Non-lysosomal glucosylceramidase inhibitors and uses thereof

Abstract

This invention discloses a compound for inhibiting glucocerebrosidase, a prodrug of the compound, and a pharmaceutical composition comprising the compound or the prodrug of the compound.

Description

Technical Field

[0001] This application relates to compounds that partially inhibit glucocerebrosidase and their uses. Background Technology

[0002] Glucoceramidinases are a group of enzymes that catalyze the hydrolysis and cleavage of the β-glycosidic bond of the glycosphingolipid glucocerebroside (GlcCer, also known as glucocerebroside) to produce D-glucose and ceramide. In humans, there are three distinct enzymes with glucocerebroside activity: lysosomal β-glucocerebroside lipase (GCase or GBA1, EC 3.2.1.45), non-lysosomal glucoceramidinase (GBA2, EC 3.2.1.45), and cytoplasmic β-glucosidase (GBA3, EC 3.2.1.21). GCase is a lysosomal enzyme encoded by the gene GBA; homozygous deletion of GBA leads to functional mutations resulting in Gaucher disease, a lysosomal storage disorder characterized by the pathological accumulation of glucocerebroside in lysosomes. 1 GBA2 is a membrane-associated protein located on the cytoplasmic side of the endoplasmic reticulum (ER) and Golgi apparatus membranes, and is also involved in the central nervous system (CNS). 2,3 GBA3 is expressed at moderate to high levels. It is a cytosolase primarily expressed in the liver. 3,4 .

[0003] Glucoceramidinase plays an important role in regulating the cellular levels of its substrate molecule glucosylceramide, a broad class of simple members of cell membrane lipids and biosynthetic precursors, namely glycosphingolipids (GSLs). 3,5 Disorders of GSL metabolism and homeostasis are associated with a range of diseases, including the neurological disorder Alzheimer's disease (AD). 6 Parkinson's disease (PD) 7 Multiple sclerosis (MS) 8 Huntington's disease (HD) 9 And amyotrophic lateral sclerosis (ALS) 10 Niemann-Pick disease type C (NPC), a lysosomal storage disease. 11 Type IV mucolipid storage disease (MLIV) 12 and Sandhoff disease 13 ; and non-alcoholic fatty liver disease (NAFLD). 14 Nonalcoholic steatohepatitis (NASH) 14 Small molecule GBA2 inhibitors have been shown to prolong lifespan and improve motor coordination in NPC rodent models. 15,16 Similarly, there is evidence that GBA2 inhibition in MLIV... 12 and Sandhoff disease 13In rodent models, it can extend lifespan and delay motor deficits. In mouse models of synucleinopathy, small molecule GBA2 inhibitors have been shown to reduce the accumulation of α-synuclein aggregates in the brain. 13 Decreased GBA2 activity has also been shown to rescue the clinical phenotype of Gaucher disease in rodent models. 17 Furthermore, research indicates that GBA2 is involved in regulating inflammatory responses. 2 Furthermore, the reduction in GBA2 activity decreased inflammation in the cystic fibrosis (CF) cell model. 18 Increased levels of glucosylceramide have also been shown to be effective in rodent models of liver disease, including nonalcoholic steatohepatitis (NASH). 19 ,hepatitis 20 Hepatocellular carcinoma (HCC) 21 Autoimmune cholangitis 22 Drug-induced liver injury (DILI) 23 .

[0004] The enzymatic activity of GBA2 can be pharmacologically blocked by iminosaccharide N-butyldeoxynojirimycin (NB-DNJ, miglusta) and N-(5-adamantane-1-yl-methoxy)pentyldeoxynojirimycin (AMP-DNM, Genz-529648); however, these compounds are not selective for GBA2 because they also exhibit inhibitory activity against other enzymes, including GCase, glucocerebroside synthase (GCS, EC2.4.1.80), and intestinal α-glucosidase. 24 .

[0005] International patent applications PCT / GB 2003 / 003099, filed on July 17, 2003, and published on January 22, 2004 as WO2004 / 007453; PCT / GB 2004 / 002450, filed on June 9, 2004, and published on December 23, 2004 as WO 2004 / 111001; PCT / GB 2004 / 002451, filed on June 9, 2004, and published on December 23, 2004 as WO 2004 / 111002; and PCT / GB 2005 / 000071, filed on January 11, 2005, and published on July 28, 2005 as WO Publication No. 2005 / 068426; PCT / NL2015 / 050188, filed on March 23, 2015, and published as WO 2015 / 147639 on October 1, 2015, involving small molecule inhibitors of GBA2. Summary of the Invention

[0006] This invention provides, in part, compounds for inhibiting nonlysosomal glucoceramitinase (GBA2), prodrugs of said compounds, uses of said compounds and prodrugs, pharmaceutical compositions comprising said compounds or prodrugs of said compounds, and methods for treating diseases and disorders regulated by GBA2 activity levels and / or glucoceramitin levels and / or glycosphingolipid metabolism or homeostasis. In some embodiments, this invention provides compositions and methods for preventing and / or treating neurological diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis (ALS), or lysosomal storage diseases, including Gaucher disease, Niemann-Pick disease type C, mucolipidemia type IV, and Sandhof disease, or liver diseases, including nonalcoholic steatohepatitis (NASH).

[0007] In one aspect, the present invention provides formula (I) or a pharmaceutically acceptable salt thereof:

[0008]

[0009] Where R 1 It can be H and R 2 It can be CH3, CH2F, or CHF2; or R 1 It can be CH3 or CH2F and R 2 It can be H; and

[0010] R 3 It could be (CH2) n R 4 Where n can be 1 or 2, and R 4 It can be cyclohexyl, cyclohexylmethyl, phenylethyl, 4-phenylcyclohexyl, spiro[2.5]oct-6-yl, spiro[3.5]non-7-yl, spiro[4.5]dec-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]dec-8-yl, 1,2,3,4-tetrahydronaphth-2-yl, 2,3-dihydro-1H-inden-2-yl, (adamantyl)methyl, (pyridin-2-yl)methyl, (benzo[d][1,3]m-dioxacyclopenten-5-yl)methyl, (2,3-dihydrophenyl) [b][1,4]dioxin-6-yl)methyl, ([1,1'-biphenyl]-4-yl)methyl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, 1-(pyridin-3-yl)piperidin-4-yl, 1-(cyclohexylcarbamoyl)piperidin-4-yl, 1-(cyclohexylthiocarbamoyl)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazacyclobutan-3-yl, 2-(thiophene-2-yl)methyl, or 2-(thiophene-3-yl)methyl, each optionally dimethylated by F, Cl, C1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropyl-2-yl, methoxymethyl, C 1-6 One or more of the alkoxy group and / or CF3 group replace one to a maximum number of substituents; or

[0011] R 3 It can be phenylethyl, optionally coated with pyrrolidone-1-yl, piperidin-1-yl, 4-morpholino, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, F, Cl, C 1-6 One or more of alkyl, cyclopropyl, propen-2-yl, OCH3 and / or CF3 replace one to a maximum number of substituents; or

[0012] R 3 It can be (1-formylpiperidin-4-yl)methyl, with the formyl group substituted by one of the following groups: C 1-6 Alkyl, C 3-7 Cycloalkyl, phenyl, thiophene-3-yl, phenylmethyl or cyclopentylmethyl, each optionally marked with F, C 1-6 One or more of alkyl, OCH3 and / or CF3 replace one to a maximum number of substituents; or

[0013] R 3 It can be Where R 5 The following can be selected from: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophene-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, phenylcarbonyl, thiazol-2-yl, benzo[d]oxazol-2-yl, and benzo[d]thiazol-2-yl, each optionally converted by F, Cl, C 1-6 Alkyl, C 1-6 One or more of alkoxy, OCF3 and / or CF3 replace one to a maximum number of substituents.

[0014] In an alternative embodiment, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt thereof:

[0015]

[0016] Where R 2 It can be CH3, CH2F, or CHF2; and

[0017] R 3 It could be (CH2) n R4 Where n can be 1 or 2, and R 4 It can be cyclohexyl, cyclohexylmethyl, phenylethyl, 4-phenylcyclohexyl, spiro[2.5]oct-6-yl, spiro[3.5]non-7-yl, spiro[4.5]dec-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]dec-8-yl, 1,2,3,4-tetrahydronaphth-2-yl, 2,3-dihydro-1H-inden-2-yl, (adamantyl)methyl, (pyridin-2-yl)methyl, (benzo[d][1,3]m-dioxacyclopenten-5-yl)methyl, (2,3-dihydrophenyl) [b][1,4]dioxin-6-yl)methyl, ([1,1'-biphenyl]-4-yl)methyl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, 1-(pyridin-3-yl)piperidin-4-yl, 1-(cyclohexylcarbamoyl)piperidin-4-yl, 1-(cyclohexylthiocarbamoyl)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazacyclobutan-3-yl, 2-(thiophene-2-yl)methyl, or 2-(thiophene-3-yl)methyl, each optionally dimethylated by F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropyl-2-yl, methoxymethyl, C 1-6 One or more of the alkoxy group and / or CF3 group replace one to a maximum number of substituents; or

[0018] R 3 It can be phenylethyl, optionally coated with pyrrolidone-1-yl, piperidin-1-yl, 4-morpholino, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, F, Cl, C 1-6 One or more of alkyl, cyclopropyl, propen-2-yl, OCH3 and / or CF3 replace one to a maximum number of substituents; or

[0019] R 3 It can be (1-formylpiperidin-4-yl)methyl, with the formyl group substituted by one of the following groups: C 1-6 Alkyl, C 3-7 cycloalkyl, phenyl, thiophene-3-yl, phenylmethyl or cyclopentylmethyl, each optionally marked with F, C 1-6 One or more of alkyl, OCH3 and / or CF3 replace one to a maximum number of substituents; or

[0020] R 3 It can be Where R 5The group may be selected from the following groups, including: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophene-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, phenylcarbonyl, thiazol-2-yl, benzo[d]oxazol-2-yl, and benzo[d]thiazol-2-yl, each optionally marked with F, Cl, or C. 1-6 Alkyl, C 1-6 One or more of alkoxy, OCF3 and / or CF3 replace one to a maximum number of substituents.

[0021] In an alternative embodiment, the present invention provides a compound of formula (Ib) or a pharmaceutically acceptable salt thereof:

[0022]

[0023] Where R 1 It can be CH3 or CH2F; and

[0024] R 3 It could be (CH2) n R 4 Where n can be 1 or 2, and R 4 It can be cyclohexyl, cyclohexylmethyl, phenylethyl, 4-phenylcyclohexyl, spiro[2.5]oct-6-yl, spiro[3.5]non-7-yl, spiro[4.5]dec-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]dec-8-yl, 1,2,3,4-tetrahydronaphth-2-yl, 2,3-dihydro-1H-inden-2-yl, (adamantyl)methyl, (pyridin-2-yl)methyl, (benzo[d][1,3]m-dioxacyclopenten-5-yl)methyl, (2,3-dihydrophenyl) [b][1,4]dioxin-6-yl)methyl, ([1,1'-biphenyl]-4-yl)methyl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, 1-(pyridin-3-yl)piperidin-4-yl, 1-(cyclohexylcarbamoyl)piperidin-4-yl, 1-(cyclohexylthiocarbamoyl)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazacyclobutan-3-yl, 2-(thiophene-2-yl)methyl, or 2-(thiophene-3-yl)methyl, each optionally dimethylated by F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropyl-2-yl, methoxymethyl, C 1-6 One or more of the alkoxy group and / or CF3 group replace one to a maximum number of substituents; or

[0025] R 3It can be phenylethyl, optionally coated with pyrrolidone-1-yl, piperidin-1-yl, 4-morpholino, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, F, Cl, C 1-6 One or more of alkyl, cyclopropyl, propen-2-yl, OCH3 and / or CF3 replace one to a maximum number of substituents; or

[0026] R 3 It can be (1-formylpiperidin-4-yl)methyl, with the formyl group substituted by one of the following groups: C 1-6 Alkyl, C 3-7 Cycloalkyl, phenyl, thiophene-3-yl, phenylmethyl or cyclopentylmethyl, each optionally marked with F, C 1-6 One or more of alkyl, OCH3 and / or CF3 replace one to a maximum number of substituents; or

[0027] R 3 It can be Where R 5 The following can be selected from: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophene-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, phenylcarbonyl, thiazol-2-yl, benzo[d]oxazol-2-yl, and benzo[d]thiazol-2-yl, each optionally converted by F, Cl, C 1-6 Alkyl, C 1-6 One or more of alkoxy, OCF3 and / or CF3 replace one to a maximum number of substituents.

[0028] In an alternative embodiment, the present invention provides a compound of formula (Ic) or a pharmaceutically acceptable salt thereof:

[0029]

[0030] Where R 3 It could be (CH2) n R 4 Where n can be 1 or 2, and R 4It can be cyclohexyl, cyclohexylmethyl, phenylethyl, 4-phenylcyclohexyl, spiro[2.5]oct-6-yl, spiro[3.5]non-7-yl, spiro[4.5]dec-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]dec-8-yl, 1,2,3,4-tetrahydronaphth-2-yl, 2,3-dihydro-1H-inden-2-yl, (adamantyl)methyl, (pyridin-2-yl)methyl, (benzo[d][1,3]m-dioxacyclopenten-5-yl)methyl, (2,3-dihydrophenyl) [b][1,4]dioxin-6-yl)methyl, ([1,1'-biphenyl]-4-yl)methyl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, 1-(pyridin-3-yl)piperidin-4-yl, 1-(cyclohexylcarbamoyl)piperidin-4-yl, 1-(cyclohexylthiocarbamoyl)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazacyclobutan-3-yl, 2-(thiophene-2-yl)methyl, or 2-(thiophene-3-yl)methyl, each optionally dimethylated by F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropyl-2-yl, methoxymethyl, C 1-6 One or more of the alkoxy group and / or CF3 group replace one to a maximum number of substituents; or

[0031] R 3 It can be phenylethyl, optionally coated with pyrrolidone-1-yl, piperidin-1-yl, 4-morpholino, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, F, Cl, C 1-6 One or more of alkyl, cyclopropyl, propen-2-yl, OCH3 and / or CF3 replace one to a maximum number of substituents; or

[0032] R 3 It can be (1-formylpiperidin-4-yl)methyl, with the formyl group substituted by one of the following groups: C 1-6 Alkyl, C 3-7 cycloalkyl, phenyl, thiophene-3-yl, phenylmethyl or cyclopentylmethyl, each optionally marked with F, C 1-6 One or more of alkyl, OCH3 and / or CF3 replace one to a maximum number of substituents; or

[0033] R 3 It can be Where R 5The following can be selected from: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophene-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, phenylcarbonyl, thiazol-2-yl, benzo[d]oxazol-2-yl, and benzo[d]thiazol-2-yl, each optionally converted by F, Cl, C 1-6 Alkyl, C 1-6 One or more of alkoxy, OCF3 and / or CF3 replace one to a maximum number of substituents.

[0034] In an alternative embodiment, the present invention provides a compound of formula (Id) or a pharmaceutically acceptable salt thereof:

[0035]

[0036] Where R 3 It could be (CH2) n R 4 Where n can be 1 or 2, and R 4 It can be cyclohexyl, cyclohexylmethyl, phenylethyl, 4-phenylcyclohexyl, spiro[2.5]oct-6-yl, spiro[3.5]non-7-yl, spiro[4.5]dec-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]dec-8-yl, 1,2,3,4-tetrahydronaphth-2-yl, 2,3-dihydro-1H-inden-2-yl, (adamantyl)methyl, (pyridin-2-yl)methyl, (benzo[d][1,3]m-dioxacyclopenten-5-yl)methyl, (2,3-dihydrophenyl) [b][1,4]dioxin-6-yl)methyl, ([1,1'-biphenyl]-4-yl)methyl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, 1-(pyridin-3-yl)piperidin-4-yl, 1-(cyclohexylcarbamoyl)piperidin-4-yl, 1-(cyclohexylthiocarbamoyl)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazacyclobutan-3-yl, 2-(thiophene-2-yl)methyl, or 2-(thiophene-3-yl)methyl, each optionally dimethylated by F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropyl-2-yl, methoxymethyl, C 1-6 One or more of the alkoxy group and / or CF3 group replace one to a maximum number of substituents; or

[0037] R 3It can be phenylethyl, optionally coated with pyrrolidone-1-yl, piperidin-1-yl, 4-morpholino, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, F, Cl, C 1-6 One or more of alkyl, cyclopropyl, propen-2-yl, OCH3 and / or CF3 replace one to a maximum number of substituents; or

[0038] R 3 It can be (1-formylpiperidin-4-yl)methyl, with the formyl group substituted by one of the following groups: C 1-6 Alkyl, C 3-7 Cycloalkyl, phenyl, thiophene-3-yl, phenylmethyl or cyclopentylmethyl, each optionally marked with F, C 1-6 One or more of alkyl, OCH3 and / or CF3 replace one to a maximum number of substituents; or

[0039] R 3 It can be Where R 5 The following can be selected from: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophene-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, phenylcarbonyl, thiazol-2-yl, benzo[d]oxazol-2-yl, and benzo[d]thiazol-2-yl, each optionally converted by F, Cl, C 1-6 Alkyl, C 1-6 One or more of alkoxy, OCF3 and / or CF3 replace one to a maximum number of substituents.

[0040] In an alternative embodiment, the present invention provides a compound of formula (Ie) or a pharmaceutically acceptable salt thereof:

[0041]

[0042] Where R 6 and R 7 It can be independently selected from: H, F, Cl, C 1-6 Alkyl, OCH3, phenyl, cyclopropyl, vinyl, methoxymethyl, 2-fluoropropyl-2-yl, and / or CF3. In some embodiments, R 6 It can be H, and R 7 It can be CF3, 2-fluoropropyl-2-yl, isopropyl, or tert-butyl. In some embodiments, R 6 It can be CF3, 2-fluoroprop-2-yl, isopropyl, or tert-butyl, and R7 It can be H.

[0043] In an alternative embodiment, the present invention provides a compound of formula (If) or a pharmaceutically acceptable salt thereof:

[0044]

[0045] Where R 6 and R 7 It can be independently selected from the following groups, including: H, F, Cl, C. 1-6 Alkyl, OCH3, phenyl, cyclopropyl, vinyl, methoxymethyl, 2-fluoropropyl-2-yl and / or CF3.

[0046] In an alternative embodiment, the present invention provides a compound of formula (Ig) or a pharmaceutically acceptable salt thereof:

[0047]

[0048] Where R 8 R 9 and R 10 It can be independently selected from the following groups, including: pyrrolidone-1-yl, piperidin-1-yl, 4-morpholino, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, H, F, Cl, C 1-6 Alkyl, cyclopropyl, propen-2-yl, OCH3, and / or CF3. In some embodiments, R 8 R 9 and R 10 It can be independently selected from: H, F, Cl, tetrahydro-2H-pyran-4-yl, 4-morpholino, pyrrolidine-1-yl and piperidin-1-yl.

[0049] In an alternative embodiment, the present invention provides a compound of formula (Ih) or a pharmaceutically acceptable salt thereof:

[0050]

[0051]

[0052] Where R 8 R 9 and R 10 It can be independently selected from: H, F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropyl-2-yl, methoxymethyl, C 1-6Alkyl groups and / or CF3.

[0053] In an alternative embodiment, the present invention provides a compound of formula (Ii) or a pharmaceutically acceptable salt thereof:

[0054]

[0055] Where R 8 R 9 and R 10 It can be independently selected from the following groups, including: H, F, Cl, C. 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropyl-2-yl, methoxymethyl, C 1-6 Alkyl groups and / or CF3. In some embodiments, R 8 R 9 and R 10 It can be independently selected from the following groups, including H, F and CF3.

[0056] In an alternative embodiment, the present invention provides a compound of formula (Ij) or a pharmaceutically acceptable salt thereof:

[0057]

[0058] Where R 11 It can be selected from the following groups, including: C 1-6 Alkyl, C 3-7 cycloalkyl, phenyl, thiophene-3-yl, phenylmethyl or cyclopentylmethyl, each optionally marked with F, C 1-6 One or more of alkyl, OCH3 and / or CF3 replace one to a maximum number of substituents.

[0059] In an alternative embodiment, the present invention provides a compound of formula (Ik) or a pharmaceutically acceptable salt thereof:

[0060]

[0061] Where R 12 The derivative may be phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophene-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, or phenyl carbonyl, each optionally converted by F, Cl, C 1-6 Alkyl, C 1-6 One or more of alkoxy, OCF3, and / or CF3 replace one to a maximum number of substituents. In some embodiments, R 12It may be selected from the following groups, including: 2-(trifluoromethyl)phenyl, 2-(trifluoromethyl)pyridin-3-yl, 3-(trifluoromethyl)pyridin-2-yl, 4-(trifluoromethyl)pyridin-2-yl, 5-(trifluoromethyl)pyridin-3-yl, 6-(trifluoromethyl)pyridin-2-yl, 4-(trifluoromethyl)pyrimidin-5-yl and 4-(trifluoromethyl)thiazolyl-2-yl.

[0062] In an alternative embodiment, the present invention provides a compound of formula (Il) or a pharmaceutically acceptable salt thereof:

[0063]

[0064] Where R 12 The group may be selected from the following groups, including: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophene-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, or phenyl carbonyl, each optionally marked with F, Cl, or C. 1-6 Alkyl, C 1-6 One or more of alkoxy, OCF3, and / or CF3 replace one to a maximum number of substituents. In some embodiments, R 12 It can be selected from: 2-(trifluoromethyl)phenyl, 2-(trifluoromethyl)pyridin-3-yl, 3-(trifluoromethyl)pyridin-2-yl, 4-(trifluoromethyl)pyridin-2-yl, 5-(trifluoromethyl)pyridin-3-yl, 6-(trifluoromethyl)pyridin-2-yl, 4-(trifluoromethyl)pyrimidin-5-yl and 4-(trifluoromethyl)thiazolyl-2-yl.

[0065] In alternative embodiments, the present invention provides a compound of formula (Im) or a pharmaceutically acceptable salt thereof:

[0066]

[0067] Where R 12 The group may be selected from the following groups, including: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophene-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, or phenyl carbonyl, each optionally marked with F, Cl, or C. 1-6 Alkyl, C 1-6 One or more of alkoxy, OCF3, and / or CF3 replace one to a maximum number of substituents. In some embodiments, R 12 It may be selected from the following groups, including: 2-(trifluoromethyl)phenyl, 2-(trifluoromethyl)pyridin-3-yl, 3-(trifluoromethyl)pyridin-2-yl, 4-(trifluoromethyl)pyridin-2-yl, 5-(trifluoromethyl)pyridin-3-yl, 6-(trifluoromethyl)pyridin-2-yl, 4-(trifluoromethyl)pyrimidin-5-yl and 4-(trifluoromethyl)thiazolyl-2-yl.

[0068] In alternative embodiments, the present invention provides compounds of formula (In) or pharmaceutically acceptable salts thereof:

[0069]

[0070] Where R 12 The group may be selected from the following groups, including: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophene-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, or phenyl carbonyl, each optionally marked with F, Cl, or C. 1-6 Alkyl, C 1-6 One or more of alkoxy, OCF3, and / or CF3 replace one to a maximum number of substituents. In some embodiments, R 12 It may be selected from the following groups, including: 2-(trifluoromethyl)phenyl, 2-(trifluoromethyl)pyridin-3-yl, 3-(trifluoromethyl)pyridin-2-yl, 4-(trifluoromethyl)pyridin-2-yl, 5-(trifluoromethyl)pyridin-3-yl, 6-(trifluoromethyl)pyridin-2-yl, 4-(trifluoromethyl)pyrimidin-5-yl and 4-(trifluoromethyl)thiazolyl-2-yl.

[0071] In alternative embodiments, the compound may be a prodrug; the compound may inhibit non-lysosomal glucosinolate ceramidinase (GBA2); the compound may inhibit GBA2 (e.g., mammalian GBA2); the compound may inhibit wild-type GBA2; or the compound may inhibit mutant GBA2.

[0072] In alternative embodiments, compounds according to formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ii), formula (Ij), formula (Ik), formula (Il), formula (Im), or formula (In) may exhibit enhanced selectivity and / or permeability.

[0073] In alternative embodiments, compounds according to formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ii), formula (Ij), formula (Ik), formula (Il), formula (Im), or formula (In) may exhibit enhanced selectivity and / or permeability.

[0074] In alternative embodiments, compounds according to formula (Ie), formula (Ig), formula (Ik), formula (Il), formula (Im) or formula (In) may exhibit enhanced selectivity and / or permeability.

[0075] In alternative embodiments, compounds according to formula (Ic), formula (Ie), formula (Ig), formula (Ik), formula (Il), formula (Im), or formula (In) may exhibit enhanced selectivity. In alternative embodiments, compounds according to formula (Ie) may exhibit enhanced selectivity. In alternative embodiments, compounds according to formula (Ig) may exhibit enhanced selectivity. In alternative embodiments, compounds according to formula (Ik) or formula (Il) may exhibit enhanced selectivity. In alternative embodiments, compounds according to formula (Im) or formula (In) may exhibit enhanced selectivity.

[0076] In alternative embodiments, compounds according to formulas (Ic), (Ie), (Ig), (Ii), (Ik), (Il), (Im), or (In) can achieve higher brain concentrations when administered in vivo. In alternative embodiments, compounds according to formula (Ie) can achieve higher brain concentrations when administered in vivo. In alternative embodiments, compounds according to formula (Ig) can achieve higher brain concentrations when administered in vivo. In alternative embodiments, compounds according to formula (Ii) can achieve higher brain concentrations when administered in vivo. In alternative embodiments, compounds according to formula (Ik) or (Il) can achieve higher brain concentrations when administered in vivo. In alternative embodiments, compounds according to formula (Im) or (In) can achieve higher brain concentrations when administered in vivo.

[0077] In alternative embodiments, the present invention provides pharmaceutical compositions comprising the compounds described herein or pharmaceutically acceptable salts thereof, combined with a pharmaceutically acceptable carrier.

[0078] In alternative embodiments, the present invention provides a method for inhibiting GBA2 in a subject in need, or for treating a neurological disorder, lysosomal storage disease, or liver disease in a subject in need, said method by administering to the subject an effective amount of a compound of formula (I) as described in the present invention, including any one or more of formulas (Ia)-(In), or a pharmaceutically acceptable salt thereof.Neurological disorders can include, but are not limited to, Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), addiction, anxiety, arrhythmia-telangiectasia (AT), attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), Becker muscular dystrophy (BMD), bipolar disorder (BD), Blue's disease, cerebellar ataxia, peroneal muscular dystrophy (CMT), chronic fatigue syndrome, corticobasal degeneration (CBD), boxer's dementia, Lewy body dementia (DLB), and Degerin' syndrome. Sotas syndrome, diffuse neurofibrillary tangles with calcification, Down syndrome, Duchenne muscular dystrophy (DMD), epilepsy, essential tremor (ET), familial British dementia, familial Danish dementia, fibromuscular atrophy, Parkinson's syndrome associated with chromosome 17 (FTDP-17), Friedreich ataxia, Gerstmann-Strauss disease, glaucoma, Guardio Parkinson's syndrome, Guillain-Barré syndrome, Hallevorden-Spatz disease (neurodegeneration with brain iron accumulation type 1), insomnia, Lambert-Eton myasthenic syndrome (LEMS), major depressive disorder (MDD), migraine, mild cognitive impairment Cognitive impairment (MCI), multiple infarct dementia, multiple system atrophy (MSA), myasthenia gravis, myotonic dystrophy (including DM1 and DM2 types), neuronal ceroid lipofuscin deposition disease (including types 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10), neuropathy (including peripheral neuropathy, autonomic neuropathy, neuritis, neurotrophic disorders), oculopharyngeal muscular dystrophy, pain, globus pallidus-pontine substantia nigra degeneration, Guam Parkinson's syndrome-dementia syndrome, Pick's disease (PiD), post-encephalitis Parkinson's syndrome (PEP), primary lateral sclerosis (PLS), prions (including Creutzfeldt-Jakob disease (CJD), variants) Creutzfeldt-Jakob disease (vCJD), fatal familial insomnia and kuru, progressive cortical gliosis, progressive supranuclear palsy (PSP), Richardson syndrome, schizophrenia, seizures, spinal cord injury, spinal muscular atrophy (SMA), spinocerebellar ataxia (including types 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 28 and 29), stroke, subacute sclerosing panencephalitis, tangled dementia, tardive dyskinesia, Tourette syndrome (TS), vascular dementia or Wilson's disease.

[0079] Lysosomal storage diseases can be, but are not limited to, Gaucher disease (including types I, II, and III), Niemann-Pick disease (including types A, B, and C), mucolipid storage diseases (including types I, II, III, IV, VI, and VII), tendon xanthomas, Fabry disease, Fabry disease, GM1 ganglioside storage disease, Krab disease, metachromatic leukodystrophy (MLD), polysulfatase deficiency, Pompe disease, Sandhof disease, or Tessachs disease.

[0080] Liver diseases can include non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), Alagille syndrome, alcohol-related liver disease, alpha-1 antitrypsin deficiency, autoimmune hepatitis, autoimmune cholangitis, benign liver tumors, biliary atresia, cirrhosis, Crigler-Najjar syndrome, drug-induced liver injury (DILI), galactosemia, Gilbert syndrome, hemochromatosis, hepatic encephalopathy, hepatocellular carcinoma (HCC), intrahepatic cholestasis of pregnancy (ICP), lysosomal acid lipase deficiency (LAL-D), liver cysts, liver cancer, neonatal jaundice, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), Reye's syndrome, type I glycogen storage disease, or viral hepatitis (including types A, B, C, D, and E).

[0081] In alternative embodiments, the present invention provides a method for treating a neurological disease in a subject in need, namely, administering to the subject an effective amount of any one or more of the compounds of formula (Ic), (Ie), (Ig), (Ii), (Ik), (Il), (Im), or (In) described in the present invention, or a pharmaceutically acceptable salt thereof. In alternative embodiments, the present invention provides a method for treating a subject's neurological disease by administering to a subject in need an effective amount of a compound of formula (Ie) described in the present invention or a pharmaceutically acceptable salt thereof. In alternative embodiments, the present invention provides a method for treating a subject's neurological disease by administering to a subject in need an effective amount of a compound of formula (Ig) described in the present invention or a pharmaceutically acceptable salt thereof. In alternative embodiments, the present invention provides a method for treating a subject's neurological disease by administering to a subject an effective amount of a compound of formula (Ik) described in the present invention or a pharmaceutically acceptable salt thereof. In alternative embodiments, the present invention provides a method for treating a subject's neurological disease by administering to a subject in need an effective amount of a compound of formula (Il) described in the present invention or a pharmaceutically acceptable salt thereof. In an alternative embodiment, the present invention provides a method for treating a neurological disease in a subject by administering to a subject in need an effective amount of a compound of formula (Im) as described in the present invention or a pharmaceutically acceptable salt thereof. In an alternative embodiment, the present invention provides a method for treating a subject in need by administering to a subject in need an effective amount of a compound of formula (In) as described in the present invention or a pharmaceutically acceptable salt thereof.

[0082] In alternative embodiments, administration may reduce the enzyme activity level of GBA2 in the subject. In alternative embodiments, administration may modulate the levels of glucosylceramide and / or glycosphingolipids in the subject. In alternative embodiments, administration may increase the level of glucosylceramide in the subject. In alternative embodiments, administration may increase the level of ganglioside GM1 in the subject. In alternative embodiments, administration may modulate the levels of ceramide and / or glucosylsphingosine and / or sphingosine-1-phosphate (S1P) in the subject. The subject may be a human.

[0083] In an alternative aspect, the present invention provides the use of an effective amount of a compound of formula (I) of the present invention, including any one or more of formulas (Ia)-(In), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament. The medicament may be used to inhibit GBA2, to treat conditions regulated by GBA2, or to treat neurological disorders, lysosomal storage diseases, or liver diseases.

[0084] The content of this invention may not necessarily describe all the features of this invention. Detailed Implementation

[0085] This invention partially provides compounds that inhibit non-lysosomal glucosinolate ceramitaase (GBA2) and their uses.

[0086] "Non-lysosomal glucoceramitinase" or "GBA2" refers to a non-lysosomal membrane-associated enzyme (EC 3.2.1.45) located on the cytoplasmic side of the ER and Golgi apparatus membranes, possessing glucoceramitin activity, which catalyzes the hydrolytic cleavage of the β-glycosidic bond in glycolipid glucoceramitin. Alternative names for GBA2 include: NLGase, glucoceramitinase β2, β-glucocerebrosidase 2, β-glucosidase 2, glucoceramitinase 2, bile acid β-glucosidase, "glucosidase, β(bile acid)2", KIAA1605, DKFZp762K054, SPG46, and AD035. In some embodiments, GBA2 may be mammalian GBA2, such as rat, mouse, or human GBA2. GBA2 may be wild-type GBA2 or mutant GBA2. In some embodiments, GBA2 may be wild-type mammalian GBA2, such as rat, mouse, or human wild-type GBA2. In some embodiments, GBA2 may be a mutant mammalian GBA2, such as a rat, mouse, or human mutant GBA2. In some embodiments, GBA2 may have a sequence as shown in any of the following accession numbers: Q9HCG7, Q69ZF3, D3DRP2, Q5TCV6, Q96A51, Q96LY1, Q96SJ2, Q9H2L8, Q5M868, or O16581. In alternative embodiments, GBA2 may have an alternative splice isoform sequence as shown in any of the following accession numbers: Q9HCG7-1, Q9HCG7-2, Q9HCG7-3. In alternative implementations, GBA2 may be encoded by a sequence shown in any of the following accession numbers: NP_065995.1, NP_001317589.1, NP_766280.2, NP_001013109.2, NM_020944, NM_172692, NM_001330660, XM_011517973, XP_005251583.1, XP_006716 872.1, XP_011516275.1, XP_016870426.1, XP_016870427.1, XP_016870428.1, XP_016870429.1, XP_016870430.1, XP_016870431.1, XP_016870432.1, XP_016870433.1, XP_016870434.1, or XP_016870435.1. In an alternative implementation, human GBA2 may have the following sequence:

[0087]

[0088]

[0089] In an alternative embodiment, human GBA2 may have a nucleic acid sequence encoding a nucleic acid molecule shown in SEQ ID NO: 1.

