the determination of Papp in LLC-PK1 cells. In alternative modalities, "enhanced permeability" means a Papp value in the range of 2 x 10 “6 cm / s to 35 x 10“ 6 cm / s in the test described below for the determination of Papp in LLC-PK1 cells.
[42] In some embodiments, a compound according to the invention exhibits superior selectivity in inhibiting a 0-GlcNAcase. In some embodiments, one or more of the compounds according to the invention are more selective for a 0-GlcNAcase over a β-hexosaminidase. In some embodiments, one or more of the compounds selectively inhibit the activity of a mammalian O-GlcNAcase on a mammalian β-hexosaminidase. In some embodiments, a selective inhibitor of an O-GlcNAcase does not substantially inhibit a β-hexosaminidase. In some embodiments, β-hexosaminidase is a mammalian β-hexosaminidase, like a rat, mouse or human β-hexosaminidase. A compound that "selectively" inhibits an O-GlcNAcase is a compound that inhibits the biological activity or function of an O-GlcNAcase, but does not substantially inhibit the biological activity or function of a β-hexosaminidase. For example, in some embodiments, a selective inhibitor of an O-GlcNAcase selectively inhibits the dividing of 2-acetamido-2-deoxy-β-D-glucopyranoside (0-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 the hyperphosphorylation of a tau protein and / or inhibits the formation of NFTs. By "inhibit", "inhibition" or "inhibiting" is meant a decrease by any value between 10% and 90%, or by any integer value between 30% and 60%, or above 100%, or a decrease for 1 time, 2 times, 5 times, 10 times or more. It should be understood that inhibition does not require complete inhibition. In some embodiments, a selective inhibitor of an O-GlcNAcase raises or increases the levels of O-GlcNAc, for example, levels of protein or polypeptide modified by O-GlcNAc, in cells, tissues or organs (for example, in brain tissue , muscle or heart (cardiac) and in animals. By "raising" or "increasing", it means an increase by any value between 10% and 90%, or any whole number between 30% and 60%, or above 100%, or an increase by 1 time, 2 times, 5 times, 10 times, 15 times, 25 times, 50 times, 100 times or more.In some embodiments, a selective inhibitor of a 0- GlcNAcase exhibits a ratio selectivity, as described here, 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, 10000, 25000, 50000, 75000, or any value within or about the described range.
[43] One or more of the compounds of the present invention elevate levels of O-GlcNAc in polypeptides or proteins modified by O-GlcNAc in vivo specifically via interaction with an O-GlcNAcase enzyme, and are effective in treating conditions that require or respond to inhibition of O-GlcNAcase activity.
[44] In some embodiments, one or more of the compounds of the present invention are usable as agents that produce a decrease in tau phosphorylation and NET formation. In some embodiments, one or more of the compounds are thus usable to treat Alzheimer's disease and related tauopathies. In some embodiments, one or more of the compounds are thus able to treat Alzheimer's disease and related tauopathies by decreasing the phosphorylation of tau and reducing the formation of NET as a result of increasing the levels of tau O-GlcNAc. In some embodiments, one or more of the compounds produces an increase in the levels of O-GlcNAc modification in polypeptides or proteins modified by O-GlcNAc, and are thus usable for the treatment of disorders responsive to such increases in O-GlcNAc modification; these disorders include, but are not limited to, neurodegenerative, inflammatory, cardiovascular, and immune regulatory diseases. In some embodiments, a compound is also usable as a result of other biological activities related to its ability to inhibit the activity of glycosidase enzymes. In alternative embodiments, one or more of the compounds of the invention are valuable tools in the study of the physiological role of 0-GlcNAc at the level of cells and organisms.
[45] In alternative embodiments, the invention provides methods of enhancing or raising the levels of modification of 0-GlcNAc in protein, 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 the formation of NFTs, in animal subjects, such as veterinary and human subjects.
[46] In specific embodiments, the invention provides compounds generally described by Formula (I) and the salts, prodrugs, and enantiomeric forms thereof:

[47] As specified in Formula (I): R1 and R2 can be, independently, H or F; R3 can be OR5 and R4 can be H, or R3 can be H and R4 can be OR5; each R5 can be, independently, H or Ci-g acyl; R6 can be H, F, or OR5; R7 can be selected from the group consisting of: H, F, C1-3 alkyl, C2_8 alkenyl, C2_8 alkynyl, each excluding hydrogen and optionally substituted from one to the maximum number of substituents with one or more fluorine or OH; Rb can be selected from the group consisting of: C1-8 alkyl, C2_8 alkenyl, C2_8 alkynyl, C3-6 cycloalkyl, aryl and heteroaryl, optionally substituted from one to the maximum number of substituents with one or more fluorine or OH; or R7 and R3 and the carbon atom to which they are attached can come together to form vinyl; and each R9 can be independently selected from the group consisting of: H, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and C1-S alkoxy, wherein C1-6 alkyl, C3_6 alkenyl, C3_6 alkynyl, or C2-6 alkoxy can optionally be substituted from one to the maximum number of substituents with one or more of fluorine, OH, or methyl, or the two R9 groups can be connected together with the nitrogen atom to which they are attached to forming a ring, said ring, optionally independently substituted from one to the maximum number of substituents with one or more of fluorine, OH, or methyl; where when R6 is OR5, then R is different from F.
[48] In some embodiments, R1 as specified in Formula (I) may be H or F. In some embodiments, R1 may be F.
[49] In some embodiments, R4 as specified in Formula (I) may be H or F. In some embodiments, R ~ may be F.
[50] In some embodiments, RJ as specified in Formula (I) can be H, OH, or OC (O) R10, where R10 can be H, C1-6 alkyl, or C3-6 cycloalkyl. In some embodiments, R3 can be either H or OH. In some modalities, R3 can be H.
[51] In some embodiments, R4 as specified in Formula (I) can be H, OH, or OC (O) R10, where R10 can be H, C1-6 alkyl, or C3-6 cycloalkyl. In some embodiments, R4 can be either H or OH. In some embodiments, R4 can be OH.
[52] In some embodiments, Rb as specified in Formula (I) can be H, F, OH, or 00 (0) R10, where R10 can be H, C1-6 alkyl, or C3-s cycloalkyl. In some embodiments, R6 may be H or OH.
[53] In some embodiments, R7 as specified in Formula (I) can be selected from the group consisting of: H, F, C1-6 alkyl, C2_8 alkenyl, C2_8 alkynyl, each excluding hydrogen optionally substituted from one to the maximum number of substituents with one or more fluorine or OH. In some embodiments, R can be either H or CH3.
[54] In some embodiments, R8 as specified in Formula (I) can be selected from the group consisting of: C1-3 alkyl, C2_3 alkenyl, C2_3 alkynyl, C3-6 cycloalkyl, aryl and heteroaryl, optionally substituted from one to the maximum number of substituents with one or more fluorine or OH. In some embodiments, R8 can be CH3 or CF3.
[55] In some embodiments, R 'and R8 and the carbon atom to which they are attached, as specified in Formula (I), can come together to form vinyl.
[56] In some embodiments, each R9 as specified in Formula (I) can be independently selected from the group consisting of: H, C2-6 alkyl, C3_s alkenyl, C3-S alkynyl, and C2-6 alkoxy, where C1-6 alkyl, C3- and alkenyl, C3- and alkynyl, or C2-6 alkoxy can optionally be substituted from one to the maximum number of substituents with one or more of fluorine, OH, or methyl. In some embodiments, each Ry can be, independently, H, CH3, or CH2CH3.
[57] In some embodiments, the two R9 groups as specified in Formula (I) can be connected together with the nitrogen atom to which they are attached to form a ring, said ring, optionally, independently substituted from one to the maximum number of substituents with one or more fluorine, OH, or methyl.
[58] In some embodiments, NR92 as specified in aN * »n Formula (I), can be
RR, optionally substituted where X can be CR112, NR11, 0, 0 = 0, 0 (0 = 0), (0 = 0) 0, NR11 (0 = 0), or (0 = 0) NR11; wherein each R11 may independently be H or C1-4 alkyl; and n can be an integer between 0 and 3. In some embodiments, NR92 can be 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, morpholin-4-yl, 1-piperizinyl, azetidine-2-ona- optionally substituted 1-yl, pyrrolidine-2-one-l-yl, or piperid-2-one-l-yl. In some modalities, NR92
can be or.
[59] In specific embodiments of the invention, compounds according to Formula (I) include the compounds described in Table 1.
















[60] As appreciated by one skilled in the art, Formula (I) above can also be represented alternatively as follows:

[61] As used here, the singular forms "one / one", "e", and "o / a" include references in the plural, unless the context clearly indicates otherwise. For example, "a compound" refers to one or more of such compounds, while "the enzyme" includes a particular enzyme as well as other members of the family and their equivalents, as known to those skilled in the art.
[62] Throughout this application, it is contemplated that the term "compound" or "compounds" refers to compounds discussed herein and includes precursors and derivatives of the compounds, including derivatives protected above, 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.
[63] The compounds of the present invention can contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomeric mixtures and diastereomers. Additional asymmetric centers may be present depending on the nature of the various substituents on the molecule. Each symmetric center will independently produce two optical isomers and it is intended that all possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this invention. Any formulas, structures or compound names described in this report that do not specify a particular stereochemistry must mean encompassing any and all existing isomers as described above and their mixtures in any proportion. When stereochemistry is specified, the invention means encompassing a particular stereomer in pure form or as a part of the mixture with other isomers in any proportion.
[64] "Alkyl" refers to a straight or branched chain hydrocarbon group consisting only of carbon and hydrogen atoms, containing no unsaturation and including, for example, one to ten carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, and that is attached to the rest of the molecule by a single bond. In alternative embodiments, the alkyl group may contain 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 one to six carbon atoms, such as 1, 2, 3, 4, 5, or 6 carbon atoms. Unless stated otherwise specified in the report, the alkyl group may be optionally substituted by one or more substituents as described herein. Unless otherwise stated specifically here, it is understood that the substitution can occur on any carbon in the alkyl group.
[65] "Alkenyl" refers to a straight or branched chain hydrocarbon group consisting only of carbon and hydrogen atoms, containing at least one double bond and including, for example, 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 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 three to six carbon atoms, such as 3, 4, 5, or 6 carbon atoms. Unless stated otherwise specified in the report, the alkenyl group may be optionally substituted by one or more substituents as described herein. Unless otherwise stated specifically here, it is understood that the substitution can occur on any carbon in the alkenyl group.
[66] "Alquinyl" refers to a straight or branched chain hydrocarbon group consisting only of carbon and hydrogen atoms, containing at least one triple bond and including, for example, two to ten carbon atoms. In alternative embodiments, the alkynyl group may contain two to eight carbon atoms, such as 2, 3, 4, 5, 6, 7, or 8 carbon atoms. In alternative embodiments, the alkynyl group can contain three to six carbon atoms, such as 3, 4, 5, or 6 carbon atoms. Unless stated otherwise specified in the report, the alkynyl group can be optionally substituted by one or more substituents as described herein.
[67] "Aryl" refers to a phenyl group, an aromatic ring including 6 carbon atoms. Unless otherwise specifically stated herein, the term "aryl" means to include aryl groups optionally substituted by one or more substituents as described herein.
[68] "Heteroaryl" refers to an aromatic ring group containing one or more heteroatoms in the ring, for example, N, 0, 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 otherwise specifically stated herein, the term "heteroaryl" is intended to include heteroaryl groups optionally substituted by one or more substituents as described herein.
[69] "Acyl" refers to a group of the formula -C (O) Ra, where Ra is C1-10 alkyl or a C1-6 alkyl group or a C3-15 cycloalkyl group as described herein. The alkyl or cycloalkyl group (s) can optionally be substituted as described herein.
[70] "Aloxy" refers to a group of the formula -ORb, where Rb is a C1-10 alkyl or C1-6 alkyl group as described herein. The alkyl group (s) can be optionally substituted as described herein.
[71] "Cycloalkyl" refers to a hydrocarbon group, stable, monovalent, monocyclic, bicyclic or tricyclic consisting only of carbon and hydrogen atoms, having for example 3 to 15 carbon atoms, and which is saturated and fixed to the rest of the molecule by a single bond. In alternative modalities, the cycloalkyl group can contain three to six carbon atoms, such as 3, 4, 5, or 6 carbon atoms. Unless otherwise stated specifically here, the term "cycloalkyl" is intended to include cycloalkyl groups that are optionally substituted as described herein.
[72] In some embodiments, two R9 groups as specified in Formula (I) can be connected together with the nitrogen atom to which they are attached to form a ring. In these modalities, "ring" refers to a monocyclic group containing stable nitrogen, having 3 to 6 members that can be saturated or monounsaturated. In alternative embodiments, the ring may include atoms of C, H and N. In other embodiments, the ring may include heteroatoms, for example, 0 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, azetidine-2-one-l-yl, pyrrolidine-2-one-1-yl, piperid-2-one-l-yl, 1,2-oxazetidine-2-yl, isoxazolidin-2-yl, and 1,2 -oxazinan-2-yl. The ring in these embodiments can optionally be replaced as described herein.
[73] "Optional" or "optionally" means that the subsequently described event of circumstances may or may not occur and that the description includes cases in which the said event or circumstance occurs one or more times and cases 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 include 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 C1-6 alkyl or alkenyl. Therapeutic indications
[74] The invention provides methods of treating conditions that are modulated, directly or indirectly, by an O-GlcNAcase enzyme or by levels of protein modified by 0-GlcNAc, for example, a condition that benefits by inhibiting an O enzyme -GlcNAcase or by an increase in protein levels modified by 0-GlcNAc. Such conditions include, without limitation, glaucoma, schizophrenia, tauopathies such as Alzheimer's disease, neuro degenerative diseases, cardiovascular diseases, diseases associated with inflammation, diseases associated with immunosuppression and cancers. One or more of the compounds of the invention are also usable in the treatment of diseases or disorders related to O-GlcNAcase deficiency or overexpression or O-GlcNAc accumulation or depletion, or any disease or disorder responsive to glucosidase inhibition therapy. These diseases and disorders include, but are not limited to, glaucoma, schizophrenia, neurodegenerative disorders such as Alzheimer's disease (AD), or cancer. These diseases and disorders can also include diseases or disorders related to build-up or deficiency in the OGT enzyme. Also included is a method of protecting or treating target cells expressing proteins that are modified by O-GlcNAc residues, whose deregulation of the modification results in disease or pathology. The term "treatment" as used herein includes treatment, prevention, and improvement.
[75] In alternative embodiments, the invention provides methods of increasing or increasing levels of O-GlcNAc protein modification in animal subjects, such as veterinary and human subjects. This elevation of O-GlcNAc levels may be useful for the prevention or treatment of Alzheimer's disease; prevention or treatment of other neurodegenerative diseases (for example, Parkinson's disease, Huntington's disease); provide neuroprotective effects; prevent damage to cardiac tissue; and treating diseases associated with inflammation or immunosuppression.
[76] In alternative embodiments, the invention provides methods of selectively inhibiting an O-GlcNAcase enzyme in animal subjects, such as veterinary and human subjects.
[77] 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. Thus, a compound of the invention can be used to study and treat AD and other tauopathies.
[78] In general, the methods of the invention are carried out by administering a compound according to the invention to an individual in need of it, 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 usable in the treatment of a disorder in which regulation of O-GlcNAc protein modification is involved, or any condition as described herein. Disease states of interest include Alzheimer's disease (AD) and related neurodegenerative tauopathies, in which abnormal hyperphosphorylation of the tau protein associated with a microtubule is involved in the pathogenesis of the disease. In some embodiments, a compound can be used to block hyperphosphorylation of tau while maintaining high levels of O-GlcNAc in tau, thus providing a therapeutic benefit.
[79] The effectiveness of a compound in treating the pathology associated with the accumulation of toxic tau species (for example, Alzheimer's disease and other tauopathies) can be confirmed by testing a compound's ability to block the formation of tau species toxic in established models of transgenic and / or cellular animal121-123 disease. 33, j4
[80] Tauopathies that can be treated with a compound of the invention include: Alzheimer's disease, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), argyrophilic grain dementia, Bluit's disease, corticobasal degeneration (CBD) , pugilistic dementia, diffuse neurofibrillary tangles with calcification, Down syndrome, British familial dementia, Danish familial dementia, fronto temporal dementia with chromosome 17-linked parkinsonism (FTDP-17), Gerstmann-Straussler-Scheinker disease, guadeloupe parkinsonism, disease Hallevorden-Spatz (neurodegeneration with type 1 brain iron accumulation), multiple system atrophy, myotonic dystrophy, Niemann-Pick disease (type C), Pallido-ponto-nigral degeneration, Guam parkinsonism-dementia complex, Pick's disease (PiD), post-encephalitic parkinsonism (PEP), prion diseases (including Creutzfeldt-Jakob disease (CJD), variant of Creutzfeldt-Jakob disease (vCJD), insomnia fatal familial nia, and kuru), progressive supercortical gliosis, progressive supranuclear palsy (PSP), Richardson's syndrome, subacute sclerosing panencephalitis, tangle-only dementia, and glaucoma.
[81] One or more of the compounds of this invention are also usable in the treatment of conditions associated with tissue damage or stress, stimulating cells, or promoting cell differentiation. Thus, in some embodiments, a compound of this invention can be used to give a therapeutic benefit in various medical conditions or procedures involving stress on cardiac tissue, including but not limited to: ischemia; bleeding; hypovolemic shock, myocardial infarction, an intervention cardiology procedure, cardiac bypass surgery; fibrinolytic therapy; angioplasty; and stent placement.
[82] The effectiveness of a compound in the treatment of pathologies associated with cell stress (including ischemia, hemorrhage, hypovolemic shock, myocardial infarction, and other cardiovascular disorders) can be confirmed by testing a compound's ability to prevent cell damage in tests established from cell stress, lüd'119,120 and to prevent tissue damage and promote functional recovery in animal models of ischemia-reperfusion, 1,11 and trauma-hemorrhage .73,115,118
[83] Compounds that selectively inhibit O-GlcNAcase activity can be used to treat diseases that are associated with inflammation, including, but not limited to, inflammatory or allergic diseases, such as asthma, allergic rhinitis, lung hypersensitivity diseases, hypersensitivity pneumonitis, eosinophilic pneumonitis, delayed type hypersensitivity, atherosclerosis, interstitial lung disease (ILD) (eg, idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, systemic sclerosis or dermatomyositis); systemic anaphylaxis or hypersensitivity response, drug allergy, insect bite allergy, autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Guillain-Barre syndrome, systemic lupus erythematosus, myasthenia gravis, glomerulonephritis, thyroiditis, thyroiditis immune, graft rejection, including allograft rejection or graft-versus-host disease, inflammatory bowel diseases, such as Crohn'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, (for example, necrotizing, cutaneous and hypersensitivity vasculitis); eosinophilic myote, eosinophilic fasciitis; and cancers.
[84] In addition, compounds that affect levels of protein modification 0-GlcNAc can be used for the treatment of diseases associated with immunosuppression, such as in individuals undergoing chemotherapy, radiation therapy, marked wound healing and treatment of burns, therapy for autoimmune disease or other drug therapies (for example, corticosteroid therapy) or a combination of conventional drugs used to treat autoimmune diseases and graft / transplant rejection, which causes immunosuppression; or immunosuppression due to congenital deficiency due to receptor or other causes.
[85] One or more of the compounds of the invention may be usable for the treatment of neurodegenerative diseases, including Parkinson's disease and Huntington's disease. Other conditions that can be treated are those triggered, affected or in any other way correlated with post-translational levels of protein 0-GlcNAc modification. It is hoped that one or more of the compounds of this invention may be usable for the treatment of such conditions and in particular, but not limited to, the following for which association with levels of 0-GlcNAc in proteins has been established: rejection at graft, in particular but not limited to solid organ transplants, such as heart, lung, liver, kidney and pancreas transplants, (for example, 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's lymphoma and melanoma; epilepsy, pain, fibromyalgia, or stroke, for example, for neuroprotection after a stroke. Pharmaceutical and Veterinary Compositions, Dosages and Administration
[86] Pharmaceutical compositions including compounds according to the invention, or for use according to the invention, are contemplated to be within the scope of the invention. In some embodiments, pharmaceutical compositions including an effective amount of a compound of Formula (I) are provided.
[87] The compounds of Formula (I) and their pharmaceutically acceptable salts, enantiomers, solvates, and derivatives are usable 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 an individual.
[88] In some embodiments, a compound according to the invention, or for use according to the invention, can be supplied in combination with any other active agents or pharmaceutical compositions where such a combination therapy is usable to modulate O activity -GlcNAcase, for example, to treat neurodegenerative, inflammatory, cardiovascular, or immunoregulatory diseases, or any condition described here. In some embodiments, a compound according to the invention, or for use according to the invention, can be supplied in combination with one or more agents usable in the prevention or treatment of Alzheimer'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, Phenserina, 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; Β-amyloid aggregation and / or fibrillation inhibitors, such as Alzhemed ™ (3APS, Tramiprosate, 3-amino-l-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-HTla 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 anti-Aβ monoclonal 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, Huperzina A, etc .; Type L 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 activated proliferator receptor (PPAR) gamma agonists such as Avandia® (Rosglitazone), etc. ; Phosphodiesterase IV (PDE4) inhibitors, such as MK-0 952, 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 enhancers, 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 receiver modulators, such as AC-3933, NGD 97-1, CP-457920, etc .; • Benzodiazepine receptor agonists, such as SB-737552 (S-8510), AC-3933, etc .; • Noradrenaline releasing agents, such as T-588, T-817MA, etc.
[89] It should be understood that the combination of compounds according to the invention, or for use according to the invention, with agents for Alzheimer's, is not limited to the examples described here, but includes the combination with any agent usable for the treatment of Alzheimer's disease. The combination of compounds according to the invention, or for use according to the invention, and other agents for Alzheimer's can be administered separately or together. The administration of one agent can be before, simultaneously with, or subsequent to the administration of the other agent (s).
[90] In alternative embodiments, a compound can be provided as a "prodrug" or protected forms, which release the compound after administration to an individual. For example, a compound can carry a protecting group, which is removed by hydrolysis in body fluids, for example, in the bloodstream, thereby releasing the active compound or is oxidized or reduced in the body fluids to release the compound. Thus, a "prodrug" means to indicate a compound that can be converted under a physiological condition or by solvolysis to a biologically active compound of the invention. Thus, the term "prodrug" refers to a metabolic precursor to a compound of the invention that is pharmaceutically acceptable. A prodrug can be inactive when administered to an individual in need of it, but is converted in vivo to an active compound of the invention. Pro-drugs are typically rapidly transformed in vivo to give the parent compound of the invention, for example, by hydrolysis in the blood. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in an individual.
[91] The term "prodrug" also means to include any covalently linked vehicles that release the active compound of the invention in vivo when such a prodrug is administered to an individual. Pro-drugs of a compound of the invention can 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 or in vivo manipulation, to the parent compound of the invention. Pro-drugs include compounds of the invention in which a hydroxy, amino or mercapto group is attached to any group which, when the prodrug of the compound of the invention is administered to a mammalian individual, 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 alcohol benzoate derivatives and acetamide, formamide, and benzamide derivatives of amine functional groups in one or more of the compounds of the invention and the like.
[92] A discussion of prodrugs can be found in "Smith and Williams' Introduction to the Principles of Drug Design," H.J. Smith, Wright, 2a. ed., 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); The Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pp 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 herein in their entirety for reference.
[93] Appropriate prodrug forms of one or more of the compounds of the invention include modalities in which one or more R5, as specified in Formula (I), is C (O) R, where R is alkyl, alkenyl, optionally substituted alkynyl, aryl, or heteroaryl. In these cases, the ester groups can be hydrolyzed in vivo (for example, in body fluids), releasing the active compounds in which each R5 is H. The preferred prodrug modalities of the invention include compounds of Formula (I) in which a or more R5 is C (O) CH3.
[94] Compounds according to the invention, or for use according to the invention, can be supplied 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 an individual such as a mammal, e.g., humans, cattle, sheep, etc. If desired, treatment with a compound according to the invention can be combined with existing or more traditional therapies for the therapeutic indications described here. Compounds according to the invention can be supplied chronically or intermittently. "Chronic" administration refers to the administration of the compound (s) in a continuous mode, as opposed to an acute mode, in order to maintain the initial therapeutic effect (activity) over a long period of time. "Intermittent" administration is treatment that is not done consecutively without interruption, but, on the contrary, is of a cyclical nature. The terms "administration", "administrable", or "administering" as used herein are to be understood as meaning to provide a compound of the invention to the individual in need of treatment.
[95] "The pharmaceutically acceptable vehicle, diluent or excipient" includes, without limitation, any adjuvant, vehicle, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent , suspension agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved, for example, by the United States Food and Drug Administration or other government agency that is acceptable for use in humans or pets.
[96] A compound of the present invention can be administered in the form of a pharmaceutically acceptable salt. In such cases, pharmaceutical compositions according to 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 improved pharmacokinetic properties on the active ingredient when compared with the free form of the active ingredient or other salt form previously described.
[97] A "pharmaceutically acceptable salt" includes addition salts of both acid and base. A "pharmaceutically acceptable acid addition salt" refers to salts that retain the biological efficacy and properties of 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, acid citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
[98] The "pharmaceutically acceptable base addition salt" refers to salts that retain the biological effectiveness and properties of free acids, which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, 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, substituted primary, secondary and tertiary amine salts 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, and piperidine, and piperidine, and piperidine, and piperidine, and piperidine; . Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
[99] 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, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrite, calcium edetate, methylsulfate, cansylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate ( embonate), stolate, palmitate, esilate, pantothenate, fumarate, phosphate / diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamus, stearate, glycolylsanilate, sulfate, hexylresorcinate, subacetate, hydradromide, hydrochloride, hydrobromide, hydrobromide, hydrobromide, hydrobromide, hydrobromide, hydrobromide, hydrobromide, hydrobromide, hydrobromide, hydrobromide, hydrochloride, hydrochloride, hydrochloride, hydrochloride, succinate, hydrobromide, hydrochloride, hydrobromide, hydrochloride, hydrochloride, hydrochloride, hydrochloride, hydrochloride, hydrochloride, hydrochloride. naphthoate, theoclate, iodide, tosylate, isothionate, trietiodide, lactate, panoate, valerate, and the like.
[100] The pharmaceutically acceptable salts of a compound of the present invention can be used as a dosage to modify the characteristics of solubility or hydrolysis, or can be used in sustained release or pro-drug formulations. Also, the pharmaceutically acceptable salts of a compound of this invention can include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine , ornithine, choline, N, N'-dibenzylethylene diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenothyl amine, diethylamine, piperazine, tris (hydroxymethyl) aminomethane, and detetramethyl ammonium hydroxide.
[101] Pharmaceutical formulations will typically include one or more vehicles acceptable for the mode of administration of the preparation, whether by injection, inhalation, topical administration, washing or other modes appropriate for the selected treatment. Suitable carriers are those known in the art for use in such modes of administration.
[102] The appropriate pharmaceutical compositions can be formulated by means known in the art and their mode of administration and dose determined by one skilled in the art. For parenteral administration, a compound can be dissolved in sterile water or saline or a pharmaceutically acceptable carrier used for administration of non-water-soluble compounds like those used for vitamin K. For enteral administration, the compound can be administered in a tablet form , capsule or dissolved in liquid. The tablet or capsule can be coated enterally, or in a sustained release formulation. Many suitable formulations are known, including, polymeric or protein microparticles encapsulating a compound to be released, ointments, gels, hydrogels, or solutions that can be used topically or locally to administer a compound. A sustained-release adhesive or implant can be employed to give release over a period of practitioners versed in the subject are described in Remington: the Science and Practice of Pharmacy by Alfonso Gennaro, 20th ed., Williams and Wilkins, (2000). Formulations for parenteral administration may, for example, contain excipients, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated naphthalenes. The biocompatible, biodegradable lactide / lactide / glycolide copolymer, or biocompatible, polyoxyethylene-polyoxypropylene copolymers can 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 pump, implantable infusion systems, and liposomes. Inhalation formulations may contain excipients, for example, lactose, or they may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or they may be oily solutions for administration in the form of nasal drops or with a gel.
[103] A compound or pharmaceutical composition according to the present invention can be administered orally or non-orally, for example, intramuscularly, intraperitoneally, intravenously, intracisternal injection or infusion, subcutaneous, transdermal or transmucosal injection. pharmaceutical product according to this invention or for use in this invention can be administered by means of a medical device or apparatus such as an implant, graft, prosthesis, stent, etc. Implants can be thought of as intended to contain and release these 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 can be administered alone or as a mixture with a pharmaceutically acceptable carrier, for example, as solid formulations such as tablets, capsules, granules, powders, etc .; liquid formulations such as syrups, injections, etc .; injections, drops, suppositories, pensions. In some embodiments, pharmaceutical compounds or compositions according to the invention or for use in this invention can be administered by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes and can be formulated, alone or together, in unit formulations of appropriate dosage containing pharmaceutically acceptable vehicles, adjuvants and conventional non-toxic carriers suitable for each route of administration.
[104] A compound of the invention can 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 bird species (for example, chickens). One or more of the compounds of the invention can also be effective for use in humans. The term "individual" or alternatively referred to herein as "patient" is intended to refer to an animal, preferably a mammal, more 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 can be used in the treatment of animals. Thus, as used here, an "individual" can be a human, non-human primate, rat, mouse, cow, horse, swine, sheep, goat, dog, cat, etc. The individual may be suspected of having or at risk of having a condition requiring modulation of O-GlcNAcase activity.
[105] An "effective amount" of a compound according to the invention includes a therapeutically effective amount or the prophylactically effective amount. The "therapeutically effective amount" refers to an effective amount, in dosages and for periods of time necessary to achieve the desired therapeutic result, such as inhibition of an O-GlcNAcase, elevation of 0-GlcNAc levels, inhibition of tau phosphorylation, or any condition described here. The therapeutically effective amount of a compound can vary according to factors such as the stage of the disease, age, sex and weight of the individual and the ability of the compound to elicit a desired response in the individual. Dosage regimens can be adjusted to give the optimal therapeutic response. The therapeutically effective amount is also one in which any toxic or harmful effects of the compound have a higher value than the therapeutically beneficial effects. A "prophylactically effective amount" refers to an effective amount, in 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 here. Typically, a prophylactic dose is used in individuals before or at an earlier stage of the disease, so that the prophylactically effective amount may be less than the therapeutically effective amount. An appropriate range for therapeutically or prophylactically effective amounts of a compound can be any integer from 0.1 nM - O, 1M, 0.1 nM - 0.05M, 0.05 nM - 15pM or 0.01 nM - 10pM.
[106] In alternative modalities, in the treatment or prevention of conditions that require modulation of O-GlcNAcase activity, an appropriate dosage level will generally be about 0.01 to 500 mg per kg of an individual's body weight per day, and can be administered in single 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 dosing frequency for any particular patient can be varied and will depend on a variety of factors including the activity of the specific compound used, the metabolic stability and the extent of action of this compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, combination of drugs, the severity of the particular condition, and the patient in therapy.
[107] It should be noted that dosage values may vary with the severity of the condition being treated. For any particular individual, the specific dosage regimens can be adjusted over time according to the individual's need to judge the professional judgment of the person administering or supervising the administration of the compositions. The dosage ranges specified here are exemplary only and do not limit the dosage ranges that can be selected by health workers. The amount of active compound (s) in the composition may vary according to factors such as the individual's disease state, age, sex, and weight. Dosage regimens can be adjusted to give the optimal therapeutic response. For example, a single cake can be administered, several divided doses can be administered over time or the dose can be proportionally reduced or increased as indicated by the requirements of the therapeutic situation. It may be advantageous to formulate parenteral compositions in unit dosage 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 an appropriate safety profile for therapeutic use. Toxicity of a compound of the invention can be determined using standard techniques, for example, by testing on cell cultures or experimental animals and determining the therapeutic index, that is, the ratio between LD50 (the lethal dose for 50% of the population) and the LD100 (the lethal dose for 100% of the population). In some circumstances, however, such as in conditions of severe illness, it may be necessary to administer substantial excesses of the compositions.
[108] In the compounds of generic Formula (I), atoms can exhibit their natural isotopic abundances, or one or more of the atoms can be artificially enriched in a particular isotope having the same atomic number, but a different atomic mass or mass number of the atomic mass or mass number predominantly found in nature. The present invention is intended to include all appropriate isotopic variations of the compounds of generic Formula (I). For example, isotopic forms other than hydrogen (H) include protium (XH), deuterium (2H) and tritium (3H). Procium is the predominant hydrogen isotope found in nature. The deuterium enrichment can give some therapeutic advantages, such as increasing the half-life in vivo or reducing the dosage requirements, or it can provide a compound usable as a standard for the characterization of biological samples. The isotopically enriched compounds within the 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 here using appropriate isotopically enriched reagents and / or intermediates. Other Uses and Tests
[109] A compound of Formula (I) can be used in screening tests for compounds that 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 can be measured using any tests, as described herein or known to the person skilled in the art. For example, a fluorescence or UV-based test known in the art can be used. A "test compound" is any naturally occurring or artificially derived chemical compound. Test compounds can include, without limitation, peptides, polypeptides, synthesized organic molecules, naturally occurring organic molecules, and nucleic acid molecules. A test compound can "compete" with a compound known as a compound of Formula (I) by, for example, interfering with inhibition of O-GlcNAcase-dependent cleavage of 0-GlcNAc or by interfering with a biological response induced by a compound of Formula (I).
[110] Generally, the test compound can exhibit any value between 10% and 200%, or above 500%, modulation when compared to a compound of Formula (I) or another reference compound. For example, a test compound can 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 integer or negative from 60% to 100% modulation, or any positive or negative integer above 100% modulation. A compound that is a negative modulator will generally decrease modulation with respect to an unknown compound, while a compound that is a positive modulator will in general increase modulation with respect to a known compound.
[111] In general, test compounds are identified from large libraries of 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 the test extracts or compounds is not critical to the method (s) of the invention. Thus, virtually any number of chemical extracts or compounds can be screened using the exemplary methods described here. Examples of such extracts or compounds include, but are not limited to, extracts based on plants, fungi, prokaryotes or animals, fermentation broths, and synthetic compounds, as well as modification of existing compounds. Numerous methods are also available to generate random or directed synthesis (e.g., semi-synthesis or total synthesis) of any number of chemical compounds, including, but not limited to, compounds based on saccharide, lipid, peptide and nucleic acid. Libraries of synthetic compounds are commercially available. Alternatively, libraries of natural compounds in the form of bacterial extracts, fungi, plants, and animals are commercially available from several sources, including Biotics (Sussex, UK), Xenova (Slough, UK), Harbor Branch Oceanographic Institute (Ft. Pierce, FL , USA), and PharmaMar, MA, USA. In addition, natural and synthetically produced libraries are produced, if desired, according to methods known in the art, for example, by standard methods of extraction and fractionation. In addition, if desired, any library or compound is readily modified using standard chemical, physical or biochemical methods.
[112] When a crude extract is found to modulate O-GlcNAcase-dependent cleavage inhibition of 0-GlcNAc, or any biological response induced by a compound of Formula (I), another fractionation of the positive lead extract is necessary to isolate the chemical constituents responsible for the observed effect. Thus, the objective of the extraction, fractionation, and purification processes is the careful characterization and identification of a chemical entity within the crude extract having O-GlcNAcase inhibitory activities. The same tests described here for detecting activities in mixtures of compounds can be used to purify the active component and test its derivatives. Fractionation and purification methods for such heterogeneous extracts are known in the art. If desired, compounds shown to be usable agents for treatment are chemically modified according to methods known in the art. Compounds identified as being of therapeutic, prophylactic, diagnostic, or other value can subsequently be analyzed using an appropriate animal model, as described herein over those known in the art.
[113] In some embodiments, one or more of the compounds are useful in the development of animal models for studying deficiency-related diseases or disorders without O-GlcNAcase, O-GlcNAcase overexpression, O-GlcNAc accumulation, O depletion -GlcNAc, and to study the treatment of diseases and disorders related to O-GlcNAcase deficiency or overexpression, or O-GlcNAc accumulation or depletion. These diseases and disorders include neurodegenerative diseases, including Alzheimer's disease, and cancer.
[114] Various alternative embodiments and examples of the invention are described here. These modalities and examples are illustrative and should not be construed as limiting the scope of the invention. EXAMPLES
[115] The following examples are intended to illustrate modalities of the invention and are not intended to be considered in a limiting way. Abbreviations ABCN = 1,1'-azobis (cyclohexane-carbonitrile) AcCl = acetyl chloride AIBN = azobisisobutyronitrile BCI3 = boron trichloride BnBr = benzyl bromide BU4NI = tetra-n-butylammonium iodide BOC20 = di-terc-butyl dicarbonate BzCl = benzoyl chloride DAST = diethylamino sulfur trifluoride DCM = dichloromethane DIPEA = diisopropylethylamine DMAP = 4-dimethylaminopyridine DMF = N, N-dimethylformamide DMP = Dess-Martin periodinane DMSO = dimethyl sulfoxide Et3N = triethylamine E2 = triethylamine pentamethylbenzene TBDMSC1 = tert-butyldimethylsilyl chloride TBAF = tetra-n-butylammonium fluoride TMSCF3 = (trifluoromethyl) trimethylsilane TFA = 2,2,2-trifluoroacetic acid THF = tetrahydrofuran thio-CDI = 1,1'-thiol 2 (3aR, 5R, 6R, 7R, 7aR) -7 ~ fluor-5 - ((S) -1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3 , 2-d] thiazol-6-ol (3aR, 5R, 6R, 7R, 7aR) -7-fluor-5 - ((R) -1-hydroxyethyl) -2- (methylamino) -5,6,7 , 7a-tetrahydro-3aH-pyran [3,2-d] thiazole -6- ol

[116] To a suspension of (3aR, 5R, 6S, 7R, 7aR) -2- (methylamino) -5- (hydroxymethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d ] thiazole-6,7-diol (8.50 g, 37.0 mmol) in DMF (60 mL) was added DIPEA (2.0 mL), Boc20 (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 / hexane, to obtain ((3aR, 5R, 6S, 7R, 7aR) - 6,7-dihydroxy-5- (hydroxymethyl) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) tert-butyl carbamate as a white solid (11.8 g, 96%), XH NMR (400 MHz, CDC13) 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).
[117] 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, BzCl (10.1 g, 72.0 mmol) was added slowly. After the addition the mixture was stirred at room temperature for 5 h. Saturated aqueous NH4 Cl solution (100 mL) was added, and the organic layer was collected. The aqueous layer was further extracted with DCM (3 x 50 ml). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was separated on silica gel by automatic column flash chromatography (EtOAc / hexanes, 1: 4 to 1: 1), producing ((3aR, 5R, 6S benzoate) , 7R, 7aR) -6- (benzoyloxy) -2 - ((tert-butoxycarbonyl) (methyl) amino) -7-hydroxy-5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-5-yl) methyl as a white solid (4.20 g, 22%). XH NMR (400 MHz, CDCl3) 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 = 1.1 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).
[118] To a solution of the above material (7.91 g, 14.6 mmol) in anhydrous DCM (100 mL) at -78 ° C under N2, DAST (11.8 g, 73.0 mmol) was added. After the addition the mixture was stirred at room temperature for 72 h. The reaction mixture was then cooled to -78 ° C, diluted with DCM (100 ml), and then quenched with saturated aqueous NaHCO2 (150 ml). The organic layer was collected, and the aqueous phase was extracted with DCM (2 x 100 ml). The combined extract was dried over anhydrous Na2SO4. 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: 4), producing ((3aR, 5R, 6R) benzoate , 7R, 7aR) -6- (benzoyloxy) -2- ((tert-butoxycarbonyl) (methyl) amino) -7-fluor-5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-5-yl) methyl as a white solid (6.10 g, 77%). 2H NMR (400 MHz, CDC13) 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 = 7.2Hz, 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).
[119] A mixture of the above material (6.10 g, 11.2 mmol) and K2CO3 (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), yielding ((3aR, 5R, 6R, 7R, 7aR) -7-fluor-6-hydroxy-5 - (hydroxymethyl) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) tert-butyl carbamate as a white solid (3.25 g, 86 %). XH NMR (400 MHz, CDC13) 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).
[120] 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 TBDMSC1 (0.452 g, 3, 00 mmol). The mixture was stirred at room temperature for 72 h and diluted with Et2O (100 ml) and brine (100 ml). The organic layer was collected, and the aqueous phase was extracted with Et2O (50 ml). The combined extract was washed with H2O (50 ml) and dried over Na2SO4. anhydrous. 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), producing ((3aR, 5R, 6R, 7R , 7aR) -5 - ((((tert-butyldimethylsilyl) oxy) methyl) - 7-fluor-6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyran [3,2- d] thiazol-2- il) tert-butyl (methyl) carbamate as a white foam (1.10 g, 93%). XH NMR (400 MHz, CDC12) 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).
[121] At 0 ° C, to a solution of the above material (1.06 g, 2.35 mmol) and BU4NI (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 adding NaH, BnBr (0.703 g, 4.11 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 16 h and diluted with Et2O (60 ml) and saturated NH4 Cl (50mL). The organic layer was collected, and the aqueous phase was extracted with Et2O (2 x 30 ml). The combined extract was washed with brine (40 ml) and dried over anhydrous Na2SO4. 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: 4), producing ((3aR, 5R, 6R, 7R , 7aR) -6- (benzyloxy) -5 - ((((tert-butyldimethylsilyl) oxy) methyl) -7-fluor-5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- 2-yl) tert-butyl (methyl) carbamate as a sticky oil (1.22 g, 96%). 1H NMR (400 MHz, CDCl3) 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).
[122] 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 the addition, the reaction mixture was stirred at room temperature for 2h and diluted with EtOAc (20 ml) and brine (50 ml). The organic layer was collected, and the aqueous phase was extracted with EtOAc (2 x 50 ml). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by flash column chromatography (EtOAc / hexanes, 1: 5 to 1: 2), producing ((3aR, 5R, 6R, 7R , 7aR) - 6- (benzyloxy) -7-fluor-5- (hydroxymethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) carbamate tert-butyl as a white solid (0.96 g, 100%). 1H NMR (400 MHz, CDCla) δ 7.37-7.29 (m, 5H), 6.09 (d, J = 6.1 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).
[123] 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 Et2O (20 mL), and then concentrated to dryness. Aqueous NaHCO3 saturated (30 ml) with Na2S20.3 (2 g) was added, and the mixture was extracted with EtOAc (2 x 50 ml). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by flash column chromatography (EtOAc / hexanes, 1: 5 to 1: 2), producing ((3aR, 5S, 6R, 7R , 7aR) - tert 6- (benzyloxy) -7-fluor-5-formyl-5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) carbamate -butyl as a white solid (1.02 g, 68%). XH NMR (400 MHz, CDC13) 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).
[124] To a solution of the above material (0.150 g, 0.350 mmol) in anhydrous THF (10 mL) under N2 was added MeMgBr (1.4 M in THF / toluene, 0.60 mL, 0.84 mmol). After the addition the mixture was stirred at room temperature for 2h. The reaction was quenched with saturated aqueous NH4Cl (10 mL), and then extracted with EtOAc (3 * 15 mL). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic column flash chromatography (EtOAc / hexanes, 1:10 to 1: 2), producing ((3aR, 5R, 6R, 7R , 7aR) -6- (benzyloxy) - 7-fluor-5 - ((R and S) -1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- Mixed tert-butyl 2-yl) (methyl) carbamate as an off-white foam (0.115 g, 75%) with a diastereomeric ratio of 1: 3.2 based on XH NMR.
[125] 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 N2, BC12 (1.0 M in DCM, 0, 8 mL, 0.8 mmol). The mixture was stirred at ~ 3 h while the temperature of the cooling bath was heated to 0 ° C. The reaction mixture was cooled to -78 ° C, quenched with MeOH / DCM mixture, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH / DCM, 1:12), yielding a mixture of the title compounds as a pale yellow solid (0.055 g, 85%). The mixture was then separated by Agilent 1200 by preparative HPLC (column C18, 19 x 50 mm, 5 µm; mobile phase, water with 0.03% NH4OH, and CH3CN (from 3% to 100% in 15 min); detector, 220 nm), yielding (3aR, 5R, 6R, 7R, 7aR) -7-fluor-5 - ((S) -1-hydroxyethyl) -2- (methylamino) —5,6,7,7a — tetrahydro — 3aH —Pyran [3,2 — d] thiazole — 6— ol (19 mg) and (3aR, 5R, 6R, 7R, 7aR) -7-fluor-5 - ((R) -1- hydroxyethyl) -2- ( methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol (5.5 mg) both as white solids. Example 1: 3HRMN (400 MHz, CD3OD) ô 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); 13C NMR (100 MHz, CD3OD) 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: 1HRMN (400 MHz, D2O) δ 6.29 (d, J = 6.9Hz, 1H), 4.83 (td , J = 4.2, 45.4 Hz, 1H), 4, 4 4-4.2 9 (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 and 4 (3aR, 5R, 6R, 7R, 7aR) -2- (ethylamino) -7-fluor-5 - ((S) -1- hydroxyethyl) -5 6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol (3aR, 5R, 6R, 7R, 7aR) -2- (ethylamino) -7-fluor-5 - ((R) -1- hydroxyethyl) -5.6 , 7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol

[126] To a suspension of (3aR, 5R, 6S, 7R, 7aR) -2- (ethylamino) -5- (hydroxymethyl) -5,6,7,7 a-tetrahydro-3aH-pyran [3,2- d] thiazole-6,7-diol (35.0 g, 141 mmol) in DMF (300 mL) cooled to 15 ° C, DIPEA (6.0 mL), Boc20 (61.5 g, 282 mmol) was added 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 obtain ((3aR, 5R, 6S , 7R, 7aR) 6,7-dihydroxy-5- (hydroxymethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (ethyl) tert-carbamate butyl as a white solid (31.5 g, 64% yield). XH NMR (400 MHz, CDCl3) 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).
[127] 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 At 0 ° C, BzCl (1.33 g, 9.50 mmol) was added slowly. After the addition the mixture was stirred at room temperature overnight. Saturated aqueous solution of NH4Cl (50 mL) was added, and the organic layer was collected. The aqueous layer was further extracted with DCM (2 x 40 ml). The combined extract was dried over anhydrous Na2SÜ4. 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), producing ((3aR, 5R, 6S, 7R, 7aR) - 6- (benzoyloxy) -2 - ((tert-butoxycarbonyl) (ethyl) amino) -7-hydroxy-5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole -5-yl) methyl as a white solid (0.67 g, 26%). XH NMR (400 MHz, CDCI3) 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, 9.2Hz, 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 = 7.2hz, 3H).
[128] To a solution of the above material (3.00 g, 5.39 mmol) in anhydrous DCM (30 mL) at -78 ° C, JC under N2, was added DAST (5.44 g, 33.8 mmol) . After the addition the mixture was stirred at room temperature for 48 h. The reaction mixture was then cooled to -78 ° C, diluted with DCM (50 ml), and then quenched with saturated aqueous NaHCO3 (70 ml). The organic layer was collected, and the aqueous phase was extracted with DCM (2 x 50 ml). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic column flash chromatography (EtOAc / hexanes, 1:10 to 1: 4), producing ((3aR, 5R, 6R) benzoate , 7R, 7aR) -6- (benzoyloxy) -2- ((tert-butoxycarbonyl) (ethyl) amino) -7-fluor-5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-5-yl) methyl as a white solid (2.15 g, 71%). XH NMR (400 MHz, CDC13) 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 = 7.2Hz, 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).
[129] A mixture of the above material (2.15 g, 3.85 mmol) and K3CO3 (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 chromatography yielding ((3aR, 5R, 6R, 7R, 7aR) -7-fluor-6-hydroxy-5- (hydroxymethyl) -5,6,7,7a-tetrahydro-3aH- tert-butyl pyran [3,2-d] thiazol-2-yl) (ethyl) carbamate as a white solid (1.25 g, 93%). 2H NMR (400 MHz, CDC13) 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).
[130] 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 TBDMSC1 (0.583 g, 3.87 mmol). The mixture was stirred at room temperature for 72 h, and then diluted with Et2O (100 ml) and brine (100 ml). The organic layer was collected, and the aqueous phase was extracted with Et2O (50 ml). The combined extract was washed with H2O (50 ml) and dried over anhydrous Na2SO4. 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), producing ((3aR, 5R, 6R, 7R , 7aR) -5 - ((((tert-butyldimethylsilyl) oxy) methyl) - 7-fluor-6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyran [3,2- d] thiazol-2- il) tert-butyl (ethyl) carbamate as a colorless sticky oil (1.66 g, 100%). XH NMR (500 MHz, CDC12) 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).
[131] At 0 ° C, to a solution of the above material (1.63 g, 3.51 mmol) and BU4NI (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 adding NaH, BnBr (1.20 g, 7.00 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 16 h and diluted with Et2O (60 ml) and saturated NH4 Cl (50mL). The organic layer was collected, and the aqueous phase was extracted with Et2O (2 x 30 ml). The combined extract was washed with brine (40 ml) and dried over anhydrous Na2SO4. 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: 4), producing ((3aR, 5R, 6R, 7R , 7aR) -6- (benzyloxy) -5 - ((((tert-butyldimethylsilyl) oxy) methyl) -7-fluor-5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- 2-yl) (ethyl) tert-butyl carbamate as a sticky oil (1.90 g, 98%). XH NMR (400 MHz, CDCl ) 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).
[132] At 0JC, 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 the addition, the reaction mixture was stirred at room temperature for 2h and diluted with EtOAc (20 ml) and brine (50 ml). The organic layer was collected, and the aqueous phase was extracted with EtOAc (2 x 50 ml). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by flash column chromatography (EtOAc / hexanes, 1: 5 to 1: 2), producing ((3aR, 5R, 6R, 7R , 7aR) - 6- (benzyloxy) -7-fluor-5- (hydroxymethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (ethyl) carbamate tert-butyl as a white solid (1.43 g, 95%). ZH NMR (400 MHz, CDC13) δ 7.38-7.28 (m, 5H), 6.06 (d, J = 7.1 Hz, 1H), 5.32 (ddd, J = 1.3, 3.1, 45.2Hz, 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).
[133] 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 Et2O (20 ml), and then concentrated to dryness. Aqueous NaHCO3 saturated (20 ml) with Na2S2θ3 (2 g) was added, and the mixture was extracted with EtOAc (2 x 30 ml). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by flash column chromatography (EtOAc / hexanes, 1: 5 to 1: 2), producing ((3aR, 5S, 6R, 7R , 7aR) - tert 6- (benzyloxy) -7-fluor-5-formyl-5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (ethyl) carbamate -butyl as a white solid (0.36 g, 81%). XH NMR (400 MHz, CDCl3) 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).
[134] To a solution of the above material (0.357 g, 0.85 mmol) in anhydrous THF (10 mL) under N2 was added MeMgBr (1.4 M in THF / toluene, 1.4 mL, 2.0 mmol) . After the addition the mixture was stirred at room temperature for 2h. The reaction was quenched with saturated aqueous NH4Cl (10 mL), and then extracted with EtOAc (3 x 15 mL). The combined extract was dried over anhydrous Na2SO4. After purification on silica gel by flash column chromatography (EtOAc / hexanes, 1:10 to 2: 3), ((3aR, 5R, 6R, 7R, 7aR) - 6- (benzyloxy) -7-fluor-5 - tert-butyl ((R and S) -1-hydroxyethyl) -5,6,7,7a- tetrahydro-3aH-pyran [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 XH NMR.
[135] 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 N2, BC13 (1.0 M in DCM, 0, 8 mL, 0.8 mmol). The mixture was stirred at ~ 3 h while the temperature of the cooling bath was heated to 0 ° C. The reaction mixture was cooled to -78 ° C, quenched with MeOH / DCM mixture, and then concentrated to dryness. After purification on silica gel by flash column chromatography (1.0 M NH3 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 by Agilent 1200 by preparative HPLC (column, C18, 19 x 50 mm, 5 µm; mobile phase, water with 0.03% NH4OH, and CH3CN (from 10% to 45% in 10 min); detector , 220 nm), yielding (3aR, 5R, 6R, 7R, 7aR) -2- (ethylamino) -7-fluor-5 - ((S) -1-hydroxyethyl) -5,6,7,7a- tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol (45 mg) as a white solid; 1HRMN (400 MHz, D2O) δ6.25 (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 (3aR, 5R, 6R, 7R, 7aR) -2- (ethylamino) -7-fluor-5 - ((R) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH -pyran [3,2-d] thiazole-6-ol (30 mg) as a white solid ^ HRMN (400 MHz, D20) δ6.28 (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 and 6 (3aR, 5R, 6R, 7R, 7aR) -2- (dimethylamino) -7-fluor-5 - ((S) -1- hydroxyethyl) -5 6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole-6-ol (3aR, 5R, 6R, 7R, 7aR) -2- (dimethylamino) -7-fluor-5 - ((R) -1- hydroxyethyl) -5.6 , 7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol

[136] At 0 ° C, for a solution of (3aR, 5R, 6S, 7R, 7aR) -2- (dimethylamino) -5- (hydroxymethyl) -5,6,7,7a-tetrahydro-3aH-pyran [ 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) TBDMSC1 (10.0 g , 66.3 mmol). The mixture was stirred at room temperature for 24 h and diluted with Et2O (100 ml) and brine (100 ml). The organic layer was collected, and the aqueous phase was extracted with Et2O (100 ml). The combined extract was washed with H2O (100 ml) and dried over anhydrous Na2SO2. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic column flash chromatography (EtOAc / hexanes, 1: 5 to 1: 1), producing (3aR, 5R, 6R, 7R, 7aR) - 7 - (((tert-butyldimethylsilyl) oxy) -5- ((((tert-butyldimethylsilyl) oxy) methyl) -2- (dimethylamino) -5,6,7,7 a-tetrahydro-3aH-pyran [3 , 2-d] thiazol-6-ol as a colorless sticky oil (5.95 g, 60%). XH NMR (500 MHz, CDCl3) 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), 0.066 (s, 6H).
[137] 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 NaHCO3 (100 ml). The organic layer was collected, and the aqueous phase was extracted with EtOAc (100 ml). The combined extract was washed with H2O (100 ml) and dried over anhydrous Na2SO4. After filtration the solvent was evaporated with hexanes under reduced pressure, and the residue was purified on silica gel by automatic column flash chromatography (EtOAc / hexanes, 1:10 to 1: 4), yielding (3aR, 5R, 6R, 7R , 7aR) -7- (((tert-butyldimethylsilyl) oxy) -5- ((((tert-butyldimethylsilyl) oxy) methyl) -2- (dimethylamino) - 5,6,7,7a-tetrahydro-3aH-pyran [3 , 2-d] thiazol-6-yl benzoate as a white solid (6.85 g, 88%). XH NMR (400 MHz, CDCl3) 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).
[138] To a solution of the above material (9.30 g, 16.0 mmol) in MeOH (100 mL) was bubbled HCI (g) for 2 min. The reaction mixture was then stirred at room temperature for 2 hours. The solvent was removed, and the residue was neutralized with saturated aqueous NaHCO3 (150 ml). The aqueous phase was extracted with EtOAc (6 x 80 ml). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure to obtain (3aR, 5R, 6S, 7R, 7aR) -2- (dimethylamino) -7-hydroxy-5- (hydroxymethyl) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-yl benzoate as a white solid (5.4 g, 96%). 2H NMR (400 MHz, CDC13) 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).
[139] 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 NaHCO3 (100 ml). The organic layer was collected, and the aqueous phase was extracted with EtOAc (2 x 50 ml). The combined extract was dried over anhydrous Na2SO4. After filtration the solvent was evaporated with hexanes under reduced pressure, and the residue was purified on silica gel by automatic column flash chromatography (EtOAc / hexanes, 1: 5 to 10: 1), producing ((3aR, 5R, 6S, 7R, 7aR) -6- (benzoyloxy) -2- (dimethylamino) -7-hydroxy-5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-5-yl) methyl as a white solid (4.20 g, 67%). XH NMR (400 MHz, CDCl3) 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).
[140] The above material (0.410 g, 0.898 mmol) was converted to the corresponding fluoride by treatment with DAST, using the procedure described in Example 3. The reaction mixture was stirred at room temperature for 16 h. After purification on silica gel by automatic column flash chromatography (EtOAc / hexanes, 1: 3 to 1: 2 benzoate), ((3aR, 5R, 6R, 7R, 7aR) - 6- (benzoyloxy) -2- ( dimethylamino) -7-fluor-5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-5-yl) methyl was obtained as a white foam (0.380 g, 92%). XH NMR (500 MHz, CDCl3) 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).
[141] The above material (0.375 g, 0.818 mmol) was deprotected using the procedure described in Example 3. After purification on silica gel by flash column chromatography (1.0 M NH3 in MeOH / DCM, 1:12), (3aR, 5R, 6R, 7R, 7aR) -2- (dimethylamino) -7-fluor-5- (hydroxymethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- 6-0I was obtained as a white solid (0.190 g, 93%). 1HRMN (400 MHz, CD3OD) ô 6.35 (d, J = 6.7Hz, 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).
[142] The above material (1.30 g, 5.19 mmol) was converted to the corresponding silyl ether using the procedure described in Example 3. After purification on silica gel by flash column chromatography (EtOAc / hexanes, 1 : 10 to 1: 1), (3aR, 5R, 6R, 7R, 7aR) -5 - (((tert-butyldimethylsilyl) oxy) methyl) -2- (dimethylamino) -7-fluor- 5,6,7, 7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol was obtained as a white solid (1.84 g, 97%). 1H NMR (400 MHz, CDCls) 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).
[143] The above material (1.80 g, 4.94 mmol) was protected by benzyl, then the silyl ether was cleaved, using the procedure described in Example 3. After purification on silica gel by automatic column flash chromatography (EtOAc / hexanes, 2: 3 to 5: 1), ((3aR, 5R, 6R, 7R, 7aR) -6- (benzyloxy) -2- (dimethylamino) -7-fluor- 5,6,7,7a -tetrahydro-3aH-pyran [3,2-d] thiazol-5-yl) methanol was obtained as a white solid (2.02 g, 91% over 2 steps). XH NMR (400 MHz, CDC13) 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).
[144] To a solution of DMSO (0.172 g, 2.20 mmol) in anhydrous DCM (10 mL) at -78 ° C under N3, oxalyl chloride (0.261 g, 2.06 mmol) was added slowly, and the mixture it was stirred at ~ -30 ° C for 45 min. The mixture was then cooled to -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 2h the reaction mixture was cooled again to -78 ° C, and Et3N (0.334 g, 3.31 mmol) was added. The mixture was stirred at ~ -30 ° C for an additional 30 min, and then was quenched with H2 O (20 ml). The organic layer was collected, and the aqueous phase was extracted with DCM (2 x 10 mL). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure to give the crude product (3aR, 5S, 6R, 7R, 7aR) -6- (benzyloxy) -2- (dimethylamino) -7-fluor- 5,6,7,7a -tetrahydro-3aH-pyran [3,2-d] thiazol-5-carbaldehyde as pale yellow foam. Under N2 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 the addition the mixture was stirred at room temperature for 2h. The reaction was quenched with saturated aqueous NaHCCu (20 mL), and then extracted with EtOAc (3 x 30 mL). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by flash column chromatography (EtOAc / hexanes, 2: 3 to 5: 1), producing mixture (R and S) —1 - ((3aR, 5R, 6R, 7R, 7aR) -6- (benzyloxy) -2- (dimethylamino) -7-fluor- 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole -5-yl) ethanol as a pale yellow solid (0.24 g, 79%) with a diastereomeric ratio of 1: 4 based on XH NMR.
[145] The above material (0.240 g, 0.677 mmol) was deprotected with BC13 using the procedure described in Example 3. After purification on silica gel by flash column chromatography (1.0 M NH3 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 x 25 cm, 5 µm, Chiral-P (IC) 002S09IC00CJ-MI001; mobile phase, phase A, hexane; phase B, ethanol with 0.1% DEA (10% ethanol, 30 min); detector, 220 nm), yielding (3aR, 5R, 6R, 7R, 7aR) -2- (dimethylamino) -7-fluor-5 - ((S) -1-hydroxyethyl) -5,6,7,7 α-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol (68 mg) as a white solid; 1HRMN (400 MHz, D2O) 06.24 (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 (3aR, 5R, 6R, 7R, 7aR) -2- (dimethylamino) -7-fluor -5 - ((R) - 1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole-6-ol (22 mg), as a white solid ^ HRMN ( 400 MHz, D2O) δ6.26 (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. HEAD >> Examples 7 and 8 (3aR, 5S, 6R, 7R, 7aR) -2- (ethylamino) -7-fluor-5 - ((R) -2,2,2-trifluor-1-hydroxyethyl) -5 , 6,7,7a-tetrahydro-3aH-pyran [3,2- d] thiazol-6-ol e (3aR, 5S, 6R, 7R, 7aR) -2- (ethylamino) -7-fluor-5- ( (S) -2,2,2-trifluor-1-hydroxyethyl) -5,6,7,7a ~ tetrahydro 3aH pyran [3,2-d] thiazol-6-ol