[0090] In some embodiments, one or more compounds of the present invention can inhibit the activity of GBA2, for example, by inhibiting its ability to cleave glucose from glucosamine or from a suitable substrate molecule such as 4-methylumbelliferone-β-D-glucopyranoside. “Inhibit,” “inhibition,” or “inhibiting” means any reduction in the activity of GBA2 between about 10% and about 90%, or between about 30% and about 60%, or more than about 100%, or a reduction of about 1, 2, 5, 10, or more times compared to a reference sample or compound, or compared to wild-type GBA2. It is understood that complete inhibition is not required. In some implementations, the suppression may be temporary, such as lasting 5-60 minutes, 1-5 hours, 1-12 hours, 1-24 hours, 24-48 hours, 1-2 days, 1-5 days, 1-7 days, 1-14 days, 1-28 days, or any specific time within any of these ranges, such as 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 60 minutes, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, or 9 hours. The duration of inhibition can be 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 1.5 days, 2 days, 2.5 days, 3 days, 3.5 days, 4 days, 4.5 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days. In some embodiments, the inhibition may be localized. For example, one or more compounds described in this invention may inhibit GBA2 in specific cellular compartments, such as the endoplasmic reticulum (ER) or Golgi apparatus; or one or more compounds described in this invention may inhibit GBA2 in specific tissue types (e.g., the brain or liver).

[0091] In some embodiments, one or more compounds of the present invention can specifically bind to GBA2. In alternative embodiments, one or more compounds of the present invention can specifically bind to the active site of GBA2. In some embodiments, one or more compounds of the present invention that specifically bind to the active site of GBA2 can also inhibit the activity of GBA2. In alternative embodiments, one or more compounds of the present invention can specifically bind to human nonlysosomal glucosylceramidinase (GBA2) instead of human lysosomal glucosylceramidinase (GCase) and / or human cytosolic glucosylceramidinase (GBA3). In alternative embodiments, one or more compounds of the present invention can specifically bind to human nonlysosomal glucosylceramidinase (GBA2) relative to human glucosylceramidinase (GCS). In alternative embodiments, one or more compounds of the present invention can specifically bind to human nonlysosomal glucosylceramidinase (GBA2) relative to intestinal α-glucosidase, wherein the intestinal α-glucosidase can be sucrase-isomaltase or maltase-glucosylamylase. "Specific binding" refers to a compound binding to GBA2 but not substantially binding to other molecules in the sample, such as lactase, sucrase, maltase, isomaltase, sucrase-isomaltase, glucosylamylase, maltase-glucosylamylase, glucosylceramide synthase, α-glucosidase II, ERα-glucosidase, intestinal α-glucosidase, glycogen phosphorylase, acid α-glucosidase, β-hexosaminease, O-glucosidase, GCase, or GBA3. "Non-substantial combination" means a combination within the range of approximately 5 to approximately 100,000 times, or approximately 10 to approximately 100,000 times, or approximately 1,000 to approximately 100,000 times, or at least approximately 5, 10, 20, 50, 100, 200, 500, 1,000, 1,500, 2,000, 2,500, or 3,000 times. 3500, 4000, 4500, 5000, 6000, 7000, 10,000, 25,000, 50,000, 75,000 or any value within or near the range described, where “binding specificity” means the ratio of the respective binding constants, i.e. Ki(other molecules) / Ki(GBA2), or the ratio of the corresponding IC50 values, i.e. IC50(other molecules) / IC50(GBA2).Examples of compounds exhibiting enhanced binding specificity include, but are not limited to, the compounds of Examples 7, 9, 11, 12, 13, 20, 24, 45, 49, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 70, 71, 73, 114, 115, 116, 117, 118, 119, 120, 129, 131, 136, 137, 138, 139, 140, 141, 142, 147, 151, or 152. In some embodiments, one or more compounds of the present invention may exhibit enhanced binding specificity or enhanced selectivity compared to suitable reference compounds such as N-butyldeoxynojirimycin (NB-DNJ, miglust) or N-(5-adamantane-1-yl-methoxy)pentyl)-deoxynojirimycin (AMP-DNM, Genz-529648). In some embodiments, “enhanced binding specificity” or “enhanced selectivity” means any value between about 10% and about 100% of the measured binding specificity (as defined above) compared to a suitable reference compound, or any integer value between about 10% and about 100%, such as about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, or an increase of about 1 to about 100,000 times, or about 5 times to about 100,000 times, or about 10 times to about 100,000 times, or about 100 times to about 100,000 times, or about 1,000 times to Within the range of approximately 100,000 times, or at least approximately 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 6000, 7000, 10,000, 25,000, 50,000, 75,000, 100,000, or any value within or near the range, or more.

[0092] In some embodiments, one or more compounds of the present invention can inhibit the cleavage of glucose from glucoceramide by GBA2. In some embodiments, one or more compounds of the present invention can inhibit the aggregation of α-synuclein and / or inhibit the formation of Lewy bodies. “inhibit,” “inhibition,” or “inhibiting” means any reduction between about 10% and about 90%, or between about 30% and about 60%, or more than about 100%, or a reduction of about 1, 2, 5, 10, or more, compared to a reference sample or compound, or to wild-type GBA2. It is understood that complete inhibition is not required. In some embodiments, inhibition may be temporary.

[0093] In some embodiments, one or more compounds of the present invention can reduce inflammation in the CNS. In some embodiments, one or more compounds of the present invention can reduce α-synuclein aggregation and / or Lewy body formation. “decreasing” or “decrease” means any value between about 5% and about 90%, or any value between about 30% and about 60%, or more than about 100%, or a reduction of about 1, 2, 5, 10, 15, 25, 50, 100, or more, compared to a reference sample or compound.

[0094] In some embodiments, one or more compounds of the present invention can increase glucoceramide levels. In some embodiments, one or more compounds of the present invention can increase glycosphingolipid levels. In some embodiments, one or more compounds of the present invention can increase GM1 ganglioside levels. "Elevating," "enhancing," or "increasing" means any increase between about 5% and about 90%, or between about 30% and about 60%, or more than about 100%, or an increase of about 1, 2, 5, 10, 15, 25, 50, 100, or more times compared to a reference sample. In some embodiments, one or more compounds of the present invention can increase glucoceramide and / or glycosphingolipid and / or GM1 ganglioside levels in the brain.

[0095] In some embodiments, one or more compounds of the present invention can increase GCase activity levels and / or GCase protein levels in vivo, and can effectively treat conditions requiring or responding to enhanced GCase activity. In some embodiments, one or more compounds of the present invention can specifically increase GCase activity levels and / or GCase protein levels in vivo through interaction with GBA2, and can effectively treat conditions requiring or responding to enhanced GCase activity. "elevating," "enhancing," or "increasing" means any value between about 5% and about 100% compared to a reference sample, or compared to wild-type or mutant GCase, such as about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, or about 1, 2, 5, 10, 15, 25, 50, 100, or more.

[0096] In some embodiments, one or more compounds described in this invention may exhibit enhanced permeability. Permeability can be assessed using a variety of standard experimental techniques, including but not limited to in situ perfusion, ex vivo tissue diffusion, in vitro cell monolayers (e.g., Caco-2 cells, MDCK cells, LLC-PK1 cells), and artificial cell membranes (e.g., PAMPA assay); for measuring effective permeability (P... eff ) or apparent permeability (P app Suitable techniques for determining P include those described by Volpe in AAPS Journal, 2010, 12(4), 670-678. In some embodiments, when one or more of these assay methods are used to determine P... eff or P appIn some embodiments, one or more of the compounds described in this invention may exhibit enhanced permeability. In some embodiments, compounds exhibiting enhanced permeability may exhibit greater oral absorption. In some embodiments, compounds exhibiting enhanced permeability may exhibit greater brain permeability when administered in vivo. In some embodiments, compounds exhibiting enhanced permeability may achieve higher brain concentrations when administered in vivo. Examples of compounds exhibiting higher brain concentrations when administered in vivo include, but are not limited to, the compounds of Examples 7, 12, 45, 49, 70, and 85. In some embodiments, compounds exhibiting enhanced permeability may exhibit a higher brain / plasma concentration ratio when administered in vivo. In some embodiments, “enhanced permeability” means a measured P compared to a suitable reference compound (e.g., N-butyldeoxynojirimycin (NB-DNJ, miglust) or N-(5-adamantane-1-yl-methoxy)pentyl)-deoxynojirimycin (AMP-DNM, Genz-529648)). eff or P app Increase by any value between about 10% and about 100%, or increase by any integer value between about 10% and about 100%, such as about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, or increase by about 1, 2, or 3 times or more. In some embodiments, “enhanced permeability” means that P is measured using an in vitro cell monolayer. app The appropriate method for measurable P app Value (i.e., a value greater than zero). In some implementations, "enhanced permeability" means measuring P using an in vitro cell monolayer. app The appropriate method is greater than 2×10 -6 P cm / s app Value. In an alternative implementation, "enhanced permeability" refers to the measurement of P using an in vitro cell monolayer. app Among the appropriate methods, P app Value in 2×10 -6 cm / s to 40×10 -6Within the range of cm / s. In some embodiments, "higher brain concentration" means any value between about 10% and about 100% when the compound is administered in vivo, compared to a suitable reference compound such as, for example, N-butyldeoxynojirimycin (NB-DNJ, miglusta) or N-(5-adamantane-1-yl-methoxy)pentyl)-deoxynojirimycin (AMP-DNM, Genz-529648), or any integer value between about 10% and about 100%, such as about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, or about 1, 2, or 3, 4, 5, 10, 20, 30, 40, or 50 times, or more.

[0097] The “reference compound” or “control” can be a carbohydrate-mimicking iminosaccharide described in the literature that is a GBA2 inhibitor. Examples of reference compounds or controls as GBA2 inhibitors include, but are not limited to, N-butyldeoxynojirimycin (NB-DNJ, miglusta) and N-(5-adamantane-1-yl-methoxy)pentyl)-deoxynojirimycin (AMP-DNM, Genz-529648). 24 .

[0098] In some embodiments, the present invention provides compounds generally described by formula (I), including any one or more of formulas (Ia)-(In), and their salts, prodrugs, and enantiomers:

[0099]

[0100] As shown in equation (I): R 1 It can be H and R 2 It can be CH3, CH2F, or CHF2; or R 1 It can be CH3 or CH2F and R 2 It can be H; and

[0101] R 3 It could be (CH2) n R 4 Where n can be 1 or 2, and R 4It can be cyclohexyl, cyclohexylmethyl, phenylethyl, 4-phenylcyclohexyl, spiro[2.5]oct-6-yl, spiro[3.5]non-7-yl, spiro[4.5]dec-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]dec-8-yl, 1,2,3,4-tetrahydronaphth-2-yl, 2,3-dihydro-1H-inden-2-yl, (adamantyl)methyl, (pyridin-2-yl)methyl, (benzo[d][1,3]m-dioxacyclopenten-5-yl)methyl, (2,3-dihydrophenyl) [b][1,4]dioxin-6-yl)methyl, ([1,1'-biphenyl]-4-yl)methyl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, 1-(pyridin-3-yl)piperidin-4-yl, 1-(cyclohexylcarbamoyl)piperidin-4-yl, 1-(cyclohexylthiocarbamoyl)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazacyclobutan-3-yl, 2-(thiophene-2-yl)methyl, or 2-(thiophene-3-yl)methyl, each optionally dimethylated by F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropyl-2-yl, methoxymethyl, C 1-6 One or more of the alkoxy group and / or CF3 group replace one to a maximum number of substituents; or

[0102] R 3 It can be phenylethyl, optionally coated with pyrrolidone-1-yl, piperidin-1-yl, 4-morpholino, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, F, Cl, C 1-6 One or more of alkyl, cyclopropyl, propen-2-yl, OCH3 and / or CF3 replace one to a maximum number of substituents; or

[0103] R 3 It can be (1-formylpiperidin-4-yl)methyl, with the formyl group substituted by one of the following groups: C 1-6 Alkyl, C 3-7 Cycloalkyl, phenyl, thiophene-3-yl, phenylmethyl or cyclopentylmethyl, each optionally marked with F, C 1-6 One or more of alkyl, OCH3 and / or CF3 replace one to a maximum number of substituents; or

[0104] R 3 It can be Where R 5The following can be selected from: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophene-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, phenylcarbonyl, thiazol-2-yl, benzo[d]oxazol-2-yl, and benzo[d]thiazol-2-yl, each optionally converted by F, Cl, C 1-6 Alkyl, C 1-6 One or more of alkoxy, OCF3 and / or CF3 replace one to a maximum number of substituents.

[0105] In some implementations, R shown in formula (I) 1 It can be H, CH3, or CH2F. In some implementations, R 1 It can be CH3. In some implementations, R 1 It can be CH2F. In some implementations, R 1 It can be H, provided that R is true. 2 Not H.

[0106] In some implementations, R shown in formula (I) 2 It can be H, CH3, CH2F, or CHF2. In some implementations, R 2 It can be CH2F. In some implementations, R 2 It can be CHF2. In some implementations, R 2 It can be CH3. In some implementations, R 2 It can be H, provided that R is true. 1 Not H.

[0107] In some implementations, R described in formula (I) 3 It could be (CH2) n R 4 Where n can be 1 or 2, and R 4It can be cyclohexyl, cyclohexylmethyl, phenylethyl, 4-phenylcyclohexyl, spiro[2.5]oct-6-yl, spiro[3.5]non-7-yl, spiro[4.5]dec-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]dec-8-yl, 1,2,3,4-tetrahydronaphth-2-yl, 2,3-dihydro-1H-inden-2-yl, (adamantyl)methyl, (pyridin-2-yl)methyl, (benzo[d][1,3]m-dioxacyclopenten-5-yl)methyl, (2,3-dihydrophenyl) [b][1,4]dioxin-6-yl)methyl, ([1,1'-biphenyl]-4-yl)methyl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, 1-(pyridin-3-yl)piperidin-4-yl, 1-(cyclohexylcarbamoyl)piperidin-4-yl, 1-(cyclohexylthiocarbamoyl)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazacyclobutan-3-yl, 2-(thiophene-2-yl)methyl, or 2-(thiophene-3-yl)methyl, each optionally dimethylated by F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropyl-2-yl, methoxymethyl, C 1-6 One or more of alkoxy and / or CF3 replace one to a maximum number of substituents; or R 3 It may be phenylethyl, optionally modified by one or more of the following compounds: pyrrolidone-1-yl, piperidin-1-yl, 4-morpholino, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, F, Cl, C. 1-6 Alkyl, cyclopropyl, propen-2-yl, OCH3 and / or CF3 substitution; or R 3 It can be (1-formylpiperidin-4-yl)methyl, with the formyl group substituted by one of the following groups: C 1-6 Alkyl, C 3-7 Cycloalkyl, phenyl, thiophene-3-yl, phenylmethyl or cyclopentylmethyl, each optionally marked with F, C 1-6 One or more of alkyl, OCH3 and / or CF3 replace one to a maximum number of substituents; or R 3 It can be Where R 5 The following can be selected from: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophene-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, phenylcarbonyl, thiazol-2-yl, benzo[d]oxazol-2-yl, and benzo[d]thiazol-2-yl, each optionally converted by F, Cl, C1-6 Alkyl, C 1-6 One or more of alkoxy, OCF3 and / or CF3 replace one to a maximum number of substituents.

[0108] In some implementation schemes, R 3 It could be (CH2) n R 4 Where n can be 1 or 2, and R 4 It can be cyclohexyl, cyclohexylmethyl, phenylethyl, 4-phenylcyclohexyl, spiro[2.5]oct-6-yl, spiro[3.5]non-7-yl, spiro[4.5]dec-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]dec-8-yl, 1,2,3,4-tetrahydronaphth-2-yl, 2,3-dihydro-1H-inden-2-yl, (adamantyl)methyl, (pyridin-2-yl)methyl, (benzo[d][1,3]m-dioxacyclopenten-5-yl)methyl, (2,3-dihydrophenyl) [b][1,4]dioxin-6-yl)methyl, ([1,1'-biphenyl]-4-yl)methyl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, 1-(pyridin-3-yl)piperidin-4-yl, 1-(cyclohexylcarbamoyl)piperidin-4-yl, 1-(cyclohexylthiocarbamoyl)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazacyclobutan-3-yl, 2-(thiophene-2-yl)methyl, or 2-(thiophene-3-yl)methyl, each optionally dimethylated by F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropyl-2-yl, methoxymethyl, C 1-6 One or more of alkoxy and / or CF3 may replace one to a maximum number of substituents.

[0109] In some implementation schemes, R 3 It can be phenylethyl, optionally coated with pyrrolidone-1-yl, piperidin-1-yl, 4-morpholino, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, F, Cl, C 1-6 One or more of alkyl, cyclopropyl, propen-2-yl, OCH3 and / or CF3 replace one to a maximum number of substituents.

[0110] In some implementation schemes, R 3 It can be (1-formylpiperidin-4-yl)methyl, with the formyl group substituted by one of the following groups: C 1-6 Alkyl, C 3-7Cycloalkyl, phenyl, thiophene-3-yl, phenylmethyl or cyclopentylmethyl, each optionally marked with F, C 1-6 One or more of alkyl, OCH3 and / or CF3 replace one to a maximum number of substituents.

[0111] In some implementation schemes, R 3 It can be Where R 5 The following can be selected from: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophene-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, phenylcarbonyl, thiazol-2-yl, benzo[d]oxazol-2-yl, and benzo[d]thiazol-2-yl, each optionally converted by F, Cl, C 1-6 Alkyl, C 1-6 One or more of alkoxy, OCF3, and / or CF3 replace one to a maximum number of substituents. In some embodiments, R 3 It could be (CH2) n R 4 Where n can be 1, and R 4 It can be cyclohexyl or 1-phenylpiperidin-4-yl, each optionally coated with F, Cl, or C. 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropyl-2-yl, methoxymethyl, C 1-6 One or more of alkoxy and / or CF3 may replace one to a maximum number of substituents.

[0112] In some implementation schemes, R 3It can be cyclohexylmethyl, (4,4-dimethylcyclohexyl)methyl, (4,4-difluorocyclohexyl)methyl, (4,4-dichlorocyclohexyl)methyl, (4-ethylcyclohexyl)methyl, ((1s,4S)-4-vinylcyclohexyl)methyl, ((1s,4S)-4-isopropylcyclohexyl)methyl, ((1r,4R)-4-isopropylcyclohexyl)methyl, 4-(tert-butyl)cyclohexyl)methyl, ((1s,4S)-4-(tert-butyl)cyclohexyl)methyl, ((1r,4R)-4-(tert-butyl)cyclohexyl)methyl, ((1s,4S)-4-(tert-butyl)cyclohexyl)methyl, ((1r,4R)-4-(tert-butyl)cyclohexyl)methyl, ((1s,4S)-4-(trifluoromethyl)cyclohexyl)methyl, ((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl (hexyl)methyl, ((1s,4S)-4-(2-fluoroprop-2-yl)cyclohexyl)methyl, ((1r,4R)-4-(2-fluoroprop-2-yl)cyclohexyl)methyl, ((trans)-3-(trifluoromethyl)cyclohexyl)methyl, ((cis)-3-(trifluoromethyl)cyclohexyl)methyl, ((1s,4S)-4-methoxycyclohexyl)methyl, ((1r,4R)-4-methoxycyclohexyl)methyl, (4-(methoxymethyl)cyclohexyl)methyl, ((1s,4S)-4-cyclopropylcyclohexyl)methyl, ((1r,4R)-4-cyclopropylcyclohexyl)methyl, (4-phenylcyclohexyl)methyl, (spiro[2.5]octyl-6-yl) )methyl, (spiro[3.5]non-7-yl)methyl, (spiro[4.5]dec-8-yl)methyl, 2-cyclohexylethyl, 2-(4,4-difluorocyclohexyl)ethyl, 2-((1s,4S)-4-(trifluoromethyl)cyclohexyl)ethyl, 2-((1r,4R)-4-(trifluoromethyl)cyclohexyl)ethyl, 2-(adamantane-1-yl)ethyl, 3-cyclohexylpropyl, phenethyl, 2-methylphenethyl, 2-methoxyphenethyl, 2-fluorophenethyl, 2-chlorophenethyl, 2,3-difluorophenethyl, 2,4-difluorophenethyl, 2,5-difluorophenethyl, 3,4-difluorophenethyl, 2-fluoro-4-methoxyphenethyl, 3-chloro-2-fluoro Phenylacetyl, 4-chloro-2-fluorophenethyl, 5-chloro-2-fluorophenethyl, 2,6-difluorophenethyl, 3-chloro-2,6-difluorophenethyl, 2,6-difluoro-4-(prop-1-en-2-yl)phenethyl, 2,6-difluoro-4-isopropylphenethyl, 2,6-difluoro-3-isopropylphenethyl, 4-cyclopropyl-2,6-difluorophenethyl, 2,6-difluoro-4-(trifluoromethyl)phenethyl, 2,6-difluoro-4-(pyrrolidone-1-yl)phenethyl, 2,6-difluoro-4-(piperidin-1-yl)phenethyl, 2,6-difluoro-4-morpholinophenethyl, 4-butoxy-2,6-difluorophenethyl, 4-(cyclopropylmethoxy)-2,6-Difluorophenylethyl, 4-((tetrahydrofuran-3-yl)oxy)phenylethyl, 4-((tetrahydro-2H-pyran-3-yl)oxy)phenylethyl, 4-((tetrahydro-2H-pyran-4-yl)oxy)phenylethyl, 4-phenoxyphenylethyl, 4-((tetrahydrofuran-3-yl)methoxy)phenylethyl, (R)-2-phenylpropyl, (S)-2-phenylpropyl, 2-([1,1'-biphenyl]-4-yl)ethyl, 2-(3,5-difluoro-[1,1'-biphenyl]-4-yl)ethyl, 2-(benzo[d][1,3]m-dioxacyclopenten-5-yl)ethyl, 2-(6-fluorobenzo[d][1,3]m-dioxacyclopenten-5-yl)ethyl, 2-(2,2-difluorobenzo[d][ [1,3] m-dioxanepenten-5-yl)ethyl, 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl, 2-(thiophen-2-yl)ethyl, 2-(thiophen-3-yl)ethyl, 2-(pyridin-2-yl)ethyl, 3-phenylpropyl, 3-(2-fluorophenyl)propyl, 3-(4-fluorophenyl)propyl, 3-(thiophen-2-yl)propyl, 3-(thiophen-3-yl)propyl, (1-phenylpiperidin-4-yl)methyl, (1-(2-fluorophenyl)piperidin-4-yl)methyl, (1-(3-fluorophenyl)piperidin-4-yl)methyl, (1-(4-fluorophenyl)piperidin-4-yl)methyl, (1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)methyl, (4-methyl (1-Phenylopirin-4-yl)methyl, (4-fluoro-1-phenylpiperidin-4-yl)methyl, 2-(1-phenylpiperidin-4-yl)ethyl, (1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl, (1-isobutyrylpiperidin-4-yl)methyl, (1-neopentylpiperidin-4-yl)methyl, (1-butyrylpiperidin-4-yl)methyl, (1-(3-methylbutyryl)piperidin-4-yl)methyl, (1-(3,3-dimethylbutyryl)piperidin-4-yl)methyl, (1-(2-cyclopentylacetyl)piperidin-4-yl)methyl, (1-(cyclopropanecarbonyl)piperidin-4-yl)methyl, (1-(cyclobutanecarbonyl)piperidin-4-yl)methyl, (1-(cyclopentanecarbonyl)piperidin -4-yl)methyl, (1-(cyclohexanecarbonyl)piperidin-4-yl)methyl, (1-((1s,4s)-4-(tert-butyl)cyclohexanecarbonyl)piperidin-4-yl)methyl, (1-((1r,4r)-4-(tert-butyl)cyclohexanecarbonyl)piperidin-4-yl)methyl, (1-(4-methoxycyclohexanecarbonyl)piperidin-4-yl)methyl, (1-(4-(trifluoromethyl)cyclohexanecarbonyl)piperidin-4-yl)methyl, (1-benzoylpiperidin-4-yl)methyl, (1-(3-(trifluoromethyl)benzoyl)piperidin-4-yl)methyl, (1-(2-phenylacetyl)piperidin-4-yl)methyl, (1-(thiophene-3-carbonyl)piperidin-4-yl)methyl, ((5S,8s)-3,3-Dimethyl-2-oxaspiro[4.5]dec-8-yl)methyl, (1,2,3,4-tetrahydronaphthyl-2-yl)methyl, (2,3-dihydro-1H-inden-2-yl)methyl, 2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenethyl, (1-(pyridin-3-yl)piperidin-4-yl)methyl, (1-(cyclohexylcarbamoyl)piperidin-4-yl)methyl, (1-(cyclohexylthiocarbamoyl)piperidin-4-yl)methyl, (1-((1S,2R)-2-(trifluoromethyl)cyclohexyl)azacyclobutane-3-yl)methyl, ((R)-1-phenylpyrrolidine-3-yl)methyl, ((R)-1-(o-tolyl) (R)-1-(2-(trifluoromethyl)phenyl)pyrrolidine-3-yl)methyl, (R)-1-(2-(trifluoromethyl)phenyl)pyrrolidine-3-yl)methyl, (R)-1-(2-fluorophenyl)pyrrolidine-3-yl)methyl, (R)-1-(3-fluorophenyl)pyrrolidine-3-yl)methyl, (R)-1-(2-(trifluoromethoxy)phenyl)pyrrolidine-3-yl)methyl, (R)-1-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-yl)methyl, (R)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-yl)methyl, (R)-1-(4-(trifluoromethyl)pyrrolidine ...6-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-yl)methyl, (R)-1-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-yl)methyl, (R)-1-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-yl)methyl, (R)-1-(6-(trifluoromethyl) (R)-1-(pyridin-3-yl)pyrrolidine-3-yl)methyl, (R)-1-(4-methylpyridin-3-yl)pyrrolidine-3-yl)methyl, (R)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidine-3-yl)methyl, (R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidine-3-yl)methyl, (R)-1-(2-(trifluoromethyl)pyridin-3-yl)pyrrolidine-3-yl)methyl, (R)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidine-3-yl)methyl, (R)-1-(thiophen-3-yl)pyrrolidine- 3-yl)methyl, ((R)-1-(benzo[d]thiazolyl-4-yl)pyrrolidine-3-yl)methyl, (S)-(1-(4-(trifluoromethyl)benzoyl)pyrrolidine-3-yl)methyl, ((R)-1-(o-tolyl)piperidin-3-yl)methyl, ((R)-1-(2-fluorophenyl)piperidin-3-yl)methyl, ((R)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl, ((R)-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl, ((R)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl, 3-fluorophenylethyl, 4-fluorophenylethyl, 3,4-Dichlorophenethyl, 3-(trifluoromethyl)phenethyl, 4-(trifluoromethyl)phenethyl, ((R)-1-(benzo[d]thiazol-2-yl)pyrrolidine-3-yl)methyl, ((R)-1-(2-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl, 4-(3,5-dimethylisoxazol-4-yl)-2,6-difluorophenethyl, 4-(3,5-dimethyl-1H-pyrazol-4-yl)-2,6-difluoro Phenethyl, ((R)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidine-3-yl)methyl, ((R)-1-(benzo[d]oxazol-2-yl)pyrrolidine-3-yl)methyl, ((R)-1-(5-isopropylthiazol-2-yl)piperidin-3-yl)methyl, ((R)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl, ((R)-1-(benzo[d]thiazol-2-yl)piperidin -3-yl)methyl, ((R)-1-(benzo[d]thiazo-4-yl)piperidin-3-yl)methyl, ((S)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidine-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidine-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidine-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidine-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidine-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)pyrimidin-2-yl)pyrrolidine-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)pyrimidin-2-yl)pyrrolidine-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)pyrimidin-2-yl)pyrrolidine-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)pyrimidin-5 ... (S)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-yl)methyl, (S)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl, (S)-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl, or (S)-1-(4-(trifluoromethyl)thiazolyl-2-yl)piperidin-3-yl)methyl.

[0113] In some implementation schemes, R 1 It can be H and R 2 It can be CH3. In some implementations, R 1 It can be H and R 2 It can be CH2F. In some implementations, R 1 It can be H and R 2 It can be CHF2. In some implementations, R 1 It can be CH3 and R 2 It can be H. In some implementations, R 1 It can be CH2F and R 2 It can be H.

[0114] In some implementation schemes, R 1 It can be H; R 2 It can be CH3; and R 3 It could be (CH2) n R4 Where n can be 1, and R 4 It can be cyclohexyl or 1-phenylpiperidin-4-yl, each optionally coated with F, Cl, or C. 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropyl-2-yl, methoxymethyl, C 1-6 One or more of alkoxy and / or CF3 may replace one to a maximum number of substituents.

[0115] In some implementation schemes, R 1 It can be H; R 2 It can be CH3; and R 3 It can be (4-phenylcyclohexyl)methyl, (4-(2-fluoroprop-2-yl)cyclohexyl)methyl, (4-(methoxymethyl)cyclohexyl)methyl, (spiro[2.5]oct-6-yl)methyl, (spiro[3.5]non-7-yl)methyl, (spiro[4.5]dec-8-yl)methyl, (2-adamantyl)ethyl, 2-(benzo[d][1,3]m-dioxacyclopenten-5-yl)ethyl, 2-(2,3-dihydrobenzo[b][1,4]dioxacyclohexen-6-yl)ethyl, 2-([1,1'-biphenyl]-4-yl)ethyl, 2-(pyridin-2-yl)ethyl, each optionally coated with F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropyl-2-yl, methoxymethyl, C 1-6 One or more of alkoxy and / or CF3 may replace one to a maximum number of substituents.

[0116] In some implementation schemes, R 1 It can be H; R 2 It can be CH3; and R 3 It can be phenylethyl, optionally coated with pyrrolidone-1-yl, piperidin-1-yl, 4-morpholino, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, F, Cl, C 1-6 One or more of alkyl, cyclopropyl, propen-2-yl, OCH3 and / or CF3 replace one to a maximum number of substituents.

[0117] In some implementation schemes, R 1 It can be H; R 2 It can be CH3; and R 3 It can be (1-formylpiperidin-4-yl)methyl, with the formyl group substituted by one of the following groups: C 1-6 Alkyl, C3-7 cycloalkyl, phenyl, thiophene-3-yl, phenylmethyl or cyclopentylmethyl, each optionally marked with F, C 1-6 One or more of alkyl, OCH3 and / or CF3 replace one to a maximum number of substituents.

[0118] In some implementation schemes, R 1 It can be H; R 2 It can be CH3; and R 3 It can be Where R 5 The following can be selected from: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophene-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, phenylcarbonyl, thiazol-2-yl, benzo[d]oxazol-2-yl, and benzo[d]thiazol-2-yl, each optionally converted by F, Cl, C 1-6 Alkyl, C 1-6 One or more of alkoxy, OCF3, and / or CF3 replace one to a maximum number of substituents. In some embodiments, R 3 It could be (CH2) n R 4 Where n can be 1, and R 4 It can be cyclohexyl or 1-phenylpiperidin-4-yl, each optionally coated with F, Cl, or C. 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropyl-2-yl, methoxymethyl, C 1-6 One or more of alkoxy and / or CF3 may replace one to a maximum number of substituents.

[0119] In some implementation schemes, R 1 It can be H; R 2 It can be CH3; and R 3It can be (4-ethylcyclohexyl)methyl, ((1s,4S)-4-isopropylcyclohexyl)methyl, ((1r,4R)-4-isopropylcyclohexyl)methyl, ((1s,4S)-4-(tert-butyl)cyclohexyl)methyl, ((1r,4R)-4-(tert-butyl)cyclohexyl)methyl, ((1s,4S)-4-(trifluoromethyl)cyclohexyl)methyl, ((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl, ((1s,4S)-4-(2-fluoroprop-2-yl)cyclohexyl)methyl, ((1r,4R ... (1s,4S)-4-cyclopropylcyclohexyl)methyl, (1r,4R)-4-cyclopropylcyclohexyl)methyl, 2-(1s,4S)-4-(trifluoromethyl)cyclohexyl)ethyl, 2-(1r,4R)-4-(trifluoromethyl)cyclohexyl)ethyl, 2,5-difluorophenylethyl, 3-chloro-2-fluorophenylethyl, 5-chloro-2-fluorophenylethyl, 2,6-difluorophenylethyl, 3-chloro-2,6-difluorophenylethyl, 2,6-difluoro-4-(prop-1-en-2-yl)phenylethyl, 2,6-difluoro-4-isopropylphenylethyl, 2,6-difluoro -3-Isopropylphenethyl, 4-Cyclopropyl-2,6-Difluorophenethyl, 2,6-Difluoro-4-(pyrrolidin-1-yl)phenethyl, 2,6-Difluoro-4-(piperidin-1-yl)phenethyl, 2,6-Difluoro-4-morpholinophenethyl, 4-Butoxy-2,6-Difluorophenethyl, 4-(Cyclopropylmethoxy)-2,6-Difluorophenethyl, 2-([1,1'-biphenyl]-4-yl)ethyl, 2-(3,5-Difluoro-[1,1'-biphenyl]-4-yl)ethyl, 2-(benzo[d][1,3]m-dioxacyclopenten-5-yl)ethyl, 2-(6- Fluorobenzo[d][1,3]m-dioxacyclopenten-5-yl)ethyl, 2-(2,2-difluorobenzo[d][1,3]m-dioxacyclopenten-5-yl)ethyl, 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl, (1-(2-fluorophenyl)piperidin-4-yl)methyl, (1-(3-fluorophenyl)piperidin-4-yl)methyl, (1-(4-fluorophenyl)piperidin-4-yl)methyl, (1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)methyl, (2,3-dihydro-1H-inden-2-yl)methyl, (1,2,3,4-Tetrahydronaphth-2-yl)methyl, ((R)-1-(2-(trifluoromethyl)phenyl)pyrrolidine-3-yl)methyl, ((S)-1-(2-(trifluoromethyl)phenyl)pyrrolidine-3-yl)methyl, ((R)-1-phenylpyrrolidine-3-yl)methyl, ((R)-1-(thiophen-3-yl)pyrrolidine-3-yl)methyl, ((R)-1-(2-(trifluoromethyl)pyridin-3-yl)pyrrolidine-3-yl)methyl, ((R)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidine-3-yl)methyl, ((R)-1-(2-fluorophenyl)piperidin-3-yl)methyl, ((R)-1-(2-fluorophenyl)piperidin-3-yl)methyl (R)-1-(3-fluorophenyl)pyrrolidine-3-yl)methyl, (R)-1-(o-tolyl)pyrrolidine-3-yl)methyl, (R)-1-(thiophen-3-yl)pyrrolidine-3-yl)methyl, (R)-1-(2-trifluoromethyl)piperidin-3-yl)pyrrolidine-3-yl)methyl, (R)-1-(4-(trifluoromethyl)piperidin-3-yl)pyrrolidine-3-yl)methyl, (R)-1-(2-fluorophenyl)piperidin-3-yl)methyl, (R)-1-(2-(fluorophenyl)pyrrolidine-3-yl)methyl, (R)-1-(3-fluorophenyl)pyrrolidine-3-yl)methyl , ((R)-1-(o-tolyl)piperidin-3-yl)methyl, ((R)-1-(benzo[d]thiazo-4-yl)pyrrolidine-3-yl)methyl, ((R)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl, ((R)-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl, ((R)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl, 2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenethyl, ((S)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidine-3-yl)methyl, ((S)-1-(4- (trifluoromethyl)pyridin-3-yl)pyrrolidine-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidine-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)thiazolyl-2-yl)pyrrolidine-3-yl)methyl, ((S)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl, ((S)-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl, or ((S)-1-(4-(trifluoromethyl)thiazolyl-2-yl)piperidin-3-yl)methyl.