[146] For a solution of ((3aR, 5S, 6R, 7R, 7aR) - 6- (benzyloxy) -7-fluor-5-formyl-5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazol-2-yl) (ethyl) tert-butyl carbamate (0.410 g, 0.936 mmol) and TMSCF3 (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 the addition, the reaction mixture was stirred at room temperature for 2h. 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 solution reaction was then diluted with EtOAc (20 ml) and brine (30 ml). The organic layer was collected, and the aqueous phase was extracted with EtOAc (20 ml). The combined extract was dried over anhydrous Na2SO4. 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), producing ((3aR, 5R, 6R, 7R , 7aR) -6- (benzyloxy) -7-fluor-5 - ((R and S) -2,2,2-trifluor-1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazol-2-yl) (ethyl) tert-butyl carbamate as a pale yellow oil (0.355 g, 75%) with a diastereomeric ratio of 1: 1.05 based on XH NMR.
[147] The above material (0.350 g, 0.688 mmol) was deprotected with BC13 using the procedure described in Example 3. Purification and separation on silica gel by flash column chromatography (1.0 M NH3 in MeOH / DCM, 1: 15) gave (3aR, 5S, 6R, 7R, 7aR) -2- (ethylamino) -7-fluor-5 - ((R) - 2,2,2-trifluor-1-hydroxyethyl) -5,6,7 , 7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol (0.082 g, 37%) as a white solid; XH NMR (400 MHz, CD3OD) 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); 13C NMR (100 MHz, CD3OD) 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. (3aR, 5S, 6R, 7R, 7aR) -2- (ethylamino) -7-fluor-5 - ((S) -2,2,2-trifluor-1-hydroxyethyl) -5,6,7 , 7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol (0.074 g, 34%), as a white solid; XH NMR (400 MHz, CD3OD) 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 = 7.2hz, 3H); 13C NMR (100 MHz, CD3OD) 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.
[148] The following examples were synthesized according to procedures analogous to those described for Examples 7 and 8.

Examples 11 and 12 (3aR, 5S, 6R, 7R, 7aR) -2- (dimethylamino) -7-fluor-5 - ((R) - 2,2,2-trifluor-1-hydroxyethyl) -5,6, 7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol (3aR, 5S, 6R, 7R, 7aR) -2- (dimethylamino) -7-fluor-5 - ((S) -2,2,2-trifluor-1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol

[149] ((3aR, 5R, 6R, 7R, 7aR) -6- (benzyloxy) -2- (dimethylamino) -7-fluor-5,6,7,7a-tetrahydro-3aH-pyran [3,2- d] thiazol-5-yl) methanol (0.290 g, 0.852 mmol) was subjected to Swern's oxidation as described for Example 5 to produce (3aR, 5S, 6R, 7R, 7aR) -6- (benzyloxy) -2 - (dimethylamino) - 7-fluor-5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-5-crude carbaldehyde, which was treated with TMSCF3 as described for Example 9. After purification on silica gel by automatic column flash chromatography (EtOAc / hexanes, 2: 3 to 4: 1), ((3aR, 5R, 6R, 7R, 7aR) -6- (benzyloxy) -7-fluor-5- ( (R and S) -2,2,2-trifluor-1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (dimethyl) carbamate tert-butyl was obtained as a pale yellow solid (0.230 g, 66%) with a diastereomeric ratio of 1.4: 1 based on 1H NMR.
[150] The above material (0.230 g, 0.563 mmol) was deprotected with BCI3 using the procedure described in Example 3. Purification and separation on silica gel by flash column chromatography (1.0 M NH3 in MeOH / DCM, 1: 16) gave (3aR, 5S, 6R, 7R, 7aR) -2- (dimethylamino) -7-fluor-5 - ((R) - 2,2,2-trifluor-1-hydroxyethyl) -5,6,7 , 7a-tetrahydro-3aH-pyran [3,2-d] thiazole-6-0I (0.060 g, 33%) as a white solid; XH NMR (400 MHz, CD3OD) 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); 13C NMR (100 MHz, CD3OD) δ 166, 08, 126, 42 (g, 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. (3aR, 5S, 6R, 7R, 7aR) -2- (dimethylamino) -7-fluor-5- ((S) -2,2,2-trifluor-1-hydroxyethyl) -5,6,7 , 7a-tetrahydro-3aH-pyran [3,2- d] thiazol-6-ol (0.074 g, 41%) as a white solid; XH NMR (400 MHz, CD3OD) δ 6.32 (d, J = 6.4 Hz, 1H), 4.90 (ddd, J = 3.2, 4.3.46.2Hz, 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); 13C NMR (100 MHz, CD3OD) 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 and 14 (3aR, 5R, 6S, 7aR) -2- (ethylamino) -5 - ((S) -1-hydroxyethyl) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2- d] thiazol-6-ol e (3aR, 5R, 6S, 7aR) -2- (ethylamino) -5 - ((R) -1-hydroxyethyl) - 5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazole-6-ol

[151] A mixture of ((3aR, 5R, 6S, 7R, 7aR) - 6- (benzoyloxy) -2 - ((tert-butoxycarbonyl) (ethyl) amino) -7-hydroxy-5,6,7,7a -tetrahydro-3aH-pyran [3,2-d] thiazol-5-yl) methylabenzoate (2.60 g, 4.68 mmol) and thio-CDI (90% technical, 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 by flash column chromatography (EtOAc / hexanes, 1: 3 to 2: 3), producing (3aR, 5R, 6S, 7R, 7aR) -7- ((IH-imidazol-1-carbonothioyl) oxy) -5 - ((benzoyloxy) methyl) -2 - ((tert-butoxycarbonyl) (ethyl) amino) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazol-6-yl benzoate as a yellow solid (3.00 g, 96%). XH NMR (400 MHz, CDCl3) 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, 9,2hz, 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).
[152] 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 toluene / anhydrous THF mixture (30/40 ml) was stirred at reflux for 4 h. After cooling, the solvent was removed under reduced pressure, and the residue was purified by flash column chromatography (EtOAc / hexanes, 1:10 to 1: 3), producing ((3aR, 5R, 6S, 7aR) -6 benzoate) -6 - (benzoyloxy) -2 - ((tert-butoxycarbonyl) (ethyl) amino) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-5-yl) methyl as a white solid (1.60 g, 66%). XH NMR (400 MHz, CDC13) δ 8, 03-7, 94 (m, 4H), 7.57-7.52 (m, 2H), 7.44-7.35 (m, 4H), 6, 07 (d, J = 7.2Hz, 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 = 7.2hz, 3H ).
[153] The above material (1.6 g, 3.0 mmol) was deprotected with benzoyl with K2CO3 using the procedure described in Example 3. After purification on silica gel by flash column chromatography (MeOH / DCM, 1:20 ), ethyl ((3aR, 5R, 6S, 7aR) -6-hydroxy-5- (hydroxymethyl) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) tert-butyl carbamate (0.86 g, 87%) was obtained as a white solid.
[154] The above material (0.820 g, 2.48 mmol) was protected with mono-TBDMS using the procedure described in Example 3. After purification on silica gel by automatic column flash chromatography (EtOAc / hexanes, 1: 5 a 1: 2), ((3aR, 5R, 6S, 7aR) -5 - ((((tert-butyldimethylsilyl) oxy) methyl) -6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazol-2-yl) (ethyl) tert-butyl carbamate (0.71 g, 64%) was obtained as a white solid.
[155] The above material (0.710 g, 2.24 mmol) was protected with benzyl using the procedure described in Example 3. After purification on silica gel by automatic column flash chromatography (EtOAc / hexanes, 1:10 to 1: 4), ((3aR, 5R, 6S, 7aR) -6- (benzyloxy) -5 - ((((tert-butyldimethylsilyl) oxy) methyl) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazol-2-yl) (ethyl) tert-butyl carbamate (0.77 g, 64%) was obtained as a colorless sticky oil.
[156] The above material (0.770 g, 1.43 mmol) was deprotected with TBAF silyl using the procedure described in Example 3. After purification on silica gel by flash column chromatography (EtOAc / hexanes, 1: 5a 1 : 1), ((3aR, 5R, 6S, 7aR) -6- (benzyloxy) -5- (hydroxymethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- 2 tert-butyl -yl) (ethyl) carbamate was obtained as a colorless sticky foam (0.61 g, 100%). XH NMR (400 MHz, CDCl3) 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).
[157] 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 (0.12 g, 1.2 mmol) in H2O / DCM (3/5 mL) N-bromosuccinimide (NBS) (0.054 g, 0.30 mmol) was added. The mixture was stirred at ~ 12 ° C for 30 min, and extracted with DCM (2 x 10 ml). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic column flash chromatography (EtOAc / hexanes, 1:10 to 1: 1), producing ((3aR, 5S, 6S, 7aR ) Tert-Butyl -6- (benzyloxy) -5-formyl-5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (ethyl) carbamate as a foam undefined white (0.075 g, 75%). XH NMR (400 MHz, CDCl3) δ 9.61 (s, 1H), 7.35-7.26 (m, 5H), 6.00 (d, J = 7.2hz, 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).
[158] The above material (0.065 g, 0.15 mmol) was treated with MeMgBr using the procedure described in Example 3. After purification on silica gel by flash column chromatography (EtOAc / hexanes, 1:10 to 2: 3), ((3aR, 5R, 6S, 7aR) -6- (benzyloxy) -5 - ((R and S) -1-hydroxyethyl) - 5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazol-2-yl) (ethyl) tert-butyl carbamate was obtained as a white foam (0.046 g, 70%) with a 1: 1.3 diastereomeric ratio based on XH NMR.
[159] The above material (0.170 g, 0.389 mmol) was deprotected with BC13 using the procedure described in Example 3. After purification on silica gel by flash column chromatography (1.0 M NH3 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 by Agilent 1200 by preparative HPLC (column, C18, 19 x 50 mm, 5um; mobile phase, water with 0.03% NH4OH, and CH3CN (10%; 70% in 8 min); detector , 220 nm), yielding (3aR, 5R, 6S, 7aR) -2- (ethylamino) -5- ((S) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazol-6-ol (26 mg) as a white solid; 1HRMN (400 MHz, D20) 06, 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. (3aR, 5R, 6S, 7aR) -2- (ethylamino) -5 - ((R) -1-hydroxyethyl) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d ] thiazol-6-ol (22 mg) as a white solid; XHRMN (400 MHz, D2O) 06, 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-fluor-2- (methylamino) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- 6-ol

[160] A diastereomeric mixture of ((3aR, 5R, 6R, 7R, 7aR) -6- (benzyloxy) -7-fluor-5 - ((R and S) -1-hydroxyethyl) -5,6,7, Tert-butyl 7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) carbamate (0.560 g, 1.27 mmol), obtained as described for Example 1, and thio-CDI (90% technical, 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 flash column chromatography (EtOAc / hexanes, 1: 3 to 1: 1), producing a pale yellow sticky oil. A mixture of the sticky oil, BujSnH (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 flash column chromatography (EtOAc / hexanes, 1:10 to 1: 4), producing ((3aR, 5R, 6R, 7R, 7aR) -6- (benzyloxy) - 5-ethyl-7-fluor-5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) tert- butyl as a colorless oil (0.28 g, 52%). XH NMR (400 MHz, CDC13) 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).
[161] 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 N2, BC13 (1, 0 M in DCM, 2.5 mL, 2.5 mmol). The mixture was stirred at ~ 3 h while the temperature of the cooling bath was heated to 0 ° C. The reaction mixture was cooled to -78 ° C, quenched with MeOH / DCM mixture, and then residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH / DCM, 1:15) , producing (3aR, 5R, 6R, 7R, 7aR) -5-ethyl-7-fluor-2- (methylamino) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazole- 6-ol as a white solid (0.099 g, 64%). ] H NMR (400 MHz, CD3OD) 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); 13C NMR (100 MHz, CD3OD ) 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 = ^, 1 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 and 17 (3aR, 5R, 6S, 7aR) -5 - ((S) -1-hydroxyethyl) -2- (methylamino) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2- d] thiazol-6-ol e (3aR, 5R, 6S, 7aR) -5 - ((R) -1-hydroxyethyl) -2- (methylamino) - 5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazole-6-ol

[162] The material described above, 1 - ((3aR, 5R, 6S, 7aR) -6- (benzyloxy) -2- (methylamino) -5,6,7,7 a-tetrahydro-3aH-pyran [3, 2-d] thiazol-5-yl) ethanol (0.180 g, 0.558 mmol), was deprotected with BC13 using the procedure described in Example 20. After purification on silica gel by flash column chromatography (1.0 M NH3 in MeOH / DCM, 1:12), (3aR, 5R, 6S, 7aR) -5 - ((S) -1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazol-6-ol was obtained as a white solid (0.105 g, 81%) and as a mixture of diastereomers.
[163] The above diastereomeric mixture (95mg, 0.41mmol) was separated by preparative HPLC under the following conditions: [(Agilent 1200): Column, X-Bridge C18; mobile phase, 50 mmol / L NH4HCO3 in water with 0.05% NH4OH and CH3CN (CH3CN 5% to 20% in 10 min); detector, 220 nm UV] to obtain (3aR, 5R, 6S, 7aR) -5 - ((S) -1-hydroxyethyl) -2- (methylamino) - 5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazol-6-ol (fastest eluting isomer, 33.8 mg) as a white solid. (ES, m / z): [M + H] +233, 0; XH NMR (300 MHz, D2O) 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), 2.04-2.0 8 (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-pyran [3,2-d] thiazole- 6-0I (slower-eluting isomer, 21.7 mg) as a white solid. (ES, m / z): [M + H] +2 33.0; XH NMR (300 MHz, D2O) 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 ). Examples18 and 19 (3aR, 5R, 6S, 7aR) -2- (dimethylamino) -5 - ((S) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d ] thiazol-6-ol and (3aR, 5R, 6S, 7aR) -2- (dimethylamino) -5 - ((R) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3 , 2-d] thiazole-6-ol

[164] For a solution of (3aR, 5S, 6S, 7aR) - 6- (benzyloxy) -2- (dimethylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole -5-carbaldehyde (1.04 g) in anhydrous THF (30 ml) at 0 ° C was added the MeMgBr solution (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 H2 O (50 ml), extracted with EtOAc (2 x 40 ml). The combined extract was dried over anhydrous Na2SO4. The solvents were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting 2% -5% 2 M NH3 MeOH solution in DCM to give 1 - ((3aR, 5R, 6S, 7aR) -6- (benzyloxy) -2- (dimethylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-5-yl) ethanol (0.840 g, 77%) as a foam pale yellow. MS m / z 337.2 (M + 1, 100%); XH NMR (400 MHz, CDC13) showed that this was a mixture of two diastereomers, with a ratio of -60: 40.
[165] To a solution of the above material (0.260 g, 0.774 mmol) in DCM (5 mL) at -78 ° C was added the solution of BCI3 in DCM (1.0 M, 1.55 mL, 1.55 mmol ). The mixture was slowly warmed 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 abruptly cool the reaction. Solvents were evaporated and the residue was treated with MeOH three more times. The crude product was purified by silica gel column chromatography, eluting with 2% -5% 2 M NH3 MeOH solution in DCM to produce (3aR, 5R, 6S, 7aR) -2- (dimethylamino) - 5- (1 -hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2- d] thiazole-6-0I (0.086 g, 45%) as a white solid. MS m / z 247.1 (M + 1, 100%); 1H NMR (400 MHz, MeOD) showed that this was a mixture of two diastereomers, with a ~ 60: 40 ratio.
[166] The above mixture (77.3 mg) was separated by preparative HPLC with the following conditions [(preparative HPLC from Agilent 1200; Column: Sun Fire Prep C18.19 * 50mm 5um; mobile phase: 0.03% water NH4OH and CH3CN (5% CH3CN up to 35% in 10 min; detector: UV 220nm))] to produce (3aR, 5R, 6S, 7aR) -2- (dimethylamino) -5- ((S) -1-hydroxyethyl) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol (fastest eluting isomer) as a white solid (26.3 mg); [M + H] +247.1; NMR (300 MHz, D2O) 56, 22 (d, J = 6.9Hz, 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-pyran [3,2-d] thiazole -6-ol (slower-eluting isomer) as a white solid (18 mg). [M + H] 247.1; H NMR (300 MHz, D2O) 56, 23 (d, J = 6.9Hz, 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 and 21 (3aR, 5S, 6S, 7aR) -2- (methylamino) -5 - ((R) -2,2,2-trifluor-1-hydroxyethyl) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazole-6-01 e (3aR, 5S, 6S, 7aR) -2- (methylamino) -5 - ((S) -2,2,2-trifluor-1-hydroxyethyl ) -5,6,7,7a-tetrahydro-3aH-pyran [3,2- d] thiazol-6-ol

[167] A debenzoate mixture of ((3aR, 5R, 6S, 7R, 7aR) -6- (benzoyloxy) -2 - ((tert-butoxycarbonyl) (methyl) amino) -7-hydroxy-5,6,7, 7a-tetrahydro-3aH-pyran [3,2-d] thiazol-5-yl) methyl (5.00 g, 9.21 mmol) and thio-CDI (90% technical, 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 column flash chromatography (EtOAc / hexanes, 1:10 to 2: 3), producing (3aR, 5R, 6S, 7R benzoate , 7aR) -7- ((IH-imidazol-1-carbonothioyl) oxy) -5 - ((benzoyloxy) methyl) - 2 - ((tert-butoxycarbonyl) (methyl) amino) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-yl as a pale yellow solid (5.60 g, 93%). XH NMR (400 MHz, CDClj) 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 = 1.1 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, 9.2hz, 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).
[168] A mixture of the above material (5.60 g, 8.58 mmol), Bu3SnH (5.84 g, 17.0 mmol) and ABCN (0.15 g, 0.60 mmol) in anhydrous toluene / THF mixture (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 column flash chromatography (EtOAc / hexanes, 1:10 to 1: 2), producing ((3aR, 5R, 6S, 7aR) -6- (benzoyloxy) -2 - ((tert-butoxycarbonyl) (methyl) amino) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-5-yl) methyl as a white solid (3.20 g, 71%). XH NMR (400 MHz, CDC13) 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).
[169] A mixture of the above material (3.20 g, 6.08 mmol) and K2CO3 (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), yielding ((3aR, 5R, 6S, 7aR) -6-hydroxy-5- (hydroxymethyl) -5 , 6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) tert-butyl carbamate as a white solid (1.82 g, 94%). 2H NMR (400 MHz, CDCl3) 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).
[170] 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 TBDMSC1 (0.952 g, 6.32 mmol). The mixture was stirred at room temperature for 16 h and diluted with Et2O (100 ml) and brine (100 ml). The organic layer was collected, and the aqueous phase was extracted with Et2O (50 ml). The combined extract was washed with H2O (50 ml) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic column flash chromatography (EtOAc / hexanes, 1:10 to 1: 2), producing ((3aR, 5R, 6S, 7aR ) -5- ((((tert-butyldimethylsilyl) oxy) methyl) -6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2- 11) (methyl) carbamate tert-butyl as a colorless sticky oil (2.30 g, 93%). XH NMR (400 MHz, CDC13) 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).
[171] At 0 ° C, to a solution of the above material (2.78 g, 6.45 mmol) and Bu4NI (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 adding NaH, BnBr (1.93 g, 11.3 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 16 h, and diluted with Et2 <D (100 ml) and saturated NH4 Cl (100 ml). The organic layer was collected, and the aqueous phase was extracted with Et2O (2 x 40 mL). The combined extract was washed with brine (80 ml) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic column flash chromatography (EtOAc / hexanes, 1:10 to 1: 4), producing ((3aR, 5R, 6S, 7aR ) -6- (benzyloxy) -5- ((((tert-butyldimethylsilyl) oxy) methyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl ) tert-butyl carbamate as a colorless sticky oil (2.76 g, 82%). XH NMR (400 MHz, CDC13) 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).
[172] 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 the addition, the reaction mixture was stirred at room temperature for 2h and diluted with EtOAc (40 ml) and brine (80 ml). The organic layer was collected, and the aqueous phase was extracted with EtOAc (2 x 50 ml). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by flash column chromatography (EtOAc / hexanes, 1: 5 to 1: 1), producing ((3aR, 5R, 6S, 7aR ) - 6- (benzyloxy) -5- (hydroxymethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) tert-butyl carbamate as a colorless sticky foam (2.0 g, 94%). XH NMR (400 MHz, CDC13) 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).
[173] 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 Et2 <D (30 ml), and then concentrated to dryness. Aqueous NaHCO3 saturated (30 ml) with Na2S2O3 (2 g) was added, and the mixture was extracted with EtOAc (2 x 50 ml). The combined extract was dried over anhydrous Na3SO4. 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 2: 3), producing ((3aR, 5S, 6S, 7aR ) Tert-butyl 6- (benzyloxy) -5-formyl-5,6,7,7a-tetrahydro-3aH-pyran [3,2- d] thiazol-2-yl) (methyl) carbamate as a white foam (0.57 g, 86%). XH NMR (500 MHz, CDCl3) δ 9.63 (s, 1H), 7.36-7.27 (m, 5H), 6.04 (d, J = 7.2hz, 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).
[174] To a solution of the above material (0.17 g, 0.42 mmol) and TMSCF3 (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 the addition, the reaction mixture was stirred at room temperature for 2h. 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 solution reaction was then diluted with EtOAc (20 ml) and brine (30 ml). The organic layer was collected, and the aqueous phase was extracted with EtOAc (20 ml). The combined extract was dried over anhydrous Na2SÜ4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified and separated on silica gel by automatic column flash chromatography (EtOAc / hexanes, 1: 4 to 1: 1), producing ((3aR, 5R, 6S , 7aR) -6- (benzyloxy) -5- ((S) -2,2,2-trifluor-1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] tert-butyl thiazol-2-yl) (methyl) carbamate (0.060 g, 30%) as a pale yellow oil; XH NMR (400 MHz, CDCI3) δ 7.33-7.27 (m, 5H), 6.01 (d, J = 1.4 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). ((3aR, 5R, 6S, 7aR) -6- (benzyloxy) -5 - ((R) -2,2,2-trifluor-1-hydroxyethyl) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2- d] thiazol-2-yl) (methyl) tert-butyl carbamate (0.052 g, 26%) as pale yellow oil; XH NMR (400 MHz, CDCl3) 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).
[175] For ((3aR, 5R, 6S, 7aR) -6- (benzyloxy) -5- ((R) -2,2,2-trifluor-1-hydroxyethyl) -5,6,7,7a-tetrahydro -3aH-pyran [3,2- d] thiazol-2-yl) (methyl) tert-butyl carbamate (0.052 g, 0.11 mmol) and PMB (0.10 g, 0.67 mmol) in anhydrous DCM (5 ml) at -78 ° C under N3, BC13 (1.0 M in DCM, 0.60 ml, 0.60 mmol) was added. The mixture was stirred at ~ 3 h while the temperature of the cooling bath was heated to 0 ° C. The reaction mixture was cooled to -78 ° C, quenched with MeOH / DCM mixture, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH / DCM, 1:12), yielding (3aR, 5S, 6S, 7aR) -2- (methylamino) -5 - (( R) - 2,2,2-trifluor-1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol as a white solid (0.023 g, 74 %). 1HRMN (400 MHz, CD3OD) ô 6.21 (d, J = 6.4Hz, 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); 13C NMR (100 MHz, CD3OD) δ 163, 69, 126, 47 (q, J = 281.2hz), 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.
[176] For ((3aR, 5R, 6S, 7aR) -6- (benzyloxy) -5 - ((S) -2,2,2-trifluor-1-hydroxyethyl) -5,6,7,7a-tetrahydro -3aH-pyran [3,2- d] thiazol-2-yl) (methyl) tert-butyl 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 ;, BC13 (1.0 M in DCM, 0.60 ml, 0.60 mmol) was added. The mixture was stirred at ~ 3 h while the temperature of the cooling bath was heated to 0 ° C. The reaction mixture was cooled to -78 ° C, quenched with MeOH / DCM mixture, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH / DCM, 1:12), yielding (3aR, 5S, 6S, 7aR) -2- (methylamino) -5 - (( S) - 2,2,2-trifluor-1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol as a white solid (0.030 g, 82 %). XHRMN (400 MHz, CD3OD) δ 6.15 (d, J = 6.5Hz, 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 ); 13C NMR (100 MHz, CD30D) 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 and 23 (3aR, 5S, 6S, 7aR) -2- (dimethylamino) -5 - ((R) -2,2, 2-trifluor-1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2- d] thiazol-6-ol e (3aR, 5S, 6S, 7aR) -2- (dimethylamino) -5 - ((S) - 2,2,2-trifluor-1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol

[177] For a solution of (3aR, 5S, 6S, 7aR) - 6- (benzyloxy) -2- (dimethylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole -5-carbaldehyde (0, 650 g) in anhydrous THF (15 mL) at room temperature was TMSCF3 (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 hours. 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 NaHC03 (30 ml), extracted with EtOAc (2 * 20 ml). The combined extract was dried over anhydrous Na2SO4. The solvents were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with 1% -3% 2 M NH3 MeOH solution in DCM to give 1 - ((3aR, 5R, 6S, 7aR) -6- (benzyloxy) -2- (dimethylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-5-yl) -2,2,2-trifluorethanol (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 their XH NMR spectrum (400 MHz, CDC13).
[178] To a solution of the above material (0.260 g, 0.774 mmol) in DCM (5 mL) at -78 ° C was added the solution of BC13 in DCM (1.0 M, 1.34 mL, 1.34 mmol ). The mixture was slowly warmed 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 abruptly cool the reaction. Solvents were evaporated and the residue was treated with MeOH three more times. The crude product was purified by silica gel column chromatography, eluting with 2% -5% 2M NHj MeOH solution in DCM to produce (3aR, 5S, 6S, 7aR) -2- (dimethylamino) -5- ( 2,2,2-trifluor-1-hydroxyethyl) -5,6,7,7 a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol (0.044 g, 22%) as a yellow foam pale. MS m / z 301.1 (M + 1, 100%). An estimation ratio of the two diastereomers was 70:30 based on their XH NMR spectrum (400 MHz, MeOD). Examples24 and 25 (3aR, 5S, 6R, 7R, 7aR) -7-fluor-2- (methylamino) -5 - ((R) - 1,1, 1-trifluor-2-hydroxypropane-2-yl) -5 , 6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol e (3aR, 5S, 6R, 7R, 7aR) -7-fluor- 2- (methylamino) -5- ( (S) -1,1, 1-trifluor-2-hydroxypropane-2-yl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol

[179] For a solution of ((3aR, 5S, 6R, 7R, 7aR) - 6- (benzyloxy) -7-fluor-5-formyl-5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazol-2-yl) (methyl) tert-butyl carbamate (0.930 g, 2.19 mmol) in anhydrous THF (15 mL), at 0 ° C and under N2, MeMgBr (1 , 4 M in THF / toluene, 3.0 mL, 5.2 mmol). After the addition the mixture was stirred at room temperature for 3 h. The reaction was quenched with saturated aqueous NaHCCu (30 ml), and then extracted with EtOAc (3 * 30 ml). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was dissolved in DCM (40 ml) and BOC2O (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 flash column chromatography (EtOAc / hexanes, 1:10 to 1: 2), producing ((3aR, 5R, 6R, 7R, 7aR) -6- (benzyloxy) - Tert-butyl 7-fluor-5- (1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) carbamate as a foam undefined white (0.767 g, 80%), which contained two diastereomers.
[180] The above material (0.767 g, 1.74 mmol) was oxidized with DMP using the procedure described in Example 29. After purification on silica gel by flash column chromatography (EtOAc / hexanes, 1:10 to 1: 2), ((3aR, 5S, 6R, 7R, 7aR) -5-acetyl-6- (benzyloxy) -7-fluor- 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] tert-butyl thiazol-2-yl) (methyl) carbamate was obtained as a white foam (0.39 g, 51%). XH NMR (400 MHz, CDC13) 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 = ll, 2hz, 1H), 4.65 (d, J = ll, 2hz, 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).
[181] The above material (0.375 g, 0.856 mmol) was subjected to the addition of TMSCF3 as described for Example 29. The product mixture was purified and separated on silica gel by flash column chromatography (EtOAc / hexanes, 1 : 20 to 1: 4), producing ((3aR, 5S, 6R, 7R, 7aR) -6- (benzyloxy) -7-fluor-5- ((S) -1,1,1-trifluor-2-hydroxypropane -2-yl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) tert-butyl carbamate (0.13 g, 30%) as a white foam; XH NMR (400 MHz, CDC13) 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). It was also isolated ((3aR, 5S, 6R, 7R, 7aR) - 6- (benzyloxy) -7-fluor-5 - ((R) -1,1,1-trifluor-2-hydroxypropane-2-yl) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) tert-butyl carbamate (0.20 g, 46%) as a white foam; NMR (400 MHz, CDC13) 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).
[182] The above material, ((3aR, 5S, 6R, 7R, 7aR) - 6- (benzyloxy) -7-fluor-5 - ((S) -1,1,1-trifluor-2-hydroxypropane-2 -yl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) tert-butyl carbamate (0.130 g, 0.256 mmol), was deprotected with BC13 using the procedure described in Example 20. After purification on silica gel by flãsh column chromatography (1.0 M NH3 in MeOH / DCM, 1:15), (3aR, 5S, 6R, 7R, 7aR) -7-fluor -2- (methylamino) -5- ((S) - 1,1,1-trifluor-2-hydroxypropane-2-yl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d ] thiazol-6-ol was obtained as a white solid (0.073 g, 90%). XHRMN (400 MHz, CD3OD) 06, 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); 13C NMR (100 MHz , CD3OD) δ 164.36 (d, J = 2.5 Hz), 127.43 (q, J = 285.3 Hz), 93.67 (d, J = 111.4 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.
[183] The above material, ((3aR, 5S, 6R, 7R, 7aR) - 6- (benzyloxy) -7-fluor-5 - ((R) -1,1,1-trifluor-2-hydroxypropane-2 -yl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) tert-butyl carbamate (0.200 g, 0.394 mmol), was deprotected with BC13 using the procedure described in Example 20. After purification on silica gel by flash column chromatography (1.0 M NH3 in MeOH / DCM, 1: 15), (3aR, 5S, 6R, 7R, 7aR) -7-fluor -2- (methylamino) -5- ((R) - 1,1,1-trifluor-2-hydroxypropane-2-yl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d ] thiazol-6-ol was obtained as a white solid (0.114 g, 91%). XHRMN (400 MHz, CD3OD) 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); 13C NMR (100 MHz , CD3OD) δ 164.35 (d, J = 2.7 Hz), 127.35 (g, 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. Examples26 and 27 (3aR, 5S, 6R, 7R, 7aR) -2- (ethylamino) -7-fluor-5 - ((R) -1,1,1-trifluor-2-hydroxypropane-2-yl) -5 , 6,7,7a-tetrahydro-3aH-pyran [3,2 — d] thiazole — 6 — ol e (3aR, 5S, 6R, 7R, 7aR) —2— (ethylamino) -7-fluor-5- ( (S) -1,1, 1-trifluor-2-hydroxypropane-2-yl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol

[184] Aldehyde ((3aR, 5S, 6R, 7R, 7aR) - 6- (benzyloxy) -7-fluor-5-formyl-5,6,7,7a-tetrahydro-3aH-pyran [3,2- d] tert-butyl thiazol-2-yl) (ethyl) carbamate (0.42 g, 0.96 mmol) was subjected to the addition of MeMgBr as described for Example 24. After purification on silica gel by flash chromatography on automatic column (EtOAc / hexanes, 1:10 to 2: 3), ((3aR, 5R, 6R, 7R, 7aR) -6- (benzyloxy) -7-fluor-5- (1-hydroxyethyl) -5.6 , 7,7a-tetrahydro-3aH-pyran [3,2- d] thiazol-2-yl) (ethyl) tert-butyl carbamate was obtained as a white foam (0.30 g, 69%), which contained two diastereomers.
[185] The above material (0.30 g, 0.66 mmol) was oxidized with DMP using the procedure described in Example 29. After purification on silica gel by automatic column flash chromatography (EtOAc / hexanes, 1:10 to 1: 2), ((3aR, 5S, 6R, 7R, 7aR) -5-acetyl-6- (benzyloxy) -7-fluor- 5,6,7,7a-tetrahydro-3aH-pyran [3,2- d] tert-butyl thiazol-2-yl) (ethyl) carbamate was obtained as a clear oil (0.20 g, 67%). XH NMR (400 MHz, CDCl3) 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).
[186] The above material (0.200 g, 0.442 mmol) was subjected to the addition of TMSCF3 as described for Example 29. The product mixture was purified and separated on silica gel by flash column chromatography (EtOAc / hexanes, 1 : 20 to 1: 4), producing ((3aR, 5S, 6R, 7R, 7aR) -6- (benzyloxy) -7-fluor-5- ((S) -1,1, 1- trifluor-2-hydroxypropane -2-yl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (ethyl) tert-butyl carbamate (0.057 g, 25%) as a white foam; NMR (400 MHz, CDCI3) 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). It was also isolated ((3aR, 5S, 6R, 7R, 7aR) -6- (benzyloxy) -7-fluor-5 - ((R) -1,1,1-trifluor-2-hydroxypropane-2-yl) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (ethyl) tert-butyl carbamate (0.10 g, 43%) as a white foam; 2H NMR (400 MHz, CDCl3) 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).
[187] The above material, ((3aR, 5S, 6R, 7R, 7aR) - 6- (benzyloxy) -7-fluor-5 - ((S) -1,1,1-trifluor-2-hydroxypropane-2 -yl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (ethyl) tert-butyl carbamate (0.057 g, 0.11 mmol), was deprotected with BC13 using the procedure described in Example 20. After purification on silica gel by flssh column chromatography (1.0 M NH3 in MeOH / DCM, 1:17), (3aR, 5S, 6R, 7R, 7aR) -2- (ethylamino) -7-fluor-5- ((S) - 1,1,1-trifluor-2-hydroxypropane-2-yl) -5,6,7,7a-tetrahydro-3aH-pyran [3 , 2-d] thiazol-6-ol was obtained as a white solid (0.031 g, 85%). XHRMN (400 MHz, CD3OD) 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); 13C NMR (100 MHz, CD3OD) 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.
[188] The above material, ((3aR, 5S, 6R, 7R, 7aR) -6- (benzyloxy) -7-fluor-5 - ((R) -1,1,1-trifluor-2-hydroxypropane- 2 -yl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (ethyl) tert-butyl carbamate (0.100 g, 0.191 mmol), was deprotected with BC13 using the procedure described in Example 20. After purification on silica gel by flash column chromatography (1.0 M NH3 in MeOH / DCM, 1:17), (3aR, 5S, 6R, 7R, 7aR) -2- ( ethylamino) -7-fluor-5- ((R) - 1,1,1-trifluor-2-hydroxypropane-2-yl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d ] thiazole-6-0I was obtained as a white solid (0.053 g, 84%), 1HRMN (400 MHz, CD3OD) δ6.26 (d, J = 6.8Hz, 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 = 7.2hz, 3H); 13C NMR (100 MHz, CD30D) 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 = 27.2Hz), 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-fluor-5- (1,1,1-trifluor-2-hydroxypropane-2-yl) -5,6,7, 7a ~ tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol

[189] To a solution of DMSO (0.275 g, 3.50 mmol) in anhydrous DCM (5 mL) at -78 ° C under N2, oxalyl chloride (0.422 g, 3.32 mmol) was added dropwise. The mixture was stirred at —30 ° C for 30 min and cooled to -78 ° C again. The solution of ((3aR, 5R, 6R, 7R, 7aR) -6- (benzyloxy) -2- (dimethylamino) -7-fluor-5,6,7,7a-tetrahydro-3aH-pyran [3,2- d] thiazol-5-yl) methanol (0.465 g, 1.37 mmol) in anhydrous DCM (5 ml) was added. After stirring at ~ -30 ° C for 2h the reaction mixture was cooled again to -78 ° C and Et3N (0.624 g, 6.18 mmol) was added. The mixture was stirred at ~ -30 ° C for an additional 30 min, and then was quenched with H2 O (20 ml). The organic layer was collected and the aqueous phase was extracted with DCM (2 x 10 mL). The combined extracts were dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to give the crude aldehyde product. This was purified by silica gel column chromatography, eluting with 30% - 60% EtOAc in hexanes to produce (3aR, 5S, 6R, 7R, 7aR) -6- (benzyloxy) -2- (dimethylamino) -7- fluor-5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-5-carbaldehyde (0.190 g, 41%) as a pale yellow foam. MS ra / z 339.1 (M + 1, 100%).
[190] To a solution of the above aldehyde (0.170 g, 0.503 mmol) in anhydrous THF (5 mL) at 0 ° C was added the MeMgBr solution (1.4 M in 1: 3 THF / toluene, 0.90 mL , 1.26 mmol) drop by drop. The reaction was then stirred at room temperature for 2 hours. The mixture was diluted with H2O (10 ml), extracted with EtOAc (2 x 10 ml). The combined extracts were dried over anhydrous Na2SO4. The solvents were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with 1% -2% 2 M NH3 MeOH solution in DCM to give 1- ((3aR, 5R, 6R, 7R, 7aR) -6- (benzyloxy) -2- (dimethylamino) - / - fluorol, 7,7-tetrahydro-3aH-pyran [3,2-d] thiazol-5-yl) ethanol (0.115 g, 65%) as a pale yellow foam. MS ra / z 355.2 (M + 1, 100%); XH NMR (400 MHz, CDC13) showed that this was a mixture of two diastereomers, with a ~ 4: 1 ratio.
[191] To a solution of the above material (0.110 g, 0.311 mmol) in dried 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 NaHCO3 (10 ml) and 1 M Na2S2O3 (3 ml) and extracted with DCM (2 x 10 ml). The extracts were dried over Na2SO4 and the solvents were evaporated to give the crude product. This was purified by silica gel column chromatography, eluting with 1% NH4OH in 1: 1 hexanes-EtOAc to give 1 - ((3aR, 5S, 6R, 7R, 7aR) -6- (benzyloxy) -2- ( dimethylamino) -7-fluor-5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-5-yl) ethanone (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% / NMR (400 MHz, CDCl3) 07.28-7.38 (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).
[192] To a solution of the above material (0.074 g, 0.21 mmol) in anhydrous THF (4 mL) at room temperature was added TMSCF3 (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 hours. 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 NaHCO3 (10 ml), extracted with EtOAc (2 x 10 ml). The combined extract was dried over anhydrous Na2SO4. 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-fluor- 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-5-yl) -1,1,1-trifluorpropane-2-ol (0.055 g, 62%) as a pale yellow syrup. MS m / z 423.1 (M + 1, 100%). The XH NMR spectrum (400 MHz, CDCl3) showed that this was a mixture of the two diastereomers, with a ~ 56: 44 ratio.
[193] To a solution of the above material (0.055 g, 0.13 mmol) in DCM (2 mL) at -78 ° C was added the solution of BCI3 in DCM (1.0 M, 0.16 mL, 0, 16 mmol). The mixture was slowly warmed 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 abruptly cool the reaction. Solvents were evaporated and the residue was treated with MeOH three more times. The crude product was purified by silica gel column chromatography, eluting with 30% -100% EtOAc in hexanes to produce (3aR, 5S, 6R, 7R, 7aR) -2- (dimethylamino) - 7-fluor-5- (1,1,1-trifluor-2-hydroxypropane-2-yl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-0I (0.0344 g, 80 %) as a white solid. MS m / z 333.1 (M + 1, 100%); The dexH NMR spectrum (400 MHz, MeOD) showed that this was a mixture of the two diastereomers, with a ~ 56: 44 ratio. Examples 29 and 30 (3aR, 5S, 6S, 7aR) -2- (methylamino) -5 - ((R) -1,1,1-trifluor-2-hydroxypropane-2-yl) -5,6,7, 7a-tetrahydro-3aH-pyran [3,2- d] thiazol-6-ol (3aR, 5S, 6S, 7aR) -2- (methylamino) -5 - ((S) - 1,1,1-trifluor -2-hydroxypropane-2-yl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol

[194] For a solution of ((3aR, 5S, 6S, 7aR) - 6- (benzyloxy) -5-formyl-5,6,7,7a-tetrahydro-3aH-pyran [3,2- d] thiazole- Tert-Butyl 2-yl) (methyl) carbamate (0.920 g, 2.26 mmol) in anhydrous THF (20 mL) at 15 ° C was added to the MeMgBr solution (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 was quenched with saturated aqueous NaHCO3 solution (30 ml). The mixture was extracted with EtOAc (2 x 30 ml), and the combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic column flash chromatography (MeOH / DCM, 0: 4 to 1: 4), producing ((3aR, 5R, 6S, 7aR Tert-butyl) -6- (benzyloxy) -5- (1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) carbamate (0.350 g, 37%) as a white foam; The XH NMR (400 MHz, CDCl ) For this material indicated that it contained two diastereomers, with a ratio of 1: 2. The unprotected side product 1 - ((3aR, 5R, 6S, 7aR) -6- (benzyloxy) -2- (methylamino) -5,6,7,7 a-tetrahydro-3aH-pyran [[3,2 -d] thiazol-5-yl) ethanol (0.300 g, 41%) as a white solid; XH NMR (400 MHz, CDCI3) for this material indicated that it contained two diastereomers, with a ratio of 1: 1.4.
[195] For a solution of ((3aR, 5R, 6S, 7aR) - 6- (benzyloxy) -5- (1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2- d] tert-butyl thiazol-2-yl) (methyl) carbamate (0.406 g, 0.961 mmol) in dried DCM (20 mL) DMP (0.615 g, 1.45 mmol) was added. The reaction mixture was stirred at room temperature for 3 h, and then concentrated. The residue was diluted with saturated aqueous NaHCO3 solution (20 ml) and 1 M Na2S2O3 aqueous solution (5 ml), and extracted with EtOAc (2 x 20 ml). The combined extract was dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by flash column chromatography (EtOAc / hexanes, 1: 4 to 2: 3), producing ((3aR, 5S, 6S, 7aR Tert-butyl) -5-acetyl-6- (benzyloxy) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) carbamate (0.32 g), which was impure and used in the next step without further purification.
[196] To a solution of the above material and TMSCF3 (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 the 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 solution reaction was then diluted with EtOAc (20 ml) and brine (30 ml). The organic layer was collected, and the aqueous phase was extracted with EtOAc (20 ml). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified and separated on silica gel by automatic column flash chromatography (EtOAc / hexanes, 1: 4 to 1: 1), producing ((3aR, 5S, 6S , 7aR) -6- (benzyloxy) -5 - ((S) -1,1,1-trifluor-2-hydroxypropane-2-yl) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2- d] tert-butyl thiazol-2-yl) (methyl) carbamate (0.11 g, 23% over two steps) as a pale yellow oil; XH NMR (400 MHz, CDCl3) δ 7.35-7.27 (m, 5H), 6.06 (d, J = 1.1 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, isolated ((3aR, 5S , 6S, 7aR) -6- (benzyloxy) -5 - ((R) ~ 1,1, l-trifluor-2-hydroxypropane-2-yl) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazol-2-yl) (methyl) tert-butyl carbamate (0.16 g, 34% over two steps), as a pale yellow oil; XH NMR (400 MHz, CDC13) δ 7, 34-7.27 (m, 5H), 6.05 (d, J = 1.6 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).
[197] The protected material, ((3aR, 5S, 6S, 7aR) -6- (benzyloxy) -5- ((S) -1, 1,1-trifluor-2-hydroxypropane-2-yl) - 5, 6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) tert-butyl carbamate (0.105 g, 0.214 mmol), was deprotected using BC13, as described for the Example 20. After purification on silica gel by flash column chromatography (1.0 M NH3 in MeOH / DCM, 1: 12), (3aR, 5S, 6S, 7aR) -2- (methylamino) -5 - ((S ) -1,1,1-trifluor-2-hydroxypropane-2-yl) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol was obtained as a white solid (0.051 g, 79%). 1HRMN (400 MHz, CD3OD) δ 6.18 (d, J = 6.8Hz, 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); 13C NMR (100 MHz, CD3OD) 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.
[198] The protected material, ((3aR, 5S, 6S, 7aR) - 6- (benzyloxy) -5- ((R) -1, 1,1-trifluor-2-hydroxypropane-2-yl) - 5, 6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) tert-butyl carbamate (0.160 g, 0.326 mmol), was deprotected using BCI3, as described for the Example 20. After purification on silica gel by flash column chromatography (1.0 M NH3 in MeOH / DCM, 1:12), (3aR, 5S, 6S, 7aR) -2- (methylamino) -5 - ((R ) -1,1,1-trifluor-2-hydroxypropane-2-yl) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol was obtained as a white solid (0.072 g, 73%). XHRMN (400 MHz, CD3OD) δ 6.18 (d, J = 6.8Hz, 1H), 4.44-4.41 (m, 1H), 4.19- 4.15 (m, 1H), 3 , 67 (d, J = 1.4 Hz, 1H), 2.85 (s, 3H), 2.29-2.24 (m, 1H), 2.09-2.03 (m, 1H), 1.31 (s, 3H); 13C NMR (100 MHz, CD3OD) 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.
[199] The following examples were synthesized according to procedures analogous to the schemes and examples described above.

Example 33 (3aR, 5R, 6R, 7R, 7aR) -2-amino-7-fluor-5 - ((S) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6- ol

[200] To a (2S, 3R, 4R, 5S, 6R) -6- (acetoxymethyl) -3-aminotetrahydro-2H-pyran-2,4,5-triyl triacetate hydrochloride (14.0 g, 36.5 mmol) in MeCN (160 mL) DIPEA (5.16 g, 40.0 mmol) and allyl isothiocyanate (7.92 g, 79.9 mmol) were added. 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 flash column chromatography (EtOAc / hexanes, 1: 2 to 2: 1), producing 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 NaHCOa (60 ml). The organic layer was collected and the aqueous layer was extracted with DCM once (40 ml). The combined organic extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated to dryness under reduced pressure. The residue was dissolved in DCM (160 ml), and Boc20 (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 flash column chromatography (EtOAc / hexanes, 1: 10 to 2: 3), producing a white foam. The white foam was dissolved in dry MeOH (150 ml), in which NH3 was bubbled (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 ally ((3aR, 5R, 6S, 7R, 7aR) -6,7- dihydroxy -5- (hydroxymethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) tert-butyl carbamate as a white solid (9.02 g, 69% in 4 steps). XH NMR (400 MHz, CD3OD) δ 6.12 (d, J = 6.2Hz, 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).
[201] To a solution of the above material (7.02 g, 19.4 mmol), DI PEA (6.29 g, 48.7 mmol) and DMAP (0.040 g, 0.33 mmol) in DCM (150 mL ), at 15 ° C, BzCl (6.03 g, 42.9 mmol) was added slowly. After the addition the mixture was stirred at room temperature for 5 h. Saturated aqueous NH4C1 solution (40 mL) was added, and the organic layer was collected. The extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was separated on silica gel by flash column chromatography (EtOAc / hexanes, 1:10 to 2: 3), producing (3aR, 5R, 6S, 7R, 7aR) -2- (allyl (tert-butoxycarbonyl) amino) -5- ((benzoyloxy) methyl) -7-hydroxy-5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-yl as a white solid (2.80 g, 25%). XH NMR (400 MHz, CDCl3) 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).
[202] To a solution of the above material (2.40 g, 4.22 mmol) in anhydrous DCM (30 mL), at -78 ° C under N2, was added DAST (4.32 g, 2.68 mmol) . After the addition the mixture was stirred at room temperature for 2 days. At -78Â ° C, the reaction mixture was diluted with DCM (20 ml), and then was quenched by the addition of saturated aqueous NaHCO3 dropwise. The organic layer was collected, and the aqueous phase was extracted with DCM (2 x 30 ml). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic column flash chromatography (EtOAc / hexanes, 1:20 to 1: 4), producing (3aR, 5R, 6R, 7R, 7aR) -2- (allyl (tert-butoxycarbonyl) amino) -5- ((benzoyloxy) methyl) -7-fluor-5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- 6-yl benzoate as a white solid (1.70 g, 70%), 1H NMR (400 MHz, CDCl3) 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 = 1.1 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).
[203] A mixture of the above material (1.70 g, 2.98 mmol) and K2CO3 (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), producing ally ((3aR, 5R, 6R, 7R, 7aR) -7-fluor-6-hydroxy-5- (hydroxymethyl) ) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) tert-butyl carbamate as a white solid (1.07 g, 99%). XH NMR (400 MHz, CD3OD) 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).
[204] 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 TBDMSC1 (0.478 g, 3.17 mmol). The mixture was stirred at room temperature for 5 h and diluted with Et2O (100 ml) and brine (100 ml). The organic layer was collected, and the aqueous phase was extracted with Et2O (50 ml). The combined extract was washed with H2O (50 ml) and dried over anhydrous Na2SO4. 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: 2), producing ally ((3aR, 5R, 6R, 7R, 7aR) -5 - ((((tert-butyldimethylsilyl) oxy) methyl) -7-fluor-6-hydroxy-5, 6, 7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole-2 -yl) tert-butyl carbamate as a white solid (1.36 g, 97%). XH NMR (400 MHz, CDCl3) 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).
[205] At 0 ° C, to a solution of the above material (0.720 g, 1.51 mmol) and Bu4NI (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 adding allyl bromide (0.365 g, 3.02 mmol). The mixture was stirred at room temperature for 5 h, diluted with Et2O (50 ml) and washed with saturated NaHCO3 (50 ml). The organic layer was collected, and the aqueous phase was extracted with Et2O (30 ml). The combined extract was washed with brine (50 ml) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by flash column chromatography (EtOAc / hexanes, 1:20 to 1: 4), producing ally ((3aR, 5R, 6R, 7R, 7aR) -6- (allyloxy) -5 - ((((tert-butyldimethylsilyl) oxy) methyl) -7-fluor-5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole -2-yl) tert-butyl carbamate as a pale yellow sticky oil (0.675 g, 87%). XH NMR (400 MHz, CDCl3) 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).
[206] 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 the 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 phase was extracted with EtOAc (20 ml). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic column flash chromatography (EtOAc / hexanes, 1: 5 to 1: 2), producing ally ((3aR, 5R, 6R, 7R, 7aR) -6- (allyloxy) -7-fluor-5- (hydroxymethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) tert-carbamate -butyl as a colorless oil (0.53 g, 100%) H NMR (400 MHz, CDCl3) 56.07 (d, J = 1.1 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).
[207] 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 Et2O (30 ml), and then concentrated to dryness. Aqueous NaHCO3 saturated (30 ml) with Na2S2O3 (2 g) was added, and the mixture was extracted with EtOAc (2 x 30 ml). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by flash column chromatography (EtOAc / hexanes, 1: 4 to 2: 3), producing the corresponding aldehyde as a colorless oil (0 , 47 g). To this material in anhydrous THF (15 mL) at 0 ° C was added the MeMgBr solution (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 was quenched with saturated NaHC03 solution (30 ml). The mixture was extracted with EtOAc (2 x 30 ml), and the combined extracts were dried over anhydrous Na2SO4. 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: 2), producing ally ((3aR, 5R, 6R, 7R, 7aR) -6- (allyloxy) -7-fluor-5- (1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) carbamate tert-butyl (0.29 g, 53%), as a mixture of two diastereomers in a 2.6: 1 ratio, as indicated by XH NMR.
[208] Under argon, for the above material (0.168 g, 0.403 mmol) in 1,4-dioxane (10 mL) Et3N (0.164 g, 1.62 mmol), HCOOH (0.118 g, 2.43 mmol) was added . The solution was bubbled with argon for 30 s, and Pd (PPh3) 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 flash column chromatography (MeOH / DCM, 1:40 to 1:20), producing ((3aR , 5R, 6R, 7R, 7aR) -7-fluor-6-hydroxy-5 - ((S) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) tert-butyl carbamate as an undefined white solid (0.083 g, 85%). 1HRMN (400 MHz, CD3OD) ô 6.21 (d, J = 7, lHz, 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); 13C NMR (100 MHz, CD3OD) δ 162.83, 155.73, 94.85 (d, J = 177.4Hz), 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.
[209] A solution of the above material (0.0562 g, 0.167 mmol) in dry MeOH (5 mL) was bubbled with HCI (g) for 30 s. After stirring at room temperature for 5 h the reaction mixture was concentrated to dryness. The residue was neutralized with 1.0 M NH3 in MeOH, and purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH / DCM, 1: 5) to obtain (3aR, 5R, 6R, 7R, 7aR) -2-amino-7-fluor-5 - ((S) -1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol as a white solid (0.0387 g, 98%). 1HRMN (400 MHz, CD3OD) δ 6.36 (d, <7 = 7.0 Hz, IH), 4.85 (td, J = 4.2, 47.1 Hz, IH), 4.38-4, 32 (m, IH), 4.00-3.92 (m, 2H), 3.28 (dd, J = 2'7 '9 <3 Hz, IH), 1.21 (d, J = 6, 6 Hz, 1H); 13C NMR (100 MHz, CD3OD) δ 165.10 (d, J = 2.3 Hz), 95.64 (d, J = 177.3Hz), 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-fluor-5 - ((S) -1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazole-6- Ol