[0120] In a specific embodiment of the present invention, the compounds according to formula (I) include the compounds described in Table 1.

[0121] Table 1

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146] As those skilled in the art will understand, the above equation (I) can also be replaced by the following:

[0147]

[0148] As used in this invention, the singular forms “an,” “an,” and “the” include plural references unless the context clearly specifies otherwise. For example, “compound” refers to one or more such compounds, while “enzyme” includes specific enzymes as well as other equivalents of family members known to those skilled in the art.

[0149] Throughout this application, the term "compound" is intended to mean the compound discussed in this invention and includes precursors and derivatives of said compounds, including acyl-protected derivatives, and pharmaceutically acceptable salts of said compounds, precursors, and derivatives. This invention also includes prodrugs of said compounds, pharmaceutical compositions comprising said compounds and pharmaceutically acceptable carriers, and pharmaceutical compositions comprising prodrugs of said compounds and pharmaceutically acceptable carriers.

[0150] The compounds of the present invention may contain one or more asymmetric centers other than those specified in formula (Ia)-(In), and thus may exist as a single enantiomer, a mixture of diastereomers, and a single diastereomer. Such additional asymmetric centers may exist depending on the nature of the various substituents on the molecule. Each such additional asymmetric center will independently produce two optical isomers, and all such possible optical and diastereomers of the mixture, as a pure or partially purified compound, are intended to be included within the scope of the present invention. Any formula, structure, or name of the compounds described in this specification (without specifying a particular stereochemistry of the additional asymmetric center) is intended to cover any and all existing isomers as described above and mixtures thereof in any proportion. When the stereochemistry of an additional asymmetric center is specified, the present invention is intended to cover the specific isomer, either pure or as part of a mixture with other isomers in any proportion.

[0151] "Alkyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without unsaturated bonds, including, for example, 1 to 10 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, and connected to the rest of the molecule by single bonds. In alternative embodiments, the alkyl group may contain 1 to 8 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. In alternative embodiments, the alkyl group may contain 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5, or 6 carbon atoms. Unless specifically stated otherwise in the specification, the alkyl group may optionally be substituted with one or more substituents as described in this invention. Unless specifically stated otherwise in this invention, it should be understood that substitution can occur on any carbon atom of the alkyl group.

[0152] "Cycloalkyl" refers to a stable monovalent monocyclic, bicyclic, or tricyclic hydrocarbon group consisting only of carbon and hydrogen atoms, having, for example, 3 to 15 carbon atoms, and being saturated and connected to the rest of the molecule by single bonds. In alternative embodiments, the cycloalkyl group may contain 3 to 6 carbon atoms, for example 3, 4, 5, or 6 carbon atoms. Unless specifically stated otherwise in this invention, the term "cycloalkyl" means including cycloalkyl groups optionally substituted as described in this invention.

[0153] "Alkoxy" refers to the formula -OR a The groups, wherein each R a Independently, it is C as described in this invention. 1-10 Alkyl or C 1-6 Alkyl or C 1-5 Alkyl groups may be optionally substituted as described in this invention.

[0154] "Optional" or "optionally" means that the situation described below may or may not occur, and the description includes situations in which the event or situation occurs once or more and situations in which it does not occur. For example, "optionally substituted alkyl" means that an alkyl group may or may not be substituted, and the description includes substituted alkyl groups and unsubstituted alkyl groups, and the alkyl group may be substituted once or more. Examples of optionally substituted alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, etc. Examples of suitable optional substituents include, but are not limited to, H, F, Cl, CH3, OH, OCH3, CF3, CHF2, CH2F, and CN.

[0155] Treatment indications

[0156] This invention partially provides treatment methods for conditions that are directly or indirectly regulated by the GBA2 enzyme or GBA2 activity level, for example, conditions that benefit from inhibiting the GBA2 enzyme or by reducing the GBA2 enzyme activity level. Such conditions may include, but are not limited to, neurological disorders such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis (ALS); lysosomal storage diseases such as Gaucher disease, Niemann-Pick disease type C, mucolipidemia type IV, and Sandhof's disease; and liver diseases such as non-alcoholic steatohepatitis (NASH). Therefore, one or more compounds of this invention can be used to treat subjects who are at risk of or have been diagnosed with various neurological or other diseases. The term "treatment" as used herein may include treatment, prevention, and / or improvement.

[0157] In alternative embodiments, one or more compounds of the present invention may also be used to treat diseases or disorders associated with deficiency or overexpression of GBA2 or accumulation or depletion of glucoceramide, or any disease or disorder that responds to glycosidase inhibitor therapy or glycosidase inhibition therapy. Such diseases and disorders may include, but are not limited to, neurological diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis (ALS), as well as lysosomal storage diseases such as Gaucher disease, Niemann-Pick disease type C, mucolipidemia type IV, and Sandhof's disease, and liver diseases such as non-alcoholic steatohepatitis (NASH). Such diseases and disorders may also include those associated with accumulation or deficiency of the enzyme glucoceramide synthase or dysregulation of glycosphingolipid metabolism and / or homeostasis. Methods for protecting or treating target cells expressing GBA2, whose dysregulation can lead to disease or pathology are also included.

[0158] In alternative embodiments, the present invention provides a method for reducing the level of GBA2 enzyme activity in animal subjects, such as veterinarians and human subjects. This reduction in GBA2 activity levels can be used to prevent or treat neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis (ALS)); provide neuroprotection; prevent damage to dopaminergic neurons; and prevent or treat lysosomal storage diseases (e.g., Gaucher disease, Niemann-Pick disease type C, mucolipidemia type IV, and Sandhof's disease); as well as prevent or treat liver diseases (e.g., non-alcoholic steatohepatitis (NASH)).

[0159] In alternative embodiments, the present invention provides a method for inhibiting the GBA2 enzyme in animal subjects, such as veterinarians and human subjects.

[0160] In alternative embodiments, the present invention provides a method for reducing CNS inflammation in animal subjects, such as veterinarians, and human subjects. Target disease states may include neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis (ALS), wherein neuroinflammation is involved in the pathogenesis of the disease. In some embodiments, the compounds described in the present invention can be used to prevent, treat, or improve conditions by reducing the activity level of the GBA2 enzyme, thereby providing an effective treatment.

[0161] In alternative embodiments, the present invention provides methods for inhibiting α-synuclein aggregation or Lewy body formation in animal subjects, such as veterinarians, and human subjects. Target disease states may include Parkinson's disease (PD) and related neurodegenerative synucleinopathy, wherein abnormal aggregation of α-synuclein is associated with disease pathogenesis. In some embodiments, the compounds described in this invention can be used to provide an effective treatment by blocking α-synuclein aggregation through reducing GBA2 enzyme activity levels.

[0162] The compounds of this invention can treat neurological diseases including, but not limited to: Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), addiction, anxiety, arrhythmia-telangiectasia (AT), attention deficit / hyperactivity disorder (ADHD), autism spectrum disorder (ASD), Becker muscular dystrophy (BMD), bipolar disorder (BD), Blue's disease, cerebellar ataxia, peroneal muscular dystrophy (CMT), chronic fatigue syndrome, corticobasal degeneration (CBD), boxer's dementia, and Lewy body dementia. DLB, Degerin-Sottas syndrome, diffuse neurofibrillary tangles with calcification, Down syndrome, Duchenne muscular dystrophy (DMD), epilepsy, essential tremor (ET), familial British dementia, familial Danish dementia, fibromuscular atrophy, Parkinson's syndrome associated with chromosome 17 (FTDP-17), Friedreich ataxia, Gerstmann-Strauss disease, glaucoma, Guardio Parkinson's syndrome, Guillain-Barré syndrome, Hallevorden-Spatz disease (neurodegeneration with brain iron accumulation type 1), insomnia, Lambert-Eton myasthenic syndrome (LEMS), major depressive disorder (MDD), paraphilia Headache, mild cognitive impairment (MCI), multiple infarct-related dementia, multiple system atrophy (MSA), myasthenia gravis, myotonic dystrophy (including DM1 and DM2 types), neuronal ceroid lipofuscin deposition disease (including types 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10), neuropathy (including peripheral neuropathy, autonomic neuropathy, neuritis, neurotrophic disorders), oculopharyngeal muscular dystrophy, pain, globus pallidus-pontine degeneration, Guam Parkinson's syndrome-dementia syndrome, Pick's disease (PiD), post-encephalitis Parkinson's syndrome (PEP), primary lateral sclerosis (PLS), prions (including Creutzfeldt-Jakob disease (CJD)). Variant Creutzfeldt-Jakob disease (vCJD), fatal familial insomnia and kuru, progressive cortical gliosis, progressive supranuclear palsy (PSP), Richardson syndrome, schizophrenia, seizures, spinal cord injury, spinal muscular atrophy (SMA), spinocerebellar ataxia (including types 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 28 and 29), stroke, subacute sclerosing panencephalitis, tangled dementia, tardive dyskinesia, Tourette syndrome (TS), vascular dementia or Wilson's disease.

[0163] Lysosomal storage diseases that can be treated with the compounds of this invention include, but are not limited to: Gaucher disease (including types I, II and III), Niemann-Pick disease (including types A, B and C), mucolipidosis (including types I, II, III, IV, VI and VII), cerebral tendon xanthomas, Fabry disease, Fabry disease, GM1 ganglioside storage disease, Krab disease, metachromatic leukodystrophy (MLD), polysulfatase deficiency, Pompe disease, Sandhof disease, or Tessachs disease.

[0164] The liver diseases that can be treated by the compounds of this invention include, but are not limited to: non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), Alagille syndrome, alcohol-related liver disease, α-1 antitrypsin deficiency, autoimmune hepatitis, autoimmune cholangitis, benign liver tumors, biliary atresia, cirrhosis, Crigler-Najjar syndrome, drug-induced liver injury (DILI), galactosemia, Gilbert syndrome, hemochromatosis, hepatic encephalopathy, hepatocellular carcinoma (HCC), intrahepatic cholestasis of pregnancy (ICP), lysosomal acid lipase deficiency (LAL-D), liver cysts, liver cancer, neonatal jaundice, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), Reye's syndrome, type I glycogen storage disease, or viral hepatitis (including types A, B, C, D, and E).

[0165] In some embodiments, the compounds described in this invention can be used to treat diseases involving dysregulation of GBA2 enzyme activity levels, or any of the conditions described in this invention.

[0166] Other conditions that can be treated using one or more of the compounds described in this invention are those triggered, affected, or otherwise related to GBA2 enzyme activity levels. One or more compounds of this invention are intended for use in treating such conditions, particularly but not limited to Parkinson's disease, Gaucher disease, Niemann-Pick disease type C, mucolipidemia type IV, and Sandhof disease.

[0167] Drugs and veterinary compositions, dosage and administration

[0168] Pharmaceutical compositions comprising compounds described in or used in accordance with the present invention are considered to be within the scope of the present invention. In some embodiments, a pharmaceutical composition is provided comprising an effective amount of a compound of formula (I), including any one or more of formulas (Ia)-(In).

[0169] Compounds of formula (I), including any one or more of formulas (Ia)-(In), and their pharmaceutically acceptable salts, enantiomers, solvates, or derivatives may be useful because they may have pharmacological activity in animals (including humans). In some embodiments, one or more of the compounds described in this invention may be stable in plasma when administered to a subject (e.g., a human).

[0170] Typically, the compounds described in this invention can be administered to a subject in need of them, or come into contact with cells or samples, such as pharmaceutical compositions containing a therapeutically effective amount of a compound according to formula (I) (including any one or more of formulas (Ia)-(In)).

[0171] In some embodiments, the compounds described herein or for the purposes described herein may be provided in combination with any other active agent or pharmaceutical composition, wherein such combination therapy may be used to inhibit GBA2 activity levels, for example, to treat neurological disorders, lysosomal storage diseases, liver diseases, or any of the conditions described herein. In some embodiments, the compounds described herein or for the purposes described herein may be provided in combination with one or more agents that may be used to prevent or treat Parkinson's disease. Examples of such agents may include, but are not limited to:

[0172] • L-DOPA;

[0173] • Peripheral dopa decarboxylase inhibitors (DDCIs), such as carbidopa

[0174] • Combination of carbidopa / levodopa

[0175] • Combination of carbidopa / levodopa / entacapone

[0176] Amantadine

[0177] • Dopamine antagonists, such as bromocriptine Peglit Praxesor Ropinirole Trivastal ), Camembert Apomorphine Rotigotin (AY-27,110), second receptor (DAR-0100) Epicryptine (β-dihydroergocryptine), N-propylnoraporphine (NPA), quinolones (EMD-49,980) (PNU-95,666), Pardorino, Aprindo, etc.;

[0178] Monoamine oxidase-B (MAO-B) inhibitors, such as selegiline Resagilan ( AGN 1135), safenamide, etc.;

[0179] Anticholinergic drugs, such as benztropine Diphenhydramine Offena Benthesin ( benzhexol, trihex), etc.;

[0180] Catechol-O-methyltransferase (COMT) inhibitors, such as entacapone Tocapone Niticacapone, Nebicapone, etc.;

[0181] Adenosine A 2A Receptor antagonists, such as itratheline (KW-6002), pradendron, femeprazole (JP-1730), SCH-420814, BIIA-014, Lu AA4707, etc.;

[0182] • Metabolic glutamate receptor 5 (mgluR5) modulators, such as dipamoate;

[0183] AMPA receptor antagonists, such as perampanel wait;

[0184] Anticonvulsants, such as zonisamide wait;

[0185] • Nicotinic acetylcholine receptor (nAChR) agonists, such as nicotine, ABT-418, WAY-317, 538 (SEN-12333), EVP-6124, MEM 3454, nelfecitan, etc.

[0186] Acetylcholinesterase inhibitors (AChEIs), such as (Donepezil), (Rivastigmine), (Razadyne galantamine), (Tacrine), Huperzine A, phenylserine, Debio-9902SR (ZT-1SR), Zanapazol (TAK0147), Gansmin, NP7557, etc.;

[0187] • Atypical antipsychotics, such as clozapine; or

[0188] Modafinil

[0189] It is understood that the combination of compounds described or used in this invention with agents that can be used to treat Parkinson's disease is not limited to the examples described in this invention, but can include combinations with any agent that can be used to treat Parkinson's disease. The combination of compounds described or used in this invention with other agents for treating Parkinson's disease can be administered alone or in combination. One agent can be administered before, simultaneously with, or after the administration of other agents.

[0190] In some embodiments, the compounds described herein or used for the purposes described herein may be provided in combination with one or more agents for the prevention or treatment of Gaucher disease. Examples of such agents may include, but are not limited to:

[0191] • Recombinant human GCase enzyme replacement therapy, such as imiglanase velaglucerase alfa taliglucerase alfa wait;

[0192] • Glucose-ceramide synthase inhibitors, such as EXEL-0346, Genz-123346, and Ebola. (Genz-112638), etc.;

[0193] Bisphosphonates, such as zoledronic acid Alendronate sodium etidronate Chlorphosphate Tiluphosphonate pamidronate Neliphosphonates Opadronate, Ibandronate Risephosphonates wait;

[0194] Antiepileptic drugs, such as ( Carbamazepine), (Ethylsuccinylamine), (non-amino ester), (Tigabe), (levetiracetam), (lamotrigine) (Pregabalin) (Gabapentin) (Phenytoin) (Topiramate), (Oxcarbazepine) ( Valproate, valproic acid (zonisamide) (Diazepam) (Lauracipa), (Clonazepam) (perampanel), Oxtellar (Oxcarbazepine), etc.; or

[0195] Gene therapy.

[0196] It is understood that the combination of compounds described in this invention or for the purposes described in this invention with agents that can be used to treat Gaucher disease is not limited to the examples described in this invention, but can include combinations with any agent used to treat Gaucher disease. The combination of compounds described in this invention or compounds for the purposes described in this invention with other agents used to treat Gaucher disease can be administered alone or in combination. Administration of one agent can be before, simultaneously with, or after administration of other agents.

[0197] In alternative embodiments, the compounds of the present invention may be provided as a "prodrug" or as a protective form, which releases the compound upon administration to a subject. For example, the compound may carry a protecting group that is cleaved by hydrolysis in bodily fluids (e.g., in the bloodstream) to release the active compound, or oxidized or reduced in bodily fluids to release the compound. Thus, "prodrug" means a compound that can be converted into the bioactive compound of the present invention under physiological conditions or by solvent degradation. Therefore, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of the compound of the present invention. When administered to a subject in need, the prodrug may be inactive but can be converted in vivo into the active compound of the present invention. Prodrugs are typically rapidly converted in vivo to produce the parent compound of the present invention, for example, by hydrolysis in the blood. Prodrug compounds generally offer advantages in subjects such as solubility, tissue compatibility, or delayed release.

[0198] The term "prodrug" also includes any covalently bound carrier that, when administered to a subject, releases the active compound of the invention in vivo. Prodrugs of the compounds of the invention can be prepared by modifying functional groups present in the compounds of the invention in such a way that the modification cleaves into the parent compound of the invention in conventional operation or in vivo. Prodrugs include compounds of the invention in which a hydroxyl, amino, or thiol group is bonded to any group that, when administered to a mammalian subject, cleaves the group to form a free hydroxyl, free amino, or free thiol group, respectively. Examples of prodrugs include, but are not limited to, acetates, formate esters, and benzoate esters of acetamide, formamide, and benzamide derivatives with alcohol and amine functional groups in one or more compounds of the invention.

[0199] Discussions of prodrugs can be found in the following literature: “Introduction to the Principles of Drug Design”, Smith & Williams, Wright, 2nd 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); A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pgs 113-191 (Harwood Academic Press, 1991); Higuchi, T., et al., “Prodrugs as Novel Delivery Systems”, ACSSymposium Series, Vol. 14; or Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0200] Suitable prodrug forms of one or more compounds of the present invention may include embodiments in which one or more OH groups as shown in formula (I), including any one or more of formulas (Ia)-(In), can be protected as OC(O)R, wherein R may be an optionally substituted C1-6 Alkyl groups. In these cases, the ester group can be hydrolyzed in vivo (e.g., in body fluids), releasing the OH group and the active compound. Preferred prodrug embodiments of the present invention may include compounds of formula (I), including any one or more of formulas (Ia)-(In), wherein one or more OH groups may be protected with an acetate ester, such as OC(O)CH3.

[0201] The compounds described in this invention or for the purposes described herein may be provided alone or in combination with other compounds in the presence of liposomes, nanoparticles, adjuvants, or any pharmaceutically acceptable carrier, diluent, or excipient, in a form suitable for administration to a subject, such as a mammal, like a human, cow, sheep, etc. If desired, the treatment with the compounds described in this invention may be combined with more conventional and existing therapies for the therapeutic indications described in this invention. The compounds of this invention may be administered long-term or intermittently. "Long-term administration" means administration of the compound in a continuous manner, as opposed to acute administration, in order to maintain the initial therapeutic effect (activity) over an extended period. "Intermittent administration" means treatment that is not continuous and uninterrupted, but rather periodic. These terms, as used herein, "administration," "administrable," or "administering," should be understood to mean providing the compounds of this invention to a subject in need of treatment.

[0202] "Pharmaceutically acceptable carriers, diluents, or excipients" may include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration or other government agencies for use in humans or livestock.

[0203] The compounds of the present invention can be administered in the form of pharmaceutically acceptable salts. In this case, the pharmaceutical compositions of the present invention may comprise salts of such compounds, preferably physiologically acceptable salts known in the art. In some embodiments, the term "pharmaceutically acceptable salt" as used herein refers to the active ingredient of a compound of formula I, including any one or more of formulas (Ia)-(In) used in their salt forms, particularly wherein the salt form improves the pharmacokinetic properties of the active ingredient compared to its free form or other previously disclosed salt forms.

[0204] "Pharmaceutically acceptable salts" can include both acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" refer to those salts that retain the bioavailability and properties of the free base, and can be composed of inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.).

[0205] "Pharmaceutically acceptable base addition salts" refer to those salts that retain the biologically or otherwise desired bioavailability and properties of the free acid. These salts can be prepared by adding an inorganic or organic base to the free acid. Derivative salts of inorganic bases may include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Derivative salts of organic bases may include, but are not limited to, the following salts: primary amines, secondary amines, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, halamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. The particularly preferred organic bases may be isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0206] Therefore, the term "pharmaceutically acceptable salt" includes all acceptable salts, including but not limited to acetates, lacturonates, benzenesulfonates, laurates, benzoates, malates, bicarbonates, maleates, bisulfates, mandelates, tartrates, methanesulfonates, borates, methyl bromide, bromide, methyl nitrite, calcium EDTA, methyl sulfate, camphor sulfonate, mucilages, carbonates, naphthalene sulfonates, chlorides, nitrates, clavulanates, N-methylglucosamine, citrates, ammonium salts, dihydrochlorides, oleates, and EDTA. Salts, oxalates, ethanedisulfonates, dihydroxynaphthalates, etolates, palmitates, ethanesulfonates, pantothenates, fumarates, phosphates / bisphosphates, glucono-p-phosphates, polygalacturonic acids, gluconates, salicylates, glutamine, stearates, glycine benzenesulfonates, sulfates, hexyl isophthalate, hypoacetate, hydroxyamines, succinates, hydrobromide, tannates, hydrochlorides, tartrates, hydroxynaphthalene, theophylline salts, iodides, toluenesulfonates, isosulfates, trithiohydrochlorides, lactates, pantothenates, valerates, etc.

[0207] Pharmaceutically acceptable salts of the compounds of this invention can be used as agents to alter solubility or hydrolysis properties, or in sustained-release or prodrug formulations. Furthermore, pharmaceutically acceptable salts of the compounds of this invention may include substances formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and bases such as ammonia, ethylenediamine, N-methylglutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenylethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.

[0208] Pharmaceutical formulations typically include one or more carriers with an acceptable mode of administration, such as injection, inhalation, topical administration, irrigation, or other methods suitable for the selected treatment. Suitable carriers may be those known in the art for such modes of administration.

[0209] Suitable pharmaceutical compositions can be formulated using methods known in the art, and their administration routes and dosages are determined by those skilled in the art. For parenteral administration, the compound can be dissolved in sterile water or saline or in a pharmaceutically acceptable carrier used for the administration of non-water-soluble compounds, such as carriers for vitamin K. For enteral administration, the compound can be administered in tablet, capsule, or liquid form. Tablets or capsules can be enteric-coated or formulated as sustained-release formulations. Many suitable formulations are known, including polymer or protein microparticles, ointments, gels, hydrogels, or solutions for the local administration of the compound. Sustained-release patches or implants can be used to prolong the release time. Many techniques known to those skilled in the art are described in Remington: The Science & Practice of Pharmacy by Alfonso Gennaro, 20 th ed., Williams & Wilkins, (2000). Parenteral formulations may contain, for example, excipients, polyalkylene glycols such as polyethylene glycol, plant-derived oils, or hydrogenated naphthalene. Biocompatible, biodegradable lactide polymers, lactide / glycolic acid copolymers, or polyoxyethylene-polyoxypropylene copolymers can be used to control the release of the compound. Other potential parenteral delivery systems that can be used to modulate the compound may include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Inhalation formulations may contain excipients such as lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate, and deoxycholate, or may be oily solutions administered as nasal drops or gels.

[0210] The compounds or pharmaceutical compositions of the present invention can be administered orally or non-orally, such as intramuscular, intraperitoneal, intravenous, intracisional injection or infusion, subcutaneous injection, percutaneous or mucosal routes. In some embodiments, the compounds or pharmaceutical compositions of the present invention or for the purposes described herein can be administered via medical devices or appliances such as implants, grafts, prostheses, stents, etc. Implants can be designed to contain and release these compounds or compositions. One example is an implant made of a polymer material suitable for releasing the compound over a period of time. The compounds can be administered alone or in combination with pharmaceutically acceptable carriers, such as solid dosage forms, such as tablets, capsules, granules, powders, etc.; liquid dosage forms, such as syrups, injections, etc.; injections, drops, suppositories, vaginal suppositories. In some embodiments, the compounds or pharmaceutical compositions of the present invention or for the purposes described herein can be administered via inhalation sprays, nasal, vaginal, rectal, sublingual or local routes, and can be formulated alone or together into formulations containing conventional, non-toxic, pharmaceutically acceptable carriers, adjuvants and mediators suitable for each route of administration.

[0211] The compounds of this invention can be used to treat animals, including mice, rats, horses, cattle, sheep, dogs, cats, and monkeys. However, the compounds of this invention can also be used in other organisms, such as bird species (e.g., chickens). One or more compounds of this invention are also effective for use in humans. The term "subject," or alternatively "patient" in this invention, is intended to refer to an animal, preferably a mammal, and most preferably a human, that has become the subject of treatment, observation, or experimentation. However, one or more compounds, methods, and pharmaceutical compositions of this invention can be used to treat animals. Accordingly, as used in this invention, "subject" can be a human, a non-human primate, rat, mouse, cattle, horse, pig, sheep, goat, dog, cat, etc. The subject may be suspected of having a condition that may require inhibition of GBA2 activity or be at risk of having a condition that may require inhibition of GBA2 activity.

[0212] The "effective amount" of the compounds described in this invention can include a therapeutically effective amount or a preventatively effective amount. A "therapeuticly effective amount" refers to an effective amount that achieves the desired therapeutic outcome (e.g., inhibition of GBA2, reduction of GBA2 enzyme activity levels, inhibition of α-synuclein aggregation, or any of the conditions described in this invention) within the necessary dose and time period. The therapeutically effective amount of a compound can vary depending on factors such as an individual's disease state, age, sex, weight, and the compound's ability to elicit a desired response in the individual. Dosing regimens can be adjusted to provide an optimal therapeutic response. A therapeutically effective amount can also be an amount in which the therapeutic effect effectively outweighs any toxic or harmful effects of the compound. A "preventatively effective amount" can refer to an effective amount that achieves a desired preventative outcome within the necessary dose and time period, such as inhibition of GBA2, reduction of GBA2 enzyme activity levels, inhibition of α-synuclein aggregation, or any of the conditions described in this invention. Typically, the preventative dose can be administered to the subject before or at an early stage of the disease, and therefore the preventatively effective amount can be less than the therapeutically effective amount. The appropriate range for the therapeutic or preventative effective amount of a compound can be any integer from 0.1 nM to 0.1 M, 0.1 nM to 0.05 M, 0.05 nM to 15 μM, or 0.01 nM to 10 μM.

[0213] In alternative embodiments, in the treatment or prevention of conditions where inhibition of GBA2 activity may be necessary, appropriate dose levels may typically be about 0.01-500 mg / kg subject body weight / day, and may be administered in single or multiple doses. In some embodiments, dose levels may be about 0.1-250 mg / kg / day. It should be understood that the specific dose level and frequency of administration for any particular patient can vary and may depend on a variety of factors, including the activity of the particular compound used, the metabolic stability and duration of action of the compound, age, weight, general health condition, sex, diet, route and timing of administration, excretion rate, drug combination, severity of the particular condition, and the patient being treated.

[0214] It should be noted that dosage values ​​may vary depending on the severity of the condition to be alleviated. For any particular subject, a specific dosage regimen may be adjusted over time according to individual needs and the professional judgment of the dosing physician or composition monitoring. The dosage ranges described in this invention are merely exemplary and do not limit the dosage ranges that a medical practitioner may choose. The amount of active compound in the composition may vary depending on factors such as the subject's disease state, age, sex, and weight. Dosing regimens may be adjusted to provide the best therapeutic response. For example, a single bolus injection may be administered, several separate doses may be administered over time, or the dose may be proportionally reduced or increased depending on the urgency of the treatment situation. Formulating parenteral compositions in dosage units may be advantageous for administration and dosage uniformity. Generally, the compounds of this invention should be used without causing substantial toxicity, and as described in this invention, one or more compounds may exhibit a safety profile suitable for therapeutic use. The toxicity of the compounds of this invention can be determined using standard techniques, such as by testing in cell cultures or laboratory animals, and determining the therapeutic index, i.e., the ratio between the LD50 (50% lethal dose in a population) and the LD100 (100% lethal dose in a population). However, in some cases, such as in severe illness conditions, it may be necessary to administer an actual excessive amount of the composition.

[0215] In compounds of general formula (I), including any one or more of formulas (Ia)-(In), atoms may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched with a specific isotope, i.e., having the same number of atoms but with an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. This invention is intended to include all suitable isotopic variants of compounds of general formula (I), including any one or more of formulas (Ia)-(In). For example, different isotopic forms of hydrogen (H) include protium (¹H), deuterium (²H), and tritium (³H). Protium is the predominant hydrogen isotope found in nature. Enrichment of deuterium may provide certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide compounds that can be used as standards for characterizing biological samples. Isotope-enriched compounds of general formula (I), including any one or more of formulas (Ia)-(In), can be prepared by the following steps: using conventional techniques well known to those skilled in the art or by methods similar to those described in the embodiments of the present invention, using appropriate isotope-enriching reagents and / or intermediates.

[0216] Other uses

[0217] In alternative embodiments, one or more compounds of the present invention may be used to study the physiological effects of GBA2 at the cellular and organismal levels. In some embodiments, one or more compounds may be used to develop animal models for studying diseases or conditions that may be associated with GBA2 deficiency, GBA2 overexpression, accumulation of glucoceramide, depletion of glucoceramide, accumulation of glycosphingolipids, and depletion of glycosphingolipids, as well as for studying treatments for diseases and conditions that may be associated with GBA2 deficiency or overexpression, or accumulation or depletion of glucoceramide, or accumulation or depletion of glycosphingolipids. Such diseases and conditions may include, but are not limited to, neurological diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis (ALS); lysosomal storage diseases, including Gaucher disease, Niemann-Pick disease type C, mucolipidemia type IV, and Sandhof's disease; or liver diseases, including non-alcoholic steatohepatitis (NASH).

[0218] The efficacy of compounds in treating pathologies associated with lysosomal storage diseases (e.g., Gaucher disease, Niemann-Pick disease type C, mucolipid storage disease type IV, or Sandhof disease) can be demonstrated using standard techniques, such as testing the ability of compounds to prevent, treat, or improve disease symptoms in established cellular and / or transgenic animal disease models. 12,13,15,16,25 .

[0219] This document describes various alternative embodiments and examples of the invention. These embodiments and examples are illustrative and should not be construed as limiting the scope of the invention.

[0220] Example

[0221] The following examples are intended to illustrate embodiments of the present invention and are not intended to be interpreted in a limiting manner.

[0222] abbreviation

[0223] ABCN = 1,1'-azobis(cyclohexanecarboxynitrile)

[0224] BzCl = Benzoyl chloride

[0225] DAST = diethylaminosulfur trifluoride

[0226] DCM = dichloromethane

[0227] DIAD = diisopropyl azodicarbonate

[0228] DIPEA = diisopropylethylamine

[0229] DMA = dimethylacetamide

[0230] DMAP = 4-Dimethylaminopyridine

[0231] DMF = N,N-dimethylformamide

[0232] DMP = Des Martin periodine

[0233] Et₂O = Diethyl ether

[0234] HOAc = Acetic acid

[0235] LAH = Lithium Aluminum Hydrogen

[0236] MeOH = methanol

[0237] MsCl = Methylsulfonyl chloride

[0238] RT = room temperature

[0239] TBDMSCl = tert-butyldimethylsilyl chloride

[0240] TFA = 2,2,2-trifluoroacetic acid

[0241] THF = Tetrahydrofuran

[0242] Example 1

[0243] (2R,3R,4R,5S)-1-(cyclohexylmethyl)-2-methylpiperidine-3,4,5-triol

[0244]

[0245] HOAc (0.10 mL, 1.75 mmol) was added to a stirred solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (43 mg, 0.10 mmol) and cyclohexaneformin (23 mg, 0.20 mmol) in anhydrous MeOH (5 mL), and the mixture was stirred for 30 min. NaBH3CN (13 mg, 0.20 mmol) was added, and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was quenched at 0 °C with a saturated aqueous solution of NaHCO3. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid silica gel chromatography to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(cyclohexylmethyl)-2-methylpiperidine as an oil (49 mg, 95%). ESI MS m / z 514.32 [M+H] + .