[210] At 0 ° C, the solution of ((3aR, 5R, 6R, 7R, 7aR) -7-fluor- 6-hydroxy-5- (hydroxymethyl) -5,6,7,7a-tetrahydro-3aH- pyran [3,2-d] thiazol-2-yl) (methyl) tert-butyl carbamate (9.00 g, 26.8 mmol) and imidazole (9.09 g, 133 mmol) in anhydrous DMF (60 mL ) TBDMSC1 (14.1 g, 93.5 mmol) was added. The mixture was stirred at room temperature for 16 h, diluted with Et2O (200 ml) and washed with brine (2 x 200 ml). The organic layer was collected, and the aqueous phase was extracted with Et2O (2 x 100 mL). The combined extract was washed with brine (100 ml) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic column flash chromatography (EtOAc / hexanes, 0 to 1: 6), producing ((3aR, 5R, 6R, 7R, 7aR ) -6- (((tert-butyldimethylsilyl) oxy) -5 - ((((tert-butyldimethylsilyl) oxy) methyl) -7-fluor-5,6,7,7a-tetrahydro-3aH-pyran [3,2-d ] tert-butyl thiazol-2-yl) (methyl) carbamate as a colorless oil (16.0 g, 100%). XH NMR (400 MHz, CDCl3) δ 6.10 (d, 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).
[211] At 0 ° C, to a solution of the above material (16.0 g) in a DCM / MeOH mixture (100 ml, 1: 4) was added AcCl (0.32 g, 4.1 mmol). After the mixture was stirred at room temperature for 24 h, NaHCO3 powder (1 g) was added, and the suspension was stirred at 30 min. The solvent was then evaporated under reduced pressure, and the residue was dissolved in DCM (100 ml) and washed with saturated aqueous NaHC03 (50 mL). The organic layer was collected, and the aqueous phase was extracted with DCM (2 x 80 mL). The combined extract was dried over anhydrous Na2SO4. After filtration the filtrate was treated with Boc30 (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 flash column chromatography (EtOAc / hexanes, 1:10 to 1: 3), yielding ((3aR, 5R, 6R, 7R, 7aR) -6- ((tert-butyldimethylsilyl) oxy) -7-fluor-5- (hydroxymethyl) -5,6,7,7a-tetrahydro -3aH-pyran [3,2- d] thiazol-2-yl) (methyl) tert-butyl carbamate as a white foam (11.6 g, 96%), 1 H NMR (400 MHz, CDCl 3) δ 6, 10 (d, J = 1.1 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).
[212] 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 2h the reaction solution was concentrated at room temperature to approximately 100 ml, and then diluted with Et2O (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 Et2O (200 mL) and the solid was filtered off. The ether solution was washed with saturated aqueous NaHCO (200 mL) ), and the aqueous phase was extracted with Et2O (2 x 50 ml). The combined extract was dried over anhydrous MgSO4. After filtration, the solvent was evaporated under reduced pressure to produce ((3aR, 5S, 6R, 7R, 7aR) - 6 - ((tert-butyldimethylsilyl) oxy) -7-fluor-5-formyl-5,6,7,7a - tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) crude tert-butyl carbamate (11.8 g). This crude material was used in the next step without further purification.
[213] To a solution of the above material (11.8 g) in anhydrous THF (200 ml) under 0 ° C N2a was added MeMgBr (1.4 M in THF / toluene, 42.0 ml, 58.8 mmol). After the addition the mixture was stirred at room temperature for 2h. The reaction was quenched with saturated aqueous NaHC03 (200 mL), and the reaction mixture was extracted with EtOAc (200 mL) and DCM (2 x 50 mL). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure. The residue was dissolved in DCM (100 mL) and treated with Boc20 (3g) 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 obtain ((3aR, 5R, 6R, 7R, 7aR) - 6 - (((tert-butyldimethylsilyl) oxy) -7-fluor-5- (1-hydroxyethyl) -5,6,7,7a tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl ) tert-butyl carbamate as a mixture of two diastereomers (6.60 g, 57% two steps).
[214] 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 Na2SO4. 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 obtain ((3aR, 5R, 6R, 7R, 7aR) -7-fluor-6-hydroxy-5- ((S) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole-2 -yl) tert-butyl (methyl) carbamate (3.77 g, 76%). 1H NMR (400 MHz, CDCl3) 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).
[215] 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 TBDMSC1 (0.502 g, 3, 33 mmol). The mixture was stirred at room temperature for 16 h, diluted with Et2O (100 ml) and washed with brine (2 x 100 ml). The organic layer was collected, and the aqueous phase was extracted with Et2O (50 ml). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by flash column chromatography (EtOAc / hexanes, 0 to 1: 3), producing ((3aR, 5S, 6R, 7R, 7aR ) -5- ((S) -1- ((tert-butyldimethylsilyl) oxy) ethyl) -7-fluor-6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) tert-butyl as a white foam (0.919 g, 75%). XH NMR (500 MHz, CDCl3) 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).
[216] 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 Et2O (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 into a silica gel plug and the product eluted with (EtOAc / hexanes, 1: 4), producing (( 3aR, 5R, 7R, 7aR) -5- ((S) -1- ((tert-butyldimethylsilyl) oxy) ethyl) -7-fluor-6-oxo-5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) tert-butyl carbamate as a white foam (0.90 g, 100%). XH NMR (400 MHz, CDC13) 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).
[217] 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 to 0 ° C, and NaBH4 (0.140 g, 3.70 mmol) was added. Then the mixture was stirred at 0 ° C for 20 minutes in a dry ice chip and the solvent was evaporated. The residue was dissolved in DCM (50 ml), and washed with saturated aqueous NH4Cl (50 ml). The organic layer was collected, and the aqueous phase was extracted with DCM (2 x 20 mL). The combined extract was dried over anhydrous Na2SO4. 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 2: 5), producing ((3aR, 5S, 6R, 7S , 7aR) -5- ((S) -1- ((tert-butyldimethylsilyl) oxy) ethyl) -7-fluor-6-hydroxy-5,6,7,7a- tetrahydro-3aH-pyran [3,2- d] tert-butyl thiazol-2-yl) (methyl) carbamate as a white foam (0.793 g, 8%). XH NMR (500 MHz, CDCl3) 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).
[218] To a solution of the above material (0.780 g, 1.68 mmol) in dry MeOH (20 mL) was bubbled HCI (g) for 30 s. 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 NH3 in MeOH and purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH / DCM, 1:10), yielding (3aR, 5R, 6R, 7S, 7aR) -7-fluor-5 - ((S) -1-hydroxyethyl) -2- (methylamino) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol as a white solid (0.410 g, 98%). XHRMN (500 MHz, CD3OD) δ 6, 41 (d, J = 6.7 Hz, 1H), 4.84 (td, J = 3.6 Hz, 50.1 Hz, 1H), 4.4 0-4 , 34 (m, IH), 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); 13C NMR (100 MHz, CD3OD) 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-fluor-5 - ((R) -1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazole-6-ol

[219] For a solution of ((3aR, 5S, 6R, 7S, 7aR) -6- (benzyloxy) -7-fluor-5-formyl-5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazol-2-yl) (methyl) tert-butyl carbamate (0.35 g, 0.83 mmol) in anhydrous THF (15 mL), at 0 ° C and under N2, MeMgBr (1 , 4 M in THF / toluene, 3.0 mL, 4.2 mmol). After the addition the mixture was stirred at room temperature for 2h. The reaction was quenched with saturated aqueous NaHCO3 (30 mL), and then extracted with EtOAc (30 mL) and DCM (3 x 30 mL). The combined extract was dried over anhydrous Na3SO4. 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 dried DCM (8 mL) at -78 ° C under N2, BCI3 (1.0 M in DCM, 3.0 mL, 3.0 mmol) was added. The mixture was stirred at ~ 3 h while the temperature of the cooling bath warmed up slowly to room temperature. The reaction mixture was cooled to -78 ° C, quenched with MeOH / DCM mixture, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH / DCM, 1:10), yielding (3aR, 5R, 6R, 7S, 7aR) -7-fluor-5- (( R) -1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole-6-0I as a white solid (0.039 g, 19%) . 1HRMN (400 MHz, CD3OD) δ 6, 40 (d, J = 6.7Hz, 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); 13C NMR (100 MHz, CD3OD) δ 165, 99, 91.11 (d, J = 5.31 Hz ), 90, 74 (d, J = 184.1 Hz), 76, 85 (q, J = 3flttz), 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 and 37 (3aR, 5R, 6R, 7S, 7aR) -2- (ethylamino) -7-fluor-5 - ((S) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH- pyran [3,2-d] thiazol-6-ol (3aR, 5R, 6R, 7S, 7aR) -2- (ethylamino) -7-fluor-5 - ((R) -1- hydroxyethyl) -5, 6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol

[220] For a solution of (3aR, 5R, 6R, 7S, 7aR) - 6- (tert-butyldimethylsilyloxy) -7-fluor-5- (hydroxymethyl) -5,6,7,7 a-tetrahydro-3aH- tert-butyl pyran [3,2-d] thiazol-2-yl (ethyl) carbamate (600 mg, 1.3 mmol) in DCM (30 mL) DMP (806 mg, 1.9 mmol) was added at 0 ° C. After stirring at room temperature for 2h, the reaction was quenched with mixed saturated aqueous NaHC03 (20 mL) and Na2S2O3 (20 mL). The result of the solution was extracted with DCM (3x30 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under anhydrous Na2SO4. go to give the crude aldehyde product. The aldehyde was dissolved in THF (30 ml), treated with MeMgCl (3 M in THF, 1.1 ml, 3.3 mmol) at 0 ° C ~ 25 ° C for 3 h. The reaction was then quenched with H2O (50 ml) and extracted with EtOAc (3x40 ml). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified through a silica gel column, eluted with 3% -30% EtOAc in petroleum ether to produce (3aR, 5R, 6R, 7S, 7aR) - 6- (tert-butyldimethylsilyloxy) -7-fluor- 5 - ((S) -1-hydroxyethyl) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl (ethyl) tert-butyl carbamate as a yellow oil (355 mg, 57% 2-step). (ES, m / z) [M + H] +479.0; 1 H NMR (300 MHz, CDCl 3) 56, 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-l, 14 (m, 6H), 0.87 (s, 9H), 0.12-0.06 (m , 6H).
[221] The solution of the above material (350 mg, 0.73 mmol) in MeOH (saturated with HCI gas) (10 mL) was stirred for 3 hours at room temperature. The volatiles were removed by distillation to obtain a residue, which was dissolved in MeOH (5 mL). The pH value of the solution was adjusted to 9 with saturated aqueous K2 CO3. The result of the solution was extracted with THF (3x10 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions [(Agilent 1200): Column, X-BridgePrep-C18; mobile phase, water with 0.05% ammonia and 3% acetonitrile to 13% acetonitrile in 10 min; detector, 220.254nm] to produce (3aR, 5R, 6R, 7S, 7aR) -2- (ethylamino) -7-fluor-5 - ((R) -1- hydroxyethyl) -5,6,7,7a-tetrahydro -3aH-pyran [3,2-d] thiazol-6-ol as a white solid (63 mg, 32%); (ES, m / z): [M + H] +265.0; XH NMR (300 MHz, D2O) δ6.25 (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-fluor-5 - ((S) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol as a white solid (77 mg, 391); (ES, m / z): [M + H] +2 65.0; XH NMR (300 MHz, D2O) δ6.20 (d, J = 6, 6 Hz, 1H), 4.85 (td, J = 3.6.49.2hz, 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-fluor-2- (methylamino) -5 - ((R) - 2,2,2-trifluor-1-hydroxyethyl) -5,6,7, 7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol

[222] For a solution of ((3aR, 5R, 6R, 7R, 7aR) -5- (((tert-butyldimethylsilyl) oxy) methyl) -7-fluor-6-hydroxy-5,6,7,7a- tert-butyl tetrahydro-3aH-pyran [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 Et2O (400 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 layer of NaHCO2 / silica gel layers, and the product was eluted with (EtOAc / hexanes, 1: 4), producing ((3aR, 5R, 7R, 7aR) -5- ((((tert-butyldimethylsilyl) oxy) methyl) -7-fluor-6-oxo-5,6,7,7a-tetrahydro-3aH-pyran [3,2 -d] thiazol-2-yl) (methyl) tert-butyl carbamate as a white crystalline solid (8.96 g, 97%). XH NMR (400 MHz, CDCl3) δ 6.29 (d, J = 7.0 Hz, 1H), 5.09 (dd, J = 4.1, 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).
[223] 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 to 0 ° C, and NaBH4 (1.32 g, 34.9 mmol) was added. After the mixture was stirred at 0 ° C for 20 min a dry ice chip was added and the solvent was evaporated. The residue was dissolved in DCM (100 ml), and washed with saturated aqueous NH4 Cl (100 ml). The organic layer was collected, and the aqueous phase was extracted with DCM (2 x 50 mL). The combined extract was dried over anhydrous Na2S04. 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 2: 5), producing ((3aR, 5R, 6R, 7S , 7aR) -5 - ((((tert-butyldimethylsilyl) oxy) methyl) - 7-fluor-6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyran [3,2- d] thiazol-2- il) tert-butyl (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).
[224] At 0 ° C, to a solution of the above material (1.30 g, 2.89 mmol) and Bu4NI (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 the 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 NH4 Cl (2 x 50 ml). The aqueous phase was extracted with Et2O (2 x 40 ml). The combined extract was washed with brine (50 ml) and dried over anhydrous Na2 SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic column flash chromatography (EtOAc / hexanes, 1:20 to 1: 4), producing ((3aR, 5R, 6R, 7S , 7aR) -6- (benzyloxy) -5 - ((((tert-butyldimethylsilyl) oxy) methyl) -7-fluor-5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- 2-yl) tert-butyl (methyl) carbamate as a sticky oil (1.44 g, 92%). XH NMR (400 MHz, CDCl3) δ 7.36-7.27 (m, 5H), 6.21 (d, J = 7.2hz, IH), 5.30- 5.16 (m, IH), 4.80 (d, J = 11.4 Hz, IH), 4.56 (d, J = 11.4 Hz, IH), 4.50-4.42 (m, IH), 3, 95-3 , 78 (m, 4H), 3.44 (s, 3H), 1.54 (s, 9H), 0.89 (s, 9H), 0.049 (s, 6H).
[225] 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 the 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 x 40 ml). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic column flash chromatography (EtOAc / hexanes, 1: 2 to 1: 1), producing ((3aR, 5R, 6R, 7S , 7aR) - 6- (benzyloxy) -7-fluor-5- (hydroxymethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) carbamate tert-butyl as a white solid (1.08 g, 95%), 1H NMR (400 MHz, CDCl3) δ 7.37-7.27 (m, 5H), 6.18 (d, J = 1, ^ 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).
[226] 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 Et2O (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 x 50 mL), and the solid was filtered off. The extract was washed with mixed saturated aqueous NaHC03. (30 ml) and Na2S2O3 (5 ml). The extract was collected and dried over anhydrous MgSO4. After filtration, the solvent was evaporated under reduced pressure to produce ((3aR, 5S, 6R, 7S, 7aR) -6- (benzyloxy) -7-fluor-5-formyl-5, 6, 7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) tert-butylabruto carbamate. This crude material was used in the next step without further purification.XH NMR (400 MHz, CDC13) 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).)
[227] To a solution of the above material (1.94 g, 4.57 mmol) and TMSCF3 (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 the addition, the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was cooled to 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 phase was extracted with EtOAc (50 ml). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified and separated on silica gel by automatic column flash chromatography (EtOAc / hexanes, 1:10 to 2: 3), producing ((3aR, 5R, 6R, 7S, 7aR) -6- (benzyloxy) -7-fluor-5 - ((R) -2,2,2-trifluor-1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3 , 2- d] thiazol-2-yl) (methyl) tert-butyl carbamate as a pale yellow solid (0.761 g, 34%). XH NMR (400 MHz, CDCl3) δ 7.36-7.28 (m, 5H), 6.20 (d, J = 7.5 Hz, 1H), 5, O6 (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).
[228] 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 N2, BC12 ( 1.0 M in DCM, 10.0 mL, 10.0 mmol). The mixture was stirred at ~ 5 h while the temperature of the cooling bath warmed up slowly to room temperature. The reaction mixture was cooled to - 78 ° C, quenched with MeOH / DCM mixture, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH / DCM, 1: 8), yielding (3aR, 5S, 6R, 7S, 7aR) -7-fluor-2- (methylamino ) -5 - ((R) -2,2,2-trifluor-1-hydroxyethyl) -5,6,7,7 a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol as a undefined white solid (0.373 g, 80%). XH NMR (400 MHz, CD3OD) 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); 13C NMR (100 MHz, CD3OD) δ 165, 65, 126.48 (q, J = 281.2hz), 91.27 (d, J = 183.2hz), 90.42 (d, J = 2.2hz ), 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-fluor-2- (methylamino) -5 - ((S) - 2,2,2-trifluor-1-hydroxyethyl) -5,6,7, 7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol

[229] For a solution of ((3aR, 5S, 6R, 7S, 7aR) - 6- (benzyloxy) -7-fluor-5-formyl-5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazol-2-yl) (methyl) tert-butyl carbamate (0.352 g, 0.829 mmol) and TMSCF3 (0.290g, 2.04 mmol) in anhydrous THF (15 mL) was added TBAF (1 , 0 M in THF, 0.050 mL, 0.050 mmol). After the addition, the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was cooled to 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 phase was extracted with EtOAc (20 ml). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified and separated on silica gel by automatic column flash chromatography (EtOAc / hexanes, 1:10 to 2: 3), producing ((3aR, 5R, 6R, 7S, 7aR) -6- (benzyloxy) -7-fluor-5 - ((S) -2,2,2-trifluor-1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3 , 2- d] thiazol-2-yl) (methyl) tert-butyl carbamate as a pale yellow solid (0.141 g, 34%). 2H NMR (400 MHz, CDClj) 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).
[230] 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 N2, BC12 (1, 0 M in DCM, 2.5 mL, 2.5 mmol). The mixture was stirred at ~ 4 h while the temperature of the cooling bath warmed up slowly to room temperature. The reaction mixture was cooled to - 78 ° C, quenched with MeOH / DCM mixture, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH / DCM, 1: 10), yielding (3aR, 5S, 6R, 7S, 7aR) -7-fluor-2- (methylamino ) -5 - ((S) -2,2,2-trifluor-1-hydroxyethyl) -5,6,7,7 a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol as a undefined white solid (0.076 g, 78%). XH NMR (400 MHz, CD3OD) δ 6.34 (d, J = 6.6 Hz, 1H), 4.85 (td, J = 3.8, 48.2Hz, 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); 13C NMR (100 MHz, CD3OD) 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 = 4.1 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 and 41 (3aR, 5S, 6R, 7S, 7aR) -2- (ethylamino) -7-fluor-5 - ((R) -2,2,2-trifluor-1-hydroxyethyl) -5,6, 7,7a-tetrahydro-3aH-pyran [3,2- d] thiazol-6-ol (3aR, 5S, 6R, 7S, 7aR) -2- (ethylamino) -7-fluor-5- ((S) -2,2,2-trifluor-1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol

[231] To a suspension of (3aR, 5R, 6S, 7R, 7aR) -2- (ethylamino) -5- (hydroxymethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d ] thiazole-6, 7-diol (88 g, 358 mmol) in MeOH (500 mL) was added Et3N (48.9 g, 484 mmol) and Boc20 (139 g, 637 mmol) in sequence at 25 ° C. After stirring for 10 hours, the volatiles were removed by distillation to obtain a residue, which was purified by a column of silica gel, 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 obtain (3aR, 5R, 6S, 7R, 7aR) -6,7-dihydroxy-5- (hydroxymethyl) - 5,6,7 .7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl (ethyl) tert-butyl carbamate as a white solid (90 g, 73%). (ES, m / z): [M + H] +349, 0; XH NMR (300 MHz, CDCl3) 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).
[232] A solution of the above material (80 g, 230 mmol) and imidazole (62.5 g, 919 mmol) in DMF (300 mL) was treated with TBDMSC1 (76 g, 506 mmol) for 3 h at 50 ° C. The reaction was quenched with saturated aqueous NaHC03 (1 L) and extracted with EtOAc (3x200 mL). The combined organic layer was washed with brine (3x300 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified through a column of silica gel, eluted with 3% -10% EtOAc in petroleum ether to produce (3aR, 5R, 6R, 7R, 7aR) - 7- (tert-butyldimethylsilyloxy) -5 - (( tert-butyldimethylsilyloxy) methyl) -6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl (ethyl) tert-butyl carbamate as a yellow oil (78 g , 59%). (ES, m / z): [M + H] +577.0; XH NMR (300 MHz, CDCl3) 55, 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), 1.5O (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).
[233] 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 NaHC03 (600 mL) and extracted with EtOAc (3x200 mL). The combined organic layer was washed with brine (3x200 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. 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) benzoate -7 - (tert-butyldimethylsilyloxy) -5 - ((tert-butyldimethylsilyloxy) methyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-yl as a yellow oil (80 g, 90%). (ES, m / z): [M + H] +681.0; XH NMR (300 MHz, CDCl3) 58.03 (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).
[234] The above material (80 g, 117 mmol) was treated with 1.5 M solution of HCI (g) in MeOH (300 mL) at room temperature for 12h. The solvent was removed at room temperature under vacuum to give a residue, which was dissolved in MeOH (500 ml), followed by the addition of Et3N (23.5 g, 232 mmol) and Boc30 (50.8 g, 233 mmol) at room temperature. After an additional 10 h, the volatiles were removed by distillation to obtain a residue, which was purified by a silica gel column, eluted with 10% -20% EtOAc in DCM for (3aR, 5R, 6S, 7R, darbenzoate, 7aR) -2- (tert-butoxycarbonyl) - 7-hydroxy-5- (hydroxymethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-yl as a yellow oil ( 47 g, 88%). (ES, m / z): [M + H] +453.0; XH NMR (300 MHz, CDCl3) 58.03 (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).
[235] 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 ° Ç. After stirring for 12 h at room temperature, the reaction was quenched with saturated NaHCOsaque (800 mL) and extracted with EtOAc (3x500 mL). The combined organic layer was washed with brine (3x300 ml), dried over anhydrous Na2SO4 and concentrated in vacuo. 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) benzoate - 6- (benzoyloxy) -2- {[(tert-butoxy) carbonyl] (ethyl) amino} -7-hydroxy-3aH, 5H, 6H, 7H, 7aH-pyran [3,2-d] [1,3] thiazol-5-yl] methyl as a yellow syrup (35g, 61%). (ES, m / z): [M + H] +557.0; XH NMR (300 MHz, CDClj) 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).
[236] 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 NaHCOs (400 mL) and extracted with DCM (3x200 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. 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) benzoate - 6- (benzoyloxy) -2- {[(tert-carbonyl] (ethyl) amino} -7-fluor-3aH, 5H, 6H, 7H, 7aH-pyran [3,2-d] [1,3] thiazol-5-yl] methyl as an oil yellow (14g, 70%). (ES, m / z): [M + H] +559.0; XH NMR (300 MHz, CDC13) 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).
[237] A solution of the above material (26 g, 46.5 mmol) in MeOH (200 mL) was treated with K2CO3 (0.7 g, 5 mmol) for 3h at 25 ° C. The result of the 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 for daretyl ((3aR, 5R, 6R, 7R, 7aR) -7-fluor-6-hydroxy-5- (hydroxymethyl) ) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) tert-butyl carbamate as a white solid (15 g, 92%). (ES, m / z): [M + H] +351.0; XH NMR (300 MHz, CDC13) δ 6.10 (d, J = 5.1 Hz, 1H), 4.95 (td, J = 4.45 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, 5.1 Hz, 3H).
[238] To a solution of the above material (3 g, 8.5 mmol) in DCM (50 mL) was added Et3N (1.3 g, 13 mmol), DMAP (0.2 g, 1.7 mmol) and TBDMSC1 (1.93 g, 12.7 mmol) at room temperature. After stirring for 10 hours, the reaction was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with DCM (2x30 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified through a silica gel column, eluted with 10% -20% EtOAc in petroleum ether to produce (3aR, 5R, 6R, 7R, 7aR) -5 - ((tert-butyldimethylsilyloxy) methyl) -7 -fluor-6-hydroxy-5,6,7,7 a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl (ethyl) tert-butyl carbamate as a yellow oil (3.6 g, 90%). (ES, m / z): [M + H] + 465.0; XH NMR (300 MHz, CDC13) 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) .
[239] 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 2h, the reaction was quenched with mixed saturated aqueous NaHCO3 (20 mL) and Na3S3O3 (20 mL). The solution was extracted with DCM (3x30 mL). The combined organic layer was dried over anhydrous Na3SO4 under vacuum. The residue was purified through a silica gel column, eluted with 2% -15% EtOAc in petroleum ether to produce (3aR, 5R, 7R, 7aR) -5 - ((tert-butyldimethylsilyl) methyl) -7-fluorine -6-oxo-5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl (ethyl) tert-butyl carbamate as a yellow solid (1.9g, 89%). (ES, m / z): [M + H] +463.0; XH NMR (300 MHz, CDC13) δ 6.24 (d, J = 6.9 Hz, IH), 5.05 (dd, J = 4.5, 48.6 Hz, IH), 4, 75-4 , 68 (m, IH), 4, 11-4, 0 6 (m, IH), 4, 04-3, 99 (m, IH), 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).
[240] 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 NaBH4 (296 mg, 7.8 mmol) was added. After an additional 1 hour, the reaction was quenched with ice-water (30 mL) and extracted with DCM (3x30 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified through a column of silica gel, eluted with 3% -20% EtOAc in petroleum ether to produce (3aR, 5R, 6R, 7S, 7aR) -5 - ((tert-butyldimethylsilyloxy) methyl) -7 -fluor-6-hydroxy-5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl (ethyl) tert-butyl carbamate as a yellow solid (1.2 g, 67 %). (ES, m / z): [M + H] + 465.0; XH NMR (300 MHz, CDCl3) δ 6.01 (d, J = 6.6 Hz, 1H), 4.93 (td, J = 4.3, 46.8 Hz, 1H), 4.4 4- 4.35 (m, 2H), 4, 17-4, 08 (m, 1H), 3, 96-3, 87 (m, 1H), 3, 8 6-3.7 7 (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).
[241] To a solution of the above material (2.6 g, 5.6 mmol) in DCM (50 mL) was added imidazole (816mg, 12 mmol) and TBDMSC1 (1.3 g, 8.4 mmol) at temperature environment. After stirring for 6 h, the reaction was quenched with saturated aqueous NaHC03 (50 mL) and extracted with DCM (3x30 mL). The combined organic layer was dried over anhydrous Na3SÜ4 and concentrated in vacuo. The residue was purified through a short silica gel column, eluted with 1% -20% EtOAc in petroleum ether to produce (3aR, 5R, 6R, 7S, 7aR) -6- (tert-butyldimethylsilyloxy) -5- ( (tert-butyldimethylsilyloxy) methyl) -7-fluor-5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl (ethyl) tert-butyl-carbamate as a yellow oil, which was used in the next step directly; (ES, m / z): [M + H] + 579, l.
[242] 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, JC (followed by TLC), the value of The pH of the solution was adjusted to 8-9 with Et3N. The solvent was removed at room temperature under vacuum. The residue was purified through a column of silica gel, eluted with 3% -20% EtOAc in petroleum ether to produce (3aR, 5R, 6R, 7S, 7aR) -6- (tert -butildimethylsilyloxy) - 7-fluor-5- (hydroxymethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl (ethyl) tert-butyl carbamate as a yellow oil (1.3 g, 50% 2-step). (ES, m / z): [M + H] +465.1; XH NMR (300 MHz, CDC13) 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).
[243] 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 2h, the reaction was quenched with mixed saturated aqueous NaHCC (20 mL) and Na2S2O3 (20 mL). The result of the solution was extracted with DCM (3x30 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under anhydrous Na2SO4. go to give the crude aldehyde product. The aldehyde was dissolved in THF (30 mL), treated with TMSCF3 (2 g, 14 mmol) and TBAF (350 mg, 1.1 mmol) and 4A molecular sieve 0 ° C ~ 25 ° C porl2h, then additional TBAF (1, 3 g, 4.2 mmol) was added. After an additional 2 h, the reaction was diluted with H2O (50 mL) and extracted with EtOAc (3x40 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified through a silica gel column, eluting with 3% -30% EtOAc in petroleum ether for daretyl ((3aR, 5S, 6R, 7S, 7aR) -7-fluor-6-hydroxy-5- ( (R) —2,2,2— trifluor-1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2- d] thiazol-2-yl) tert-butyl carbamate as an oil yellow (970 mg, 39% 2-step). (ES, m / z): [M + H] +419.1; 1 H NMR (300 MHz, CDCl 3) 56, 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).
[244] To a solution of the above material (380mg, 0.9mmol) in DCM (20ml) was added TFA (4mL). After 2h at room temperature, the volatiles were removed by distillation to give a residue, which was dissolved in MeOH ( 3 mL) and neutralized with concentrated ammonia. After concentration in vacuo, the crude mixture was purified by preparative HPLC with the following conditions [(Agilent 1200): Column, X-BridgePrep-Cl8; mobile phase, water with 0.05% ammonia and 10% acetonitrile to 22% acetonitrile in 10 min; detector, 220nm, 254nm] to produce (3aR, 5S, 6R, 7S, 7aR) -2- (ethylamino) -7-fluor-5 - ((S) -2,2,2-trifluor-l-hydroxyethyl) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol as a white solid (70.3 mg, 24%); (ES, m / z): [M + H] + 319.0; XH NMR (300 MHz, D2O) 56.15 (d, J = 6.6 Hz, 1H), 4.89 (td, J = 4.244 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-fluor-5 - ((R) - 2,2,2-trifluor-1-hydroxyethyl) -5,6,7,7a -tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol as a white solid (81.9 mg, 28%); (ES, m / z): [M + H] + 319.0; 1HRMN (300 MHz, D2O) 5 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 = 7.2hz, 3H ). Example 42 (3aR, 5R, 6R, 7S, 7aR) -5-ethyl-7-fluor-2- (methylamino) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- 6-ol

[245] For a solution of ((3aR, 5R, 6R, 7S, 7aR) -6- (benzyloxy) -7-fluor-5- (hydroxymethyl) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazol-2-yl) (methyl) tert-butyl carbamate (500 mg, 1.17 mmol) in DCM (20 mL) DMP (746 mg, 1.76 mmol) was added at 0 ° Ç. After stirring at room temperature for 2h, the reaction was quenched with mixed saturated aqueous NaHCC (10 mL) and Na2S2O3 (10 mL). The solution was extracted with DCM (3x30 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude aldehyde of (3aR, 5S, 6R, 7S, 7aR) -6- (benzyloxy) -7-fluor-5-formyl-5,6,7,7a-tetrahydro-3aH-pyran [3,2 -d] tert-butyl thiazol-2-yl (methyl) carbamate. This crude aldehyde was used in the next step without further purification. XH NMR (400 MHz, CDCl3) 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).
[246] The solution of the above crude material (1.17 mmol) in THF (20 mL) was treated with MeMgCl (1 M, 2.34 mL, 2.34 mmol) for 3 h at 10 ° C. The reaction was then quenched with H2O (20 mL) and extracted with EtOAc (3x30 mL). The combined organic layer was washed with brine (2x20 ml), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified through a silica gel column, eluted with 51-20% EtOAc in petroleum ether to produce (3aR, 5R, 6R, 7S, 7aR) -6- (benzyloxy) -7-fluor-5- ( (S) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl (methyl) tert-butyl carbamate as a light yellow oil (273 mg, 53% more than 2 steps). (ES, m / z) [M + H] + 441, l; XH NMR (300 MHz, CDCl3) Õ7, 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).
[247] 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 (20 mL). The result of the solution was extracted with DCM (3x50 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified through a silica gel column, eluted with 2% -5% EtOAc in petroleum ether to produce (3aR, 5R, 6R, 7S, 7aR) -6- (benzyloxy) -7-fluor-5- ((S) -1- (phenoxycarbonothioyloxy) ethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl (methyl) tert-butyl carbamate as a yellow oil ( 116 mg, 59%). (ES, m / z) [M + H] +577.0; XH NMR (300 MHz, CDC13) δ 7.46-7.29 (m, 8H), 7.2 0-7, 10 (m, 2H), 6.23 (d, J = 7.5 Hz, IH ), 5.58-5.52 (m, IH), 5, 19-5.00 (m, IH), 4.93 (d, J = 11, 1 Hz, IH), 4.68- 4, 60 (m, 1H), 4.57 (d, J = 11, 1 Hz, IH), 4.10-3.98 (m, 2H), 3.29 (s, 3H), 1.55 (s , 9H), 1.38-1.34 (m, 3H).
[248] For the solution of the above material (110 mg, 0.19 mmol) in toluene (10 mL), SnB3H (277 mg, 0.95 mmol), AIBN (31 mg, 0.19 mmol) was added. 2h at 80 ° C, the solvent was distilled to give a residue, which was purified by a silica gel column, eluted with 2% - 10% EtOAc in petroleum ether to produce (3aR, 5R, 6R, 7S, 7aR ) -6- (benzyloxy) -5-ethyl-7-fluor-5, 6, 7, 7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl (methyl) carbamate tert-butyl as one light yellow oil (57 mg, 70%). (ES, m / z) [M + H] +425.0; XH NMR (300 MHz, CDC13) δ 7.38-7.31 (m, 5H), 6, 12 (d, J = 7.5 Hz, IH), 5.19-5.01 (m, IH) , 4.88 (d, J = 11, 1 Hz, 1H), 4.54 (d, J = 11, 4 Hz, IH), 4.50-4.44 (m, 1H), 3.73- 3.64 (m, 2H), 3.33 (s, 3H), 1.58 -1.4 9 (m, 2H), 1.51 (s, 9H), 0.93 (t, J = 7 , 5 Hz, 3H).
[249] A solution of the above material (110 mg, 0.26 mmol) in DCM (10 mL) was treated with BC13 (1M, 1.3 mL, 1.3 mmol) at -78 ° C ~ -30 ° C for 2h. The reaction was then quenched with MeOH (10 mL). The volatiles were removed by distillation to give a residue, which was dissolved in MeOH (3 mL) and neutralized with concentrated ammonia. After concentration in vacuo, the crude product was purified by preparative HPLC under the following conditions [(Agilent 1200): Column, X-BridgePrep-Cl8; mobile phase, water with 0.05% ammonia and 18% acetonitrile to 38% acetonitrile in 8 min; detector, 220nm, 254nm] to produce (3aR, 5R, 6R, 7S, 7aR) -5-ethyl-7-fluor-2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazol-6-ol as a white solid (60.9 mg, 55%); (ES, m / z): [M + H] +235, 0; XH NMR (300 MHz, D2O) 56.19 (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-fluor-5- (2-hydroxypropane-2-yl) - 2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazole-6-ol

[250] For a solution of ((3aR, 5S, 6R, 7S, 7aR) -6- (benzyloxy) -7-fluor-5-formyl-5,6,7,7 a-tetrahydro ~ 3aH-pyran [3 , 2-d] thiazol-2-yl) (methyl) tert-butyl carbamate (2.0 g, 4.7 mmol) in anhydrous THF (40 mL), at 0 ° C and under N2, MeMgBr (1 , 4 M in THF / toluene, 8.0 mL, 11.2 mmol). After the addition the mixture was stirred at room temperature for 3 h. The reaction was diluted with Et2O (50 ml) and then quenched with saturated NaHCC / aqueous saturated solution (50 ml). The organic layer was collected, and the aqueous phase was extracted with DCM (3 x 40 mL). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was dissolved in DCM (40 ml) and Boc20 (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 flash column chromatography (EtOAc / hexanes, 1: 2 to 3: 2), producing ((3aR, 5R, 6R, 7S , 7aR) -6- (benzyloxy) -7-fluor-5- (1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl ) tert-butyl carbamate (1.0 g, 48%), as a mixture of diastereomers.
[251] To a solution of the above material (1.0 g, 2.3 mmol) in dried 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 it was diluted with Et2O (80 ml). After filtration through a filtered celite cake, it was washed with saturated aqueous NaHC03 (30 mL), and collected. The aqueous phase was extracted with EtOAc (2 x 40 ml). The combined extract was dried Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic column flash chromatography (EtOAc / hexanes, 1: 8 to 1: 2), producing (( 3aR, 5S, 6R, 7S, 7aR) -5-acetyl-6- (benzyloxy) -7-fluor- 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl ) tert-butyl (methyl) carbamate (0.49 g, 49%) as a white solid. XH NMR (500 MHz, CDCl3) δ 7.39-7.37 (m, 2H), 7.34-7 , 31 (m, 2H), 7.31-7.29 (m, 1H), 6.02 (d, J = 1.1 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).
[252] To a solution of the above material (0.153 g, 0.358 mmol) in anhydrous THF (10 mL), under N2, was added MeMgBr (1.4 M in THF / toluene, 0.50 mL, 0.70 mmol). After the addition the mixture was stirred at room temperature for 3 h. The reaction was quenched with saturated aqueous NaHCO3 (20 mL), and then extracted with DCM (2 x 20 mL). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was dried under a high vacuum. For the solution of the residue and PMB (0.15 g, 1.0 mmol) in dried DCM (4 mL) at -78 ° C under N2, BC13 (1.0 M in DCM, 2.6 mL, 2 , 6 mmol). The mixture was stirred at ~ 5 h while the temperature of the cooling bath warmed up slowly to room temperature. The reaction mixture was cooled to -78 ° C, quenched with MeOH / DCM mixture, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH / DCM, 1:12), yielding (3aR, 5S, 6R, 7S, 7aR) -7-fluor-5- (2 -hydroxypropane-2-yl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6- ol as a white solid (0.073 g, 79 %). 1HRMN (400 MHz, CD3OD) δ 6.15 (d, J = 6.5Hz, 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 ); 13C NMR (100 MHz, CD3OD) 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, l. Examples 44 and 45 (3aR, 5S, 6R, 7S, 7aR) -7-fluor-2- (methylamino) -5 - ((S) - 1,1, 1-trifluor-2-hydroxypropane-2-yl) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol (3aR, 5S, 6R, 7S, 7aR) -7-fluor- 2- (methylamino) -5- ((R) -1,1,1-trifluor-2-hydroxypropane-2-yl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol

[253] For a solution of ((3aR, 5S, 6R, 7S, 7aR) -5-acetyl- 6- (benzyloxy) -7-fluor-5,6,7,7a-tetrahydro-3aH-pyran [3, 2- d] tert-butyl thiazol-2-yl) (methyl) carbamate (0.310 g, 0.704 mmol) and TMSCF3 (0.299 g, 2.10 mmol) in anhydrous THF (12 mL) TBAF (1.0 M in THF, 0.040 mL, 0.040 mmol). After the 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 2h. The solution reaction was then diluted with brine (50 ml), and extracted with EtOAc (2 x 30 ml). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified and separated on silica gel by flash column chromatography (EtOAc / hexanes, 1:10 to 1: 2), producing ((3aR, 5S, 6R, 7S, 7aR) -6- (benzyloxy) -7-fluor-5- ((R) -1,1,1-trifluor-2-hydroxypropane-2-yl) -5,6,7,7a-tetrahydro-3aH -pyran [3,2-d] thiazol-2-yl) (methyl) tert-butyl carbamate (0.178 g, 50%) as a white foam, XH NMR (primary isomer) (400 MHz, CDCl3) δ 7, 37-7.28 (m, 5H), 6.18 (d, J = 1.1 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 ((3aR, 5S, 6R, 7S, 7aR) -6- (benzyloxy) -7-fluor-5 - ((S) -1,1,1-trifluor-2-hydroxypropane-2-yl) -5, 6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) tert-butyl carbamate (0.136g, 38%) as a white foam, XH NMR (secondary isomer ) (400 MHz, CDC13) δ 7.37-7.28 (m, 5H), 6.19 (d, J = 7.7 Hz, IH), 5.05 (td, J = 4.3, 45 , 7 Hz, IH), 4.94 (d, J = 10.7 Hz, IH), 4.64-4, 60 (m, IH), 4.49 (d, J = 10.7 Hz, IH ), 4.26-4.24 (m, IH), 3.90 (d, J = 7.5 Hz, IH), 3.29 (s, 3H), 3.25 (s, br, IH) , 1.54 (s, 9H), 1.37 (s, 3H). The stereochemistry of each of the isomers was randomly assigned.
[254] For a solution of ((3aR, 5S, 6R, 7S, 7aR) -6- (benzyloxy) -7-fluor-5 - ((R) -1,1,1-trifluor-2-hydroxypropane- 2 -yl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) tert-butyl carbamate (primary isomer from the addition of step TMSCF3) (0 , 18 g, 0.35 mmol) and PMB (0.15 g, 1.0 mmol) in dried DCM (5 mL) at -78 ° C under N2, BC13 (1.0 M in DCM, 2, 0 mL, 2.0 mmol). The mixture was stirred at ~ 4 h while the temperature of the cooling bath warmed up slowly to room temperature. The reaction mixture was cooled to -78 ° C, quenched with MeOH / DCM mixture, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH / DCM, 1: 13), yielding (3aR, 5S, 6R, 7S, 7aR) -7-fluor-2- (methylamino ) -5 - ((R) -1,1,1-trifluor-2-hydroxypropane-2-yl) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole-6- ol as a white solid (0.086 g, 77%). 1HRMN (600 MHz, CD3OD) δ 6.37 (d, J = 6.7Hz, 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); 13C NMR (150.9 MHz, CD3OD) δ 165, 55, 127.29 (q, J = 286, 0 Hz), 90, 86 (d, J = θ, 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, l.
[255] For a solution of ((3aR, 5S, 6R, 7S, 7aR) - 6- (benzyloxy) -7-fluor-5 - ((S) -1,1,1-trifluor-2-hydroxypropane-2 -yl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) tert-butyl carbamate (secondary isomer from the addition of step TMSCF3) (0.136 g, 0.277 mmol) and PMB (0.10 g, 0.68 mmol) in dried DCM (5 mL) at -78 ° C under N2, BC13 (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 was slowly warmed up to room temperature. The reaction mixture was cooled to -78 ° C, quenched with MeOH / DCM mixture, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH / DCM, 1: 13), yielding (3aR, 5S, 6R, 7S, 7aR) -7-fluor-2- (methylamino ) -5 - ((S) -1,1,1-trifluor-2-hydroxypropane-2-yl) - 5, 6, 7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole-6- ol as a white solid (0.081 g, 92%). 1HRMN (600 MHz, CD3OD) ô 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); 13C NMR (150.9 MHz, CD3OD) § 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, l. Examples 46 and 47 (3aR, 5R, 6S, 7R, 7aR) -7-fluor-5 - ((S) -1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH- pyran [3,2-d] thiazol-6-ol (3aR, 5R, 6S, 7R, 7aR) -7-fluor-5 - ((R) -1-hydroxyethyl) -2- (methylamino) -5, 6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol

[256] For a solution of ((3aR, 5R, 7R, 7aR) -5 - ((((tert-butyldimethylsilyl) oxy) methyl) -7-fluor-6-oxo-5, 6,7,7a- tetrahydro- 3aH-pyran [3,2-d] thiazol-2-yl) (methyl) tert-butyl carbamate (2.57 g, 5.72 mmol) in dry MeOH (50 mL), at 0 ° C, was added NaBH4 (0.295 g, 7.80 mmol). Then the mixture was stirred at 0 "C for 20 min. A dry ice chip was added, and the solvent was evaporated. The residue was dissolved in DCM (50 ml) and washed with saturated aqueous NaHCOs (50 ml). The organic layer was collected, and the aqueous phase was extracted with DCM (2 x 30 ml). The combined extract was dried over anhydrous Na2SO4. 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), yielding ((3aR, 5R, 6S, 7R, 7aR) -5 - ((((tert-butyldimethylsilyl) oxy) methyl) - 7-fluor-6-hydroxy-5, 6,7,7a-tetrahydro-3aH-pyran [3,2- d] thiazol-2-yl) (methyl) tert-butyl carbamate (0.95 g, 37%), as a sticky oil, 1H NMR ( 400 MHz, CDC13) δ 6.11 (d, J = 6.1 Hz, 1H), 4.84 (ddd, J = 3.2, 6.7, 48.2hz, 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).
[257] At 0 ° C, to a solution of the above material (0.852 g, 1.89 mmol) and Bu4NI (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 adding NaH, BnBr (0.646 g, 3.78 mmol) was added to the reaction mixture. After stirring at room temperature for 16 h the mixture was diluted with brine (60 ml) and extracted with Et2O (2 x 60 ml). The combined extract was washed with brine (60 ml) and dried over anhydrous Na2SO4. 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: 5), producing ((3aR, 5R, 6S, 7R , 7aR) -6- (benzyloxy) -5 - ((((tert-butyldimethylsilyl) oxy) methyl) -7-fluor-5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- 2-yl) tert-butyl (methyl) carbamate as a colorless sticky oil (0.980 g, 95%). 2H NMR (500 MHz, CDCla) 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).
[258] 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 hours, the reaction mixture diluted with brine (50 ml) and extracted with EtOAc (2 x 50 ml). The combined extract was dried over anhydrous Na2 SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic column flash chromatography (EtOAc / hexanes, 1: 5 to 2: 3), producing ((3aR, 5R, 6S, 7R , 7aR) -6- (benzyloxy) -7-fluor-5- (hydroxymethyl) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) carbamate tert-butyl as a white solid (0.79 g, 100%). XH NMR (400 MHz, CDC13) 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).
[259] 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 Et30 (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), yielding ((3aR, 5S, 6S, 7R, 7aR) - 6- (benzyloxy) -7-fluor-5-formyl-5,6,7,7a-tetrahydro -3aH-pyran [3,2-d] thiazol-2-yl) (methyl) tert-butyl carbamate as a white solid (0.73 g, 93%). XH NMR (400 MHz, CDCl3) 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).
[260] To a solution of the above material (0.390 g, 0.919 mmol) in anhydrous THF (8 mL) under N3 was added MeMgBr (1.4 M in THF / toluene, 3.0 mL, 4.2 mmol). After the addition the mixture was stirred at room temperature for 2h. The reaction was quenched with saturated aqueous NaHCC (30 mL), and then extracted with EtOAc (40 mL) and DCM (2 x 30 mL). The combined extract was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was dissolved in DCM (5 ml). Boc20 (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 flash column chromatography (EtOAc / hexanes, 1:10 to 1: 2), producing ((3aR, 5R, 6S, 7R, 7aR) -6- (benzyloxy) -7-fluor-5 - ((R) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) ( tert-butyl methyl) carbamate (0.116 g, 29%) as a white solid, 1HRMN (500 MHz, CDCl ) ô 7.39-7.33 (m, 5H), 6.00 (d, J = 6 , 2Hz, 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), 4.2 6-4.22 (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 ((3aR, 5R, 6S, 7R, 7aR) -6- (benzyloxy) -7-fluor-5 - ((S) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) tert-butyl carbamate (0.186 g, 46%) as a white solid, 1HRMN (500 MHz, CDCl.; -,) ô 7.38-7.30 (m, 5H), 6.12 (d, J = 6.3Hz, 1H), 5.10-4.99 (m, 1H), 4.96 (d, J = 1 1.8 Hz, IH), 4.61 (d, J = 11.8 Hz, IH), 4.54 (td, J = 6.6, 17.2 Hz, IH), 4, 15-4, 07 (m, 2H), 3.60 (dd, J = 3.1, 6.3 Hz, IH), 3.48 (s, 3H), 1.54 (s, 9H), 1.08 (d, J = 6.3 Hz, 3H).
[261] For a solution of ((3aR, 5R, 6S, 7R, 7aR) - 6- (benzyloxy) -7-fluor-5 - ((R) -1-hydroxyethyl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) tert-butyl carbamate (0.116 g, 0.264 mmol) and PMB (0.20 g, 1.3 mmol) in anhydrous DCM ( 6 ml) at -78 ° C under N2, BC13 (1.0 M in DCM, 1.2 ml, 1.2 mmol) was added. The mixture was stirred at ~ 3 h while the temperature of the cooling bath warmed up slowly to room temperature. The reaction mixture was cooled to -78 ° C, quenched with MeOH / DCM mixture and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH / DCM, 1: 10), yielding (3aR, 5R, 6S, 7R, 7aR) -7-fluor-5- (( R) -1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol as a white solid (0.064 g, 97%) .XHRMN (400 MHz, CDC13) ô 6.43 (dd, J = 1.4, 6.5Hz, 1H), 4.51 (ddd, J = 3.2, 8.2, 48.2hz, 1H) , 4.35-4.32 (m, 1H), 4.30-4.22 (m, 1H), 4.03-3, 96 (m, 1H), 3.57 (d, J = 8, 2hz, 1H), 2.86 (s, 3H), 1.20 (d, J = 6.3 Hz, 3H); 13C NMR (100 MHz, CD3OD) 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.
[262] For a solution of ((3aR, 5R, 6S, 7R, 7aR) - 6- (benzyloxy) -7-fluor-5 - ((S) -1-hydroxyethyl) -5,6,7,7 a - tetrahydro-3aH-pyran [3,2-d] thiazol-2-yl) (methyl) tert-butyl carbamate (0.180 g, 0.409 mmol) and PMB (0.20 g, 1.3 mmol) in anhydrous DCM (6 ml) at -78 ° C under N2, BC13 (1.0 M in DCM, 2.0 ml, 2.0 mmol) was added. The mixture was stirred at ~ 3 h while the temperature of the cooling bath warmed up slowly to room temperature. The reaction mixture was cooled to -78 ° C, quenched with MeOH / DCM mixture, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH / DCM, 1: 10), yielding (3aR, 5R, 6S, 7R, 7aR) -7-fluor-5- (( S) -1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol as a white solid (0.092 g, 90 %). 1HRMN (400 MHz, CDC13) 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 = 1, Hz, 1H), 2.83 (s, 3H), 1.22 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHZ, CD3OD) 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 and 49 (3aR, 5S, 6S, 7R, 7aR) -7-fluor-2- (methylamino) -5 - ((R) - 2,2,2-trifluor-1-hydroxyethyl) -5,6, 7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol (3aR, 5S, 6S, 7R, 7aR) -7-fluor-2- (methylamino) -5 - ((S) -2,2,2-trifluor-1-hydroxyethyl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol

[263] For a solution of ((3aR, 5S, 6S, 7R, 7aR) - 6- (benzyloxy) -7-fluor-5-formyl-5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazol-2-yl) (methyl) tert-butyl carbamate (0.320 g, 0.754 mmol) and TMSCF3 (0.208 g, 1.46 mmol) in anhydrous THF (8 mL) TBAF (1.0 M in THF, 0.030 mL, 0.030 mmol). After the 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 of the solution was then diluted with EtOAc (20 ml) and brine (30 ml). The organic layer was collected, and the aqueous phase was extracted with EtOAc (20 ml). The combined extract was dried over anhydrous Na2SO4. 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: 2), producing ((3aR, 5R, 6S, 7R , 7aR) -6- (benzyloxy) -7-fluor-5 - ((R) -2,2,2-trifluor-1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2- d] thiazol-2-yl) (methyl) tert-butyl carbamate as a pale yellow foam, with a 6.8: 1 mixture of diastereomers based on 1H NMR. For the solution of the yellow foam and PMB (0.20 g, 1.3 mmol) in anhydrous DCM (6 mL) at -78 ° C under N2, BC13 (1.0 M in DCM, 2.0 mL, 2.0 mmol). The mixture was stirred at ~ 3 h while the temperature of the cooling bath warmed up slowly to room temperature. The reaction mixture was cooled to - 78 ° C, quenched with MeOH / DCM mixture, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH / DCM, 1: 10), yielding (3aR, 5S, 6S, 7R, 7aR) -7-fluor-2- (methylamino ) -5 - ((R) -2,2,2-trifluor-1-hydroxyethyl) -5,6,7,7 a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol as a white solid (0.118 g, 77%) with a diastereomeric ratio of 6.8: 1 based on XH NMR. This mixture was separated by preparative HPLC with the following conditions: Column, XBridge Prep. C18, 19x150 mm; mobile phase, water with 0.05% NH4OH and CH3CN (from 5% to 25% in 10 min); Detector, UV 220nm, to produce (3aR, 5S, 6S, 7R, 7aR) -7-fluor-2- (methylamino) -5- ((S) - 2,2,2-trifluor-1-hydroxyethyl) -5 , 6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol (the fastest eluting isomer) as a white solid (65 mg, 28% overall yield), RM NMR (300 MHz, CD3OD) 06.46 (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-fluor-2- (methylamino) -5 - ((R) -2,2,2-trifluor-1-hydroxyethyl) -5,6,7,7a -tetrahydro-3aH-pyran [3,2- d] thiazol-6-ol (the slowest eluting isomer) (6.5 mg, 2.8% overall yield), XH NMR (300 MHz, CD3OD) 06 , 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.
[264] The following examples can be synthesized according to procedures analogous to the schemes and examples described above.





Biological activity Test to determine Kz values for inhibition of O-GlcNAcase activity
[265] Experimental procedure for kinetic analyzes: The enzymatic reactions were carried out in a reaction containing 50 mM NaH2PCt, 100 mM NaCI and 0.1% BSA (pH mM glucosaminide dihydrate (Sigma M2133) dissolved in ddH2O, as a substrate. of purified human O-GlcNAcase enzyme used in the reaction was 0.7 nM The test compound in varying concentrations was added to the enzyme before starting the reaction.The reaction was carried out at room temperature in a 96-well plate and was initiated with the addition of the substrate. Fluorescent product production was measured every 60 s for 45 min with a Tecan Infinite M200 plate reader with excitation at 355 nM and detected emission at 460 nM, with 4-Methylumbelliferone (Sigma M1381) used for produce a standard curve The product production curve was determined for each compound concentration tested and plotted using standard curve fitting algorithms for sigmoidal dose response curves. logistic curve adjustment of four data parameters were determined.
[266] Kz values were determined using the Cheng-Prusoff equation; the km of O-GlcNAcase for substrate was 0.2 mM.
[267] Examples 1 to 49 were tested by the assay described above and exhibited K2 values for inhibition of 0-GlcNAcase in the range 0.1 nM-10 pM. Test to determine KT values for the inhibition of β-hexosaminidase activity
[268] Experimental procedure for kinetic analyzes: The enzymatic reactions were carried out in a reaction containing 50 mM NaH2PO4, 100 mM NaCI and 0.1% BSA (pH 7.0) using 2 mM 4-Methylumbelliferyl N-acetyl-β-D - glucosaminide dihydrate (Sigma M2133) dissolved in ddH2O, as a substrate. The amount of purified human β-hexosaminidase enzyme used in the reaction was 24 nM. The test compound in varying concentrations was added to the enzyme before starting the reaction. The reaction was carried out at room temperature in a 96-well plate and was started with the addition of the substrate. Fluorescent product production was measured every 60 s for 45 min with a Tecan Infinite M200 plate reader with excitation at 355 nM and detected emission at 460 nM, with 4-Methylumbelliferone (Sigma M1381) used to produce a standard curve. The product production curve was determined for each compound concentration tested and plotted, using standard curve fitting algorithms for sigmoidal dose response curves. The values for a logistic curve fit of four data parameters were determined.
[269] K2 values were determined using the Cheng-Prusoff equation.
[270] When tested in this assay, many of the compounds described here exhibit K2 values for β-hexosaminidase inhibition in the 10 nM range greater than 100 µM.
[271] The selectivity ratio for inhibition of 0-GlcNAcase over β-hexosaminidase is defined here as:

[272] In general, the compounds described here exhibited a selectivity ratio in the range of about 10 to 100000. Thus, many compounds of the invention exhibit a high selectivity for inhibition of O-GlcNAcase over β-hexosaminidase. Test for the determination of cellular activity for compounds that inhibit O-GlcNAcase activity
[273] 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 as measured by an antibody, such as RL-2, which binds to O-GlcNAcylated protein. The amount of O-GlcNAcylated protein: RL2 antibody interaction can be measured by enzyme-linked immunosorbent test procedures (ELISA).
[274] Various tissue culture cell lines, expressing endogenous levels of O-GlcNAcase, can be used, examples include mouse PC-12, and human U-87, or SK-N-SH cells. In this test, mouse PC-12 cells were placed in 96-well plates with approximately 10,000 cells / well. Compounds to be tested were dissolved in DMSO, in a 2 or 10 mM stock solution, and then diluted with DMSO and water in a two-step process using a Tecan workstation. The cells were treated with compounds diluted for 24 h (5.4 pL in 200 pL volume of 1 well) for each final concentration of inhibitor desired to measure a compound concentration-dependent response, typically ten 3-fold dilution steps, starting from 10 pM were used to determine the concentration response curve. To prepare a cell lysate, the medium from the 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 pL of Phosphosafe reagent (Novagen Inc , Madison, WI) with protease and PMSF inhibitors. The cell lysate was collected and transferred to a new plate, which was then either coated to test the plates directly or frozen at -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.
[275] The ELISA portion of the test was performed on a 96-well black Maxisorp plate that was coated overnight at 4 ° C with 100 pL / well of cell lysate (1:10 dilution of the lysate with PBS containing protease inhibitors, phosphatase inhibitors, and PMSF). The next day, the wells were washed 3 times with 300 pL / well with washing buffer (Tris buffered saline with 0.1% Tween 20). The wells were blocked with 100 pL / well with blocking buffer (Tris buffered saline with 0.05% Tween 20 and 2.5% bovine serum albumin). Each well was then washed twice with 300 µl / well of the wash buffer. The anti-O-GlcNAc RL-2 antibody (Abeam, Cambridge, MA), diluted 1: 1000 in blocking buffer, was added to 100 µl / well. The plate was sealed and incubated at 37 ° C for 2h with gentle shaking. The wells were then washed 3 times with 300 µl / well wash buffer. To detect the amount of bound RL-2, horseradish peroxidase (HRP) conjugated to the secondary anti-mouse antibody (diluted 1: 3000 in blocking buffer) was added to 100 pL / well. The plate was incubated for 60 min at 37 ° C with gentle shaking. Each well was then washed 3 times with 300 pL / well with wash buffer. Detection reagent was added, 100 pL / well of Arnplex Ultra RED reagent (prepared by adding 30 pL of 10 mM Arnplex Ultra Red stock solution to 10 mL PBS with 18 pL 3% hydrogen peroxide, H2O2) • The reaction detection was incubated for 15 minutes at room temperature and then read with excitation at 530 nm and emission at 590 nm.
[276] The amount of O-GlcNAcylated protein, as detected by the ELISA test, was plotted for each test compound concentration using standard curve fitting algorithms for sigmoidal dose response curves. The values for a logistic curve fit of four data parameters were determined, with the inflection point of the curve being the power value for the test compound. Test for determination of apparent permeability (Papp)
[277] Bi-directional transport was evaluated in LLC-PK1 cells to determine apparent permeability (Papp) • LLC-PK1 cells can form a tight monolayer and thus can be used to evaluate vector transport of compounds from basolateral to apical (B—> A) and from apical to basolateral (A-> B).
[278] To determine Papp, LLC-PK1 cells were cultured in 96 well transcavity culture plates (Millipore). Solutions containing the test compounds (1 pM) were prepared in Hank's balanced salt solution with 10 mM HEPES. The substrate solution (150 pL) was added to either the apical (A) or basolateral (B) compartment of the culture plate, and buffer (150 pL) was added to the compartment opposite to the one containing the compound. At t = 3 h, 50 pL samples were removed from both sides of the monolayers dosed with test compound and placed in 96-well, sparkling (200 pL) or standard internal (100 pL labetolol IpM) plates was added to the samples and concentration was determined by liquid scintillation counting on a MicroBeta Wallac Trilux scintillation counter (Perkin Elmer Life Sciences, Boston, MA) or by LCMS / MS (Applied Biosystems SCIEX API 5000 triple mass mass spectrometer). [~ H] Verapamil (1 pM) was used as the positive control. The experiment was carried out in triplicate.
[279] The apparent permeability, Papp, was calculated for the following formula for samples taken at = 3 h:
where: receiver chamber volume was 0.15 ml; membrane area was 0.11 cm2; the initial concentration is the sum of the measured concentration in the donor plus the measured concentration in compartments of the recipient at = 3 h; Δ in concentration is concentration in the receiver compartment at 3 h; and Δ in time is the incubation time (3 x 60 x 60 = 10800 s). Papp was expressed as 10 “6 cm / s. Papp (LLC-PK1 cells) are the average Papp for transport from A to B and Papp for transport of BaAat = 3h:

[280] Data representative of the cell-based and permeability test data described above are shown in the following table. Some compounds of the invention have demonstrated greater potency or permeability in one or more of these tests. For comparison, the first two entries in the table show data for compounds (3aR, 5R, 6S, 7R, 7aR) -2- (ethylamino) -5- (hydroxymethyl) -5,6,7,7a-tetrahydro-3aH- pyran [3,2-d] thiazole-6,7-diol e (3aR, 5R, 6S, 7R, 7aR) -2- (dimethylamino) -5- (hydroxymethyl) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazole-6,7-diol, described in WO 2008/025170.