[0246] At -78°C and N2, a solution of BCl3 (1M DCM solution, 0.70 mL, 0.70 mmol) was added to a 3 mL anhydrous DCM solution of the above-mentioned substance (49 mg, 0.096 mmol) under stirring. The mixture was stirred at 0°C for 2 h, and then quenched with anhydrous MeOH (1 mL). The mixture was stirred at ambient temperature for 10 min. The solvent was removed under vacuum, and the residue was dissolved in a 1 M NH3 MeOH solution (10 mL) and stirred for another 10 min, and then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-1-(cyclohexylmethyl)-2-methylpiperidine-3,4,5-triol as a white solid (15 mg, 64%). 1 HNMR (400MHz, CD3OD) δ3.52-3.42(m,1H),3.12(t,J=9.0Hz,1H),3.03(dd,J=11.4,4.8Hz,1H),2.96(t,J=9.1Hz,1H),2.57(dd,J=12.8 ,8.9Hz,1H),2.11-1.85(m,4H),1.79-1.63(m,4H),1.58-1.43(m,1H),1.39-1.20(m,3H),1.19(d,J=6.1Hz,3H),1.01-0.79(m,2H); ESI MS m / z 244.18[M+H] + .

[0247] Example 2

[0248] (2R,3R,4R,5S)-1-((4,4-dimethylcyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol

[0249]

[0250] PtO2 (48 mg, 0.21 mmol) was added to a HOAc (5 mL) solution of spiro[2.5]octane-6-ylmethanol (100 mg, 0.71 mmol). The mixture was treated with hydrogen (40 psi) for 18 h. The catalyst was filtered off through diatomaceous earth, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give (4,4-dimethylcyclohexyl)methanol (51 mg, 51%) as an oil. 1 H NMR (400MHz, CDCl3) δ3.50 (d, J = 6.4Hz, 2H), 1.70-1.55 (m, 3H), 1.49-1.37 (m, 3H), 1.29-1.08 (m, 4H), 0.93 (s, 3H), 0.90 (s, 3H).

[0251] At 0°C, DMP (194 mg, 0.46 mmol) was added to an anhydrous DCM (10 mL) solution of the above substance (50 mg, 0.35 mmol), and the mixture was stirred at 0°C for 2 hours. The mixture was slowly quenched with Na₂S₃O₅ solution. The mixture was extracted with DCM (3 × 10 mL). The combined organic layers were washed with water (2 × 10 mL), separated, and dried over Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give 4,4-dimethylcyclohexaneformaldehyde as an oil (30 mg, impure).

[0252] HOAc (0.10 mL, 1.75 mmol) was added to a stirred solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (30 mg, 0.072 mmol) and 4,4-dimethylcyclohexaneformaldehyde (30 mg, 0.21 mmol) in anhydrous DCM (5 mL), and the mixture was stirred for 30 min. NaBH3CN (13 mg, 0.20 mmol) was added, and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with a saturated aqueous solution of NaHCO3 at 0 °C. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 10 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-((4,4-dimethylcyclohexyl)methyl)-2-methylpiperidine as an oil (10 mg, 26%). ESI MS m / z 542.34 [M+H] + .

[0253] At -78°C and N2, a solution of BCl3 (1M DCM solution, 0.50 mL, 0.50 mmol) was added to a stirred solution of the above substance (10 mg, 0.018 mmol) in anhydrous DCM (3 mL). The mixture was stirred at 0°C for 2 h, then quenched with anhydrous MeOH (1 mL). The mixture was stirred at ambient temperature for 10 min. The solvent was removed under vacuum, and the residue was dissolved in a 1M NH3 MeOH solution (10 mL) and stirred for another 10 min, then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-1-((4,4-dimethylcyclohexyl)methyl)-2-methylpiperidin-3,4,5-triol, as a white solid (4 mg, 82%). 1H NMR (400MHz, CD3OD) δ3.52-3.43(m,1H),3.12(t,J=9.0Hz,1H),3.03(dd,J=11.4,4.8Hz,1H),2.96(t,J=9.1Hz,1H),2.62(dd,J=12.8, 8.9Hz,1H),2.11-1.93(m,3H),1.77-1.67(m,1H),1.57-1.48(m,1H),1.47-1.37(m,3H),1.33-1.01(m,7H),0.92(d,J=5.4Hz,6H); ESI MS m / z 272.20[M+H] + .

[0254] Example 3

[0255] (2R,3R,4R,5S)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol

[0256]

[0257] Under N2, a mixture of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.090 g, 0.22 mmol), 4,4-difluorocyclohexaneformaldehyde (0.080 g, 0.54 mmol), and NaBH(OAc)3 (0.13 g, 0.60 mmol) was stirred in DCM (8 mL) at room temperature for 16 hours. The reaction mixture was diluted with a saturated aqueous solution of NaHCO3. Extraction was performed with DCM (3 × 15 mL). 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 rapid chromatography (EtOAc / hexane, 1:9 to 1:6) to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidine as a clear oil (0.10 g, 84%); ESI MS m / z 550.309 [M+H] + .

[0258] A mixture of the above-mentioned substances (0.015 g, 0.027 mmol) and Pd(OH)₂ / C (20% by weight Pd, 0.015 g, 0.028 mmol) and an aqueous solution of HCl (5 N, 1 drop) was stirred overnight in MeOH (3 mL) under hydrogen atmosphere at one atmosphere. The mixture was filtered through a diatomaceous earth filter cake, and the filtrate was collected and concentrated to dryness. The residue was neutralized with a MeOH solution of 1 M NH₃ and purified on silica gel by rapid chromatography (1 M NH₃ / MeOH / DCM, 1:7) to give (2R,3R,4R,5S)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidin-3,4,5-triol (0.0067 g, 89%) as a white solid. 1 H NMR (400MHz, CD3OD) δ3.44(ddd,J=10.5,9.0,4.8Hz,1H),3.10(t,J=9.0Hz,1H),3.01(dd,J=11.3,4.8Hz,1H),2.92(t,J=9.0 Hz,1H),2.59(dd,J=12.9,9.2Hz,1H),2.05-1.93(m,6H),1.77-1.66(m,3H),1.63-1.58(m,1H),1.30-1.10(m,5H,including 1.17(d,J=6.1Hz,3H));ESI MSm / z280.162[M+H] + .

[0259] Example 4

[0260] (2R,3R,4R,5S)-1-((4,4-dichlorocyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol

[0261]

[0262] At -78 °C and N2, BCl3 (1.5 mL of 1.0 M DCM solution, 1.5 mmol) was added to an anhydrous DCM solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidine (0.10 g, 0.18 mmol), and the mixture was stirred at 0 °C for 3 h. The reaction mixture was cooled to -78 °C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with a few drops of saturated NaHCO3 and purified by rapid chromatography on silica gel (1 M NH3 in MeOH solution / DCM, 1:7) to give (2R,3R,4R,5S)-1-((4,4-dichlorocyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol, as a white solid (0.046 g, 80%).1 H NMR (500MHz, DMSO-d6) δ4.69-4.65(m,3H),3.25-3.18(m,1H),2.89(td,J=8.8,4.3Hz,1H),2.83(dd,J=11.2,4.7Hz,1H),2.69(td,J=8. 8,5.4Hz,1H),2.48-2.41(m,3H),2.30-2.17(m,2H),1.91-1.75(m,4H),1.68-1.57(m,2H),1.32-1.16(m,2H),1.05(d,J=6.0Hz,3H); ESI MS m / z 312.105[M+H] + .

[0263] Example 5

[0264] (2R,3R,4R,5S)-1-((4-ethylcyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol

[0265]

[0266] A mixture of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-(((1s,4S)-4-vinylcyclohexyl)methyl)piperidine (0.180 g, 0.333 mmol), Pd(OH)₂ / C (20% by weight Pd, 0.20 g, 0.38 mmol), and 5 drops of concentrated HCl was stirred overnight in MeOH (25 mL) under hydrogen and one atmosphere. The mixture was filtered through a diatomaceous earth filter cake, and the filtrate was collected and concentrated to dryness under reduced pressure. The residue was neutralized with a MeOH solution of 1 M NH₃ and purified by rapid chromatography (1 M NH₃ / MeOH / DCM, 1:6) on silica gel to give (2R,3R,4R,5S)-1-((4-ethylcyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol, as a white solid (0.083 g, 92%). 1 ¹H NMR indicates that the solid contains a mixture of cis and trans isomers, with a cis:trans ratio of 0.65:0.35. 1H NMR(400MHz,DMSO-d6)δ4.74-4.59(m,3H),3.26-3.14(m,1H),2.94-2.78( m,2H),2.76-2.57(m,1.65H),2.40(dd,J=12.6,9.2Hz,0.35H),1.90-1.80 (m,1.65H),1.79-1.69(m,2H),1.64-1.56(m,1H),1.51-1.11(m,9H),1.06 (d, J=6.0Hz, 1.65H), 1.03 (d, J=6.0Hz, 1.35H), 0.90-0.69 (m, 4.35H); ESI MS m / z 272.228[M+H] + .

[0267] Example 6

[0268] (2R,3R,4R,5S)-2-methyl-1-(((1s,4S)-4-vinylcyclohexyl)methyl)piperidine-3,4,5-triol

[0269]

[0270] SOCl2 (1.55 g, 13.0 mmol) was added dropwise to an anhydrous MeOH (25 mL) solution of cis-4-(hydroxymethyl)cyclohexanecarboxylic acid (1.00 g, 6.32 mmol), and the mixture was stirred at room temperature for 4 hours. The solvent was then removed under reduced pressure, and the residue was diluted with a saturated aqueous solution of NaHCO3. After extraction with DCM (3 × 30 mL), the combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure to obtain a clear liquid. The liquid was dissolved in anhydrous DMF (20 mL), and imidazole (1.36 g, 20.0 mmol) and TBDMSCl (1.51 g, 10.0 mmol) were added at 0 °C. After stirring at room temperature for 16 h, the reaction mixture was diluted with brine (60 mL) and extracted with EtOAc (3 × 30 mL). The combined extracts were washed with brine (2 × 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 rapid chromatography (EtOAc / hexane, 1:9) to give methyl (1S,4S)-methyl-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexanecarboxylate as a clear liquid (1.60 g, 88%, two steps).

[0271] At 0 °C and N2, LAH (0.380 g, 10.0 mmol) was added to an anhydrous THF (25 mL) solution of the above substance (1.60 g, 5.58 mmol), and the mixture was stirred at 0 °C for 2 hours. Wet sodium sulfate heptahydrate (50 g) was added to quench the reaction, and the suspension was stirred for 30 minutes. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by rapid chromatography (EtOAc / hexane, 1:4 to 1:2) to obtain a clear liquid. The liquid was dissolved in DCM (40 mL), and DMP (4.50 g, 10.6 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 h to form a white suspension. Hexane (50 mL) was added, and the suspension was filtered through a diatomaceous earth filter cake. The filtrate was collected and concentrated under reduced pressure, and the residue was purified on silica gel by rapid chromatography (EtOAc / hexane, 1:20 to 1:9) to give (1s,4s)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexaneformaldehyde as a clear liquid (0.98 g, 68%, two steps). 1 H NMR (400MHz, CDCl3) δ9.70 (s, 1H), 3.37 (d, J = 6.6Hz, 2H), 2.44-2.39 (m, 1H), 2.1 6-2.06(m,2H),1.70-1.45(m,5H),1.11-0.96(m,2H),0.87(s,9H),0.02(s,6H).

[0272] At 0°C, KO was added to an anhydrous THF (40 mL) solution of methyltriphenylphosphonium bromide (1.30 g, 3.61 mmol). tBu (0.390 g, 3.50 mmol) was added, and the mixture was stirred at 0 °C for 20 min. A solution of (1s,4s)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexaneformaldehyde (0.620 g, 2.41 mmol) in anhydrous THF (10 mL) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with a saturated aqueous NH4Cl solution. Extraction was then performed with EtOAc (2 × 30 mL). The combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was dissolved in anhydrous THF (20 mL) and cooled at 0 °C. TBAF (1.0 M in THF, 5.0 mL, 5.0 mmol) was added, and the mixture was stirred at room temperature for 1 h. After dilution with brine (30 mL), the mixture was extracted with EtOAc (3 × 20 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 rapid chromatography (EtOAc / hexane, 1:4 to 1:2) to give ((1s,4s)-4-vinylcyclohexyl)methanol as a clear oil (0.26 g, 77%, two steps).

[0273] A mixture of the above substances (0.260 g, 1.85 mmol) and DMP (1.10 g, 2.59 mmol) was stirred in DCM (40 mL) at room temperature for 1 hour to form a white suspension. Hexane (20 mL) was added, and the suspension was filtered through a diatomaceous earth filter cake. The filtrate was collected and concentrated under reduced pressure, and the residue was purified on silica gel by rapid chromatography (EtOAc / hexane, 1:5) to give (1s,4s)-4-vinylcyclohexaneformaldehyde as a clear liquid (0.190 g, 74%). 1 H NMR (400MHz, CDCl3) δ9.69 (s, 1H), 5.75 (ddd, J = 17.1, 10.4, 6.3Hz, 1H), 5.00-4.89 ( m,2H),2.42-2.37(m,1H),2.17-2.00(m,3H),1.73-1.55(m,4H),1.33-1.21(m,2H).

[0274] Under N2, a mixture of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.417 g, 1.00 mmol), (1s,4s)-4-vinylcyclohexaneformaldehyde (0.19 g, 1.4 mmol), and NaBH(OAc)3 (0.45 g, 2.1 mmol) was stirred in DCM (40 mL) at room temperature for 16 hours. The reaction mixture was diluted with a saturated aqueous solution of NaHCO3. Extraction was performed using DCM (3 × 20 mL). 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 rapid chromatography (EtOAc / hexane, 1:13 to 1:9) to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-(((1s,4S)-4-vinylcyclohexyl)methyl)piperidine as a clear oil (0.39 g, 72%).

[0275] At -78°C and N2, BCl3 (1.0 M DCM solution, 3.0 mL, 3.0 mmol) was added to an anhydrous DCM (6 mL) solution of the above substance (0.180 g, 0.333 mmol), and the mixture was stirred at 0°C for 3 hours. The reaction mixture was cooled at -78°C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with 1 M NH3 MeOH solution and purified on silica gel by rapid chromatography (1 M NH3 MeOH solution / DCM, 1:6) to give (2R,3R,4R,5S)-2-methyl-1-(((1S,4S)-4-vinylcyclohexyl)methyl)piperidine-3,4,5-triol, as a white solid (0.078 g, 87%). 1 H NMR(400MHz,CD3OD)δ5.88(ddd,J=17.4,10.5,6.3Hz,1H),5.02-4.93(m,2H),3.45(d dd,J=10.5,9.0,4.8Hz,1H),3.10(t,J=9.0Hz,1H),3.02(dd,J=11.3,4.8Hz,1H),2.9 4(t,J=9.1Hz,1H),2.75(dd,J=12.9,9.2Hz,1H),2.21-2.18(m,1H),2.06-2.00(m,1H ),1.96-1.91(m,2H),1.71-1.67(m,1H),1.62-1.35(m,8H),1.18(d,J=6.1Hz,3H); ESI MS m / z 270.213[M+H] + .

[0276] Examples 7 and 8

[0277] (2R,3R,4R,5S)-1-(((1s,4S)-4-isopropylcyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol and (2R,3R,4R,5S)-1-(((1r,4R)-4-isopropylcyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol

[0278]

[0279] A mixture of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.18 g, 0.43 mmol), 4-isopropylcyclohexaneformaldehyde (0.10 g, 0.65 mmol), and NaBH(OAc)3 (0.16 g, 0.75 mmol) was stirred in DCM (10 mL) at room temperature for 16 h under N2 conditions. The reaction mixture was diluted with saturated NaHCO3 (15 mL) aqueous solution and extracted with DCM (3 × 15 mL). 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 rapid chromatography (EtOAc / hexane, 1:16 to 1:10) to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(((1S,4S)-4-isopropylcyclohexyl)methyl)-2-methylpiperidine as a clear oil (0.099 g, 41%) and (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(((1r,4R)-4-isopropylcyclohexyl)methyl)-2-methylpiperidine as a clear oil (0.027 g, 11%).

[0280] At -78 °C and N2, BCl3 (1.5 mL of 1.0 M DCM solution, 1.5 mmol) was added to an anhydrous DCM solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(((1S,4S)-4-isopropylcyclohexyl)methyl)-2-methylpiperidine (0.098 g, 0.18 mmol) in 6 mL of N2, and the mixture was stirred at 0 °C for 3 h. The reaction mixture was cooled to -78 °C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with a 1M NH3 MeOH solution and purified on silica gel by rapid chromatography (1M NH3 MeOH solution / DCM, 1:6) to give (2R,3R,4R,5S)-1-(((1s,4S)-4-isopropylcyclohexyl)methyl)-2-methylpiperidin-3,4,5-triol, a white solid (0.045 g, 88%). 1H NMR (400MHz, DMSO-d6) δ4.67-4.64(m,3H),3.24-3.16(m,1H),2.89(td,J=8.8,4.3Hz,1H),2.83(dd,J=11.2,4.8Hz,1H),2.75-2.67(m,2H),1. 92-1.84(m,1H),1.76-1.67(m,3H),1.51-1.33(m,7H),1.30-1.21(m,2 H),1.07(d,J=6.0Hz,3H),1.04-1.01(m,1H),0.83(d,J=6.7Hz,6H); ESI MS m / z286.225[M+H] + .

[0281] At -78 °C and N2, BCl3 (1.0 mL of 1.0 M DCM solution, 1.0 mmol) was added to an anhydrous DCM solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(((1r,4R)-4-isopropylcyclohexyl)methyl)-2-methylpiperidine (0.027 g, 0.049 mmol) in 5 mL of N2, and the mixture was stirred at 0 °C for 3 hours. The reaction mixture was cooled to -78 °C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with a 1M NH3 MeOH solution and purified by rapid chromatography on silica gel (1M NH3 MeOH solution / DCM, 1:6) to give (2R,3R,4R,5S)-1-(((1r,4R)-4-isopropylcyclohexyl)methyl)-2-methylpiperidin-3,4,5-triol, a white solid (0.013 g, 92%). 1 H NMR (400MHz, CD3OD) δ3.49-3.42(m,1H),3.10(t,J=9.1Hz,1H),3.02(dd,J=11.3,4.8Hz,1H),2.95(t,J=9.1Hz,1H),2.53(dd,J= 12.8,8.8Hz,1H),2.07-1.91(m,4H),1.77-1.71(m,3H),1.50-1.35(m,3H),1.17(d,J=6.1Hz,3H),1.02-0.80(m,10H,including 0.88(d,J=6.8Hz,6H)); ESI MS m / z286.226[M+H] + .

[0282] Examples 9 and 10

[0283] (2R,3R,4R,5S)-1-(((1s,4S)-4-(tert-butyl)cyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol and (2R,3R,4R,5S)-1-(((1r,4R)-4-(tert-butyl)cyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol

[0284]

[0285] A mixture of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.18 g, 0.43 mmol), 4-(tert-butyl)cyclohexanecarboxaldehyde (0.15 g, 0.89 mmol), and NaBH(OAc)3 (0.16 g, 0.75 mmol) was stirred in DCM (10 mL) at room temperature for 16 h under N2 conditions. The reaction mixture was diluted with saturated NaHCO3 (15 mL) aqueous solution and extracted with DCM (3 × 15 mL). 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 rapid chromatography (EtOAc / hexane, 1:16 to 1:10) to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(((1S,4S)-4-(tert-butyl)cyclohexyl)methyl)-2-methylpiperidine as a clear oil (0.080 g, 33%) and (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(((1r,4R)-4-(tert-butyl)cyclohexyl)methyl)-2-methylpiperidine as a clear oil (0.088 g, 36%).

[0286] At -78 °C and N2, BCl3 (1.5 mL of 1.0 M DCM solution, 1.5 mmol) was added to an anhydrous DCM solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(((1S,4S)-4-(tert-butyl)cyclohexyl)methyl)-2-methylpiperidine (0.080 g, 0.14 mmol) in 8 mL. The mixture was stirred at 0 °C for 3 hours. The reaction mixture was cooled to -78 °C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with a 1M NH3 MeOH solution and purified by rapid chromatography on silica gel (1M NH3 MeOH solution / DCM, 1:6) to give (2R,3R,4R,5S)-1-(((1s,4S)-4-(tert-butyl)cyclohexyl)methyl)-2-methylpiperidin-3,4,5-triol, a white solid (0.038 g, 91%). 1H NMR(400MHz,DMSO-d6)δ4.67-4.64(m,3H),3.24-3.16(m,1H),2.92-2.81(m,3H),2.74-2.68(m,1H),1.92-1.85(m,1H) ),1.79-1.68(m,4H),1.55-1.42(m,4H),1.28-1.18(m,1H),1.07(d,J=6.0Hz,3H),1.05-0.91(m,3H),0.81(s,9H); ESI MS m / z 300.244[M+H] + .

[0287] At -78 °C and N2, BCl3 (1.5 mL of 1.0 M DCM solution, 1.5 mmol) was added to an anhydrous DCM solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(((1r,4R)-4-(tert-butyl)cyclohexyl)methyl)-2-methylpiperidine (0.088 g, 0.15 mmol) in 8 mL of N2, and the mixture was stirred at 0 °C for 3 hours. The reaction mixture was cooled to -78 °C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with 1M NH3 in MeOH solution and purified by rapid chromatography on silica gel (1M NH3 in MeOH solution / DCM, 1:6) to give (2R,3R,4R,5S)-1-(((1r,4R)-4-(tert-butyl)cyclohexyl)methyl)-2-methylpiperidin-3,4,5-triol, a white solid (0.043 g, 93%). 1 H NMR (400MHz, DMSO-d6) δ4.66-4.63(m,3H),3.24-3.16(m,1H),2.88(td,J=8.8,4.3Hz,1H),2.82(dd,J=11.2,4.7Hz,1H),2.73-2.67(m,1H),2.39 ESIMS m / z 300.245[M+H] + .

[0288] Examples 11 and 12

[0289] (2R,3R,4R,5S)-2-methyl-1-(((1s,4S)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol and (2R,3R,4R,5S)-2-methyl-1-(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol

[0290]

[0291] Under N2, a mixture of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.195 g, 0.467 mmol), 4-(trifluoromethyl)cyclohexanecarboxaldehyde (0.150 g, 0.842 mmol), and NaBH(OAc)3 (0.212 g, 1.00 mmol) was stirred in DCM (10 mL) at room temperature for 16 hours. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (15 mL) and extracted with DCM (3 × 15 mL). 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 rapid chromatography (EtOAc / hexane, 1:12 to 1:7) to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-(((1s,4S)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine as a clear oil (0.101 g, 37%) and (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine as a clear oil (0.047 g, 17%); ESI MS m / z 582.303 [M+H] + .

[0292] At -78 °C and N2, BCl3 (1.5 mL of 1.0 M DCM solution, 1.5 mmol) was added to an anhydrous DCM solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-(((1s,4S)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine (0.10 g, 0.17 mmol) in 5 mL of N2, and the mixture was stirred at 0 °C for 3 hours. The reaction mixture was cooled to -78 °C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with a 1M NH3 MeOH solution and purified by rapid chromatography on silica gel (1M NH3 MeOH solution / DCM, 1:6) to give (2R,3R,4R,5S)-2-methyl-1-(((1s,4S)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol, a white solid (0.047 g, 89%). 1H NMR (400MHz, DMSO-d6) δ4.67-4.65(m,3H),3.25-3.18(m,1H),2.90(td,J=8.8,4.3Hz,1H),2.83(dd,J=11.2,4.8Hz,1H),2.78-2.6 8(m,2H),2.30-2.22(m,1H),1.93-1.86(m,1H),1.79-1.72(m,3H),1.65-1.50(m,4H),1.46-1.34(m,4H),1.07(d,J=6.0Hz,3H); ESI MS m / z312.170[M+H] + .

[0293] At -78 °C and N2, BCl3 (1.5 mL of 1.0 M DCM solution, 1.5 mmol) was added to an anhydrous DCM solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine (0.047 g, 0.081 mmol) in 3 mL. The mixture was stirred at 0 °C for 3 hours. The reaction mixture was cooled to -78 °C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with a 1M NH3 MeOH solution and purified by rapid chromatography on silica gel (1M NH3 MeOH solution / DCM, 1:6) to give (2R,3R,4R,5S)-2-methyl-1-(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol, a white solid (0.021 g, 84%). 1 H NMR (400MHz, DMSO-d6) δ4.67-4.64(m,3H),3.25-3.18(m,1H),2.90(td,J=8.8,4 .3Hz,1H),2.83(dd,J=11.2,4.7Hz,1H),2.70(td,J=8.8,5.4Hz,1H),2.42(dd,J =11.7,9.3Hz,1H),2.22-2.10(m,1H),1.93-1.67(m,7H),1.45-1.35(m,1H),1.3 0-1.14(m,2H),1.04(d,J=6.0Hz,3H),0.97-0.87(m,1H),0.85-0.75(m,1H);ESI MS m / z 312.164 [M+H] + .

[0294] Examples 13 and 14

[0295] (2R,3R,4R,5S)-1-(((1s,4S)-4-(2-fluoroprop-2-yl)cyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol and (2R,3R,4R,5S)-1-(((1r,4R)-4-(2-fluoroprop-2-yl)cyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol

[0296]

[0297] SOCl2 (1.55 g, 13.0 mmol) was added dropwise to an anhydrous MeOH (25 mL) solution of 1.00 g (6.32 mmol) of 4-(hydroxymethyl)cyclohexanecarboxylic acid, and the mixture was stirred at room temperature for 4 hours. The solvent was then removed under reduced pressure, and the residue was diluted with saturated NaHCO3 aqueous solution (30 mL), extracted with DCM (3 × 30 mL), and the combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure to obtain a clear liquid. The liquid was dissolved in anhydrous THF (40 mL), and MeMgBr (3.0 M in Et2O, 10 mL, 30 mmol) was added at 0 °C. After stirring at room temperature for 16 hours, the reaction mixture was diluted with saturated NH4Cl aqueous solution (50 mL) and extracted with EtOAc (5 × 50 mL). 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 rapid chromatography (EtOAc) to give 2-(4-(hydroxymethyl)cyclohexyl)prop-2-ol as a white solid (1.05 g, 96%, two steps). 1 ¹H NMR indicates that the solid contains a mixture of cis and trans isomers, with a cis:trans ratio of 0.82:0.18.

[0298] At 0 °C and N2, DIPEA (1.41 g, 10.9 mol), DMAP (0.24 g, 2.0 mmol), and BzCl (1.29 g, 9.18 mmol) were added to an anhydrous DCM (30 mL) solution of the above substances (1.05 g, 6.09 mmol). The mixture was stirred at room temperature for 16 hours, then diluted with a saturated NaHCO3 aqueous solution (50 mL), extracted with DCM (3 × 50 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 rapid chromatography (EtOAc / hexane, 1:4 to 1:1) to give methyl benzoate (4-(2-hydroxypropyl-2-yl)cyclohexyl) as a clear oil (1.68 g, 100%). 1 ¹H NMR indicates that the oil contains a mixture of cis and trans isomers (cis:trans = 0.82:0.18).

[0299] DAST (1.45 g, 9.06 mmol) was added to an anhydrous DCM (30 mL) solution of the above substance (1.65 g, 5.97 mmol) at -78 °C and N2. The mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled at -78 °C and quenched with a saturated NaHCO3 aqueous solution (50 mL). The organic layer was collected, and the aqueous layer was extracted with DCM (3 × 40 mL). 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 rapid chromatography (EtOAc / hexane, 1:19) to give methyl benzoate (4-(2-fluoroprop-2-yl)cyclohexyl) as a clear oil (1.07 g, 66%). 1 HNMR analysis indicated that the oil contained a mixture of cis and trans isomers (cis:trans = 0.82:0.18).

[0300] A mixture of the above substances (0.850 g, 3.05 mmol) and K₂CO₃ (0.80 g, 0.58 mmol) was stirred in MeOH (60 mL) at room temperature for 4 hours. The solvent was removed under reduced pressure, and the residue was diluted with a saturated aqueous solution of NaHCO₃ (40 mL), extracted with DCM (3 × 40 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 rapid chromatography (EtOAc / hexane, 1:1 to 3:2) to give (4-(2-fluoroprop-2-yl)cyclohexyl)methanol as a clear oil (0.49 g, 92%). 1 ¹H NMR indicates that the oil contains a mixture of cis and trans isomers (cis:trans = 0.82:0.18).

[0301] A mixture of the above substances (0.47 g, 2.7 mmol) and DMP (1.7 g, 4.0 mmol) was stirred in DCM (30 mL) at room temperature for 1.5 hours to form a white suspension. Hexane (20 mL) was added, and the suspension was filtered through a diatomaceous earth filter cake. The filtrate was collected and concentrated under reduced pressure, and the residue was purified on silica gel by rapid chromatography (EtOAc / hexane, 1:13 to 1:9) to give cis-4-(2-fluoroprop-2-yl)cyclohexaneformaldehyde as a clear liquid (0.21 g, 44%). 1¹H NMR (400 MHz, CDCl₃) δ 9.72 (s, ¹H), 2.50–2.43 (m, ¹H), 2.37–2.27 (m, 2H), 1.78–1.67 (m, 2H), 1.62–1.45 (m, 3H), 1.27 (s, 3H), 1.21 (s, 3H), 1.07–0.96 (m, 2H). Trans-4-(2-fluoroprop-2-yl)cyclohexanecarboxaldehyde was also isolated as a white solid (impure, estimated value 0.045 g, estimated 10%).

[0302] Under N2, a mixture of cis-4-(2-fluoroprop-2-yl)cyclohexanecarboxaldehyde (0.10 g, 0.58 mmol), (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.20 g, 0.48 mmol), and NaBH(OAc)3 (0.17 g, 0.80 mmol) was stirred in DCM (6 mL) at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 solution (20 mL) and extracted with DCM (3 × 20 mL). 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 rapid chromatography (EtOAc / hexane, 1:12 to 1:8) to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(((1s,4S)-4-(2-fluoroprop-2-yl)cyclohexyl)methyl)-2-methylpiperidine as a clear oil (0.24 g, 87%).

[0303] The mixture of the above-mentioned substance (0.24 g, 0.42 mmol) and Pd(OH)₂ / C (20% by weight Pd, 0.080 g, 0.15 mmol) and 4 drops of concentrated HCl in MeOH solution (20 mL) was stirred overnight under hydrogen atmosphere at one atmosphere. The mixture was filtered through a diatomaceous earth filter cake, the filtrate was collected and concentrated to dryness. The residue was dissolved in anhydrous pyridine (3 mL) and Ac₂O (0.5 mL) was added at 0 °C. The mixture was stirred at room temperature for 16 hours and diluted with saturated NaHCO₃ aqueous solution (20 mL), extracted with EtOAc (2 × 20 mL), and the combined extracts were dried over anhydrous Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure, and the residue was treated with 1 M NH₃ in MeOH solution (5 mL) at room temperature for 16 hours. After concentration under reduced pressure, the residue was purified on silica gel by rapid chromatography (1M NH3 / MeOH / DCM, 1:6) to obtain (2R,3R,4R,5S)-1-(((1s,4S)-4-(2-fluoroprop-2-yl)cyclohexyl)methyl)-2-methylpiperidin-3,4,5-triol (0.098 g, 77%, three steps), as a white solid. 1H NMR (400MHz, CD3OD) δ3.45 (ddd, J=10.6, 9.1, 4.8Hz, 1H), 3.11 (t, J=9.0Hz, 1H), 3.04-2.92 (m, 3H), 2.10- 2.03(m,1H),1.95-1.86(m,4H),1.66-1.37(m,6H),1.29(s,3H),1.24(s,3H),1.24-1.15(m,5H,including 1.20(d,J=6.1Hz,3H)); ESI MS m / z304.226[M+H] + .

[0304] Under N2, a mixture of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.16 g, 0.38 mmol), trans-4-(2-fluoroprop-2-yl)cyclohexaneformaldehyde (0.040 g, ~90% pure, 0.20 mmol) and NaBH(OAc)3 (0.17 g, 0.80 mmol) was stirred in DCM (6 mL) at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 solution (20 mL) and extracted with DCM (3 × 20 mL). 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 rapid chromatography (EtOAc / hexane, 1:12 to 1:8) to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(((1r,4R)-4-(2-fluoroprop-2-yl)cyclohexyl)methyl)-2-methylpiperidine as a clear oil (0.061 g, 51%).

[0305] A mixture of the above substances (0.0600 g, 0.105 mmol), Pd(OH)₂ / C (20% by weight Pd, 0.050 g, 0.094 mmol), and two drops of concentrated HCl in MeOH (15 mL) solution was stirred overnight under hydrogen atmosphere at one atmosphere. The mixture was filtered through a diatomaceous earth filter cake, and the filtrate was collected and concentrated to dryness. The residue was dissolved in anhydrous pyridine (3 mL), and Ac₂O (0.5 mL) was added to it at 0 °C. The mixture was stirred at room temperature for 16 hours, diluted with saturated NaHCO₃ aqueous solution (20 mL), extracted with EtOAc (2 × 20 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 rapid chromatography (EtOAc / hexane, 1:6 to 1:4) to give white foam. The white foam was stirred with 1 M NH₃ in MeOH (5 mL) solution at room temperature for 16 hours. After concentration under reduced pressure, the residue was purified on silica gel by rapid chromatography (1M NH3 MeOH / DCM, 1:6) to give (2R,3R,4R,5S)-1-(((1r,4R)-4-(2-fluoroprop-2-yl)cyclohexyl)methyl)-2-methylpiperidin-3,4,5-triol (0.0037 g, 12%, three steps), as a white solid. 1 H NMR (400MHz, CD3OD) δ3.46 (ddd, J=10.6, 9.1, 4.8Hz, 1H), 3.10 (t, J=9.0Hz, 1H ),3.02(dd,J=11.4,4.8Hz,1H),2.94(t,J=9.1Hz,1H),2.55(dd,J=12.9,9.0H z,1H),2.10-1.95(m,4H),1.87-1.75(m,3H),1.52-1.42(m,2H),1.29(s,3H), 1.24(s,3H),1.17(d,J=6.1Hz,3H),1.17-1.02(m,2H),0.99-0.80(m,2H);ESI m / z 304.230[M+H] + .