[281] The present invention has been described with respect to one or more embodiments. However, it will be apparent to those skilled in the art that various variations and modifications can be made without departing from the scope of the invention as defined in the claims. REFERENCES 1. C.R. Torres, G.W. Hart, J Biol Chem 1984, 259, 3308-17. 2. R.S. Haltiwanger, G.D. Holt, and G.W. Hart, J Biol Chem 1990, 265, 2563-8. 3. L.K. Kreppel, M.A. Blomberg, and G.W. Hart, J Biol Chem 1997, 272, 9308-15. 4. W.A. Lubas, et al., J Biol Chem 1997, 212, 9316-24. 5. W.A. Lubas, J.A. Hanover, J Biol Chem 2000, 215, 10983-8. 6. D.L. Dong, G.W. Hart, J Biol Chem 1994, 269, 19321-30. 7. Y. Gao, et al., J Biol chem 20 ° l, 276, 9838-45. 8. E.P. Roquemore, et. , Biochemistry 1996, 35, 3578-86. 9. S.P. Jackson, R. Tjian, Cell 1988, 55, 125-33. 10. W.G. Kelly, M.E. Dahmus, and G.W. Hart, J Biol Chem 1993, 268, 10416-24. 11. M.D. Roos, et al., Mo1 Cel1 Biol 1997, 17, 6472-80. 12. N. Lamarre-Vincent, L.C. Hsieh-Wilson, J Am Chem Soc 2003, 125, 6612-3. 13. F. Zhang, et al., Cell 2003, 115, 715-25. 14. K. Vosseller, et al., Proc Natl Acad Sci USA 2002, 99, 5313-8. 15. W.A. Lubas, et al., Biochemistry 1995, 34, 1686-94. 16. L.S. Griffith, B. Schmitz, Biochem Biophys Res Commun 1995, 213, 424-31. 17. R.N. Cole, G.W. Hart, J Neurochem 1999, 73, 418-28. 18.1. Braidman, et al., Biochem J 1974, 143, 295-301. 19. R. Ueno, C.S. Yuan, Biochim Biophys Acta 1991, 1074, 79-84. 20. C. Toleman, et al., J Biol Chem 2004, 279, 53665-73. 21. F. Liu, et al., Proc Natl Acad Sci USA 2004, 101, 10804-9. 22. T.Y. Chou, G.W. Hart, Adv Exp Med Biol 2001, 491, 413-8. 23. M. Goedert, et al., Neuron 1992, 8, 159-68. 24. M. Goedert, et al., Neuron 1989, 3, 519-26. 25. E. Kopke, et al., J Biol Chem 1993, 268, 24374-84. 26. H. Ksiezak-Reding, W.K. Liu, and S.H. Yen, Brain Res 1992, 597, 209-19. 27. P.V. Arriagada, et al., Neurology 1992, 42, 631-9. 28. K.P. Riley, D.A. Snowdon, and W.R. Markesbery, Ann Neurol 2002, 51, 567-77. 29. I. Alafuzoff, et al., Acta Neuropathol (Berl) 1987, 74, 209-25. 30. C.X. Gong, et al., J Neural Transm 2005, 112, 81338. 31. K. Iqbal, et al., J Neural Transm Suppl 2002, 30919. 32. K. Iqbal, et al., J Mol Neurosci 2003, 20, 425-9. 33. W. Noble, et al., Proc Natl Acad Sci U S A 2005, 102, 6990-5. 34. S. Le Corre, et al., Proc Natl Acad Sci U S A 2006, 103, 9673-8. 35. S.J. Liu, et al., J Biol Chem 2004, 279, 50078-88. 36. G. Li, H. Yin, and J. Kuret, J Biol Chem 2004, 279, 15938-45. 37. T.Y. Chou, G.W. Hart, and C.V. Dang, J Biol Chem 1995, 270, 18961-5. 38. X. Cheng, G.W. Hart, J Biol Chem 2001, 276, 10570-5 5. 39. X. Cheng, et al., Biochemistry 2000, 39, 11609-20. 40. L.S. Griffith, B. Schmitz, Eur J Biochem 1999, 262, 824-31. 41. K. Kamemura, G.W. Hart, Prog Nucleic Acid Res Mol Biol 2003, 73, 107-36. 42. L. Wells, et al., J Biol Chem 2004, 279, 38466-70. 43. L. Bertram, et al., Science 2000, 290, 2302-3. 44. S. Hoyer, et al., Journal of Neural Transmission 1998, 105, 423-438. 45. C.X. Gong, et al., Journal of Alzheimers Disease 2006, 9, 1-12. 46. W.J. Jagust, et al., Journal of Cerebral Blood Flow and Metabolism 1991, 11, 323-330. 47. S. Hoyer, Experimental Gerontology 2000, 35, 1363-1372. 48. S. Hoyer, in Frontiers in Clinical Neuroscience: Neurodegeneration and Neuroprotection, Vol.541, 2004, 135-152. 49 .R.N. Kalaria, S.I. Harik, Journal of Neurochemistry 1989, 53, 1083-1088. 1 0.I.A. Simpson, et al., Annals of Neurology 1994, 35, 546-551. 2 1.S.M. de la Monte, J.R. Wands, Journal of Alzheimers Disease 2005, 7, 45-61. 52 .X.W. Zhu, G. Perry, and M.A. Smith, Journal of Alzheimers Disease 2005, 7, 81-84. 53 .J.C. de la Torre, Neurological Research 2004, 26, 517-524. 54 .S. Marshall, W.T. Garvey, and R.R. Traxinger, Faseb J 1991, 5, 3031-6. 55 .S.P. Iyer, Y. Akimoto, and G.W. Hart, J Biol Chem 2003, 278, 5399-409. 56 .K. Brickley, et al. , J Biol Chem 2005, 280, 14723-32. 57 .S. Knapp, C.H. Yang, and T. Haimowitz, Tetrahedron Letters 2002, 43, 7101-7104. 58 .S.P. Iyer, G.W. Hart, J Biol Chem 2003, 238, 24608-16 16. 59 .M. Jinek, et al., Nat Struct Mol Biol 2004, 11, 1001-7. 60 .K. Kamemura, et al. , J Biol Chem 2002, 277, 19229-35. 61 .Y. Deng, et al., FASEB J. 2007, fj.07-8309com. 62 .L.F. Lau, et al., Curr Top Med Chem 2002, 2, 395-415. 63 .M.P. Mazanetz, P.M. Fischer, Nature Reviews Drug Discovery 2007, 6, 464-479. 64 .S.A. Yuzwa, et al., Nat Chem Biol 2008, 4, 483-490. 65 .P. Bounelis, et al., Shock 2004, 21 170 Suppl. 2, 58-58. 66 .N. Fulop, et al., Circulation Research 2005, 97, E28-E28. 67 .J. Liu, R.B.Marchase, and J.C. Chatham, Faseb Journal 2006, 20, A317-A317. 68 .R. Marchase, et al., PCT Int. Appl. WO 2006016904 2006. 69 .N. Fulop, et al., Journal of Molecular and Cellular Cardiology 2004, 37, 286-287. 70 .N. Fulop, et al., Faseb Journal 2005, 19, A689- A690. 71. J. Liu, R.B.Marchase, and J.C. Chatham, Journal of Molecular and Cellular Cardiology 2007, 42, 177-185. 72 .L.G. Not, et al., Faseb Journal 2006, 20, A1471-A1471. 2 3.S.L. Yang, et al., Shock 2006, 25, 600-607. 74 .L.Y. Zou, et al., Faseb Journal 2005, 19, A1224- A1224. 75 .R.B. Marchase, et al., Circulation 2004, 110, 1099-1099. 76 6. J. Liu, et al., Journal of Molecular and Cellular Cardiology 2006, 40, 303-312. 77 .J. Liu, J.C. Chatham, and R.B.Marchase, Faseb Journal 2005, 19, A691-A691. 78. T. Nagy, et al., American Journal of Physiology- Cell Physiology 2006, 290, C57-C65. 79 .N. Fulop, R.B.Marchase, and J.C. Chatham, Cardiovascular Research 2007, 73, 288-297. 80. T. Lefebvre, et al., Expert Review of Proteomics 2005, 2, 265-275. 81 .B. Henrissat, A. Bairoch, Biochem J 1993, 293 (Pt 3), 781-8. 82 .B. Henrissat, A. Bairoch, Biochem J 1996, 316 (Pt 2), 695-6. 83 .L. Wells, K. Vosseller, and G.W. Hart, Science 2001, 291, 2376-8. 84 .J.A. Hanover, FASEB J 2001, 15, 1865-76. 85. D.A. McClain, et al., Proc Natl Acad Sci USA 2002, 99, 10695-9. 86 .P.J. Yao, P.D. Coleman, J Neurosci 1998, 18, 2399-411. 87 .W.H. Yang, et al., Nature Cell Biology 2006, 8, 1074-U53. 88 .B. Triggs-Raine, D.J.Mahuran, and R.A. Gravel, Adv Genet 2001, 44, 199-224. 89. D. Zhou, et al., Science 2004, 1786-89. 90. G. Legler, et al., Biochim Biophys Acta 1991, 1080, 89-95. 91. M. Horsch, et al., Eur J Biochem 1991, 197, 815-8. 92. J. Liu, et al., Chem Biol 2001, 8, 701-11. 93. S. Knapp, et al., J. Am. Chem. Soc. 1996, 118, 6804-6805. 94. V.H. Lillelund, et al., Chem Rev 2002, 102, 515-53. 95. R.J. Konrad, et al., Biochem J 2001, 356, 31-41. 96. K. Liu, et al., J Neurochem 2004, 89, 1044-55. 97. G. Parker, et al., J Biol Chem 2004, 279, 20636-42. 98. E.B. Arias, J. Kim, and G.D. Ctécnicae, Diabetes 2004, 53, 921-30. 99. A. Junod, et al., Proc Soc Exp Biol Med 1967, 126, 201-5. 100. R.A. Bennett, A.E. Pegg, Cancer Res 1981, 41, 2786-90. 101. K.D. Kroncke, et al., Biol Chem Hoppe Seyler 1995, 376, 179-85. 102. H. Yamamoto, Y. Uchigata, and H. Okamoto, Nature 1981, 294, 284-6. 103. K. Yamada, et al., Diabetes 1982, 31, 749-53. 104. V. Burkart, et al., Nat Med 1999, 5, 314-9. 105. M.D. Roos, et al., Proc Assoc An Physicians 1998, 110, 422-32. 106. Y. Gao, G.J. Parker, and G.W. Hart, Arch Biochem Biophys 2000, 383, 296-302. 107. R. Okuyama, M. Yachi, Biochem Biophys Res Commun 2001, 287, 366-71. 108. N.E. Zachara, et al., J Biol Chem 2004, 279, 30133-42. 109. J.A. Hanover, et al., Arch Biochem Biophys 1999, 362, 38-45. 110. K. Liu, et al., Mol Cell Endocrinol 2002, 194, 135-46. 111. M.S. Macauley, et al., J Biol Chem 2005, 280, 25313-22. 112. B.L. Mark, et al., J Biol Chem 2001, 276, 10330-7. 113. R.S. Haltiwanger, K. Grove, and G.A. Philipsberg, J Biol Chem 1998, 273, 3611-7. 114. D.J. Miller, X. Gong, and B.D. Shur, Development 1993, 118, 1279-89. 115. L.Y. Zou, et al., Shock 2007, 27, 402-408. 116. J.B. Huang, A.J. Clark, and H.R. Petty, Cellular Immunology 2007, 245, 1-6. 117. N.E. Zachara, et al., Abstract 418 in Joint Meeting of the Society for Glycobiology and the Japanese Society of Carbohydrate Research. Honolulu, Hawaii, 2004. 118. L.Y. Zou, et al., Faseb Journal 2006, 20, A1471- A1471. 119. V. Champattanachai, R.B.Marchase, and J.C. Chatham, American Journal of Physiology-Cell Physiology 2007, 292, C178-C187. 120. V. Champattanachai, R.B.Marchase, and J.C. Chatham, American Journal of Physiology-Cell Physiology 2008, 294, C1509-C1520. 121. I. Khlistunova, et al., Current Alzheimer Research 2007, 4, 544-546. 122. P. Friedhoff, et al., Biochemistry 1998, 37, 10223-10230. 123. M. Pickhardt, et al., Journal of Biological Chemistry 2005, 280, 3628-3635.