[0306] Example 15

[0307] (2R,3R,4R,5S)-2-methyl-1-(((trans)-3-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol

[0308]

[0309] Under Ar conditions, NaBH3CN (40 mg, 95%, 0.60 mmol) was added to an anhydrous MeOH (5 mL) solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-(piperidin-4-ylmethyl)piperidine (186 mg, 0.36 mmol), trans-3-(trifluoromethyl)cyclohexanecarboxaldehyde (100 mg, 0.55 mmol), and HOAc (three drops). The mixture was stirred at room temperature for 18 hours. An aqueous solution of NaHCO3 (30 mL) was added, and the mixture was extracted with EtOAc (3 × 30 mL). 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 rapid chromatography using 20% ​​EtOAc in hexane to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-((3-(trifluoromethyl)cyclohexyl)methyl)piperidine as a white foam (140 mg, 67%). 1 1H NMR indicates that the material is a mixture of two stereoisomers.

[0310] At -78°C and under Ar conditions, a BCl3 solution (2.4 mL, 1 M DCM solution, 2.40 mmol) was added to an anhydrous DCM (2 mL) solution of the above substance (140 mg, 0.24 mmol). The mixture was stirred at -78°C for 1 h and then at 0°C for 4 h; then MeOH (20 mL) was added. The mixture was stirred at 0°C for another 2 h and then evaporated to dryness under reduced pressure. The residue was purified on silica gel by rapid chromatography (dry loading) using a solution of 10% MeOH and 2% NH3 in DCM to give a mixture of (2R,3R,4R,5S)-2-methyl-1-(((1S,3S)-3-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol and (2R,3R,4R,5S)-2-methyl-1-(((1R,3R)-3-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol (16) as a white foam (46 mg, 61%). 1 H NMR(400MHz,DMSO)δ4.70-4.66(m,3H),3.24-3.18(m,1H),3.04-2.59(m,4H),2 .30-2.78(m,1H),2.12-1.66(m,5H),1.65-1.17(m,7H),1.16-0.90(m,3H);ESI MS m / z 312.16[M+H] + .

[0311] Example 16

[0312] (2R,3R,4R,5S)-2-methyl-1-((cis)-3-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol

[0313]

[0314] Under Ar conditions, NaBH3CN (36 mg, 95%, 0.54 mmol) was added to an anhydrous MeOH (5 mL) solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-(piperidin-4-ylmethyl)piperidine (186 mg, 0.36 mmol), cis-3-(trifluoromethyl)cyclohexanecarboxaldehyde (98 mg, 0.54 mmol), and HOAc (three drops). The mixture was stirred at room temperature for 18 hours. An aqueous solution of NaHCO3 (30 mL) was added, and the mixture was extracted with EtOAc (3 × 30 mL). The combined organic extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by rapid chromatography using 20% ​​EtOAc in hexane to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-((3-(trifluoromethyl)cyclohexyl)methyl)piperidine as a white foam (100 mg, 48%). 1 HNMR indicates that the substance is a mixture of two stereoisomers.

[0315] At -78°C and under Ar conditions, a BCl3 solution (1.7 mL, 1 M DCM solution, 1.70 mmol) was added to an anhydrous DCM (2 mL) solution of the above substance (100 mg, 0.17 mmol). The mixture was stirred at -78°C for 1 h and then at 0°C for 4 h; then MeOH (20 mL) was added. The mixture was stirred at 0°C for another 2 h and then evaporated to dryness under reduced pressure. The residue was purified on silica gel by rapid chromatography (dry loading) using a solution of 10% MeOH and 2% NH3 in DCM to give a mixture of (2R,3R,4R,5S)-2-methyl-1-(((1R,3S)-3-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol and (2R,3R,4R,5S)-2-methyl-1-(((1S,3R)-3-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol as a white foam (38 mg, 67%). 1H NMR (400MHz, DMSO) δ4.68-4.57(m,3H),3.23-3.19(m,1H),2.96-2.78(m,2H),2.77-2.65(m,1H),2.48-2.44( m,1H),2.27-2.21(m,1H),2.15-1.44(m,8H),1.42-1.10(m,2H),1.05(d,J=6.0Hz,3H),0.85-0.50(m,2H); ESI MS m / z312.16[M+H] + .

[0316] Examples 17 and 18

[0317] (2R,3R,4R,5S)-1-(((1s,4S)-4-methoxycyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol and (2R,3R,4R,5S)-1-(((1r,4R)-4-methoxycyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol

[0318]

[0319] LAH (245 mg, 6.45 mmol) was added to an anhydrous THF (10 mL) solution of 4-methoxycyclohexanecarboxylic acid (340 mg, 2.15 mmol) at 0 °C, and the mixture was stirred at 0 °C for 1 hour. The mixture was slowly quenched with saturated NaHCO3 and filtered. The solid was washed with EtOAc. The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure to give crude (4-methoxycyclohexyl)methanol as an oil (320 mg).

[0320] At 0°C, DMP (689 mg, 1.63 mmol) was added to an anhydrous DCM (10 mL) solution of the above substance (180 mg, 1.25 mmol), and the mixture was stirred at 0°C for 2 hours. The mixture was slowly quenched with Na2S3O5 solution. The mixture was extracted with DCM (3 × 20 mL). The combined organic layers were washed with water (2 × 10 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give (1S,4S)-4-methoxycyclohexaneformaldehyde as an oil (67 mg, 38%). 1¹H NMR (400MHz, CDCl₃) δ 9.64 (d, J = 1.3 Hz, 1H), 3.39 (dq, J = 5.7, 2.9 Hz, 1H), 3.33 (s, 3H), 2.28 (ttd, J = 8.9, 4.2, 1.2 Hz, 1H), 1.93–1.74 (m, 4H), 1.73–1.55 (m, 4H). (1r, 4r)-4-methoxycyclohexaneformaldehyde was also isolated as an oil (20 mg, 11%). 1 H NMR (400MHz, CDCl3) δ9.67 (d, J = 1.3Hz, 1H), 3.38 (s, 3H), 3.20-3.08 (m, 1H), 2.31-2.20 (m, 1H), 2.16-2.00 (m, 4H), 1.45-1.25 (m, 4H).

[0321] HOAc (0.10 mL, 1.75 mmol) was added to a stirred solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (80 mg, 0.19 mmol) and (1s,4s)-4-methoxycyclohexaneformaldehyde (55 mg, 0.39 mmol) in anhydrous MeOH (5 mL), and the mixture was stirred for 30 min. NaBH3CN (24 mg, 0.39 mmol) was added, and the resulting mixture was stirred at room temperature for 18 h. The reaction was quenched at 0 °C with a saturated aqueous solution of NaHCO3, and the mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to obtain (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(((1s,4S)-4-methoxycyclohexyl)methyl)-2-methylpiperidine as an oil (92 mg, 95%). 1 H NMR (400MHz, CDCl3) δ7.40-7.26 (m, 15H), 4.97 (dd, J = 13.3, 10.9Hz, 2H), 4.85 (d, J = 11. 0Hz,1H),4.78-4.57(m,3H),3.59(td,J=9.8,4.5Hz,1H),3.51(t,J=9.0Hz,1H),3.43(s, 1H),3.33(s,3H),3.16-2.98(m,2H),2.57(dd,J=12.8,8.6Hz,1H),2.26(dd,J=9.3,6.0 Hz, 1H), 2.10-1.93 (m, 2H), 1.90-1.80 (m, 2H), 1.62-1.22 (m, 7H), 1.19 (d, J = 6.1Hz, 3H).

[0322] Pd(OH)₂ / C (20 wt.%, 8.6 mg, 0.012 mmol) and 6N HCl (0.1 mL) were added to a 10 mL EtOH solution of the above substance (90 mg, 0.16 mmol). The mixture was treated with hydrogen (1 atm) for 18 h. The catalyst was filtered off through diatomaceous earth, and the solvent was evaporated under reduced pressure. The residue was dissolved in a 1 M NH₃ MeOH solution (10 mL) and stirred for another 10 min, then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-1-(((1s,4S)-4-methoxycyclohexyl)methyl)-2-methylpiperidin-3,4,5-triol, a white solid (30 mg, 67%). 1 H NMR (400MHz, CD3OD) δ3.51-3.43(m,2H),3.32(s,3H),3.12(t,J=9.0Hz,1H),3.03(dd,J=11.4,4.8Hz,1H),2.95(t,J=9.1Hz,1H),2.63(dd,J =12.8,8.9Hz,1H),2.09-2.01(m,1H),2.00-1.92(m,2H),1.91-1.82(m,2H),1.67-1.41(m,5H),1.36-1.23(m,2H),1.19(d,J=6.1Hz,3H); ESI MS m / z274.20[M+H] + .

[0323] HOAc (0.10 mL, 1.75 mmol) was added to a stirred solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (40 mg, 0.096 mmol) and (1r,4r)-4-methoxycyclohexaneformaldehyde (20 mg, 0.14 mmol) in anhydrous MeOH (5 mL), and the mixture was stirred for 30 min. NaBH3CN (12 mg, 0.19 mmol) was added, and the resulting mixture was stirred at room temperature for 18 h. The reaction was quenched at 0 °C with a saturated aqueous solution of NaHCO3, and the mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to obtain (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(((1r,4R)-4-methoxycyclohexyl)methyl)-2-methylpiperidine as an oil (34 mg, 65%).

[0324] Pd(OH)₂ / C (20 wt.%, 8.6 mg, 0.012 mmol) and 6N HCl (0.1 mL) were added to a 10 mL EtOH solution of the above substance (30 mg, 0.055 mmol). The mixture was treated with hydrogen (1 atm) for 18 h. The catalyst was filtered off through diatomaceous earth, and the solvent was evaporated under reduced pressure. The residue was dissolved in a 1 M NH₃ MeOH solution (10 mL) and stirred for another 10 min, then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-1-(((1r,4R)-4-methoxycyclohexyl)methyl)-2-methylpiperidin-3,4,5-triol, a white solid (12 mg, 80%). 1 H NMR (400MHz, CD3OD) δ3.51-3.43(m,1H),3.36(s,3H),3.21-3.08(m,2H),3.03(dd,J=11.4,4.8Hz,1H),2.95(t,J=9.1Hz,1H),2 .55(dd,J=12.8,8.9Hz,1H),2.15-1.92(m,6H),1.81-1.72(m,1H),1.54-1.40(m,1H),1.27-1.08(m,5H),1.05-0.83(m,2H); ESI MS m / z 274.20[M+H] + .

[0325] Example 19

[0326] (2R,3R,4R,5S)-1-((4-(methoxymethyl)cyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol

[0327]

[0328] Under Ar conditions, NaBH(OAc)3 (84 mg, 0.39 mmol) was added to an anhydrous DCM (5 mL) solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-(piperidin-4-ylmethyl)piperidine (82 mg, 0.19 mmol) and 4-(methoxymethyl)cyclohexaneformaldehyde (33 mg, 0.21 mmol). The mixture was stirred at room temperature for 18 hours. An aqueous solution of NaHCO3 (30 mL) was added, and the mixture was extracted with EtOAc (3 × 30 mL). The combined organic extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by rapid chromatography using 20% ​​EtOAc in hexane to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-((4-(methoxymethyl)cyclohexyl)methyl)-2-methylpiperidine, a mixture of cis and trans isomers (92 mg, 85%).

[0329] At -78°C and Ar, a solution of BCl3 (1.3 mL, 1 M DCM solution, 1.3 mmol) was added to an anhydrous DCM (5 mL) solution of the above substance (92 mg, 0.17 mmol). The mixture was stirred at -78°C for 1 h and at 0°C for 4 h; MeOH (20 mL) was added. The mixture was stirred at 0°C for another 2 h and evaporated to dryness. The residue was purified by rapid chromatography on silica gel using a solution of 10% MeOH and 2% NH3 in DCM to give a mixture of (2R,3R,4R,5S)-1-((4-(methoxymethyl)cyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol as a white foam (35 mg, 74%); this substance was separated into a mixture of cis and trans isomers. 1 H NMR (400MHz, CD3OD) δ3.57-3.40(m,1H),3.35-3.31(m,3.5H),3.22(d,J=6.4Hz,1 .5H),3.18-3.09(m,1H),3.04(dd,J=11.3,4.8Hz,1H),2.97(t,J=9.1Hz,1H),2.8 1(dd,J=12.9,9.3Hz,0.25H),2.81(dd,J=12.9,9.3Hz,0.75H),2.17-1.90(m,4H) ,1.87-1.69(m,2H),1.56-1.33(m,4H),1.57-1.54(m,3H),1.11-0.75(m,3H);ESI MSm / z 288.2 [M+H] + .

[0330] Example 20

[0331] (2R,3R,4R,5S)-1-(((1s,4S)-4-cyclopropylcyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol

[0332]

[0333] Under ice cooling, a borane-dimethyl sulfide complex (2.25 g, 29.7 mmol) was added to a THF (100 mL) solution of cis-cyclohexane-1,4-dicarboxylic acid monomethyl ester (3.7 g, 19.8 mmol). The mixture was stirred for 15 minutes and then stirred at room temperature for 4 hours. MeOH (5 mL) was added, and the mixture was evaporated under reduced pressure. 1 M NaOH (20 mL) was added to the residue, and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (EtOAc / hexane, 1:4) on silica gel to give (1S,4S)-methyl-4-(hydroxymethyl)cyclohexanecarboxylate methyl ester (2.35 g, 69%) as an oil. 1 H NMR (500MHz, CDCl3) δ3.65 (s, 3H), 3.45 (dd, J = 6.3, 0.9Hz, 2H), 2.56-2.53 (m, 1 H),2.01-1.94(m,2H),1.89-1.85(m,1H),1.63-1.49(m,5H),1.31-1.21(m,2H).

[0334] At 0°C, DMP (2.8 g, 6.7 mmol) was added to an anhydrous DCM (35 mL) solution of the above-mentioned substance (0.78 g, 4.52 mmol) under stirring. After stirring at room temperature for 2 hours, the reaction mixture was quenched with a 1:1 mixture of 1 M Na₂S₂O₃: saturated NaHCO₃ (20 mL) and stirred further for 30 min, then diluted with DCM (40 mL). The organic matter was separated, dried over anhydrous Na₂SO₄, and concentrated. The crude residue was purified by rapid chromatography (EtOAc / hexane, 1:4) on silica gel to give methyl (1S,4S)-4-formylcyclohexanecarboxylate (0.57 g, 74%) as an oil. 1 H NMR (400MHz, CDCl3) δ9.61(s,1H),3.61(s,3H),2.45-2.37(m,1H),2.35-2.29(m,1H),1.94-1.85(m,2H),1.75-1.59(m,6H).

[0335] At 0 °C, KOtBu (0.5 g, 4.4 mmol) was added to a mixture of methyltriphenylphosphonium bromide (1.5 g, 4.4 mmol) and anhydrous THF (15 mL). The mixture was stirred for 30 min, and then methyl (1S,4S)-methyl-4-formylcyclohexanecarboxylate (0.5 g, 2.9 mmol) pre-dissolved in anhydrous THF (10 mL). The mixture was warmed to room temperature and stirred for 2 h, and then concentrated under reduced pressure. The resulting crude residue was purified by rapid chromatography (EtOAc / hexane, 1:4) on silica gel to give methyl (1S,4S)-methyl-4-vinylcyclohexanecarboxylate (0.5 g, 68%) as an oil. 1 H NMR (400MHz, CDCl3) δ5.78 (ddd, J=17.1, 10.5, 6.3Hz, 1H), 4.98-4.89 (m, 2H), 3.65 (s, 3H), 2.50 (ddd, J=10.4,5.9,4.4Hz,1H),2.16-2.05(m,1H),2.03-1.92(m,2H),1.63-1.51(m,4H),1.46-1.36(m,2H).

[0336] At 0 °C, diethylzinc (1.0 M hexane, 3.5 mL, 3.5 mmol) was added to a mixture of the above substances (0.20 g, 1.18 mmol) and DCE (8 mL), followed by chloroiodomethane (0.51 mL, 7.08 mmol). The mixture was stirred at 0 °C for 2 h, then at room temperature for 2 h, and quenched with a saturated aqueous NH4Cl solution. The reaction mixture was partitioned between DCM and water, the organic matter was separated, dried over anhydrous Na2SO4, and concentrated. The crude residue was purified on silica gel by rapid chromatography (EtOAc / hexane, 1:4) to give methyl (1S,4S)-methyl-4-cyclopropylcyclohexanecarboxylate (0.18 g, 83.6%) as an oil. 1 HNMR(400MHz, CDCl3)δ3.67(s,3H),2.48(tt,J=6.3,4.3Hz,1H),2.02-1.92(m,2H),1.64-1.49(m,4 H),1.48-1.38(m,2H),0.71-0.62(m,1H),0.61-0.51(m,1H),0.41-0.32(m,2H),0.04-0.03(m,2H).

[0337] Under Ar conditions and with stirring, 0.11 g (3.12 mmol) of LAH was added in portions to a cooled (0°C) solution of the above substance (0.19 g, 1.04 mmol) in 5 mL of anhydrous THF. The mixture was stirred at 0°C for 2.5 h, then under reflux for 5 h until the starting material disappeared. The mixture was diluted with EtOAc and washed with 1.0 M HCl, water, and brine. The organic matter was dried over anhydrous Na₂SO₄ and concentrated to give ((1s,4s)-4-cyclopropylcyclohexyl)methanol (0.13 g, 84%) as an oil. 1 H NMR (400MHz, CDCl3) δ3.54 (d, J=6.8Hz, 2H), 1.62 (ttd, J=10.2, 6.8, 3.0Hz, 1H), 1.57-1.48 (m, 7H ),1.48-1.39(m,2H),0.80-0.71(m,1H),0.68-0.60(m,1H),0.42-0.35(m,2H),0.04-0.01(m,2H).

[0338] At 0°C, DMP (0.55 g, 1.3 mmol) was added to a stirred solution of the above substance (0.135 g, 0.87 mmol) in anhydrous DCM (6 mL). After stirring at room temperature for 2 hours, the reaction mixture was quenched with a 1:1 mixture of 1 M Na₂S₂O₃: saturated NaHCO₃ (20 mL) and stirred for another 30 min, then diluted with DCM (40 mL). The organic matter was separated, dried over anhydrous Na₂SO₄, and concentrated. The crude residue was purified by rapid chromatography (EtOAc / hexane, 1:9) on silica gel to give (1S,4S)-4-cyclopropylcyclohexaneformaldehyde (0.06 g, 45%) as an oil. 1 H NMR(500MHz, CDCl3)δ9.70(s,1H),2.37-2.33(m,1H),2.09-2.01(m,2H),1.69-1.60(m,2H),1 .59-1.51(m,2H),1.29-1.20(m,2H),0.57-0.50(m,2H),0.40-0.33(m,2H),0.04-0.02(m,2H).

[0339] Add a few drops of AcOH to an anhydrous MeOH solution (5 mL) of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.2 g, 0.5 mmol) and (1s,4s)-4-cyclopropylcyclohexaneformaldehyde (0.06 g, 0.40 mmol), and stir the mixture at room temperature for 10 minutes. Add sodium cyanoborohydride (0.032 g, 0.50 mmol) and stir the reaction overnight at room temperature. Concentrate the mixture and dilute with EtOAc (30 mL), and wash the organic matter with a saturated aqueous solution of NaHCO3. The organic matter was dried and concentrated with anhydrous Na2SO4, and the crude residue was purified by rapid chromatography (EtOAc / hexane, 1:9) on silica gel to obtain (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(((1s,4S)-4-cyclopropylcyclohexyl)methyl)-2-methylpiperidine (0.11 g, 50.9%) as a yellow solid. 1 H NMR (500MHz, CDCl3) δ7.39-7.27(m,15H),4.98(dd,J=16.1,10.9Hz,2H),4.85(d,J=11.0Hz,1H),4.77- 4.65(m,2H),4.63(d,J=10.8Hz,1H),3.64-3.58(m,1H),3.57-3.49(m,1H),3.16-3.04(m,2H),2.69(dd, J=12.8,9.0Hz,1H),2.29(dq,J=12.4,6.2Hz,1H),2.08-1.97(m,2H),1.60-1.45(m,8H),1.41-1.29(m, 2H),1.24-1.19(m,2H),0.81-0.72(m,1H),0.68-0.61(m,1H),0.45-0.38(m,2H),0.09-0.03(m,2H); ESI MS m / z 554.349[M+H] + .

[0340] At -78°C under Ar conditions, BCl3 (1.0 M DCM solution, 0.95 mL, 0.95 mmol) was added to a DCM (5 mL) solution of the above substance (0.1 g, 0.18 mmol), and the mixture was stirred for 2 hours while the bath temperature reached 0°C. The mixture was further stirred at 0°C for 2 hours, and then quenched by the slow addition of MeOH (2 mL). After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. The resulting residue was dissolved in a mixture of AcO / pyridine (4.5 mL, 1:9) and stirred overnight, and then evaporated under reduced pressure. Then, 2 M NH3 / MeOH solution (8 mL) was added to the crude product, the mixture was stirred overnight, and concentrated to dryness. The residue was separated and purified on silica gel by rapid chromatography (MeOH / DCM, 1:9) to obtain (2R,3R,4R,5S)-1-(((1s,4S)-4-cyclopropylcyclomethyl)methyl)-2-methylpiperidine-3,4,5-triol (0.02 g, 39.2%), a white solid. 1 H NMR (400MHz, CD3OD) δ3.51-3.43(m,1H),3.15-3.09(m,1H),3.05(dd,J=11.3,4.8Hz ,1H),3.00-2.94(m,1H),2.80(dd,J=12.9,9.2Hz,1H),2.10-2.04(m,1H),2.02-1.94 (m,2H),1.75-1.63(m,1H),1.63-1.48(m,6H),1.47-1.38(m,2H),1.22(d,J=6.1Hz, 3H),0.83-0.74(m,1H),0.67-0.59(m,1H),0.46-0.39(m,2H),0.07-0.02(m,2H); ESI MS m / z284.218[M+H] + .

[0341] Example 21

[0342] (2R,3R,4R,5S)-1-(((1r,4R)-4-cyclopropylcyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol

[0343]

[0344] At -5°C, methyl chloroformate (1.0 mL, 10.8 mmol) was added to a solution of trans-1,4-cyclohexanedicarboxylic acid monomethyl ester (1.86 g, 10 mmol) in THF (60 mL) and Et3N (1.5 mL, 10.8 mmol), while maintaining the temperature between -5°C and 0°C. After 1 hour, the mixture was added to a solution of NaBH4 (0.8 g, 21.6 mmol) in water (30 mL) through a sleeve at 10°C. The reaction mixture was further stirred at 10°C for 30 minutes, then quenched with 1N HCl to pH 1. The mixture was partitioned with EtOAc, and the organic matter was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified on silica gel by rapid chromatography (EtOAc / hexane, 1:9) to give methyl (1r,4r)-methyl-4-(hydroxymethyl)cyclohexanecarboxylate (1.34 g, 77.8%) as an oil. 1 H NMR (400MHz, CDCl3)3.66(s,3H),3.64-3.46(m,2H),2.35-2.20(m,1H),2.13-1.97(m,2H),1.93-1.79(m,1H),1.60-1.33(m,4H),1.05(m,2H).

[0345] At 0°C, DMP (2.2 g, 5.2 mmol) was added to a 10 mL solution of anhydrous DCM containing the above-mentioned substance (0.6 g, 3.48 mmol) under stirring. After stirring at room temperature for 2 hours, the reaction mixture was quenched with a 1:1 mixture of 1 M Na₂S₂O₃ and saturated NaHCO₃ (20 mL), and stirred for another 30 min, followed by dilution with DCM (40 mL). The organic matter was separated, dried over anhydrous Na₂SO₄, and concentrated. The crude residue was purified by rapid chromatography (EtOAc / hexane, 1:4) on silica gel to give (1r,4r)-methyl-4-formylcyclohexanecarbamate (0.36 g, 60.7%) as an oil. 1 H NMR (500MHz, CDCl3) δ9.50 (s, 1H), 3.54 (s, 3H), 2.24-2.08 (m, 2H), 2.0-1.9 (m, 4H), 1.37 (qt, J = 13.6, 3.4Hz, 2H), 1.18 (qt, J = 12.6, 3.4Hz, 2H).

[0346] At 0 °C, KOtBu (0.36 g, 3.2 mmol) was added to a mixture of methyltriphenylphosphonium bromide (1.14 g, 3.2 mmol) and anhydrous THF (8 mL). The mixture was stirred for 30 min, and then methyl (1r,4r)-methyl-4-formylcyclohexanecarboxylate (0.36 g, 2.12 mmol) pre-dissolved in anhydrous THF (8 mL). The mixture was warmed to room temperature and stirred for 2 h, and then concentrated under reduced pressure. The resulting crude residue was purified by rapid chromatography (EtOAc / hexane, 1:4) on silica gel to give methyl (1r,4r)-methyl-4-vinylcyclohexanecarboxylate (0.25 g, 70%) as an oil. 1 H NMR (400MHz, CDCl3) δ5.71 (ddd, J=17.1, 10.4, 6.4Hz, 1H), 4.99-4.81 (m, 2H), 3.62 (s, 3H), 2.20 (t t,J=12.3,3.6Hz,1H),2.02-1.85(m,3H),1.85-1.73(m,2H),1.48-1.37(m,2H),1.13-1.02(m,2H).

[0347] At 0 °C, diethylzinc (1.0 M hexane, 4.4 mL, 4.4 mmol) was added to a mixture of the above substances (0.25 g, 1.48 mmol) and DCE (8 mL), followed by chloroiodomethane (0.65 mL, 8.88 mmol). The mixture was stirred at 0 °C for 2 h, then at room temperature for 2 h, and quenched with a saturated aqueous NH4Cl solution. The reaction mixture was partitioned between DCM and water, the organic matter was separated, dried over anhydrous Na2SO4, and concentrated. The crude residue was purified on silica gel by rapid chromatography (EtOAc / hexane, 1:4) to give (1r,4r)-methyl-4-cyclopropylcyclohexanecarboxylate (0.24 g, 88.9%) as an oil. 1 H NMR (400MHz, CDCl3) δ3.63 (s, 3H), 2.21 (tt, J = 12.2, 3.6Hz, 1H), 1.99-1.90 (m, 2H), 1.89-1.81 (m, 2H), 1.33 (tdd,J=13.1,12.0,3.4Hz,2H),1.13-1.00(m,2H),0.50-0.38(m,2H),0.38-0.30(m,2H),0.05-0.03(m,2H).

[0348] Under Ar conditions and with stirring, 0.15 g (3.95 mmol) of LAH was added in portions to 5 mL of anhydrous THF solution of the above substance (0.24 g, 1.31 mmol) cooled (0 °C). The mixture was stirred at 0 °C for 2.5 h, then stirred under reflux for 5 h until the starting material disappeared. The mixture was diluted with EtOAc and washed with 1.0 M HCl, water, and brine. The organic matter was dried over anhydrous Na₂SO₄ and concentrated to give ((1r,4r)-4-cyclopropylcyclohexyl)methanol (0.19 g, 94%) as an oil. 1 H NMR (400MHz, CDCl3) δ3.44(d,J=6.4Hz,2H),1.91-1.70(m,4H),1.45(tdt,J=12.0,6.4,3.2Hz,1H),1.10(qd,J=13.1,12.7, 3.2Hz, 2H), 0.88 (qd, J=12.7, 3.2Hz, 2H), 0.46 (dddd, J=13.1, 11.3, 7.6, 3.8Hz, 2H), 0.39-0.32 (m, 2H), 0.08-0.00 (m, 2H).

[0349] At 0°C, DMP (0.78 g, 1.84 mmol) was added to a stirred solution of the above substance (0.19 g, 1.23 mmol) in anhydrous DCM (5 mL). After stirring at room temperature for 2 hours, the reaction mixture was quenched with a 1:1 mixture of 1 M Na₂S₂O₃ and saturated NaHCO₃ (20 mL), and stirred further for 30 min, then diluted with DCM (40 mL). The organic matter was separated, dried over anhydrous Na₂SO₄, and concentrated. The crude residue was purified by rapid chromatography (EtOAc / hexane, 1:9) on silica gel to give (1r,4r)-4-cyclopropylcyclohexaneformaldehyde (0.14 g, 74.7%) as an oil. 1 H NMR (400MHz, CDCl3) δ9.59(s,1H),2.22-2.11(m,1H),2.06-1.84(m,4H),1.27-1.04(m,4H),0.52-0.40(m,2H),0.40-0.33(m,2H),0.04(m,2H).

[0350] Add a few drops of AcOH to an anhydrous MeOH solution (8 mL) of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.23 g, 0.55 mmol) and (1r,4r)-4-cyclopropylcyclohexaneformaldehyde (0.07 g, 0.46 mmol), and stir the mixture at room temperature for 10 minutes. Add sodium cyanoborohydride (0.034 g, 0.55 mmol), and stir the reaction overnight at room temperature. Concentrate the mixture and dilute with EtOAc (30 mL), and wash the organic matter with a saturated aqueous solution of NaHCO3. The organic matter was dried and concentrated with anhydrous Na2SO4, and the crude residue was then purified by rapid chromatography (EtOAc / hexane, 1:9) on silica gel to obtain (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(((1r,4R)-4-cyclopropylcyclohexyl)methyl)-2-methylpiperidine (0.1 g, 39.2%) as a yellow solid. 1 H NMR(400MHz, CDCl3) δ7.39-7.26(m,15H),4.97(dd,J=14.9,10.9Hz,2H),4.85(d,J=11.0Hz,1H),4.78-4.58 (m,3H),3.59(td,J=9.7,4.5Hz,1H),3.51(t,J=9.0Hz,1H),3.16-2.99(m,2H),2.44(dd,J=12.8,8.7Hz,1H), 2.29-2.21(m,1H),2.09-1.92(m,2H),1.90-1.77(m,3H),1.73-1.61(m,1H),1.39-1.28(m,1H),1.18(d,J=6. 1Hz,3H),1.15-0.99(m,2H),0.87-0.65(m,2H),0.54-0.41(m,2H),0.40-0.33(m,2H),0.08-0.04(m,2H); ESI MS m / z 554.354[M+H] + .

[0351] At -78°C under Ar conditions, BCl3 (0.9 mL of 1.0 M DCM solution, 0.9 mmol) was added to a DCM solution of the above substance (0.1 g, 0.18 mmol) in 5 mL of water, and the mixture was stirred for 2 hours while the bath temperature reached 0°C. The mixture was stirred further at 0°C for 2 hours, and then quenched by the slow addition of MeOH (2 mL). After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. The resulting residue was neutralized with NH4OH (0.5 mL) and concentrated again under reduced pressure. The crude residue was purified by rapid chromatography (MeOH / DCM, 1:9) on silica gel to give (2R,3R,4R,5S)-1-(((1r,4R)-4-cyclopropylcyclohexyl)methyl)-2-methylpiperidin-3,4,5-triol (0.039 g, 77%) as a white solid. 1 H NMR (400MHz, CD3OD) δ3.55 (td, J=9.9, 4.5Hz, 1H), 3.23-3.13 (m, 2H), 3.07 (t, J= 9.0Hz,1H),2.77-2.68(m,1H),2.39-2.14(m,3H),2.01-1.84(m,3H),1.75(dt,J =12.7,3.1Hz,1H),1.61-1.50(m,1H),1.26(d,J=6.2Hz,3H),1.23-1.07(m,2H), 1.02-0.80(m,2H),0.54-0.43(m,2H),0.41-0.36(m,2H),0.09-0.03(m,2H); ESI MS m / z 284.218 [M+H] + .

[0352] Example 22

[0353] (2R,3R,4R,5S)-2-methyl-1-((4-phenylcyclohexyl)methyl)piperidine-3,4,5-triol

[0354]

[0355] To a solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.2 g, 0.5 mmol) in DCM (8 mL), 4-phenylcyclohexaneformaldehyde (0.18 g, 1.0 mmol) and Na(OAc)3BH (0.2 g, 1.0 mmol) (mL, 0.77 mmol) were added. The reaction was stirred overnight at room temperature and then diluted with DCM (25 mL). The organic matter was washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (EtOAc / hexane, 1:9) on silica gel to give a 1:1 cis / trans mixture of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-((4-phenylcyclohexyl)methyl)piperidine (0.19 g, 64%) as an oil. ESI MS m / z 590.329 [M+H] + .

[0356] At -78°C under Ar conditions, BCl3 (1.7 mL of 1.0 M DCM solution, 1.7 mmol) was added to a DCM solution of the above substance (0.1 g, 0.17 mmol) in 5 mL of BCl3. The mixture was stirred for 2 hours while the bath temperature was raised to 0°C. The mixture was stirred at 0°C for another 2 hours, and then quenched by the slow addition of MeOH (2 mL). After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. The resulting residue was neutralized with NH4OH (0.5 mL) and concentrated again under reduced pressure. The crude residue was purified by rapid chromatography (MeOH / DCM, 1:9) on silica gel to give (2R,3R,4R,5S)-2-methyl-1-((4-phenylcyclohexyl)methyl)piperidine-3,4,5-triol (0.047 g, 86.5%) as a white solid. 1 1H NMR analysis indicated that the substance was an approximately 1:1 mixture of cis / trans isomers; ESI MS m / z 320.21 [M+H] + .

[0357] Example 23

[0358] (2R,3R,4R,5S)-2-methyl-1-(spiro[2.5]oct-6-ylmethyl)piperidine-3,4,5-triol

[0359]

[0360] KO was added to a stirred solution of methyltriphenylphosphonium bromide (10.7 g, 300 mmol) in anhydrous THF (100 mL) at 0 °C and N2. tBu (3.36 g, 300 mmol) was added and stirred for 30 minutes. Then, ethyl 4-oxocyclohexanecarboxylate (3.4 g, 200 mmol) was dissolved in 20 mL of THF and added dropwise to the mixture under N2, and the reaction was allowed to proceed at room temperature for 3 hours. The reaction was quenched with a saturated aqueous solution of NaHCO3. The mixture was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give ethyl 4-methylenecyclohexanecarboxylate as an oil (2.25 g, 67%). 1 H NMR(400MHz, CDCl3) δ4.67(d,J=1.5Hz,2H),4.15(q,J=7.1Hz,2H),2.46(tt,J=11.0,3.6Hz,1 H), 2.36 (dt, J = 12.7, 3.7Hz, 2H), 2.15-1.94 (m, 4H), 1.69-1.50 (m, 2H), 1.28 (t, J = 7.1Hz, 3H).