权利要求:
Claims (15)
[0001]
1) Compound characterized by the fact that it is Formula 2)) or a pharmaceutically acceptable salt thereof:
[0002]
2. A compound according to claim 1, characterized by the fact that: R1 and R2 are H, or R1 is H and R2 is F, or R1 is F and R2 is H; R3 is H and R4 is OH, or R3 is OH and R4 is H; R6 is H or OH; R7 is H or CH3; Is R8 CH3 OR CF ; and each R9 is independently selected from the group consisting of: H, CH3, CH3CH3 and, or NR93 is azetidin-1-yl.
[0003]
3. Compound according to claim 1, characterized by the fact that at least one of R4, R2, and R6 is F.
[0004]
4. Compound according to claim 1, characterized by the fact that: R1 is H and R2 is F, or R1 is F and R2 is H; R3 is H; and the symbol R4 represents OR5.
[0005]
5. Compound according to claim 1, characterized by the fact that a compound is selected from the following group: (3aR, 5R, 6R, 7R, 7aR) -7-fluoro-5 - ((S) -1- hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7R, 7aR) -7-fluoro-5 - ((R) -1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6R, 7R, 7aR) -2- (ethylamino) -7-fluoro-5- ((S) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6R, 7R, 7aR) -2- (ethylamino) -7-fluoro-5 - (((R) ~ 1 ~ hydroxyethyl) -5,6 / 7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6R, 7R, 7aR) -2- (dimethylamino) -7-fluoro-5- ((S) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6R, 7R, 7aR) -2- (dimethylamino) -7-fluoro-5 - ((R) -1- hydroxyethyl) -5,6, 7'7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5S, 6R, 7R / 7aR) -2- (ethylamino) -7-fluoro-5 - ((R) -2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7R, 7aR) -2- (ethylamino) -7-fluoro-5- ((S) -2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7R, 7aR) -7-fluoro-2- (methylamino) -5 - ((R) - 2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7R, 7aR) -7-fluoro-2- (methylamino) -5 - ((S) - 2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7R, 7aR) -2- (dimethylamino) -7-fluoro-5 - ((R) - 2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7R, 7aR) -2- (dimethylamino) -7-fluoro-5 - ((S) - 2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6S, 7aR) -2- (ethylamino) -5 - ((S) -1-hydroxyethyl) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- 6-ol; (3aR, 5R, 6S, 7aR) -2- (ethylamino) -5 - ((R) -1-hydroxyethyl) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- 6-ol; (3aR, 5R, 6R, 7R, 7aR) -5-ethyl-7-fluoro-2- (methylamino) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole-6- ol; (3aR, 5R, 6S, 7aR) -5 - ((S) -1-hydroxyethyl) -2- (methylamino) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- 6-ol; (3aR, 5R, 6S, 7aR) -5 - ((R) -1-hydroxyethyl) -2- (methylamino) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- 6-ol; (3aR, 5R, 6S, 7aR) -2- (dimethylamino) -5 - ((S) -1-hydroxyethyl) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- 6-ol; (3aR, 5R, 6S, 7aR) -2- (dimethylamino) -5 - ((R) -1-hydroxyethyl) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- 6-ol; (3aR, 5S, 6S, 7aR) -2- (methylamino) -5 - ((R) -2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazole-6-01; (3aR, 5S, 6S, 7aR) -2- (methylamino) -5 - ((S) -2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazole-6-01; (3aR, 5S, 6S, 7aR) -2- (dimethylamino) -5 - ((R) -2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazol-6-ol; (3aR, 5S, 6S, 7aR) -2- (dimethylamino) -5 - ((S) -2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazol-6-ol; (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-pyran [3,2-d] thiazol-6-ol; (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-pyran [3,2-d] thiazol-6-ol; (3aR, 5 S, 6R, 7R, 7aR) -2- (ethylamino) -7-fluoro-5 - ((R) -1,1,1 -trifluoro-2-hydroxypropan-2-yl) -5.6 , 7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (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-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7R, 7aR) -2- (dimethylamino) -7-fluoro-5- (1,1,1-trifluoro-2-hydroxypropan-2-yl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6S, 7aR) -2- (methylamino) -5 - ((R) -1,1,1-trifluoro-2-hydroxypropan-2-yl) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6S, 7aR) -2- (methylamino) -5 - ((S) -1,1,1-trifluoro-2-hydroxypropan-2-yl) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7R, 7aR) -2- (azetidin-1-yl) -7-fluoro-5 - ((S) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH- pyran [3,2-d] thiazol-6-ol; (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-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7R, 7aR) -2-amino-7-fluoro-5 - ((S) -1- hydroxyethyl) -5,6,7 / 7a-tetrahydro-3aH-pyran [3,2- d] thiazole-6-ol; (3aR, 5R, 6R, 7S, 7aR) -7-fluoro-5 - ((S) -1-hydroxyethyl) -2- (methylamino) - 5,6,7,7a — tetrahydro - 3aH — pyran [3, 2 d] thiazole 6 µm; (3aR, 5R, 6R, 7S, 7aR) -7-fluoro-5 - ((R) -1-hydroxyethyl) -2- (methylamino) -5,6 '7> 7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6R, 7S, 7aR) -2- (ethylamino) -7-fluoro-5- ((S) -1- hydroxyethyl) -5,6, 7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6R, 7S, 7aR) -2- (ethylamino) -7-fluoro-5 - ((R) -1- hydroxyethyl) -5, 7> 7a-tetrahydro-3aH-pyran [3,2- d] thiazole-6-ol; (3aR, 5S, 6R, 7S, 7aR) -7-fluoro-2- (methylamino) -5 - ((R) - 2 2 2-trifluoro-1_hydroxyethyl) -5,6,7,7a-tetrahydro-3aH- pyran [3,2-d] thiaz ° 16-ol; (3aR, 5S, 6R, 7S, 7aR) -7-fluoro-2- (methylamino) -5 - ((S) - 2 2 2-trifluoro-1_hydroxyethyl) -5,6,7,7a-tetrahydro-3aH- pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7S, 7aR) -2- (ethylamino) -7-fluoro-5 - ((R) -2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7S, 7aR) -2- (ethylamino) -7-fluoro-5 - ((S) -2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7S, 7aR) -5-ethyl-7-fluoro-2- (methylamino) - 567 7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7S, 7aR) -7-fluoro-5- (2-hydroxypropan-2-yl) -2- (methylamino) -5,6'7'7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5S, 6R, 7S, 7aR) -7-fluoro-2- (methylamino) -5- ((S) - 11 i-trifluoro ~ 2-hydroxypropan-2-yl) -5,6,7, 7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7S, 7aR) -7-fluoro-2- (methylamino) -5 - ((R) - 11 i-trifluoro-2_hydroxypropan-2-yl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6S, 7R / 7aR) -7-fluoro-5- ((S) -1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6S, 7R, 7aR) -7-fluoro-5 - ((R) -1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5S, 6S, 7R, 7aR) -7-fluoro-2- (methylamino) -5 - ((R) - 2 2 2-trifluoro-1_hydroxyethyl) -5,6,7,7a-tetrahydro-3aH- pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6S, 7R, 7aR) -7-fluoro-2- (methylamino) -5 - ((S) - 2 2 2-trifluoro-1-hydroxyethyl) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6S, 7S, 7aR) -7-fluoro-5 - ((S) -1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6R, 7aR) -5 - ((S) -1-hydroxyethyl) -2- (methylamino) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- 6-ol; (3aR, 5R, 6R, 7S, 7aR) -2- (dimethylamino) -7-fluoro-5- ((S) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6R, 7S, 7aR) -2- (dimethylamino) -7-fluoro-5 - ((R) -1- hydroxyethyl) -5,7,7a-tetrahydro-3aH-pyran [3,2- d] thiazole-6-ol; (3aR, 5S, 6R, 7S, 7aR) -2- (dimethylamino) -7-fluoro-5 - ((R) - 2 2 2-trifluoro-l'hydroxyethyl) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7S, 7aR) -2- (dimethylamino) -7-fluoro-5 - ((S) - 2 2 2-trifluoro-1 "hydroxyethyl) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5 S, 6R, 7S, 7aR) -2- (ethylamino) -7-fluoro-5 - ((R) -1,1,1 -trifluoro-2-hydroxypropan-2-yl) -5.6 , 7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5 S, 6R, 7S, 7aR) -2- (ethylamino) -7-fluoro-5- ((S) -1,1,1 -trifluoro-2-hydroxypropan-2-yl) -5.6 , 7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7S, 7aR) -2- (dimethylamino) -7-fluoro-5- (1, 1, 1-trifluoro-2-hydroxypropan-2-yl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7S, 7aR) -2- (azetidin-1-yl) -7-fluoro-5 - ((S) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH- pyran [3,2-d] thiazol-6-ol; (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-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7S, 7aR) -2- (azetidin-1-yl) -7-fluoro-5 - ((R) - 2 2 2-trifluoro'l_hydroxyethyl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7S, 7aR) -7-fluoro-5 - ((S) -1-hydroxyethyl) -2- (pyrrolidin-1-yl) -5,6,7,7a-tetrahydro-3aH- pyran [3,2-d] thiazol-6-ol; (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-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7R, 7aR) -7-fluoro-5 - ((R) -2-fluoro-1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH- pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7R, 7aR) -5 - ((R) -2,2-difluor-1-hydroxyethyl) -7-fluoro-2- (methylamino) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7S, 7aR) -7-fluoro-5 - ((R) -2-fluoro-1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH- pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7S, 7aR) -5 - ((R) -2,2-difluor-1-hydroxyethyl) -7-fluoro-2- (methylamino) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7R, 7aR) -7-fluoro-5 - ((S) -1-hydroxypropyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6R, 7R, 7aR) -5 - ((S) -3,3-difluoro-1-hydroxypropyl) -7-fluoro-2- (methylamino) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7R, 7aR) -7-fluoro-2- (methylamino) -5- ((S) - 3,3,3-trifluoro-1_hydroxypropyl) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7R, 7aR) -5 - ((S) -cyclopropyl (hydroxyl) methyl) -7-fluoro-2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7R, 7aR) -5 - ((S) -cyclobutyl (hydroxyl) methyl) -7-fluoro-2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7R, 7aR) -5 - ((S) -cyclopentyl (hydroxyl) methyl) - 7-fluoro-2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7S, 7aR) -7-fluoro-5 - ((S) -1-hydroxypropyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6R, 7S, 7aR) -5 - ((S) -3,3-difluoro-1-hydroxypropyl) -7-fluoro-2- (methylamino) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7S, 7aR) -7-fluoro-2- (methylamino) -5- ((S) - 3,3,3-trifluoro-1_hydroxypropyl) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7S, 7aR) -5 - ((S) -cyclopropyl (hydroxyl) methyl) -7-fluoro-2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7S, 7aR) -5 - ((S) -cyclobutyl (hydroxyl) methyl) - 7-fluoro-2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7S, 7aR) -5 - ((S) -cyclopentyl (hydroxyl) methyl) -7-fluoro-2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7S, 7aR) -7-fluoro-2- (methylamino) -5-vinyl- 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole-6- ol; (3aR, 5R, 6S, 7S, 7aR) -7-fluoro-2- (methylamino) -5- (2,2,2-trifluoroethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-01; or a pharmaceutically acceptable salt of any of them.
[0006]
6. Compound according to claim 1, characterized by the fact that the compound is selected from the group comprising: (3aR, 5R, 6R, 7R, 7aR) -7-fluoro-5 - ((S) - 1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7R, 7aR) -2- (ethylamino) -7-fluoro-5 - ((S) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5S, 6R, 7R, 7aR) -2- (ethylamino) -7-fluoro-5 - ((R) -2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7R, 7aR) -7-fluoro-2- (methylamino) -5 - ((R) - 2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6S, 7aR) -5 - ((S) -1-hydroxyethyl) -2- (methylamino) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- 6-ol; (3aR, 5S, 6S, 7aR) -2- (methylamino) -5 - ((R) -2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazole-6-01; (3aR, 5R, 6R, 7S, 7aR) -7-fluoro-5 - ((S) -1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6R, 7S, 7aR) -2- (ethylamino) -7-fluoro-5- ((S) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5S, 6R, 7S, 7aR) -7-fluoro-2- (methylamino) -5 - ((R) - 2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7S, 7aR) -2- (ethylamino) -7-fluoro-5 - ((R) -2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; or a pharmaceutically acceptable salt thereof.
[0007]
Use of a compound as defined in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof characterized in that it is to prepare a composition for treating a condition that is modulated by an O-GlcNAcase, wherein the condition is selected from one or more of the group consisting of an inflammatory disease, an allergy, asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonia, delayed type hypersensitivity, atherosclerosis, interstitial lung disease (ILD) , idiopathic pulmonary fibrosis, ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, syndrome, polymyositis or dermatomyositis, systemic anaphylaxis or hypersensitivity response, drug allergy, insect bite allergy, autoimmune disease rheumatoid, psoriatic arthritis, multiple sclerosis, Guillain-Barré syndrome, lupus erit systemic ematous, myasthenia gravis, glomerulonephritis, autoimmune thyroiditis, graft rejection, allograft rejection, graft-versus-host disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, spondyloarthropathy, scleroderma, psoriasis, cell-mediated psoriasis , inflammatory dermatosis, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, cutaneous necrotizing vasculitis, and hypersensitivity vasculitis, eosinphilic lucifugus, eosiniphilic fascitis, solid organ transplant rejection, heart transplant rejection, transplant rejection lung, liver transplant rejection, kidney transplant rejection, pancreas, kidney graft transplant rejection, pulmonary allograft, epilepsy, pain, fibromyalgia, stroke and for neuroprotection.
[0008]
8. Use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
[0009]
9. Use, according to claim 8, characterized by the fact that the condition is selected from one or more of the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci ), granular argyrophilic dementia, Bluit's disease, corticobasal degeneration (CBD), boxy dementia, diffuse neurofibrillary tangles with calcification, Down's syndrome, British family dementia, Danish family dementia, frontotemporal dementia with chromosome 17-linked parkinsonism (FTDP-17) , Gerstmann-Straussler-Scheinker disease, Guadeloupean parkinsonism, Hallevorden-Spatz disease (neurodegeneration with iron accumulation in type 1 brain), multiple system atrophy, myotonic dystrophy, Niemann-Pick disease (type C), Pallido- nigral dot, Guam parkinsonism-dementia complex, Pick's disease (PiD), encephalitic post-parkinsonism (PEP), diseases caused by prions (including o Creutzfeldt-Jakob disease (CJD), variant of Creutzfeldt-Jakob disease (vCJD), fatal familial insomnia, and kuru), progressive supercortical gliosis, progressive supranuclear palsy (PSP), Richardson's syndrome, subacute sclerosing panencephalitis, dementia de tangle only, Huntington's disease, Parkinson's disease, schizophrenia, mild cognitive forgetfulness (MCI), neuropathy (including peripheral neuropathy, autonomic neuropathy, neuritis, and diabetic neuropathy) or glaucoma.
[0010]
10. Use, according to claim 9, characterized by the fact that a stress is a heart disorder.
[0011]
11. Use, according to claim 10, characterized by the fact that a cardiac disorder is selected from one or more of the group consisting of ischemia; bleeding; hypovolemic shock; myocardial infarction; an interventional cardiology procedure; Cardiac surgery; fibrinolytic therapy; angioplasty; and stent placement.
[0012]
12. Use according to any one of claims 8 to 11, characterized by the fact that the compound is selected from the group: (3aR, 5R, 6R, 7R, 7aR) -7-fluoro-5 - ((S ) -1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7R, 7aR) -7-fluoro-5 - ((R) -1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6R, 7R, 7aR) -2- (ethylamino) -7-fluoro-5- ((S) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6R, 7R, 7aR) -2- (ethylamino) -7-fluoro-5 - ((R) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6R, 7R, 7aR) -2- (dimethylamino) -7-fluoro-5- ((S) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6R, 7R, 7aR) -2- (dimethylamino) -7-fluoro-5- ((R) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5S, 6R, 7R, 7aR) -2- (ethylamino) -7-fluoro-5 - ((R) -2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7R, 7aR) -2- (ethylamino) -7-fluoro-5- ((S) -2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7R, 7aR) -7-fluoro-2- (methylamino) -5 - ((R) - 1.1.2- 2 2-trifluoro-1_hydroxyethyl) -5,6,7,7a-tetrahydro -3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7R, 7aR) -7-fluoro-2- (methylamino) -5 - ((S) - 2 2 2-trifluoro-1-hydroxyethyl) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7R, 7aR) -2- (dimethylamino) -7-fluoro-5 - ((R) - 1.1.3- trifluoro-1-hydroxyethyl) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7R, 7aR) -2- (dimethylamino) -7-fluoro-5 - ((S) - 1.1.4- trifluoro-1-hydroxyethyl) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6S, 7aR) -2- (ethylamino) -5 - ((S) -1-hydroxyethyl) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- 6-ol; (3aR, 5R, 6S, 7aR) -2- (ethylamino) -5 - ((R) -1-hydroxyethyl) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- 6-ol; (3aR, 5R, 6R, 7R, 7aR) -5-ethyl-7-fluoro-2- (methylamino) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole-6- ol; (3aR, 5R, 6S, 7aR) -5 - ((S) -1-hydroxyethyl) -2- (methylamino) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- 6-ol; (3aR, 5R, 6S, 7aR) -5 - ((R) -1-hydroxyethyl) -2- (methylamino) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- 6-ol; (3aR, 5R, 6S, 7aR) -2- (dimethylamino) -5 - ((S) -1-hydroxyethyl) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- 6-ol; (3aR, 5R, 6S, 7aR) -2- (dimethylamino) -5 - ((R) -1-hydroxyethyl) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- 6-ol; (3aR, 5S, 6S, 7aR) -2- (methylamino) -5 - ((R) -2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazole-6-01; (3aR, 5S, 6S, 7aR) -2- (methylamino) -5 - ((S) -2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazole-6-01; (3aR, 5S, 6S, 7aR) -2- (dimethylamino) -5 - ((R) -2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazol-6-ol; (3aR, 5S, 6S, 7aR) -2- (dimethylamino) -5 - ((S) -2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazol-6-ol; (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-pyran [3,2-d] thiazol-6-ol; (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-pyran [3,2-d] thiazol-6-ol; (3aR, 5 S, 6R, 7R, 7aR) -2- (ethylamino) -7-fluoro-5 - ((R) -1,1,1 -trifluoro-2-hydroxypropan-2-yl) -5.6 , 7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (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-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7R, 7aR) -2- (dimethylamino) -7-fluoro-5- (1,1,1-trifluoro-2-hydroxypropan-2-yl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6S, 7aR) -2- (methylamino) -5 - ((R) -1,1,1-trifluoro-2-hydroxypropan-2-yl) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6S, 7aR) -2- (methylamino) -5 - ((S) -1,1,1-trifluoro-2-hydroxypropan-2-yl) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7R, 7aR) -2- (azetidin-1-yl) -7-fluoro-5 - ((S) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH- pyran [3,2-d] thiazol-6-ol; (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-pyran [3,2-d] thiazole 6 ol; (3aR, 5R, 6R, 7R, 7aR) -2-amino-7-fluoro-5 - ((S) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2- d] thiazole-6-ol; (3aR, 5R, 6R, 73.7aR) -7-fluoro-5 - ((S) -1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6R, 73.7aR) -7-fluoro-5 - ((R) -1-hydroxyethyl) -2- (methylamino) -5,6, 7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6R, 73.7aR) -2- (ethylamino) -7-fluoro-5- ((S) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6R, 73.7aR) -2- (ethylamino) -7-fluoro-5 - ((R) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 53.6R, 75.7aR) -7-fluoro-2- (methylamino) -5 - ((R) - 2 2 2-trifluoro-l'hydroxyethyl) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 53.6R, 73.7aR) -7-fluoro-2- (methylamino) -5- ((S) - 2 2 2-trifluoro-l'hydroxyethyl) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7S, 7aR) -2- (ethylamino) -7-fluoro-5 - ((R) -2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7S, 7aR) -2- (ethylamino) -7-fluoro-5 - ((S) -2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7S, 7aR) -5-ethyl-7-fluoro-2- (methylamino) - 5 6 7 7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7S, 7aR) -7-fluoro-5- (2-hydroxypropan-2-yl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (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-pyran [3,2-d] thiazol-6-ol; (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-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6S, 7R / 7aR) -7-fluoro-5 - ((S) -1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6S, 7R, 7aR) -7-fluoro-5 - ((R) -1-hydroxyethyl) -2- (methylamino) -5 / 7,7a-tetrahydro-3aH-pyran [3,2- d] thiazole-6-ol; (3aR, 5S, 6S, 7R, 7aR) -7-fluoro-2- (methylamino) -5- ((R) - 2 2 2-trifluoro-1_hydroxyethyl) -5,6,7,7a-tetrahydro-3aH- pyran [3,2-d] thiaz ° 1-6-ol; (3aR, 5S, 6S, 7Rv7aR) -7-fluoro-2- (methylamino) -5 - ((S) - 2 2 2-trifluoro-1_hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazθl 6 ol; (3aR, 5R, 6S, 7S, 7aR) -7-fluoro-5 - ((S) -1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6R, 7aR) -5 - ((S) -1-hydroxyethyl) -2- (methylamino) - 5 6 7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6- ol; (3aR, 5R, 6R, 7S, 7aR) -2- (dimethylamino) -7-fluoro-5 - ((S) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6R, 7S, 7aR) -2- (dimethylamino) -7-fluoro-5 - ((R) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5S, 6R, 7S, 7aR) -2- (dimethylamino) -7-fluoro-5 - ((R) - 2 2 2-trifluoro-1-hydroxyethyl) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7S, 7aR) -2- (dimethylamino) -7-fluoro-5 - ((S) - 2 2 2-trifluoro-1_hydroxyethyl) -5,6,7,7a-tetrahydro-3aH- pyran [3,2-d] thiazol-6-ol; (3aR, 5 S, 6R, 7S, 7aR) -2- (ethylamino) -7-fluoro-5 - ((R) -1,1,1 -trifluoro-2-hydroxypropan-2-yl) -5.6 , 7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5 S, 6R, 7S, 7aR) -2- (ethylamino) -7-fluoro-5 - ((S) -1,1,1 -trifluoro-2-hydroxypropan-2-yl) -5.6 , 7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7S, 7aR) -2- (dimethylamino) -7-fluoro-5- (1,1,1-trifluoro-2-hydroxypropan-2-yl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7S, 7aR) -2- (azetidin-1-yl) -7-fluoro-5 - ((S) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH- pyran [3,2-d] thiazol-6-ol; (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-pyran [3,2-d] thiazol-6-ol; (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-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7S, 7aR) -7-fluoro-5 - ((S) -1-hydroxyethyl) -2- (pyrrolidin-1-yl) "5,6,7,7a-tetrahydro-3aH- pyran [3,2- d] thiazol-6-ol; (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-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7R, 7aR) -7-fluoro-5 - ((R) -2-fluoro-1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH- pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7R, 7aR) -5 - ((R) -2,2-difluor-1-hydroxyethyl) -7-fluoro-2- (methylamino) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7S, 7aR) -7-fluoro-5 - ((R) -2-fluoro-1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH- pyran [3,2-d] thiazole 6 ol; (3aR, 5S, 6R, 7S, 7aR) -5 - ((R) -2,2-difluor-1-hydroxyethyl) -7-fluoro-2- (methylamino) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7R, 7aR) -7-fluoro-5 - ((S) -1-hydroxypropyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6R, 7R, 7aR) -5 - ((S) -3,3-difluoro-1-hydroxypropyl) -7-fluoro-2- (methylamino) -5,6,7, 7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7R, 7aR) -7-fluoro-2- (methylamino) -5 - ((S) - 3 3 3-trifluoro-1_hydroxypropyl) -5,6,7,7a-tetrahydro-3aH- pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7R, 7aR) -5- ((S) -cyclopropyl (hydroxyl) methyl) -7-fluoro-2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7R, 7aR) -5 - ((S) -cyclobutyl (hydroxyl) methyl) -7-fluoro-2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7R, 7aR) -5 - ((S) -cyclopentyl (hydroxyl) methyl) - 7-fluoro-2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7S, 7aR) -7-fluoro-5 - ((S) -1-hydroxypropyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6R, 7S, 7aR) -5 - ((S) -3,3-difluoro-1-hydroxypropyl) -7-fluoro-2- (methylamino) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7S, 7aR) -7-fluoro-2- (methylamino) -5 - ((S) - 3 3 3-trifluoro-1_hydroxypropyl) -5,6,7,7a-tetrahydro-3aH- pyran [3,2-d] thiaz ° 1-6-ol; (3aR, 5R, 6R, 7s'7aR> -5 “((S) -cyclopropyl (hydroxyl) methyl) -7-fluoro-2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7S, 7aR) -5 - ((S) -cyclobutyl (hydroxyl) methyl) - 7-fluoro-2- (methylamino) -5, 6,7,7a-tetrahydro-3aH-pyran [3,2- d] thiazol-6-ol; (3aR, 5R, 6R, 7S, 7aR) -5 - ((S) -cyclopentyl (hydroxyl) methyl) - 7-fluoro-2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7S, 7aR) -7- fluoro-2- (methylamino) -5-vinyl- 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6S, 7S, 7aR) - 7-fluoro-2- (methylamino) -5- (2,2,2-trifluoroethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole-6-01; or a pharmaceutically acceptable salt thereof.
[0013]
13. Use according to any one of claims 8 to 12, characterized in that the compound is selected from the group: (3aR, 5R, 6R, 7R, 7aR) -7-fluoro-5 - ((S) - 1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6R, 7R, 7aR) -2- (ethylamino) -7-fluoro-5- ((S) -1- hydroxyethyl) -5,6, 7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5S, 6R, 7R, 7aR) -2- (ethylamino) -7-fluoro-5 - ((R) -2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7R, 7aR) -7-fluoro-2- (methylamino) -5 - ((R) - 2,2,2-trifluoro-1_hydroxyethyl) -5,6,7,7a-tetrahydro- 3aH-pyran [3,2-d] thiazol-6-ol; (3aR, 5R, 6S, 7aR) -5 - ((S) -1-hydroxyethyl) -2- (methylamino) - 5,6,7,7a-tetrahydro-3aH-pyran [3,2-d] thiazole- 6-ol; (3aR, 5S, 6S, 7aR) -2- (methylamino) -5 - ((R) -2,2,2-trifluoro-1-hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [ 3,2-d] thiazole-6-01; (3aR, 5R, 6R, 7S, 7aR) -7-fluoro-5 - ((S) -1-hydroxyethyl) -2- (methylamino) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5R, 6R, 7S, 7aR) -2- (ethylamino) -7-fluoro-5- ((S) -1- hydroxyethyl) -5,6,7,7a-tetrahydro-3aH-pyran [3, 2-d] thiazole-6-ol; (3aR, 5S, 6R, 7S, 7aR) -7-fluoro-2- (methylamino) -5 - ((R) - 2 2 2-trifluoro-1_hydroxyethyl) -5,6,7,7a-tetrahydro-3aH- pyran [3,2-d] thiazol-6-ol; (3aR, 5S, 6R, 7S, 7aR) -2- (ethylamino) -7-fluoro-5 - ((R) -2,2,2-trifluoro-1-hydroxyethyl) -5, β, 7,7a- tetrahydro-3aH-pyran [3,2-d] thiazol-β-ol; Or a pharmaceutically acceptable salt thereof.
[0014]
Pharmaceutical composition, characterized in that it comprises a compound as defined in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.
[0015]
15. Method for screening a selective inhibitor of a 0-GlcNAcase characterized by the fact that it comprises: a) contacting a first sample with a test compound; b) contacting a second sample with a compound of Formula (I) wherein R1 and R2 are, independently, H or F; R3 represents OR5 and R4 is H, or R3 is H and R4 is OR5; each R5 is, independently, H or C1-6 acyl; R6 is H, F, or OR5; R 'is selected from the group consisting of: H, F, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, each excluding hydrogen and F, optionally substituted with from one to the maximum number of substituents with one or more of fluorine or OH; R8 is selected from the group consisting of: C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl and C3-cycloalkyl, optionally substituted with from one to the maximum number of substituents with one or more fluorine or OH ; R7 and / or R8 and the carbon atom to which they are attached can come together to form vinyl; and each R9 is independently selected from the group consisting of: H, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and C1-6 alkoxy, where C1-S alkyl, C3-6 alkenyl, C3 alkynyl -6 or C1-6 alkoxy is optionally substituted with from one to the maximum number of substituents with one or more of fluorine, OH, or methyl, or the two R9 groups are linked together with the nitrogen atom to which they are attached to form a ring, said ring optionally substituted, independently, with from one to the maximum number of substituents with one or more of fluorine, OH, or methyl; where when R6 is OR5, R7 is different from F; and c) determine the level of inhibition of O-GlcNAcase in the first and second samples, 31/32 where a test compound is a selective inhibitor of an O-GlcNAcase if the test compound exhibits the same or greater inhibition of O- GlcNAcase when compared to the compound of Formula (I). Petition 870200080872, of 06/29/2020, p. 42/42 (I) where R1 and R2 are, independently, H or F R3 represents OR5 * and R4 is H, or R3 is H and R4 is OR5; each R5 is, independently, H or acyl Ci-e; R is H, F or OR5; R7 is selected from the group consisting of: H, F, C1-8 alkyl, C2-8 alkenyl, Cz-s alkynyl, excluding H and F, (I) where R1 and R2 are, independently, H or F; R3 represents 0R5 and R4 is H, or R3 is H and R4 is 0R5; each R5 is, independently, H or acyl CI-G; R6 is H, F, or OR5;

类似技术:

---

公开号 | 公开日 | 专利标题

---

AU2012276257B2|2017-05-18|Selective glycosidase inhibitors and uses thereof

---

US9815861B2|2017-11-14|Selective glycosidase inhibitors and uses thereof

---

AU2016202186B2|2017-10-12|Selective glycosidase inhibitors and uses thereof

---

EP2935283B1|2019-02-27|Glycosidase inhibitors and uses thereof

---

AU2013337570B2|2018-01-18|Glycosidase inhibitors and uses thereof

---

WO2014032184A1|2014-03-06|Glycosidase inhibitors and uses thereof

---

WO2012062157A1|2012-05-18|Pyrano[3,2-d]thiazol derivatives and uses thereof as selective glycosidase inhibitors

---

WO2014032188A1|2014-03-06|Glycosidase inhibitors and uses thereof

---

EP2691407A1|2014-02-05|Selective glycosidase inhibitors and uses thereof

---

US8901087B2|2014-12-02|Selective glycosidase inhibitors and uses thereof

---

WO2012159262A1|2012-11-29|Selective glycosidase inhibitors and uses thereof

同族专利:

---

公开号 | 公开日

---

KR20140043125A|2014-04-08|

---

EP2723753A4|2014-11-26|

---

RU2625308C2|2017-07-13|

---

CA2840013A1|2013-01-03|

---

EP2723753A1|2014-04-30|

---

RU2014102232A|2015-08-10|

---

WO2013000084A1|2013-01-03|

---

US20140296205A1|2014-10-02|

---

JP2014524911A|2014-09-25|

---

EP2723753B1|2017-08-02|

---

BR112013033098A2|2016-09-06|

---

CA2840013C|2021-02-09|

---

CN103889996A|2014-06-25|

---

AU2012276257A1|2014-01-23|

---

BR112013033098B8|2021-03-23|

---

JP6147737B2|2017-06-14|

---

CN103889996B|2016-02-03|

---

US9409924B2|2016-08-09|

---

MX2014000258A|2014-09-01|

---

AU2012276257B2|2017-05-18|

---

MX364602B|2019-05-02|

---

KR102054744B1|2019-12-11|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

SU1441749A1|1987-03-16|1996-01-10|Институт Тонкой Органической Химии Им.А.Л.Мнджояна|2-amino-5,5-dimethyl-4,5-dihydro-7h-pyrano-[4, 3-d]-thiazole showing tranquilizing activity|

---

JPH01180894A|1988-01-07|1989-07-18|Wako Pure Chem Ind Ltd|Novel production of amino sugar derivative|

---

JPH07316178A|1994-05-25|1995-12-05|Sankyo Co Ltd|Glycoaminooxazolines|

---

JPH09132585A|1995-11-10|1997-05-20|Shin Etsu Chem Co Ltd|Production of new amino sugar, chitooligasccharide and its analogous oligosaccharide|

---

JP4233262B2|2001-03-14|2009-03-04|生化学工業株式会社|Carbasugar amine derivatives and glycosidase inhibitors using the same|

---

JP4866515B2|2001-07-02|2012-02-01|生化学工業株式会社|Method for producing sugar oxazoline derivative|

---

WO2006016904A2|2004-04-14|2006-02-16|Uab Research Foundation|Activators of hexosamine biosynthesis as inhibitors of injury induced by ischemia or hemorrhagic shock|

---

CA2599843C|2005-03-01|2013-08-27|Simon Fraser University|Selective glycosidase inhibitors, methods of making inhibitors, and uses thereof|

---

US8334310B2|2006-08-31|2012-12-18|Simon Fraser University|Selective glycosidase inhibitors and uses thereof|

---

CN101595111A|2006-08-31|2009-12-02|西蒙·弗雷瑟大学|Selective glycosidase inhibitors and uses thereof|

---

JP5687194B2|2008-08-01|2015-03-18|サイモン フレイザー ユニバーシティ|Selective glycosidase inhibitors and uses thereof|

---

JP2011529857A|2008-08-01|2011-12-15|サイモンフレイザーユニバーシティ|Selective glycosidase inhibitors and uses thereof|

---

WO2010037207A1|2008-09-16|2010-04-08|Simon Fraser University|Selective glycosidase inhibitors and uses thereof|

---

EP2569291B1|2010-05-11|2016-04-06|Simon Fraser University|Selective glycosidase inhibitors and uses thereof|

---

WO2012061972A1|2010-11-08|2012-05-18|Alectos Therapeutics Inc.|Selective glycosidase inhibitors and uses thereof|

---

WO2012061971A1|2010-11-08|2012-05-18|Alectos Therapeutics Inc.|Selective glycosidase inhibitors and uses thereof|

---

TW201249848A|2010-11-08|2012-12-16|Merck Sharp & Dohme|Selective glycosidase inhibitors and uses thereof|

---

WO2012061927A1|2010-11-08|2012-05-18|Alectos Therapeutics, Inc.|Selective glycosidase inhibitors and uses thereof|

---

RU2609210C2|2010-12-23|2017-01-31|Алектос Терапьютикс Инк.|Selective glycosidase inhibitors and use thereof|

---

GB201103526D0|2011-03-02|2011-04-13|Summit Corp Plc|Selective glycosidase inhibitors and uses thereof|

---

EP2688899B1|2011-03-24|2017-02-22|Alectos Therapeutics Inc.|Selective glycosidase inhibitors and uses thereof|

---

WO2012129802A1|2011-03-31|2012-10-04|Alectos Therapeutics Inc.|Pyrano[3,2-d]thiazol derivatives and uses as selective glycosidase inhibitors thereof|

---

EP2691407B1|2011-03-31|2017-02-22|Alectos Therapeutics Inc.|Selective glycosidase inhibitors and uses thereof|

---

WO2013000085A1|2011-06-27|2013-01-03|Alectos Therapeutics Inc.|Selective glycosidase inhibitors and uses thereof|

---

KR102054744B1|2011-06-27|2019-12-11|알렉토스 테라퓨틱스 인크.|Selective glycosidase inhibitors and uses thereof|

---

US9701693B2|2011-06-27|2017-07-11|Alectos Therapeutics Inc.|Selective glycosidase inhibitors and uses thereof|

---

US9126957B2|2011-08-18|2015-09-08|Merck Sharp & Dohme Corp.|Selective glycosidase inhibitors and uses thereof|

---

RS54773B1|2011-08-25|2016-10-31|Merck Patent Gmbh|Pyrano [3, 2 - d][1, 3]thiazole as glycosidase inhibitors|

---

RU2707292C2|2012-05-08|2019-11-26|Мерк Шарп И Доум Корп.|Permeable glycosidase inhibitors and use thereof|

---

US9522883B2|2012-08-31|2016-12-20|Alectos Therapeutics Inc.|Glycosidase inhibitors and uses thereof|

---

EP2890676B1|2012-08-31|2018-12-05|Alectos Therapeutics Inc.|Glycosidase inhibitors and uses thereof|

---

EP2890675A4|2012-08-31|2016-01-13|Alectos Therapeutics Inc|Glycosidase inhibitors and uses thereof|

---

EP2890679A4|2012-08-31|2016-05-04|Alectos Therapeutics Inc|Glycosidase inhibitors and uses thereof|

---

EP2914604A4|2012-10-31|2016-07-20|Alectos Therapeutics Inc|Glycosidase inhibitors and uses thereof|

---

WO2014100934A1|2012-12-24|2014-07-03|Merck Sharp & Dohme Corp.|Glycosidase inhibitors and uses thereof|US8334310B2|2006-08-31|2012-12-18|Simon Fraser University|Selective glycosidase inhibitors and uses thereof|

---

JP5687194B2|2008-08-01|2015-03-18|サイモン フレイザー ユニバーシティ|Selective glycosidase inhibitors and uses thereof|

---

EP2569291B1|2010-05-11|2016-04-06|Simon Fraser University|Selective glycosidase inhibitors and uses thereof|

---

WO2012061927A1|2010-11-08|2012-05-18|Alectos Therapeutics, Inc.|Selective glycosidase inhibitors and uses thereof|

---

RU2609210C2|2010-12-23|2017-01-31|Алектос Терапьютикс Инк.|Selective glycosidase inhibitors and use thereof|

---

EP2688899B1|2011-03-24|2017-02-22|Alectos Therapeutics Inc.|Selective glycosidase inhibitors and uses thereof|

---

EP2691407B1|2011-03-31|2017-02-22|Alectos Therapeutics Inc.|Selective glycosidase inhibitors and uses thereof|

---

WO2013000085A1|2011-06-27|2013-01-03|Alectos Therapeutics Inc.|Selective glycosidase inhibitors and uses thereof|

---

US9701693B2|2011-06-27|2017-07-11|Alectos Therapeutics Inc.|Selective glycosidase inhibitors and uses thereof|

---

KR102054744B1|2011-06-27|2019-12-11|알렉토스 테라퓨틱스 인크.|Selective glycosidase inhibitors and uses thereof|

---

EP2890676B1|2012-08-31|2018-12-05|Alectos Therapeutics Inc.|Glycosidase inhibitors and uses thereof|

---

EP2890675A4|2012-08-31|2016-01-13|Alectos Therapeutics Inc|Glycosidase inhibitors and uses thereof|

---

EP2914604A4|2012-10-31|2016-07-20|Alectos Therapeutics Inc|Glycosidase inhibitors and uses thereof|

---

WO2014100934A1|2012-12-24|2014-07-03|Merck Sharp & Dohme Corp.|Glycosidase inhibitors and uses thereof|

---

BR112015030946A8|2013-06-11|2020-01-28|Harvard College|composition comprising a non-native pancreatic ß cell, method of differentiating progenitor cells into pancreatic ß cells in vitro and use of a non-native pancreatic ß cell|

---

US9994589B2|2015-12-14|2018-06-12|Amicus Therapeutics, Inc.|Compounds and methods for the treatment of alzheimer's disease and/or cerebral amyloid angiopathy|

---

AU2019214048A1|2018-02-01|2020-06-25|Japan Tobacco Inc.|Nitrogenated heterocyclic amide compound, and use thereof for medical purposes|

---

GB201907716D0|2019-05-31|2019-07-17|Smith & Nephew|Systems and methods for extending operational time of negative pressure wound treatment apparatuses|

---

GB202000274D0|2020-01-09|2020-02-26|Smith & Nephew|Systems and methods for monitoring operational lifetime of negative pressure wound treatment apparatuses|

---

GB202104922D0|2021-04-07|2021-05-19|Smith & Nephew|Temperature monitoring and control for negative pressure wound therapy systems|

---

GB202109154D0|2021-06-25|2021-08-11|Smith & Nephew|Liquid ingress protection for negative pressure wound therapy systems|

---

GB202110240D0|2021-07-16|2021-09-01|Smith & Nephew|Reduced pressure apparatuses and methods|

法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law|

---

2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|

---

2019-07-16| B07E| Notice of approval relating to section 229 industrial property law|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

---

2019-10-29| B06U| Preliminary requirement: requests with searches performed by other patent offices: suspension of the patent application procedure|

---

2020-03-10| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application according art. 36 industrial patent law|

---

2020-07-07| B09A| Decision: intention to grant|

---

2020-10-20| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 27/06/2012, OBSERVADAS AS CONDICOES LEGAIS. |

---

2021-03-09| B09W| Decision of grant: rectification|Free format text: REFERENCIA: RPI 2583 DE 07.07.2020 - CODIGO 9.1 |

---

2021-03-23| B16C| Correction of notification of the grant|Free format text: REF. RPI 2598 DE 20/10/2020 QUANTO AS REIVINDICACOES. |

优先权:

---

申请号 | 申请日 | 专利标题

---

US201161501377P| true| 2011-06-27|2011-06-27|

---

US61/501,377|2011-06-27|

---

PCT/CA2012/050433|WO2013000084A1|2011-06-27|2012-06-27|Selective glycosidase inhibitors and uses thereof|

---