[0361] TFA (1.1 mL, 16.4 mmol) was added to a stirred solution of diethylzinc (16.5 mL, 1 M hexane solution, 16.5 mmol) in 25 mL of anhydrous DCM at 0 °C and N2, and the mixture was stirred for 60 min. Then, ethyl 4-methylenecyclohexanecarboxylate (1.1 g, 6.54 mmol) was dissolved in 3 mL of DCM and added dropwise to the mixture under N2, and the reaction was carried out at 0 °C for 2 h. The reaction was quenched with water at 0 °C. The mixture was extracted with DCM (3 × 20 mL). The combined organic layers were washed with water (2 × 10 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give ethyl spiro[2,5]octane-6-carboxylate as an oil (0.90 g, 76%). 1 H NMR (400MHz, CDCl3) δ4.15 (q, J=7.1Hz, 2H), 2.33 (tt, J=10.8, 3.7Hz, 1H), 1.91 (dt, J=11.5, 3.1Hz,2H),1.77-1.52(m,4H),1.28(t,J=7.1Hz,3H),1.06-0.96(m,2H),0.35-0.18(m,4H).

[0362] At 0°C, LAH (500 mg, 13.2 mmol) was added to an anhydrous THF (10 mL) solution of the above substance (800 mg, 4.39 mmol), and the mixture was stirred at 0°C for 1 hour. The mixture was slowly quenched with saturated NaHCO3. The reaction mixture was washed with an aqueous solution of Na2SO4 and filtered. The solid was washed with EtOAc. The combined organic layers were washed with water (2 × 20 mL), separated, and dried with Na2SO4. After filtration, the solvent was evaporated under reduced pressure to give crude spiro[2,5]octane-6-ylmethanol as an oil (725 mg). 1 HNMR (400MHz, CDCl3) δ3.52 (dd, J=6.4, 1.0Hz, 2H), 1.75 (ddd, J=13.3, 8.2, 4.2Hz ,4H),1.60-1.41(m,2H),1.25-1.07(m,2H),1.01-0.87(m,2H),0.43-0.11(m,4H).

[0363] At 0°C, DMP (748 mg, 1.76 mmol) was added to an anhydrous DCM (20 mL) solution of the above substance (190 mg, 1.36 mmol), and the mixture was stirred at 0°C for 2 hours. The mixture was slowly quenched with Na2S3O5 solution. The mixture was extracted with DCM (3 × 20 mL). The combined organic layers were washed with water (2 × 10 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give spiro[2,5]octane-6-carboxaldehyde as an oil (63 mg, 34%). 1 H NMR (400MHz, CDCl3) δ9.69 (d, J=1.4Hz, 1H), 2.30 (ddtd, J=10.4, 7.3, 3.7, 1.3Hz, 1H), 1.92 (dd d,J=12.3,6.2,2.5Hz,2H),1.72-1.46(m,4H),1.10(dt,J=13.0,3.9Hz,2H),0.41-0.14(m,4H).

[0364] HOAc (0.10 mL, 1.75 mmol) was added to a stirred solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (92 mg, 0.22 mmol) and spiro[2,5]octane-6-carboxaldehyde (60 g, 0.43 mmol) in anhydrous MeOH (5 mL), and the mixture was stirred for 30 min. NaBH3CN (27 mg, 0.43 mmol) was added, and the resulting mixture was stirred at room temperature for 18 h. The reaction was quenched at 0 °C with a saturated aqueous solution of NaHCO3. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 10 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to obtain (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-(spiro[2.5]octane-6-ylmethyl)piperidine as an oil (59 mg, 50%). ESI MS m / z 540.32 [M+H] + .

[0365] At -78°C and N2, a solution of BCl3 (1M DCM solution, 0.80mL, 0.80mmol) was added to a stirred solution of the above substance (55mg, 0.10mmol) in anhydrous DCM (3mL). The mixture was stirred at 0°C for 2h and then quenched with anhydrous MeOH (1mL). The mixture was stirred at ambient temperature for 10min. The solvent was removed under vacuum, and the residue was dissolved in a 1M NH3 MeOH solution (10mL) and stirred for another 10min, and then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-2-methyl-1-(spiro[2.5]octane-6-ylmethyl)piperidine-3,4,5-triol as a white solid (17mg, 63%). 1 H NMR (400MHz, CD3OD) δ3.52-3.43(m,1H),3.12(t,J=9.0Hz,1H),3.06(dd,J=1 1.4,4.8Hz,1H),2.96(t,J=9.1Hz,1H),2.63(dd,J=12.8,8.9Hz,1H),2.11-1 .93(m,3H),1.92-1.83(m,1H),1.82-1.61(m,3H),1.61-1.47(m,1H),1.19(d ,J=6.1Hz,3H),1.18-0.99(m,2H),0.98-0.88(m,2H),0.32-0.16(m,4H); ESI m / z 270.19 [M+H] + .

[0366] Example 24

[0367] (2R,3R,4R,5S)-2-methyl-1-(spiro[3.5]non-7-ylmethyl)piperidine-3,4,5-triol

[0368]

[0369] Under Ar conditions, NaBH(OAc)3 (499 mg, 2.3 mmol) was added to an anhydrous DCM (10 mL) solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-(piperidin-4-ylmethyl)piperidine (491 mg, 1.1 mmol) and spiro[3,5]nonane-7-carboxaldehyde (179 mg, 1.12 mmol). The mixture was stirred at room temperature for 18 hours. An aqueous solution of NaHCO3 (30 mL) was added, and the mixture was extracted with EtOAc (3 × 30 mL). The combined organic extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by rapid chromatography using 20% ​​EtOAc in hexane to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-(spiro[3.5]non-7-ylmethyl)piperidine in white form (203 mg, 31%).

[0370] At -78°C and Ar, a solution of BCl3 (10 mL, 1 M DCM solution, 10 mmol) was added to an anhydrous DCM (15 mL) solution of the above substance (203 mg, 0.37 mmol). The mixture was stirred at -78°C for 1 h and at 0°C for 4 h; then MeOH (20 mL) was added. The mixture was stirred at 0°C for another 2 h and evaporated to dryness using a rotary evaporator. The residue was purified by rapid chromatography on silica gel using a solution of 10% MeOH and 2% NH3 in DCM to give (2R,3R,4R,5S)-2-methyl-1-(spiro[3.5]nonyl-7-ylmethyl)piperidine-3,4,5-triol as a white solid (88 mg, 85%). 1 H NMR(400MHz,CD3OD)δ3.70-3.50(m,1H),3.24(t,J=9.0Hz,2H),3.16(d,J=9.1Hz,1H),2.84(bs,1H) ,2.50-2.45(b,3H),1.97-1.66(m,9H),1.64-1.47(m,2H),1.44-1.21(m,5H),1.15-0.89(m,2H); ESI MS m / z284.2[M+H] + .

[0371] Example 25

[0372] (2R,3R,4R,5S)-2-methyl-1-(spiro[4,5]dec-8-ylmethyl)piperidine-3,4,5-triol

[0373]

[0374] At 0 °C, a solution of 2,2′-(cyclopentane-1,1-diyl)diacetic acid (1.50 g, 8.05 mmol) was slowly added to a suspension of LAH (1.80 g, 48.3 mmol) in anhydrous THF (60 mL), and the mixture was refluxed for 2 hours. The mixture was slowly quenched with a saturated aqueous solution of Na₂SO₄ and filtered. The solid was washed with EtOAc. The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give 2,2′-(cyclopentane-1,1-diyl)diethanol as a white solid (1.01 g, 79%). 1 HNMR (400MHz, CDCl3) δ3.76 (t, J = 6.9Hz, 4H), 1.89 (s, 2H), 1.74-1.62 (m, 8H), 1.51-1.38 (m, 4H).

[0375] At 0 °C, p-toluenesulfonyl chloride (1.27 g, 6.64 mmol) was added to an anhydrous pyridine (8 mL) solution of the above substance (500 mg, 3.16 mmol), and the mixture was stirred at room temperature for 18 hours. The mixture was slowly quenched with saturated NaHCO3 at 0 °C. The mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give cyclopentane-1,1-diylbis(ethane-2,1-diyl)bis(4-methylbenzenesulfonate) as a white solid (660 mg, 45%). 1 H NMR (400MHz, CDCl3) δ7.81-7.72(m,4H),7.44-7.33(m,4H),4.03(t,J=7.1Hz, 4H), 2.48 (s, 6H), 1.65 (t, J = 7.1Hz, 4H), 1.59-1.54 (m, 4H), 1.42-1.32 (m, 4H).

[0376] At 0 °C, a solution of dimethyl malonate (0.94 mL, 7.10 mmol) in 5 mL of THF was slowly added to a suspension of NaH (227 mg, 5.68 mmol) in 10 mL of anhydrous THF, and the mixture was stirred at 0 °C for 10 min. A solution of cyclopentane-1,1-diylbis(ethane-2,1-diyl)bis(4-methylbenzenesulfonate) (660 mg, 1.42 mmol) in 5 mL of THF was slowly added, and the mixture was stirred at 0 °C for 1 h. The mixture was refluxed for 20 h and then slowly quenched with a saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to obtain spiro[4.5]decane-8,8-dicarboxylic acid dimethyl ester, which was a clear oil (250 mg, 69%). 1 H NMR (400MHz, CDCl3) δ3.74 (s, 6H), 2.04 (dd, J = 7.6, 4.7Hz, 4H), 1.68-1.54 (m, 4H), 1.47-1.35 (m, 8H).

[0377] At room temperature, LiCl (166 mg, 3.92 mmol) and water (0.04 mL) were added to a DMSO (5 mL) solution of the above substance (250 mg, 0.98 mmol), and the mixture was stirred at 185 °C for 5 hours. The mixture was slowly quenched at 0 °C with a saturated aqueous solution of Na₂CO₃. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 10 mL), separated, and dried over Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give methyl spiro[4.5]decane-8-carboxylate as a clear oil (123 mg, 64%). 1 H NMR(400MHz, CDCl3)δ3.69(s,3H),2.34-2.21(m,1H),1.88-1.78(m,2H),1.66 -1.51(m,8H),1.44(t,J=6.9Hz,2H),1.37(t,J=7.1Hz,2H),1.33-1.24(m,2H).

[0378] At 0°C, LAH (93 mg, 2.45 mmol) was added to an anhydrous THF (5 mL) solution of the above substance (120 mg, 0.61 mmol), and the mixture was stirred at 0°C for 2 hours. The mixture was slowly quenched with a saturated aqueous solution of Na₂SO₄ and filtered. The solid was washed with EtOAc. The combined organic layers were washed with water (2 × 20 mL), separated, and dried with Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give spiro[4.5]dec-8-ylmethanol as a clear oil (101 mg, 99%). 1 H NMR (400MHz, CDCl3) δ3.48 (d, J=6.4Hz, 2H), 1.69-1.34 (m, 14H), 1.29 (td, J=13.1, 3.6Hz, 2H), 1.15-1.01 (m, 2H).

[0379] At 0°C, DMP (361 mg, 0.85 mmol) was added to an anhydrous DCM (10 mL) solution of the above substance (110 mg, 0.65 mmol), and the mixture was stirred at 0°C for 2 hours. The mixture was slowly quenched with Na2S3O5 solution. The mixture was extracted with DCM (3 × 20 mL). The combined organic layers were washed with water (2 × 10 mL), separated, and dried with Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give spiro[4,5]decane-8-carboxaldehyde as an oil (60 mg, 55%).

[0380] HOAc (0.10 mL, 1.75 mmol) was added to a stirred solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (97 mg, 0.23 mmol) and spiro[4,5]decane-8-carboxaldehyde (58 mg, 0.35 mmol) in anhydrous DCM (5 mL) and stirred for 30 min. Na(OAc)3BH (74 mg, 0.35 mmol) was added, and the resulting mixture was stirred at room temperature for 18 h. The reaction was quenched at 0 °C with a saturated aqueous solution of NaHCO3. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 10 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to obtain (2R(2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-(spiro[4.5]dec-8-ylmethyl)piperidine as an oil (115 mg, 88%). ESI MS m / z 568.37 [M+H] + .

[0381] At -78°C and N2, a solution of BCl3 (1 M DCM solution, 1.27 mL, 1.27 mmol) was added to a stirred solution of the above substance (87 mg, 0.16 mmol) in anhydrous DCM (5 mL). The mixture was stirred at 0°C for 2 h and then quenched with anhydrous MeOH (1 mL). The mixture was stirred at ambient temperature for 10 min. The solvent was removed under vacuum, and the residue was dissolved in a 1 M NH3 MeOH solution (10 mL) and stirred for another 10 min, and then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-2-methyl-1-(spiro[4.5]dec-8-ylmethyl)piperidine-3,4,5-triol as a white solid (35 mg, 77%). 1 HNMR (400MHz, CD3OD) δ3.51-3.43(m,1H),3.12(t,J=9.0Hz,1H),3.04(dd,J=11.3,4.8Hz,1H)2.96(t,J=9.1Hz,1H),2.58(dd,J=12.8,8 .8Hz,1H),2.09-1.92(m,3H),1.82-1.74(m,1H),1.68-1.41(m,10H),1.41-1.22(m,4H),1.19(d,J=6.1Hz,3H),1.14-0.92(m,2H); ESIMS m / z298.24[M+H] + .

[0382] Example 26

[0383] (2R,3R,4R,5S)-1-(((5S,8S)-3,3-dimethyl-2-oxaspiro[4.5]dec-8-yl)methyl)-2-methylpiperidine-3,4,5-

[0384] Triols

[0385]

[0386] DMP (1.19 g, 2.82 mmol) was added to an anhydrous DCM (8 mL) solution of ((5s, 8s)-3,3-dimethyl-2-oxaspiro[4.5]dec-8-yl)methanol (Bioorg. Med. Chem. Lett 2019, 29, 373) (0.37 g, 1.86 mmol). After stirring at 0 °C for 30 min, the reaction mixture was warmed to room temperature for 1.5 h. The reaction mixture was diluted with a 1:1 mixture of 1 M Na₂S₂O₃ and saturated NaHCO₃ aqueous solution (50 mL) and stirred for 30 min. DCM (30 mL) was added, and the organic matter was separated, dried over anhydrous Na₂SO₄, and concentrated. The crude residue was purified on silica gel by rapid chromatography (EtOAc / hexane, 1:1) to obtain (5s,8s)-3,3-dimethyl-2-oxaspiro[4.5]decane-8-carboxaldehyde (0.25 g, 70.7%) as a gel-like solid. 1 H NMR(500MHz, CDCl3)δ9.60(s,1H),3.59(s,2H),2.24-2.13(m,1H),1.86-1.82(m,2H) ,1.76-1.74(m,2H),1.58(d,J=1.8Hz,2H),1.48-1.32(m,4H),1.23(d,J=2.2Hz,6H).

[0387] To a solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.18 g, 0.43 mmol) in MeOH (5 mL), (5S,8S)-3,3-dimethyl-2-oxaspiro[4.5]decane-8-carboxaldehyde (0.08 g, 0.43 mmol) and acetic acid (0.3 mL) were added. After stirring at room temperature for 10 minutes, NaCNBH3 (0.04 g, 0.66 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated and then diluted with DCM (25 mL). The organic matter was washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified on silica gel by rapid chromatography (EtOAc / hexane, 1:9) to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-((3,3-dimethyl-2-oxaspiro[4.5]dec-8-yl)methyl)-2-methylpiperidine (0.17 g, 66%) as an oil. 1H NMR (500MHz, CDCl3) δ7.40-7.23(m,15H),4.96(dd,J=16.8,10.9Hz,2H),4.84(d,J=11.0Hz,1H),4.74(d,J=11.6Hz ,1H),4.64(dd,J=26.8,11.2Hz,2H),3.65(d,J=1.8Hz,2H),3.61-3.54(m,1H),3.50(t,J=9.0Hz,1H),3.09(t,J=9. 0Hz,1H),3.03(dd,J=11.5,4.7Hz,1H),2.46(dd,J=12.8,8.9Hz,1H),2.24(dq,J=12.1,6.2Hz,1H),2.07-1.94(m,2 ESI MS m / z 598.394[M+H] + .

[0388] The mixture of the above substances (0.17 g, 0.28 mmol) and Pd(OH)₂ / C (20% wt, 0.02 g) in EtOH / 2N HCl (25 / 1 mL) was stirred overnight at 50 psi hydrogen pressure. The mixture was then filtered through a diatomaceous earth filter cake, and the filtrate was collected and concentrated to dryness. NH₄OH solution (3 mL) was added to the residue, and the mixture was concentrated again. The crude residue was redissolved in pyridine (6 mL) and treated with Ac₂O (0.6 mL). After stirring overnight at room temperature, the mixture was concentrated and purified on silica gel by rapid chromatography (EtOAc / hexane, 1:1) to give (2R,3R,4R,5S)-1-((3,3-dimethyl-2-oxaspiro[4.5]dec-8-yl)methyl)-2-methylpiperidin-3,4,5-triyltriacetate, which was hydrolyzed by stirring overnight with a solution of 1M NH3 in MeOH (10 mL). The crude residue was purified on silica gel by rapid chromatography (MeOH / DCM, 1:9) to give (2R,3R,4R,5S)-1-((3,3-dimethyl-2-oxaspiro[4.5]dec-8-yl)methyl)-2-methylpiperidin-3,4,5-triol (0.052 g, 56%) as a white solid. 1H NMR (400MHz, CD3OD) δ3.69 (s, 2H), 3.46 (ddd, J = 10.5, 9.0, 4.7Hz, 1H), 3.11 (t ,J=9.0Hz,1H),3.02(dd,J=11.3,4.8Hz,1H),2.95(t,J=9.1Hz,1H),2.58(dd, J=12.9,8.8Hz,1H),2.09-1.92(m,3H),1.88-1.72(m,3H),1.67-1.59(m,3H), 1.53-1.31(m,3H),1.26(s,6H),1.19(d,J=6.1Hz,3H),1.05-0.84(m,2H);ESI MS m / z 328.245 [M+H] + .

[0389] Example 27

[0390] (2R,3R,4R,5S)-2-methyl-1-((1,2,3,4-tetrahydronaphth-2-yl)methyl)piperidine-3,4,5-triol

[0391]

[0392] At 0 °C, LAH (78 mg, 2.04 mmol) was added to an anhydrous THF (5 mL) solution of 1,2,3,4-tetrahydro-2-naphthoic acid (120 mg, 0.68 mmol), and the mixture was stirred at 0 °C for 2 hours. The mixture was slowly quenched with a saturated aqueous solution of Na₂SO₄ and filtered. The solid was washed with EtOAc. The combined organic layers were washed with H₂O (2 × 20 mL), separated, and dried over Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure to give crude (1,2,3,4-tetrahydronaphth-2-yl)methanol as a clear oil. DMP (375 mg, 0.88 mmol) was added to a solution of the obtained oil in anhydrous DCM (5 mL) at 0 °C, and the mixture was stirred at 0 °C for 2 hours. The mixture was slowly quenched with a Na₂S₃O₅ solution. The mixture was extracted with DCM (3 × 20 mL). The combined organic layers were washed with H2O (2 × 10 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give 1,2,3,4-tetrahydronaphthalene-2-carboxaldehyde as an oil (44 mg, 40%).

[0393] HOAc (0.10 mL, 1.75 mmol) was added to an anhydrous DCM (5 mL) solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (80 mg, 0.19 mmol) and 1,2,3,4-tetrahydronaphthalene-2-carboxaldehyde (40 mg, 0.25 mmol) and stirred for 30 min. NaBH(OAc)3 (52 mg, 0.25 mmol) was added, and the resulting mixture was stirred at room temperature for 18 h. The reaction was quenched at 0 °C with a saturated aqueous solution of NaHCO3. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with H2O (2 × 10 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-((1,2,3,4-tetrahydronaphthyl-2-yl)methyl)piperidine as an oil (90 mg, 84%). ESI MS m / z 562.71 [M+H] + .

[0394] At -78°C and N2, BCl3 (1M DCM solution, 0.97mL, 0.97mmol) was added to an anhydrous DCM solution (90mg, 0.16mmol) of the above substance in 5mL of N2. The mixture was stirred at 0°C for 2h, then quenched with anhydrous MeOH (1mL). The mixture was stirred at ambient temperature for 10min. The solvent was removed under vacuum, and the residue was dissolved in 1M NH3 MeOH solution (10mL) and stirred for another 10min, then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-2-methyl-1-((1,2,3,4-tetrahydronaphthyl-2-yl)methyl)piperidine-3,4,5-triol, as a white solid (15mg, 32%). 1 1H NMR analysis separated the substance into a mixture of diastereomers of approximately 1:1.2. 1 H NMR(400MHz,CD3OD)δ7.06-7.03(m,4H),3.60-3.47(m,1H),3.23-3.07(m,2H),3.04-2.6 9(m,5H),2.49-2.34(m,1H),2.21-1.83(m,5H),1.46-1.29(m,1H),1.24-1.16(m,3H); ESI MS m / z 292.19[M+H] + .

[0395] Example 28

[0396] (2R,3R,4R,5S)-1-((2,3-dihydro-1H-inden-2-yl)methyl)-2-methylpiperidin-3,4,5-triol

[0397]

[0398] At 0 °C, LAH (141 mg, 3.70 mmol) was added to an anhydrous THF (8 mL) solution of 2-indanocarboxylic acid (200 mg, 1.23 mmol), and the mixture was stirred at 0 °C for 2 hours. The mixture was slowly quenched with a saturated aqueous solution of Na₂SO₄ and filtered. The solid was washed with EtOAc. The combined organic layers were washed with H₂O (2 × 20 mL), separated, and dried over Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give (2,3-dihydro-1H-indano-2-yl)methanol as a clear oil (180 mg, 99%).

[0399] At 0°C, DMP (678 mg, 1.60 mmol) was added to an anhydrous DCM (10 mL) solution of the above substance (180 mg, 1.22 mmol), and the mixture was stirred at 0°C for 2 hours. The mixture was slowly quenched with Na₂S₃O₅ solution. The mixture was extracted with DCM (3 × 20 mL). The combined organic layers were washed with H₂O (2 × 10 mL), separated, and dried over Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give 2,3-dihydro-1H-inden-2-carboxaldehyde as an oil (130 mg, 72%).

[0400] HOAc (0.10 mL, 1.75 mmol) was added to an anhydrous DCM (5 mL) solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (80 mg, 0.19 mmol) and 2,3-dihydro-1H-indene-2-carboxaldehyde (42 mg, 0.29 mmol) and stirred for 30 min. NaBH(OAc)3 (61 mg, 0.29 mmol) was added, and the resulting mixture was stirred at room temperature for 18 h. The reaction was quenched at 0 °C with a saturated aqueous solution of NaHCO3. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with H2O (2 × 10 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-((2,3-dihydro-1H-inden-2-yl)methyl)-2-methylpiperidine as an oil (89 mg, 86%). ESI MS m / z 548.69 [M+H]+.

[0401] At -78°C and N2, BCl3 (1M DCM solution, 0.97mL, 0.97mmol) was added to an anhydrous DCM solution (5mL) of the above substance (89mg, 0.16mmol). The mixture was stirred at 0°C for 2h, then quenched with anhydrous MeOH (1mL). The mixture was stirred at ambient temperature for 10min. The solvent was removed under vacuum, and the residue was dissolved in 1M NH3 MeOH solution (10mL) and stirred for another 10min, then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-1-((2,3-dihydro-1H-inden-2-yl)methyl)-2-methylpiperidin-3,4,5-triol, as a white solid (21mg, 47%). 1 H NMR (400MHz, CD3OD) δ7.20-7.14(m,2H),7.12-7.06(m,2H),3.56-3.47(m,1H),3.18-3.11(m,2H),3.10-2.95(m,3H),2.8 5-2.65(m,3H),2.59(dd,J=15.4,6.5Hz,1H),2.35(dd,J=12.5,4.7Hz,1H),2.16-2.04(m,2H),1.17(d,J=6.1Hz,3H); ESI MS m / z278.17[M+H] + .

[0402] Example 29

[0403] (2R,3R,4R,5S)-1-(2-cyclohexylethyl)-2-methylpiperidine-3,4,5-triol

[0404]

[0405] To a solution of ((2R,3R,4R,5S)-3,4,5-tris(benzyloxy)piperidin-2-yl)methanol (0.2 g, 0.46 mmol) (J. Carb. Chem. 2017, 36, 295) in DMF (4 mL) and DIPEA (0.64 mL, 3.68 mmol), 2-cyclohexylethyl bromide (0.36 mL, 2.3 mmol) was added. The reaction mixture was heated overnight at 85 °C and then diluted with EtOAc (30 mL). The organic matter was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (EtOAc / hexane, 1:4) on silica gel to give ((2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(2-cyclohexylethyl)piperidin-2-yl)methanol (0.156 g, 62%) as a gel-like solid. 1H NMR (500MHz, CDCl3) δ7.38-7.27 (m, 15H), 4.98 (dd, J=11.0, 5.1Hz, 2H), 4.86 (d, J= 11.0Hz,1H),4.76-4.65(m,3H),3.79(s,2H),3.63-3.49(m,3H),3.10(dd,J=11.3, 4.6Hz,1H),2.76(ddd,J=13.3,10.5,5.8Hz,1H),2.50(ddd,J=13.3,10.3,5.2Hz,1 H),2.32-2.22(m,2H),1.73-1.61(m,5H),1.38-1.25(m,7H),0.97-0.83(m,2H); ESI MS m / z 544.34[M+H] + .

[0406] At 0 °C, Ph3P (0.15 g, 0.57 mmol) was added to a stirred solution of the above-mentioned substance (0.15 g, 0.28 mmol) in anhydrous DCM (15 mL), followed by CBr4 (0.19 g, 0.57 mmol). After stirring at 0 °C for 2 h, the reaction mixture was diluted with DCM (30 mL) and washed with a saturated aqueous solution of NaHCO3. The organic matter was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified by rapid chromatography (EtOAc / hexane, 1:4) on silica gel to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-(bromomethyl)-1-(2-cyclohexylethyl)piperidine (0.13 g, 74.6%) as a yellow solid. 1 H NMR (500MHz, CDCl3) δ7.38-7.27(m,15H),5.01(dd,J=14.3,10.9Hz,2H),4.84(d,J=11.0Hz, 1H),4.75(d,J=10.8Hz,1H),4.74-4.66(m,2H),3.95(dd,J=11.5,1.7Hz,1H),3.72-3.50(m, 4H),3.15(dd,J=11.2,4.9Hz,1H),2.74(q,J=9.2,5.1Hz,1H),2.69-2.57(m,1H),2.39-2.27 (m,2H),1.76-1.54(m,5H),1.39(dp,J=11.2,5.5Hz,1H),1.31-1.11(m,5H),0.92(m,2H); ESI MS m / z 606.25[M+H] + .

[0407] To a stirred solution of the above substance (0.13 g, 0.21 mmol) in anhydrous toluene (7 mL), Bu3SnH (0.085 mL, 0.31 mmol) was added, followed by ABCN (0.024 g, 0.1 mmol). The reaction mixture was heated overnight at 100 °C, then cooled and concentrated. The resulting crude mixture was purified by rapid chromatography (EtOAc / hexane, 1:4) on silica gel to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(2-cyclohexylethyl)-2-methylpiperidine (0.69 g, 40.6%) as a yellow solid. ESI MS m / z 528.34 [M+H] + .

[0408] At -78°C under Ar, BCl3 (0.85 mL of 1.0 M DCM solution, 0.85 mmol) was added to a DCM solution of the above substance (0.045 g, 0.085 mmol) in 5 mL of water. The mixture was stirred for 4 hours while the bath temperature reached room temperature. The mixture was then cooled at -78°C, and MeOH (2 mL) was carefully added. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. The resulting residue was neutralized with NH4OH (0.5 mL) and concentrated again under reduced pressure. The crude residue was purified by rapid chromatography (MeOH / DCM, 1:9) on silica gel to give (2R,3R,4R,5S)-1-(2-cyclohexylethyl)-2-methylpiperidin-3,4,5-triol (0.0053 g, 24%) as a white solid. 1 H NMR (400MHz, CD3OD) δ3.52(ddd,J=10.4,9.1,4.9Hz,1H),3.14(t,J=8.9Hz,1H),3.06-2.98(m,2H),2.90-2.80(m,1H),2.65-2.61(m,1H),2 .31-2.18(m,2H),1.80-1.64(m,5H),1.43-1.37(m,2H),1.34-1.27(m,2H),1.26-1.18(m,2H),1.25(d,J=6.1Hz,3H),1.06-0.91(m,2H); ESI MS m / z 258.20[M+H] + .

[0409] Example 30

[0410] (2R,3R,4R,5S)-1-(2-(4,4-difluorocyclohexyl)ethyl)-2-methylpiperidine-3,4,5-triol

[0411]

[0412] At 0°C, KO was added to an anhydrous DMF (20 mL) solution of (methoxymethyl)triphenylphosphonium chloride (1.3 g, 3.8 mmol). t Bu (0.43 g, 3.8 mmol) and 4,4-difluorocyclohexaneformaldehyde (0.28 g, 1.9 mmol) were mixed and stirred at room temperature for 64 hours. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (20 mL) and extracted with EtOAc (3 × 20 mL). The combined extracts were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was dissolved in a mixture of THF (10 mL) and HCl aqueous solution (5 N, 10 mL). After stirring under reflux for 5 hours, the mixture was cooled and diluted with saturated NaHCO3 aqueous solution (30 mL). After extraction with EtOAc (2 × 30 mL), the combined extracts were 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 rapid chromatography (EtOAc / hexane, 1:13 to 1:6) to give 2-(4,4-difluorocyclohexyl)acetaldehyde as a clear oil (0.21 g, 68%). 1 H NMR (500MHz, CDCl3) δ9.77 (t, J = 1.7 Hz, 1H), 2.40 (dd, J = 6.7, 1.7 Hz, 2H), 2.12-1.95 (m, 4H), 1.86-1.67 (m, 3H), 1.43-1.27 (m, 2H).

[0413] Under N2, a mixture of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.10 g, 0.24 mmol), 2-(4,4-difluorocyclohexyl)acetaldehyde (0.081 g, 0.50 mmol), and NaBH(OAc)3 (0.15 g, 0.71 mmol) was stirred in DCM (10 mL) at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 solution (10 mL) and extracted with DCM (3 × 15 mL). The combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid silica gel chromatography (EtOAc / hexane, 1:5 to 1:3) to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(2-(4,4-difluorocyclohexyl)ethyl)-2-methylpiperidine as a clear oil (0.084 g, 62%); ESI MS m / z 564.316 [M+H] + .

[0414] The mixture of the above-mentioned substance (0.080 g, 0.14 mmol), Pd(OH)₂ / C (20% by weight Pd, 0.030 g, 0.056 mmol), and one drop of concentrated HCl in MeOH solution (15 mL) was stirred overnight under hydrogen at one atmosphere. The mixture was filtered through a diatomaceous earth filter cake, the filtrate was collected and concentrated to dryness. The residue was neutralized with 1 M NH₃ in MeOH solution and purified by rapid chromatography (1 M NH₃ / MeOH / DCM, 1:7) on silica gel to give (2R,3R,4R,5S)-1-(2-(4,4-difluorocyclohexyl)ethyl)-2-methylpiperidin-3,4,5-triol (0.030 g, 73%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ4.67-4.64(m,3H),3.25-3.18(m,1H),2.87(td,J=8.8,4.3Hz,1H),2.77(dd,J=11.1,4.9Hz,1H),2.72-2.6 1(m,2H),2.32-2.25(m,1H),2.01-1.87(m,4H),1.82-1.66(m,4H),1.33-1.23(m,3H),1.19-1.10(m,2H),1.05(d,J=6.0Hz,3H); ESI MS m / z 294.177[M+H] + .

[0415] Examples 31 and 32

[0416] (2R,3R,4R,5S)-2-methyl-1-(2-((1s,4S)-4-(trifluoromethyl)cyclohexyl)ethyl)piperidine-3,4,5-triol and (2R,3R,4R,5S)-2-methyl-1-(2-((1r,4R)-4-(trifluoromethyl)cyclohexyl)ethyl)piperidine-3,4,5-triol

[0417]

[0418] At 0°C, KO was added to an anhydrous DMF (20 mL) solution of (methoxymethyl)triphenylphosphonium chloride (0.77 g, 2.5 mmol). tBu (0.28 g, 2.5 mmol) and 4-(trifluoromethyl)cyclohexaneformaldehyde (0.27 g, 1.5 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (20 mL) and then extracted with EtOAc (3 × 30 mL). The combined extracts were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was dissolved in a mixture of THF (10 mL) and HCl aqueous solution (5 N, 10 mL). After stirring under reflux for 4 hours, the mixture was cooled and diluted with saturated NaHCO3 aqueous solution (30 mL). After extraction with EtOAc (2 × 30 mL), the combined extracts were 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 rapid chromatography (EtOAc / hexane, 1:13 to 1:7) to give a mixture of cis and trans isomers of 2-(4-(trifluoromethyl)cyclohexyl)acetaldehyde (0.087 g, 29%) as a clear oil.

[0419] Under N2, a mixture of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.150 g, 0.359 mmol), the above-mentioned 2-(4-(trifluoromethyl)cyclohexyl)acetaldehyde (0.087 g, 0.45 mmol), and NaBH(OAc)3 (0.15 g, 0.71 mmol) was stirred in DCM (5 mL) at room temperature for 16 hours. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (15 mL) and extracted with DCM (3 × 15 mL). 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 rapid chromatography (EtOAc / hexane, 1:7 to 1:3) to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-(2-((1s,4S)-4-(trifluoromethyl)cyclohexyl)ethyl)piperidine as a clear oil (0.083 g, 39%) and (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-(2-((1r,4R)-4-(trifluoromethyl)cyclohexyl)ethyl)piperidine as a clear oil (0.042 g, 17%); ESI MS m / z 596.313 [M+H] + .

[0420] A mixture of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-(2-((1s,4S)-4-(trifluoromethyl)cyclohexyl)ethyl)piperidine (0.081 g, 0.14 mmol) and Pd(OH)₂ / C (20% by weight Pd, 0.050 g, 0.094 mmol) and one drop of concentrated HCl in a MeOH solution (10 mL) was stirred overnight under hydrogen and one atmosphere. The mixture was filtered through a diatomaceous earth filter cake, the filtrate was collected and concentrated to dryness. The residue was neutralized with a 1M NH3 solution of MeOH and purified by rapid chromatography (1M NH3 / MeOH / DCM, 1:6) on silica gel to give (2R,3R,4R,5S)-2-methyl-1-(2-((1s,4S)-4-(trifluoromethyl)cyclohexyl)ethyl)piperidine-3,4,5-triol (0.036 g, 79%) as a white solid. 1 H NMR (400MHz, CD3OD) δ3.47(ddd,J=101.6,9.1,4.9Hz,1H),3.09(t,J=9.0Hz,1H),2.98-2.93(m,2H),2.83-2.76( m,1H),2.56-2.48(m,1H),2.18-2.02(m,3H),2.00-1.80(m,5H),1.20(d,J=6.1Hz,3H),1.09-0.96(m,2H),); ESI MS m / z 326.172[M+H] + .

[0421] A mixture of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-(2-((1r,4R)-4-(trifluoromethyl)cyclohexyl)ethyl)piperidine (0.040 g, 0.067 mmol), Pd(OH)₂ / C (20% by weight Pd, 0.030 g, 0.056 mmol), and one drop of concentrated HCl in a MeOH solution (10 mL) was stirred overnight under hydrogen and at one atmosphere. The mixture was filtered through a diatomaceous earth filter cake, the filtrate was collected, and concentrated to dryness. The residue was neutralized with a 1M NH3 solution of MeOH and purified by rapid chromatography (1M NH3 / MeOH / DCM, 1:6) on silica gel to give (2R,3R,4R,5S)-2-methyl-1-(2-((1r,4R)-4-(trifluoromethyl)cyclohexyl)ethyl)piperidine-3,4,5-triol (0.016 g, 73%) as a white solid. 1H NMR (400MHz, CD3OD) δ3.48 (ddd, J=10.6, 9.0, 4.9Hz, 1H), 3.10 (t, J=9.0Hz, 1H), 3.00-2.93 (m, 2H), 2. 78-2.74(m,1H),2.52-2.45(m,1H),2.19-2.12(m,3H),1.71-1.50(m,11H),1.22(d,J=6.1Hz,3H); ESI MS m / z 326.171[M+H] + .

[0422] Example 33

[0423] (2R,3R,4R,5S)-1-((2-adamantane-1-yl)ethyl)-2-methylpiperidin-3,4,5-triol

[0424]

[0425] At 0 °C, DMP (612 mg, 1.44 mmol) was added to an anhydrous DCM (10 mL) solution of 2-((3r,5r,7r)-adamantane-1-yl)ethanol (200 mg, 1.11 mmol), and the mixture was stirred at 0 °C for 2 hours. The mixture was slowly quenched with Na₂S₃O₅ solution. The mixture was extracted with DCM (3 × 20 mL). The combined organic layers were washed with water (2 × 10 mL), separated, and dried over Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give 2-((3r,5r,7r)-adamantane-1-yl)acetaldehyde as an oil (128 mg, 64%).

[0426] HOAc (0.10 mL, 1.75 mmol) was added to a stirred solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (76 mg, 0.18 mmol) and 2-((3r,5r,7r)-adamantane-1-yl)acetaldehyde (65 mg, 0.37 mmol) in anhydrous MeOH (5 mL), and the mixture was stirred for 30 min. NaBH3CN (23 mg, 0.37 mmol) was added, and the resulting mixture was stirred at room temperature for 18 h. The reaction was quenched at 0 °C with a saturated aqueous solution of NaHCO3. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give (2R,3R,4R,5S)-1-(2-((3R,5R,7R)-adamantane-1-yl)ethyl)-3,4,5-tris(benzyloxy)-2-methylpiperidine as an oil (88 mg, 84%). ESI MS m / z 580.36 [M+H] + .

[0427] At -78°C and N2, an anhydrous DCM solution (8 mL) of the above-mentioned substance (150 mg, 0.26 mmol) was added to a stirred solution of the substance in anhydrous DCM (2.07 mL, 2.07 mmol). The mixture was stirred at 0°C for 2 h and then quenched with anhydrous MeOH (1 mL). The mixture was stirred at ambient temperature for 10 min. The solid formed was collected by filtration to give (2R,3R,4R,5S)-1-((2-adamantane-1-yl)ethyl)-2-methylpiperidin-3,4,5-triol, as an HCl salt (38 mg, 42%). 1 H NMR (400MHz, CD3OD) δ3.76-3.64(m,1H),3.52-3.42(m,1H),3.41-3.24(m,3H),3.25-3.06(m,2H),2. 96(t,J=11.8Hz,1H),2.05-1.96(m,3H),1.85-1.68(m,6H),1.67-1.52(m,7H),1.52-1.40(m,4H); ESI MS m / z 310.23[M+H] + .

[0428] Example 34

[0429] (2R,3R,4R,5S)-1-(3-cyclohexylpropyl)-2-methylpiperidine-3,4,5-triol

[0430]

[0431] A mixture of ((2R,3R,4R,5S)-3,4,5-tris(benzyloxy)piperidin-2-yl)methanol (0.17 g, 0.39 mmol), (3-bromopropyl)cyclohexane (0.30 g, 1.5 mmol), and DIPEA (0.22 g, 1.7 mmol) was stirred in anhydrous DMF (4 mL) at 90 °C for 16 hours. The reaction mixture was cooled to room temperature and diluted with a saturated aqueous solution of NaHCO3 (20 mL). After extraction with EtOAc (3 × 20 mL), the combined extracts were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid silica gel chromatography (EtOAc / hexane, 1:4 to 1:3) to give ((2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(3-cyclohexylpropyl)piperidin-2-yl)methanol, a pale yellow oil (0.21 g, 97%); ESI MS m / z 558.386 [M+H] + .

[0432] At 0 °C, PPh3 (0.20 g, 0.76 mmol) and CBr4 (0.20 g, 0.60 mmol) were added to anhydrous DCM (15 mL) solution of the above substance (0.21 g, 0.38 mmol), and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel rapid chromatography (EtOAc / hexane, 1:9–1:7) to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-(bromomethyl)-1-(3-cyclohexylpropyl)piperidine as a clear oil (0.17 g, 72%); ESI MS m / z 620.299 and 622.297 [M+H] + .

[0433] A mixture of the above substances (0.17 g, 0.27 mmol), Bu3SnH (0.22 g, 0.75 mmol), and ABCN (0.015 g, 0.063 mmol) was stirred at 95 °C for 4 hours in anhydrous toluene (15 mL). After cooling, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by rapid chromatography (EtOAc / hexane, 1:5 to 2:3) to give a mixture containing (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(3-cyclohexylpropyl)-2-methylpiperidine and its analogues protected by two benzyl groups.

[0434] At -78°C and N2, BCl3 (1.0 M DCM solution, 1.0 mL, 1.0 mmol) was added to an anhydrous DCM solution (5 mL) of the above mixture, and the mixture was stirred at 0°C for 3 hours. The reaction mixture was cooled to -78°C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with 1 M NH3 MeOH solution and purified on silica gel by rapid chromatography (1 M NH3 MeOH solution / DCM, 1:6) to give (2R,3R,4R,5S)-1-(3-cyclohexylpropyl)-2-methylpiperidin-3,4,5-triol as a white solid (0.018 g, 25%, two steps). 1 H NMR(500MHz,CD3OD)δ3.48(td,J=9.3,4.4Hz,1H),3.11(t,J=9.3Hz,1H),3.01-2.95(m,2H),2.75-2.69(m,1H),2.50- 2.44(m,1H),2.18(t,J=10.7Hz,2H),1.78-1.62(m,5H),1.53-1.45(m,2H),1.34-1.09(m,8H),0.95-0.87(m,2H); ESI MS m / z 272.219[M+H] + .

[0435] Example 35

[0436] (2R,3R,4R,5S)-2-methyl-1-phenylethylpiperidine-3,4,5-triol

[0437]

[0438] In a sealed tube, K₂CO₃ (1.64 g, 11.8 mmol) was added to a DMF (20 mL) solution of ((2R,3R,4R,5S)-3,4,5-tris(benzyloxy)piperidin-2-yl)methanol (641 mg, 1.48 mmol) and (2-bromoethyl)benzene (1.09 g, 5.92 mmol). The mixture was stirred at 80 °C for 18 h and cooled to ambient temperature. The reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give ((2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-phenylethylpiperidin-2-yl)methanol as a clear oil (615 mg, 77%). ESI MS m / z 538.29 [M+H] + .

[0439] At 0 °C, MsCl (0.10 mL, 1.25 mmol) was slowly added to a stirred solution of the above substance (336 mg, 0.63 mmol) in pyridine (5 mL). The reaction mixture was stirred at 50 °C for 1 h and quenched with a saturated aqueous solution of NaHCO3 (20 mL). The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by rapid chromatography on silica gel to (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-(chloromethyl)-1-phenylethylpiperidine as an oil (182 mg, 52%). ESI MS m / z 556.27, 558.27 [M+H] + .

[0440] A mixture of the above substances (90 mg, 0.24 mmol), Bu3SnH (0.065 mL, 0.24 mmol), and ABCN (20 mg, 0.08 mmol) was stirred in anhydrous toluene (10 mL) at 100 °C for 16 hours. After cooling, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel rapid chromatography to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-phenylethylpiperidine as an oil (18 mg, 20%). ESI MS m / z 522.30 [M+H] + .

[0441] To a solution of the above substance (18 mg, 0.035 mmol) in EtOH (10 mL), Pd(OH)₂ / C (20 wt.%, 8.6 mg, 0.012 mmol) and 6NHCl (0.05 mL) were added. The mixture was treated with hydrogen (1 atm) for 18 h. The catalyst was filtered off through diatomaceous earth, and the solvent was evaporated under reduced pressure. The residue was dissolved in a 1 M NH₃ solution of MeOH (10 mL) and stirred for another 10 min, then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-2-methyl-1-phenylethylpiperidine-3,4,5-triol as a white solid (3 mg, 35%). 1H NMR (400MHz, CD3OD) δ7.33-7.25(m,2H),7.23-7.16(m,3H),3.57-3.48(m,1H),3.15(t,J=8.8Hz,1H),3.09(dd,J=11.2 ,4.9Hz,1H),2.98(t,J=9.1Hz,1H),2.95-2.88(m,1H),2.87-2.70(m,3H),2.40-2.25(m,2H),1.27(d,J=5.6Hz,3H); ESI MS m / z 252.16[M+H] + .

[0442] Example 36

[0443] (2R,3R,4R,5S)-2-methyl-1-(2-methylphenethyl)piperidine-3,4,5-triol

[0444]

[0445] In a sealed tube, DIPEA (0.17 mL, 0.96 mmol) was added to a solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (52 mg, 0.12 mmol) and 1-(2-bromoethyl)-2-methylbenzene (124 mg, 0.62 mmol) in DMF (5 mL). The mixture was stirred at 80 °C for 18 h and cooled to ambient temperature. The reaction mixture was poured into ice water (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid silica gel chromatography to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-(2-methylphenylethyl)piperidine as a white solid (38 mg, 59%). ESI MS m / z 536.31 [M+H] + .

[0446] At -78°C and N2, a solution of BCl3 (1M DCM solution, 0.50 mL, 0.50 mmol) was added to a 3 mL anhydrous DCM solution of the above-mentioned substance (39 mg, 0.070 mmol) under stirring. The mixture was stirred at 0°C for 2 h, and then quenched with anhydrous MeOH (1 mL). The mixture was stirred at ambient temperature for 10 min. The solvent was removed under vacuum, and the residue was dissolved in a 1 M NH3 MeOH solution (10 mL) and stirred for another 10 min, and then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-2-methyl-1-(2-methylphenylethyl)piperidine-3,4,5-triol as a white solid (8.0 mg, 43%). 1 H NMR(400MHz,DMSO-d6)δ7.15-7.05(m,4H),4.73-4.68(m,3H),3.31-3.23(m,1H),2.96-2.88(m,2H), 2.77-2.56(m,5H),2.28(s,3H),2.20(t,J=10.6Hz,1H),2.16-2.07(m,1H),1.12(d,J=6.0Hz,3H); ESI MS m / z266.17[M+H] + .

[0447] Example 37

[0448] (2R,3R,4R,5S)-1-(2-methoxyphenethyl)-2-methylpiperidine-3,4,5-triol

[0449]

[0450] In a sealed tube, DIPEA (0.18 mL, 1.04 mmol) was added to a DMF (5 mL) solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (55 mg, 0.13 mmol) and 1-(2-bromoethyl)-2-methoxybenzene (141 mg, 0.66 mmol). The mixture was stirred at 80 °C for 18 h and cooled to ambient temperature. The reaction mixture was poured into ice water (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(2-methoxyphenylethyl)-2-methylpiperidine as a white solid (40 mg, 56%). ESI MS m / z 552.30 [M+H] + .

[0451] Pd(OH)₂ / C (20 wt.%, 8.6 mg, 0.012 mmol) and 6N HCl (0.1 mL) were added to a 10 mL EtOH solution of the above substance (40 mg, 0.072 mmol). The mixture was treated with hydrogen (1 atm) for 18 h. The catalyst was filtered off through diatomaceous earth, and the solvent was evaporated under reduced pressure. The residue was dissolved in a 1 M NH₃ MeOH solution (10 mL) and stirred for another 10 min, then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-1-(2-methoxyphenethyl)-2-methylpiperidine-3,4,5-triol as a white solid (20 mg, 98%). 1 H NMR (400MHz, CD3OD) δ7.29-7.23(m,1H),7.21(dd,J=7.4,1.7Hz,1H),6.99(d,J=8.2Hz,1H),6.92(td,J=7.4,1.0Hz,1H ),3.88(s,3H),3.72-3.61(m,1H),3.47-3.27(m,2H),3.28-3.10(m,3H),3.06-2.76(m,4H),1.45(d,J=6.3Hz,3H); ESI MS m / z282.16[M+H] + .

[0452] Example 38

[0453] (2R,3R,4R,5S)-1-(2-fluorophenylethyl)-2-methylpiperidine-3,4,5-triol

[0454]

[0455] In a sealed tube, K₂CO₃ (630 g, 5.52 mmol) was added to a solution of ((2R,3R,4R,5S)-3,4,5-tris(benzyloxy)piperidin-2-yl)methanol (300 mg, 0.69 mmol) and 1-(2-bromoethyl)-2-fluorobenzene (582 mg, 3.45 mmol) in DMF (5 mL). The mixture was stirred at 80 °C for 18 h and cooled to ambient temperature. The reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give ethyl((2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(2-fluorophenylethyl)piperidin-2-yl)methanol as a clear oil (225 mg, 59%). ESI MS m / z 556.30 [M+H]+ .

[0456] At 0 °C, PPh3 (81 mg, 0.31 mmol), imidazole (21 mg, 0.31 mmol), and iodine (30 mg, 0.24 mmol) were added to a stirred solution of the above-mentioned substance (68 mg, 0.12 mmol) in anhydrous DCM (5 mL). The resulting mixture was stirred at room temperature for 2 h and quenched with a saturated Na2S2O5 aqueous solution at 0 °C. The mixture was diluted with DCM and washed with a saturated NaHCO3 aqueous solution. The organic phase was separated and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(2-fluorophenylethyl)-2-(iodomethyl)piperidine as an oil (crude product). ESI MS m / z 666.18 [M+H] + .

[0457] A mixture of the above substances (0.12 mmol), Bu3SnH (0.048 mL, 0.18 mmol), and ABCN (15 mg, 0.06 mmol) was stirred in anhydrous toluene (10 mL) at 100 °C for 16 hours. After cooling, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel rapid chromatography to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(2-fluorophenylethyl)-2-methylpiperidine as an oil (25 mg, 38%, two steps). ESI MS m / z 540.28 [M+H] + .

[0458] At -78°C and N2, a solution of BCl3 (1M DCM solution, 0.50 mL, 0.50 mmol) was added to a stirred solution of the above substance (22 mg, 0.040 mmol) in anhydrous DCM (3 mL). The mixture was stirred at 0°C for 2 h, then quenched with anhydrous MeOH (1 mL). The mixture was stirred at ambient temperature for 10 min. The solvent was removed under vacuum, and the residue was dissolved in a 1M NH3 MeOH solution (10 mL) and stirred for another 10 min, then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-1-(2-fluorophenylethyl)-2-methylpiperidine-3,4,5-triol as a white solid (9 mg, 83%). 1H NMR (400MHz, CD3OD) δ7.29-7.19(m,2H),7.11(td,J=7.5,1.3Hz,1H),7.05(ddd,J=10.5,8.1,1.2Hz,1H),3.56-3.47(m,1H),3.14(t,J=9.0Hz,1 ESI MS m / z270.15[M+H] + .

[0459] Example 39

[0460] (2R,3R,4R,5S)-1-(2-chlorophenylethyl)-2-methylpiperidine-3,4,5-triol

[0461]

[0462] In a sealed tube, DIPEA (0.15 mL, 0.88 mmol) was added to a solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (45 mg, 0.11 mmol) and 1-(2-bromoethyl)-2-chlorobenzene (118 mg, 0.55 mmol) in DMF (5 mL). The mixture was stirred at 80 °C for 18 h and cooled to ambient temperature. The reaction mixture was poured into ice water (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid silica gel chromatography to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(2-chlorophenylethyl)-2-methylpiperidine as a white solid (29 mg, 48%). ESI MS m / z 556.26 [M+H] + .

[0463] At -78°C and N2, a solution of BCl3 (1M DCM solution, 0.50 mL, 0.50 mmol) was added to a 3 mL anhydrous DCM solution of the above-mentioned substance (28 mg, 0.050 mmol) under stirring. The mixture was stirred at 0°C for 2 h, then quenched with anhydrous MeOH (1 mL). The mixture was stirred at ambient temperature for 10 min. The solvent was removed under vacuum, and the residue was dissolved in a 1 M NH3 MeOH solution (10 mL) and stirred for another 10 min, then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-1-(2-chlorophenylethyl)-2-methylpiperidin-3,4,5-triol as a white solid (10 mg, 70%). 1 HNMR (400MHz, CD3OD) δ7.37(dd,J=7.7,1.6Hz,1H),7.31(dd,J=7.5,2.0Hz,1H),7.28-7.18(m,2H),3.58-3.49(m,1H),3.15(t,J= 9.0Hz,1H),3.10(dd,J=11.2,4.9Hz,1H),3.00-2.79(m,5H),2.42(t,J=10.9Hz,1H),2.37-2.28(m,1H),1.28(d,J=6.2Hz,3H); ESI MS m / z 286.12[M+H] + .

[0464] Example 40

[0465] (2R,3R,4R,5S)-1-(2,3-difluorophenylethyl)-2-methylpiperidine-3,4,5-triol

[0466]

[0467] Under Ar and with stirring, LAH (0.6 g, 17.4 mmol) was added in portions to a cooled (0 °C) solution of 2-(2,3-difluorophenyl)acetic acid (1.0 g, 5.8 mmol) in 15 mL of anhydrous THF. When effervescence ceased, the mixture was heated under reflux for 5 h until the starting material disappeared. The mixture was diluted with EtOAc and washed with 1.0 M HCl, water, and brine. The organic matter was dried over anhydrous Na₂SO₄ and concentrated to give 2-(2,3-difluorophenyl)ethanol (0.98 g, 98%) as an oil. 1 H NMR (400MHz, CDCl3) δ7.09-6.94(m,3H),3.83(m,2H),2.92(m,2H),2.28-2.05(m,1H).

[0468] The above substances (0.4 g, 2.5 mmol) and CBr4 (1.0 g, 3.0 mmol) were dissolved in DCM (15 mL). The mixture was cooled to 0 °C, and Ph3P (0.8 g, 3.0 mmol) was added in small portions. The reaction mixture was warmed to room temperature and stirred for 2 hours. The solvent was then removed under vacuum and purified by rapid chromatography (EtOAc / hexane, 1:4) to give 1-(2-bromoethyl)-2,3-difluorobenzene (0.5 g, 89%). 1 H NMR (400MHz, CDCl3) δ7.12-6.95 (m, 3H), 3.58 (t, J = 7.3Hz, 2H), 3.24 (td, J = 7.3, 1.3Hz, 2H).

[0469] To a solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.1 g, 0.24 mmol) in DMF (4 mL) and DIPEA (0.32 mL, 1.84 mmol), 1-(2-bromoethyl)-2,3-difluorobenzene (0.2 g, 1.0 mmol) was added. The reaction mixture was heated overnight at 85 °C and then diluted with EtOAc (30 mL). The organic matter was washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by rapid chromatography (EtOAc / hexane, 1:4) on silica gel to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(2,3-difluorophenylethyl)-2-methylpiperidine (0.049 g, 36.7%) as a gel-like solid. 1 H NMR (400MHz, CDCl3) δ7.40-7.24(m,15H),7.06-6.94(m,2H),6.89(dt,J=8.8 ,3.4Hz,1H),4.97(t,J=10.7Hz,2H),4.84(d,J=11.0Hz,1H),4.77-4.65(m,2 H),4.61(d,J=10.8Hz,1H),3.67-3.57(m,1H),3.51(t,J=9.0Hz,1H),3.17-3 .03(m,2H),2.94-2.71(m,4H),2.49-2.32(m,2H),1.22(d,J=6.1Hz,3H);ESI MS m / z558.267[M+H] + .

[0470] At -78°C under Ar conditions, BCl3 (1.0 M DCM solution, 0.87 mL, 0.87 mmol) was added to a DCM (5 mL) solution of the above substance (0.049 g, 0.087 mmol), and the mixture was stirred for 2 hours while the bath temperature was warmed to 0°C. The mixture was stirred at 0°C for the next 2 hours, and then quenched by the slow addition of MeOH (2 mL). After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. The resulting residue was neutralized with NH4OH (0.5 mL) and concentrated again under reduced pressure. The crude residue was purified by rapid chromatography (MeOH / DCM, 1:9) on silica gel to give (2R,3R,4R,5S)-1-(2,3-difluorophenylethyl)-2-methylpiperidin-3,4,5-triol (0.021 g, 87%) as a white solid. 1 H NMR (400MHz, CD3OD) δ7.15-7.04(m,3H),3.51(ddd,J=10.5,9.0,4.9Hz,1H),3.14(t,J=9.0Hz,1H),3.07(dd,J=11.2,4.9Hz ,1H),2.97-2.90(m,2H),2.89-2.78(m,3H),2.36(t,J=10.9Hz,1H),2.29(dt,J=9.1,6.1Hz,1H),1.24(d,J=6.1Hz,3H); ESI MS m / z288.137[M+H] + .

[0471] Example 41

[0472] (2R,3R,4R,5S)-1-(2,4-difluorophenylethyl)-2-methylpiperidine-3,4,5-triol

[0473]

[0474] In a sealed tube, DIPEA (0.50 mL, 2.87 mmol) was added to a solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (18 mg, 0.043 mmol) and 1-(2-bromoethyl)-2,4-difluorobenzene (200 mg, 0.91 mmol) in DMF (5 mL). The mixture was stirred at 80 °C for 18 h and cooled to ambient temperature. The reaction mixture was poured into ice water (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to obtain (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(2,4-difluorophenylethyl)-2-methylpiperidine as an oil (13 mg, 54%).

[0475] At -78°C and N2, a solution of BCl3 (1M DCM solution, 0.50 mL, 0.50 mmol) was added to a 3 mL anhydrous DCM solution of the above-mentioned substance (13 mg, 0.023 mmol) under stirring. The mixture was stirred at 0°C for 2 h, then quenched with anhydrous MeOH (1 mL). The mixture was stirred at ambient temperature for 10 min. The solvent was removed under vacuum, and the residue was dissolved in 1 M NH3 MeOH solution (10 mL) and stirred for another 10 min, then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-1-(2,4-difluorophenylethyl)-2-methylpiperidin-3,4,5-triol as a white solid (5 mg, 75%). 1 H NMR (400MHz, CD3OD) δ7.33-7.25(m,1H),6.95-6.86(m,2H),3.55-3.47(m,1H),3.13(t,J=9.0Hz,1H),3.06(dd,J=11.2,4 .9Hz,1H),2.94(t,J=9.1Hz,1H),2.91-2.74(m,4H),2.35(t,J=10.9Hz,1H),2.32-2.24(m,1H),1.24(d,J=6.2Hz,3H); ESI MS m / z288.14[M+H] + .

[0476] Example 42

[0477] (2R,3R,4R,5S)-1-(2,5-difluorophenylethyl)-2-methylpiperidine-3,4,5-triol

[0478]

[0479] Under Ar and with stirring, LAH (0.6 g, 17.4 mmol) was added in portions to 15 mL of cooled (0 °C) anhydrous THF solution of 2-(2,5-difluorophenyl)acetic acid (1.0 g, 5.8 mmol). When effervescence ceased, the mixture was heated under reflux for 5 h until the starting material disappeared. The mixture was diluted with EtOAc and washed with 1.0 M HCl, water, and brine. The organic matter was dried over anhydrous Na₂SO₄ and concentrated to give 2-(2,5-difluorophenyl)ethanol (0.9 g, 98%) as an oil. 1 H NMR (500MHz, CDCl3) δ7.00-6.91 (m, 2H), 6.87 (ddd, J = 8.9, 7.5, 3.5Hz, 1H), 3.83m, 2H), 2.86 (m, 2H), 2.28-2.10 (bs, 1H).

[0480] The above substances (0.4 g, 2.5 mmol) and CBr4 (1.0 g, 3.0 mmol) were dissolved in DCM (15 mL). The mixture was cooled to 0 °C, and Ph3P (0.8 g, 3.0 mmol) was added in small portions. The reaction mixture was warmed to room temperature and stirred for 2 hours. The solvent was then removed under vacuum, and 2-(2-bromoethyl)-1,4-difluorobenzene (0.45 g, 81%) was obtained by rapid chromatography (EtOAc / hexane, 1:4). 1 H NMR (400MHz, CDCl3) δ7.04-6.87 (m, 3H), 3.57 (t, J = 7.3Hz, 2H), 3.18 (td, J = 7.3, 1.2Hz, 2H).

[0481] To a solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.06 g, 0.14 mmol) in DMF (5 mL) and DIPEA (0.32 mL, 1.84 mmol), 2-(2-bromoethyl)-1,4-difluorobenzene (0.15 g, 0.71 mmol) was added. The reaction mixture was heated overnight at 85 °C and then diluted with EtOAc (30 mL). The organic matter was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (EtOAc / hexane, 1:4) on silica gel to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(2,5-difluorophenylethyl)-2-methylpiperidine (0.044 g, 55%) as a gel-like solid. 1H NMR (400MHz, CDCl3) δ7.39-7.27(m,15H),7.00-6.92(m,1H),6.86(td,J=8.1,7.6,4.3 Hz,2H),4.97(t,J=10.6Hz,2H),4.84(d,J=11.0Hz,1H),4.76-4.66(m,2H),4.61(d,J=1 0.9Hz,1H),3.62(bs,1H),3.50(t,J=9.0Hz,1H),3.17-3.03(m,2H),2.92-2.78(m,2H) ,2.70(t,J=7.8Hz,2H),2.43(s,1H),2.37(t,J=10.8Hz,1H),1.22(d,J=6.1Hz,3H); ESI MS m / z 558.27[M+H] + .

[0482] At -78°C under Ar conditions, BCl3 (1.0 M DCM solution, 0.78 mL, 0.78 mmol) was added to a DCM (5 mL) solution of the above substance (0.044 g, 0.078 mmol), and the mixture was stirred for 2 hours while the bath temperature was raised to 0°C. The mixture was stirred at 0°C for the next 2 hours, and then quenched by the slow addition of MeOH (2 mL). After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. The resulting residue was neutralized with NH4OH (0.5 mL) and concentrated again under reduced pressure. The crude residue was purified by rapid chromatography (MeOH / DCM, 1:9) on silica gel to give (2R,3R,4R,5S)-1-(2,5-difluorophenylethyl)-2-methylpiperidin-3,4,5-triol (0.018 g, 81.6%) as a white solid. 1 H NMR (400MHz, CD3OD) δ7.11-7.01(m,2H),6.96(ddd,J=8.6,6.4,3.7Hz,1H),3.51(ddd,J=10.5,9.0,4.9Hz,1H),3.14(t,J=9.0Hz,1H),3.06( ESI MS m / z288.13[M+H] + .

[0483] Example 43

[0484] (2R,3R,4R,5S)-1-(3,4-difluorophenylethyl)-2-methylpiperidine-3,4,5-triol

[0485]

[0486] 4-(2-bromoethyl)-1,2-difluorobenzene (0.5 g, 2.4 mmol) was added to a solution of ((2R,3R,4R,5S)-3,4,5-tris(benzyloxy)piperidin-2-yl)methanol (0.2 g, 0.46 mmol) in DMF (4 mL) and DIPEA (0.64 mL, 3.68 mmol). The reaction mixture was heated overnight at 85 °C and then diluted with EtOAc (30 mL). The organic matter was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (EtOAc / hexane, 1:4) on silica gel to give ((2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(3,4-difluorophenylethyl)piperidin-2-yl)methanol (0.2 g, 68%) as a gel-like solid. ESI MS m / z 574.272 [M+H] + .

[0487] At 0 °C, Ph3P (0.20 g, 0.78 mmol) was added to a stirred solution of the above-mentioned substance (0.2 g, 0.39 mmol) in anhydrous DCM (15 mL), followed by CBr4 (0.26 g, 0.78 mmol). After stirring at 0 °C for 2 h, the reaction mixture was diluted with DCM (30 mL) and washed with a saturated aqueous solution of NaHCO3. The organic matter was dried over anhydrous Na2SO4 and concentrated. The crude residue was purified by rapid chromatography (EtOAc / hexane, 1:4) on silica gel to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-(bromomethyl)-1-(3,4-difluorophenylethyl)piperidine (0.05 g, 21%) as a yellow solid. ESI MS m / z 638.179 [M+H] + .

[0488] The mixture of the above substances (0.087 g, 0.13 mmol) and Raney Ni (0.050 g) in EtOH was stirred overnight at 50 psi hydrogen pressure. The mixture was then filtered through a diatomaceous earth filter cake, and the filtrate was collected and concentrated to dryness. The crude product was dissolved in DCM (5 mL), and BCl3 (1.0 M in DCM, 0.8 mL, 0.8 mmol) was added dropwise at -78 °C under Ar, while the mixture was stirred for 2 h and the bath temperature was warmed to 0 °C. The mixture was stirred at 0 °C for the next 2 h, and then quenched by the slow addition of MeOH (2 mL). After stirring at room temperature for 30 min, the mixture was concentrated under reduced pressure. The resulting residue was neutralized with NH4OH (0.5 mL) and concentrated again under reduced pressure. The crude residue was purified on silica gel by rapid chromatography (MeOH / DCM, 1:9) to give (2R,3R,4R,5S)-1-(3,4-difluorophenylethyl)-2-methylpiperidine-3,4,5-triol (0.017 g, 74%) as a white solid. 1 HNMR (400MHz, CD3OD) δ7.25-7.16(m,2H),7.08(ddd,J=8.9,4.4,2.2Hz,1H),3.60(td,J=9.6,4.5Hz,1H),3.30-3. 21(m,2H),3.21-3.07(m,2H),3.06-2.96(m,1H),2.96-2.85(m,2H),2.66-2.56(m,2H),1.35(d,J=6.2Hz,3H); ESI MS m / z288.13s[M+H] + .

[0489] Example 44

[0490] (2R,3R,4R,5S)-1-(2-fluoro-4-methoxyphenethyl)-2-methylpiperidine-3,4,5-triol

[0491]

[0492] In a sealed tube, DIPEA (0.12 mL, 0.7 mmol) was added to a solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (43 mg, 0.10 mmol) and 1-(2-bromoethyl)-2-fluoro-4-methoxybenzene (121 mg, 0.52 mmol) in DMF (5 mL). The mixture was stirred at 80 °C for 18 h and cooled to ambient temperature. The reaction mixture was poured into ice water (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid silica gel chromatography to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(2-fluoro-4-methoxyphenethyl)-2-methylpiperidine, a white solid (35 mg, 61%). ESI MS m / z 570.30 [M+H] + .

[0493] Pd(OH)₂ / C (20 wt.%, 8.6 mg, 0.012 mmol) and 6N HCl (0.1 mL) were added to a 10 mL EtOH solution of the above substance (23 mg, 0.04 mmol). The mixture was treated with hydrogen (1 atm) for 18 h. The catalyst was filtered off through diatomaceous earth, and the solvent was evaporated under reduced pressure. The residue was dissolved in a 1 M NH₃ MeOH solution (10 mL) and stirred for another 10 min, then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-1-(2-fluoro-4-methoxyphenethyl)-2-methylpiperidin-3,4,5-triol as a white solid (9 mg, 75%). 1 H NMR (400MHz, CD3OD) δ7.15(t,J=8.6Hz,1H),6.74-6.61(m,2H),3.78(s,3H),3.56-3.47(m,1H),3.14(t,J=9.0Hz,1H),3.06(dd,J =11.2,4.9Hz,1H),2.96(t,J=9.1Hz,1H),2.92-2.67(m,4H),2.37(t,J=10.9Hz,1H),2.33-2.26(m,1H),1.25(d,J=6.2Hz,3H); ESI MS m / z 300.16[M+H] + .

[0494] Example 45

[0495] (2R,3R,4R,5S)-1-(3-chloro-2-fluorophenylethyl)-2-methylpiperidine-3,4,5-triol

[0496]

[0497] Under Ar conditions and with stirring, LAH (0.3 g, 8.7 mmol) was added in portions to 15 mL of anhydrous THF solution of cooled (0 °C) 2-(3-chloro-2-fluorophenyl)acetic acid (0.5 g, 2.6 mmol). When effervescence ceased, the mixture was heated under reflux for 5 h until the starting material disappeared. The mixture was diluted with EtOAc and washed with 1.0 M HCl, water, and brine. The organic matter was dried over anhydrous Na₂SO₄ and concentrated to give 2-(3-chloro-2-fluorophenyl)ethanol (0.4 g, 90%) as an oil. 1 H NMR (400MHz, CDCl3) δ7.29-6.98 (m, 3H), 3.87-3.79 (m, 2H), 2.91 (td, J = 6.4, 4.1Hz, 2H), 1.99-1.88 (m, 1H).

[0498] The above substances (0.20 g, 1.16 mmol) and CBr4 (0.5 g, 1.5 mmol) were dissolved in DCM (15 mL). The mixture was cooled to 0 °C and aliquoted into small portions, with Ph3P (0.4 g, 1.5 mmol) added. The reaction mixture was warmed to room temperature and stirred for 2 hours, then the solvent was removed under vacuum. Rapid chromatography (EtOAc / hexane, 1:4) was used to purify 1-(2-bromoethyl)-3-chloro-2-fluorobenzene (0.23 g, 82.7%). 1 H NMR (400MHz, CDCl3) δ7.79-7.62 (m, 1H), 7.60-7.44 (m, 2H), 4.02 (td, J = 7.4, 1.2Hz, 2H), 3.70-3.62 (m, 2H).

[0499] To a solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.06 g, 0.14 mmol) in DMF (5 mL) and DIPEA (0.32 mL, 1.84 mmol), 2-(2-bromoethyl)-1,4-difluorobenzene (0.16 g, 0.70 mmol) was added. The reaction mixture was heated overnight at 85 °C and then diluted with EtOAc (30 mL). The organic matter was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (EtOAc / hexane, 1:4) on silica gel to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(3-chloro-2-fluorophenylethyl)-2-methylpiperidine (0.032 g, 55%) as a gel-like solid. ESI MS m / z 574.23 [M+H] + .

[0500] At -78°C under Ar conditions, BCl3 (0.55 mL of 1.0 M DCM solution, 0.055 mmol) was added to a 5 mL solution of the above substance (0.032 g, 0.055 mmol), and the mixture was stirred for 2 hours while the bath temperature was warmed to 0°C. The mixture was stirred at 0°C for the next 2 hours, and then quenched by the slow addition of MeOH (2 mL). After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. The resulting residue was neutralized with NH4OH (0.5 mL) and concentrated again under reduced pressure. The crude residue was purified by rapid chromatography (MeOH / DCM, 1:9) on silica gel to give (2R,3R,4R,5S)-1-(3-chloro-2-fluorophenylethyl)-2-methylpiperidin-3,4,5-triol (0.014 g, 83.7%) as a white solid. 1 H NMR (400MHz, CD3OD) δ7.33(m,1H),7.23(m,1H),7.10(m,1H),3.51(td,J=9.8,4.9Hz,1H),3.14(t,J=9.0Hz,1H),3.07(dd,J= 11.2,4.9Hz,1H),2.98-2.89(m,2H),2.88-2.79(m,3H),2.36(t,J=10.8Hz,1H),2.32-2.25(m,1H),1.24(d,J=6.2Hz,3H); ESI MS m / z 304.11[M+H] + .

[0501] Example 46

[0502] (2R,3R,4R,5S)-1-(4-chloro-2-fluorophenylethyl)-2-methylpiperidine-3,4,5-triol

[0503]

[0504] In a sealed tube, K₂CO₃ (121 mg, 0.88 mmol) was added to a DMF (5 mL) solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (45 mg, 0.11 mmol) and 1-(2-bromoethyl)-4-chloro-2-fluorobenzene (130 mg, 0.55 mmol). The mixture was stirred at 80 °C for 18 h and cooled to ambient temperature. The reaction mixture was poured into ice water (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(4-chloro-2-fluorophenylethyl)-2-methylpiperidine, a white solid (15 mg, 24%). ESI MS m / z 574.25 [M+H] + .

[0505] At -78°C and N2, a solution of BCl3 (1M DCM solution, 0.50 mL, 0.50 mmol) was added to a stirred solution of the above substance (15 mg, 0.026 mmol) in anhydrous DCM (3 mL). The mixture was stirred at 0°C for 2 h, then quenched with anhydrous MeOH (1 mL). The mixture was stirred at ambient temperature for 10 min. The solvent was removed under vacuum, and the residue was dissolved in a 1M NH3 MeOH solution (10 mL) and stirred for another 10 min, then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-1-(4-chloro-2-fluorophenylethyl)-2-methylpiperidin-3,4,5-triol as a white solid (6 mg, 76%). 1 H NMR (400MHz, CD3OD) δ7.28(t,J=8.3Hz,1H),7.19-7.12(m,2H),3.55-3.45(m,1H),3.13(t,J=9.0Hz,1H),3.06( dd,J=11.2,4.9Hz,1H),2.98-2.75(m,5H),2.35(t,J=10.9Hz,1H),2.33-2.26(m,1H),1.23(d,J=6.2Hz,3H); ESI MS m / z 304.11[M+H] + .

[0506] Example 47

[0507] (2R,3R,4R,5S)-1-(5-chloro-2-fluorophenylethyl)-2-methylpiperidine-3,4,5-triol

[0508]

[0509] Under Ar conditions and with stirring, LAH (0.3 g, 8.7 mmol) was added in portions to 15 mL of cooled (0 °C) anhydrous THF solution of 2-(5-chloro-2-fluorophenyl)acetic acid (0.5 g, 2.6 mmol). When effervescence ceased, the mixture was heated under reflux for 5 h until the starting material disappeared. The mixture was diluted with EtOAc and washed with 1.0 M HCl, water, and brine. The organic matter was dried over anhydrous Na₂SO₄ and concentrated to 2-(5-chloro-2-fluorophenyl)ethanol (0.46 g, 99%) as an oil. 1 H NMR (400MHz, CDCl3) δ7.22 (dd, J=6.5, 2.7Hz, 1H), 7.15 (dddd, J=8.4, 4.2, 2.7, 0.9Hz, 1H), 6.99-6.92(m,1H),3.81(td,J=6.6,2.4Hz,2H),2.84(td,J=6.6,3.2Hz,2H),2.26(bs,1H).

[0510] The above substances (0.46 g, 2.6 mmol) and CBr4 (1.1 g, 3.4 mmol) were dissolved in DCM (15 mL). The mixture was cooled to 0 °C and aliquoted into small portions, with Ph3P (0.9 g, 3.4 mmol) added. The reaction mixture was warmed and stirred at room temperature for 2 hours, and then the solvent was removed under vacuum. Purification by rapid chromatography (EtOAc / hexane, 1:4) yielded 2-(2-bromoethyl)-4-chloro-1-fluorobenzene (0.99 g, 97%). 1 H NMR (400MHz, CDCl3) δ7.69-7.60 (m, 2H), 7.45-7.39 (m, 1H), 4.00 (t, J = 7.4Hz, 2H), 3.64-3.58 (m, 2H).

[0511] To a solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.06 g, 0.14 mmol) in DMF (5 mL) and DIPEA (0.32 mL, 1.84 mmol), 2-(2-bromoethyl)-1,4-difluorobenzene (0.16 g, 0.70 mmol) was added. The reaction mixture was heated overnight at 85 °C and then diluted with EtOAc (30 mL). The organic matter was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by rapid chromatography (EtOAc / hexane, 1:4) on silica gel to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(5-chloro-2-fluorophenylethyl)-2-methylpiperidine (0.044 g, 54%) as a gel-like solid.1 H NMR (400MHz, CDCl3) δ7.39-7.27(m,15H),7.14(dd,J=7.8,5.0Hz,2H),6.95(dd,J=10.2,7. 9Hz,1H),4.97(t,J=10.5Hz,2H),4.84(d,J=10.9Hz,1H),4.76-4.66(m,2H),4.61(d,J=10.8 Hz,1H),3.62(td,J=9.6,4.6Hz,1H),3.50(t,J=9.0Hz,1H),3.14-3.04(m,2H),2.84(m,2H), 2.69(m,2H),2.43(dd,J=9.2,6.0Hz,1H),2.37(t,J=10.8Hz,1H),1.22(d,J=6.1Hz,3H); ESI MS m / z 574.25[M+H] + .

[0512] At -78°C under Ar conditions, BCl3 (1.0 M DCM solution, 0.76 mL, 0.76 mmol) was added to a DCM (5 mL) solution of the above substance (0.044 g, 0.076 mmol), and the mixture was stirred for 2 hours while the bath temperature reached 0°C. The mixture was stirred at 0°C for the next 2 hours, and then quenched by the slow addition of MeOH (2 mL). After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. The resulting residue was neutralized with NH4OH (0.5 mL) and concentrated again under reduced pressure. The crude residue was purified by rapid chromatography (MeOH / DCM, 1:9) on silica gel to give (2R,3R,4R,5S)-1-(5-chloro-2-fluorophenylethyl)-2-methylpiperidin-3,4,5-triol (0.021 g, 93.5%) as a white solid. 1 H NMR (400MHz, CD3OD) δ7.31 (dd, J=6.5, 2.7Hz, 1H), 7.23 (ddd, J=8.8, 4.4, 2.7H z,1H),7.07(t,J=9.2Hz,1H),3.50(ddd,J=10.5,9.0,4.9Hz,1H),3.13(t,J=9. 0Hz,1H),3.06(dd,J=11.2,4.9Hz,1H),2.97-2.87(m,2H),2.86-2.77(m,3H), 2.35(t,J=10.9Hz,1H),2.28(dt,J=9.2,6.2Hz,1H),1.23(d,J=6.1Hz,3H); ESI m / z 304.11[M+H] + .

[0513] Example 48

[0514] (2R,3R,4R,5S)-1-(2,6-difluorophenylethyl)-2-methylpiperidine-3,4,5-triol

[0515]

[0516] In a sealed tube, DIPEA (0.16 mL, 0.96 mmol) was added to a solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (50 mg, 0.12 mmol) and 2-(2-bromoethyl)-1,3-difluorobenzene (132 mg, 0.60 mmol) in DMF (5 mL). The mixture was stirred at 80 °C for 18 h and cooled to ambient temperature. The reaction mixture was poured into ice water (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(2,6-difluorophenylethyl)-2-methylpiperidine, a white solid (28 mg, 42%). ESI MS m / z 558.27 [M+H] + .

[0517] At -78°C and N2, a solution of BCl3 (1M DCM solution, 0.50 mL, 0.50 mmol) was added to a stirred solution of the above substance (28 mg, 0.050 mmol) in anhydrous DCM (3 mL). The mixture was stirred at 0°C for 2 h, then quenched with anhydrous MeOH (1 mL). The mixture was stirred at ambient temperature for 10 min. The solvent was removed under vacuum, and the residue was dissolved in a 1M NH3 MeOH solution (10 mL) and stirred for another 10 min, then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-1-(2,6-difluorophenylethyl)-2-methylpiperidine-3,4,5-triol as a white solid (12 mg, 83%). 1 H NMR (400MHz, CD3OD) δ7.31-7.20(m,1H),6.99-6.89(m,2H),3.55-3.45(m,1H),3.14(t,J=9.0Hz,1H),3.07(dd ,J=11.2,4.9Hz,1H),2.98-2.77(m,5H),2.40(t,J=10.9Hz,1H),2.36-2.27(m,1H),1.23(d,J=6.2Hz,3H); ESI MS m / z 288.13[M+H] +.

[0518] Example 49

[0519] (2R,3R,4R,5S)-1-(3-chloro-2,6-difluorophenylethyl)-2-methylpiperidine-3,4,5-triol

[0520]

[0521] At 0°C, KO was added to an anhydrous DMF (30 mL) solution of (methoxymethyl)triphenylphosphonium chloride (4.30 g, 12.5 mmol). t Bu (1.40 g, 12.5 mmol) and 3-chloro-2,6-difluorobenzaldehyde (1.77 g, 10.0 mmol) were mixed and stirred at room temperature for 16 hours. The reaction was quenched with an aqueous HCl solution (2 N, 20 mL), and the mixture was extracted with EtOAc (3 × 30 mL). The combined extracts were washed with a saturated aqueous NaHCO3 solution (50 mL), brine (50 mL), and water (50 mL), and then dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was dissolved in a mixture of THF (40 mL) and an aqueous HCl solution (3 N, 40 mL). After stirring under reflux for 5 hours, the mixture was cooled and extracted with EtOAc (2 × 50 mL). The combined extracts were washed with a saturated aqueous NaHCO3 solution (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 rapid chromatography (EtOAc / hexane, 1:20 to 1:9) to give 2-(3-chloro-2,6-difluorophenyl)acetaldehyde, a pale yellow liquid (0.55 g, 28%). 1 H NMR (500MHz, CDCl3) δ9.76 (p, J=1.3Hz, 1H), 7.34 (ddd, J=8.8, 8.3, 5.7Hz, 1H), 6.91 (td, J=8.8, 1.8Hz, 1H), 3.84 (q, J=1.3Hz, 2H).

[0522] Under N2, a mixture of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.10 g, 0.24 mmol), 2-(3-chloro-2,6-difluorophenyl)acetaldehyde (0.10 g, 0.52 mmol), and NaBH(OAc)3 (0.17 g, 0.80 mmol) was stirred in DCM (10 mL) at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 solution (10 mL) and extracted with DCM (3 × 15 mL). The combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid silica gel chromatography (EtOAc / hexane, 1:12 to 1:6) to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(3-chloro-2,6-difluorophenylethyl)-2-methylpiperidine as a white solid (0.13 g, 92%); ESI MS m / z 592.236 [M+H] + .

[0523] At -78°C and N2, BCl3 (1.0 M DCM solution, 2.0 mL, 2.0 mmol) was added to an anhydrous DCM solution (5 mL) of the above substance (0.13 g, 0.22 mmol), and the mixture was stirred at 0°C for 3 hours. The reaction mixture was cooled at -78°C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with 1 M NH3 MeOH solution and purified by rapid chromatography on silica gel (1 M NH3 MeOH solution / DCM, 1:6) to give (2R,3R,4R,5S)-1-(3-chloro-2,6-difluorophenylethyl)-2-methylpiperidin-3,4,5-triol, as a white solid (0.058 g, 83%). 1 H NMR (500MHz, DMSO-d6) δ7.49(td,J=8.8,5.7Hz,1H),7.14(td,J=9.0,1.7Hz,1H),4.74-4.67(m,3H),3.27-3.18(m,1H),2.93-2. 81(m,2H),2.82-2.68(m,3H),2.70-2.60(m,2H),2.17(t,J=10.6Hz,1H),2.10(dq,J=8.9,6.1Hz,1H),1.02(d,J=6.1Hz,3H); ESI MS m / z 322.095[M+H] + .

[0524] Example 50

[0525] (2R,3R,4R,5S)-1-(2,6-difluoro-4-(prop-1-en-2-yl)phenethyl)-2-methylpiperidin-3,4,5-triol

[0526]

[0527] KO was added to a stirred anhydrous THF (60 mL) solution of (methoxymethyl)triphenylphosphonium chloride (8.57 g, 25 mmol) at 0 °C and N2. t Bu (2.81 g, 25 mmol) was added and stirred for 30 minutes. Subsequently, 4-bromo-2,6-difluorobenzaldehyde (2.21 g, 10 mmol) was dissolved in 20 mL of THF and added dropwise to the mixture under N2, reacting at room temperature for 18 h. The reaction was quenched at 0 °C with a saturated NaHCO3 aqueous solution. The mixture was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give the product as an oil containing two isomers. The oil was dissolved in THF (30 mL), and 2N HCl aqueous solution (30 mL) was added. The mixture was stirred at 80 °C for 8 h. The reaction mixture was cooled to room temperature and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to obtain 2-(4-bromo-2,6-difluorophenyl)acetaldehyde as an oil (1.27 g, 54%). 1 H NMR (400MHz, CDCl3) δ9.76 (p, J = 1.2 Hz, 1H), 7.25-7.00 (m, 2H), 3.79 (q, J = 1.3 Hz, 2H).

[0528] HOAc (0.20 mL, 3.5 mmol) was added to a stirred solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (600 mg, 1.44 mmol) and 2-(4-bromo-2,6-difluorophenyl)acetaldehyde (673 g, 2.88 mmol) in anhydrous MeOH (45 mL), and the mixture was stirred for 30 min. NaBH3CN (181 mg, 2.88 mmol) was added, and the resulting mixture was stirred at room temperature for 18 h. The reaction was quenched with a saturated aqueous solution of NaHCO3 at 0 °C. The mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(4-bromo-2,6-difluorophenylethyl)-2-methylpiperidine, a white solid (904 mg, 99%). ESI MS m / z 636.15, 638.15 [M+H] + .

[0529] Under Ar conditions, Pd(PPh3)4 (32 mg, 0.028 mmol) was added to a toluene (5 mL) solution of the above-mentioned substance (88 mg, 0.14 mmol) and pinacol 2-isopropenylboronic acid (47 mg, 0.28 mmol) under stirring, followed by the addition of K2CO3 (97 mg, 0.70 mmol) and water (1 mL). The mixture was stirred at 100 °C for 18 hours, and then water was added. The mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with water (2 × 10 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(2,6-difluoro-4-(prop-1-en-2-yl)phenethyl)-2-methylpiperidine as a white solid (60 mg, 72%). ESI MS m / z 598.27 [M+H] + .

[0530] At -78°C and N2, a solution of BCl3 (1M DCM solution, 0.50 mL, 0.50 mmol) was added to a stirred solution of the above substance (26 mg, 0.043 mmol) in anhydrous DCM (3 mL). The mixture was stirred at 0°C for 2 h, then quenched with anhydrous MeOH (1 mL). The mixture was stirred at ambient temperature for 10 min. The solvent was removed under vacuum, and the residue was dissolved in 1M NH3 MeOH solution (10 mL) and stirred for another 10 min, then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-1-(2,6-difluoro-4-(prop-1-en-2-yl)phenethyl)-2-methylpiperidin-3,4,5-triol, as a white solid (11 mg, 78%). 1 H NMR (400MHz, CD3OD) δ7.13-7.04(m,2H),5.46(t,J=1.0Hz,1H),5.18(t,J=1.5Hz,1H),3.55-3.47(m,1H),3.13(t,J=9.0Hz,1H),3.07(dd, J=11.1,5.0Hz,1H),2.96-2.77(m,5H),2.40(t,J=10.8Hz,1H),2.36-2.27(m,1H),2.13(dd,J=1.5,0.8Hz,3H),1.23(d,J=6.2Hz,3H); ESI MS m / z 328.15[M+H] + .

[0531] Example 51

[0532] (2R,3R,4R,5S)-1-(2,6-difluoro-4-isopropylphenethyl)-2-methylpiperidine-3,4,5-triol

[0533]

[0534] Pd(OH)₂ / C (20 wt%, 8.6 mg, 0.012 mmol) and 6N HCl (0.1 mL) were added to a solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(2,6-difluoro-4-(prop-1-en-2-yl)phenethyl)-2-methylpiperidine (32 mg, 0.054 mmol) in EtOH (10 mL). The mixture was treated with hydrogen (1 atm) for 18 h. The catalyst was filtered through diatomaceous earth, and the solvent was evaporated under reduced pressure. The residue was dissolved in a 1 M NH₃ MeOH solution (10 mL) and stirred for another 10 min, then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-1-(2,6-difluoro-4-isopropylphenylethyl)-2-methylpiperidine-3,4,5-triol, a white solid (13 mg, 73%). 1 H NMR (400MHz, CD3OD) δ6.87-6.80(m,2H),3.55-3.47(m,1H),3.13(t,J=9.0Hz,1H),3.07(dd,J=11.1,5.0Hz,1H) ,2.97-2.74(m,6H),2.40(t,J=10.8Hz,1H),2.35-2.27(m,1H),1.25(d,J=6.9Hz,6H),1.23(d,J=6.2Hz,3H); ESI MS m / z 330.16[M+H] + .

[0535] Example 52

[0536] (2R,3R,4R,5S)-1-(2,6-difluoro-3-isopropylphenethyl)-2-methylpiperidine-3,4,5-triol

[0537]

[0538] At 0°C and under Ar conditions, KO was added to an anhydrous dioxane (20 mL) solution of (methoxymethyl)triphenylphosphonium chloride (8.57 g, 25.0 mmol). tBu (2.81 g, 25.0 mmol). The mixture was stirred at 0 °C for 0.5 h, and then 3-bromo-2,6-difluorobenzaldehyde (2.21 g, 10.0 mmol) was added. The reaction mixture was heated to 60 °C and stirred overnight, and saturated NH4Cl aqueous solution (30 mL) was added. The mixture was extracted with EtOAc (3 × 10 mL). The combined organic extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was dissolved in HCl solution (30 mL, 6 N). The resulting mixture was stirred at 60 °C for another 2 h and cooled to room temperature. The aqueous solution was extracted with EtOAc (3 × 50 mL), and the combined organic solutions were washed with saturated NaHCO3 aqueous solution and brine, and dried over Na2SO4. The solvent was evaporated, and then rapid silica gel chromatography was performed using 30% EtOAc in hexane to give 2-(3-bromo-2,6-difluorophenyl)acetaldehyde as a white foam (1.66 g, 67%). 1 H NMR (400MHz, CDCl3) δ9.78 (t, J = 1.2 Hz, 1H), 7.52 (ddd, J = 9.1, 7.8, 5.9 Hz, 1H), 6.90 (ddd, J = 8.7, 8.7, 1.7 Hz, 1H), 3.87 (s, 2H).

[0539] Under Ar conditions, Pd(PPh3)4 (34 mg, 0.03 mmol) was added to a mixture of 2-(3-bromo-2,6-difluorophenyl)acetaldehyde (368 mg, 1.48 mmol), pinacol 2-isopropenylboronic acid (0.55 mL, 2.90 mmol), and K2CO3 (612 mg, 4.40 mmol) in anhydrous and degassed toluene (5 mL) and water (1 mL). The mixture was stirred in a sealed tube at 115 °C for 19 hours and then cooled to room temperature. Et2O (50 mL) was added, and the resulting precipitate was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by rapid chromatography on silica gel using 5% EtOAc in hexane to give ethyl 2-(2,6-difluoro-3-(prop-1-en-2-yl)phenyl)acetaldehyde (238 mg, 82%) as a white solid.

[0540] Under Ar conditions, NaBH(OAC)3 (241 mg, 1.13 mmol) was added to an anhydrous DCM (8 mL) solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-(piperidin-4-ylmethyl)piperidine (239 mg, 0.57 mmol) and 2-(2,6-difluoro-3-(prop-1-en-2-yl)phenyl)acetaldehyde (210 mg, 0.86 mmol). The mixture was stirred at room temperature for 18 hours. An aqueous solution of NaHCO3 (30 mL) was added, and the mixture was extracted with EtOAc (3 × 30 mL). The combined organic extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by rapid chromatography using a 20% EtOAc solution in hexane to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(2,6-difluoro-3-(prop-1-en-2-yl)phenethyl)-2-methylpiperidine as a white foam (320 mg, 94%). 1 H NMR (400MHz, CDCl3) δ7.46-7.20(m,15H),7.13(td,J=8.5,6.4Hz,1H),6.83(t,J=8.6Hz,1H),5. 28-5.13(m,2H),4.98(dd,J=15.3,10.9Hz,2H),4.86(d,J=11.0Hz,1H),4.73(s,2H),4.63(d,J=1 0.8Hz,1H),3.66-3.62(m,1H),3.53(t,J=9.0Hz,1H),3.20(dd,J=11.2,4.8Hz,1H),3.08(t,J=9. 0Hz, 1H), 2.96-2.62 (m, 4H), 2.54-2.37 (m, 2H), 2.21-2.05 (m, 3H), 1.27 (dd, J = 24.1, 6.6Hz, 3H).

[0541] The above substance (300 mg, 0.50 mmol), 6N HCl (0.7 mL), and EtOH (30 mL) solution were treated with hydrogen overnight in a balloon in the presence of Pd(OH)₂ (cat.). Pd(OH)₂ was removed by filtration, the solvent was evaporated, and then purified by silica gel chromatography using a DCM solution of 10% MeOH and 2% NH₃ and dry loading to give 2(2R,3R,4R,5S)-1-(2,6-difluoro-3-isopropylphenylethyl)-2-methylpiperidin-3,4,5-triol (113 mg, 70%). 1HNMR(400MHz,CD3OD)δ7.28-7.09(m,1H),7.01-6.68(m,1H),3.56-3.50(m,1H),3.24-3.16 (m,3H),3.02-2.94(m,6H),2.57(bs,1H),1.30(d,J=6.1Hz,3H),1.26(d,J=6.9Hz,6H); ESI MS m / z 330.19[M+H] + .

[0542] Example 53

[0543] (2R,3R,4R,5S)-1-(4-cyclopropyl-2,6-difluorophenylethyl)-2-methylpiperidine-3,4,5-triol

[0544]

[0545] Under Ar conditions, Pd(OAc)₂ (7 mg, 0.032 mmol) was added to a stirred solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(4-bromo-2,6-difluorophenylethyl)-2-methylpiperidine (100 mg, 0.16 mmol) and cyclopropylboronic acid (27 mg, 0.32 mmol) in toluene (5 mL), followed by tricyclohexylphosphine (0.1 mL, 0.064 mmol), K₃PO₄ (133 mg, 0.64 mmol), and water (0.3 mL). The mixture was stirred at 100 °C for 18 hours, and then water was added. The mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with water (2 × 10 mL), separated, and dried over Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(4-cyclopropyl-2,6-difluorophenylethyl)-2-methylpiperidine, a white solid (82 mg, 86%). ESI MS m / z 598.29 [M+H] + .

[0546] At -78°C and N2, a solution of BCl3 (1 M DCM solution, 1.0 mL, 1.0 mmol) was added to a stirred solution of the above substance (80 mg, 0.13 mmol) in anhydrous DCM (5 mL). The mixture was stirred at 0°C for 2 h, then quenched with anhydrous MeOH (1 mL). The mixture was stirred at ambient temperature for 10 min. The solvent was removed under vacuum, and the residue was dissolved in a 1 M NH3 MeOH solution (10 mL) and stirred for another 10 min, then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-1-(4-cyclopropyl-2,6-difluorophenylethyl)-2-methylpiperidine-3,4,5-triol, a white solid (30 mg, 71%). 1 H NMR (400MHz, CD3OD) δ6.71-6.63(m,2H),3.55-3.46(m,1H),3.13(t,J=9.0Hz,1H),3.05(dd,J=11.1,5.0Hz,1H),2.93(t,J=9.1Hz,1H),2.89 -2.73(m,4H),2.39(t,J=10.8Hz,1H),2.35-2.27(m,1H),1.96-1.87(m,1H),1.22(d,J=6.2Hz,3H),1.05-0.97(m,2H),0.73-0.66(m,2H); ESI MS m / z 328.17[M+H] + .

[0547] Example 54

[0548] (2R,3R,4R,5S)-1-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenethyl)-2-methylpiperidin-3,4,5-triol

[0549]

[0550] Under Ar conditions, a mixture of 4-bromo-2,6-difluorobenzaldehyde (4.42 g, 20.0 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (38A) (4.20 g, 20.0 mmol), Pd(PPh3)4 (1.15 g, 1.00 mmol), and an aqueous solution of K2CO3 (4.0 M, 10.0 mL, 40 mmol) in 1,4-dioxane (60 mL) was stirred at 85 °C for 16 hours and then cooled to room temperature. Brine (50 mL) was added, and the mixture was extracted with EtOAc (3 × 30 mL). The combined extracts were 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 rapid chromatography (EtOAc / hexane, 1:5 to 1:4) to give 4-(3,6-dihydro-2H-pyran-4-yl)-2,6-difluorobenzaldehyde as a white solid (1.75 g, 39%). 1 H NMR (400MHz, CDCl3) δ10.31 (s, 1H), 7.04-6.97 (m, 2H), 6.38-6.36 (m, 1H), 4.35 (q, J = 2.9Hz, 2H), 3.93 (t, J = 5.4Hz, 2H), 2.50-2.45 (m, 2H).

[0551] At -10°C, KO was added to an anhydrous THF (40 mL) solution of (methoxymethyl)triphenylphosphonium chloride (3.42 g, 10.0 mmol). tBu (1.12 g, 10.0 mmol) was added, and the mixture was stirred at -10 °C for 1 hour. 4-(3,6-dihydro-2H-pyran-4-yl)-2,6-difluorobenzaldehyde (1.00 g, 4.46 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The mixture was diluted with a saturated aqueous solution of NaHCO3 (50 mL) and extracted with EtOAc (3 × 30 mL). 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 rapid chromatography (EtOAc / hexane, 1:6) to obtain the desired product. The product was dissolved in a mixture of THF (40 mL) and HCl aqueous solution (2.5 N, 40 mL). After stirring under reflux for 5 hours, the mixture was cooled and diluted with ice water (50 mL). After extraction with EtOAc (3 × 30 mL), the combined extracts were washed with saturated NaHCO3 aqueous solution (30 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by rapid chromatography (EtOAc / hexane, 1:6 to 1:4) to give 2-(4-(3,6-dihydro-2H-pyran-4-yl)-2,6-difluorophenyl)acetaldehyde as a pale yellow solid (0.65 g, 61%, step 2). 1 H NMR(500MHz, CDCl3)δ9.75(p,J=1.3Hz,1H),7.03-6.75(m,2H),6.19(tt,J=3.1,1.6Hz,1H),4.3 2(q,J=2.8Hz,2H),3.92(t,J=5.4Hz,2H),3.86-3.68(m,2H),2.46(ttd,J=5.5,2.8,1.6Hz,2H).

[0552] Under N2, a mixture of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.208 g, 0.500 mmol), 2-(4-(3,6-dihydro-2H-pyran-4-yl)-2,6-difluorophenyl)acetaldehyde (0.16 g, 0.67 mmol), and NaBH(OAc)3 (0.21 g, 1.0 mmol) in DCM (15 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 solution (15 mL) and extracted with DCM (2 × 20 mL). 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 rapid chromatography (EtOAc / hexane, 1:6 to 1:4) to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(4-(3,6-dihydro-2H-pyran-4-yl)-2,6-difluorophenylethyl)-2-methylpiperidine as a pale yellow solid (0.29 g, 90%). ESI MS m / z 640.3328 [M+H] + .

[0553] The above substances (0.15 g, 0.26 mmol) and Pd(OH)₂ / C (20% by weight Pd, 0.075 g, 0.14 mmol) and 5 drops of concentrated HCl were stirred overnight under hydrogen atmosphere at one atmosphere in MeOH / THF (15 / 5 mL). The mixture was filtered through a diatomaceous earth filter cake, and the filtrate was collected and concentrated to dryness. The residue was neutralized with 1 M NH₃ in MeOH solution and then purified by rapid column chromatography (0.5 M NH₃ / MeOH / DCM, 1:6) on silica gel to give (2R,3R,4R,5S)-1-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenethyl)-2-methylpiperidin-3,4,5-triol (0.060 g, 70%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ6.99-6.94(m,2H),4.75-4.61(m,3H),3.98-3.90(m,2H) ,3.39(td,J=11.5,2.5Hz,2H)3.29-3.21(m,1H),2.90(td,J=8.8,4.4Hz,1H),2.8 4(dd,J=10.9,4.9Hz,1H),2.80-2.74(m,1H),2.72-2.65(m,5H),2.20(t,J=10.6H z,1H),2.12(dq,J=8.9,6.1Hz,1H),1.72-1.53(m,4H),1.06(d,J=6.1Hz,3H); ESI MS m / z 372.1970[M+H]+ .

[0554] Example 55

[0555] (2R,3R,4R,5S)-1-(2,6-difluoro-4-(trifluoromethyl)phenethyl)-2-methylpiperidine-3,4,5-triol

[0556]

[0557] Anhydrous E3 was added to a stirred solution of 1.50 g (8.24 mmol) of 1,5-difluorotrifluorotoluene (3,5-difluorotrifluorotoluene) under N2 conditions at -78 °C. t2 Add n-BuLi solution (2.5M hexane solution, 5.0 mL, 12.5 mmol) to O (70 mL) solution. Stir the mixture at -78 °C for 1 h. Add anhydrous DMF (3.19 mL, 41.2 mmol) and stir again at -78 °C for 1 h. Quench the reaction with saturated NH4Cl aqueous solution. Extract the mixture with Et2O (3 × 20 mL). Wash the combined organic layers with water (2 × 20 mL), separate, and dry with Na2SO4. After filtration, evaporate the solvent under reduced pressure, and purify the residue on silica gel by rapid chromatography to give 2,6-difluoro-4-(trifluoromethyl)benzaldehyde as a clear liquid (1.07 g, 62%). 1 H NMR (400MHz, CDCl3) δ10.40 (s, 1H), 7.35-7.27 (m, 2H).

[0558] At 0°C and N2, KO was added to a stirred solution of (methoxymethyl)triphenylphosphonium chloride (4.08 g, 11.9 mmol) in anhydrous THF (30 mL). tBu (1.33 g, 11.9 mmol) was added and stirred for 30 minutes. Then, 2,6-difluoro-4-(trifluoromethyl)benzaldehyde (1.0 g, 4.76 mmol) was dissolved in 5 mL of THF and added dropwise to the mixture under N2, reacting at room temperature for 4 h. The reaction was quenched at 0 °C with a saturated NH4Cl aqueous solution. The mixture was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give the product as an oil containing two isomers. The oil was dissolved in THF (25 mL), 2N HCl aqueous solution (25 mL) was added, and the mixture was stirred at 80 °C for 8 h. The reaction mixture was cooled to room temperature and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give 2-(2,6-difluoro-4-(trifluoromethyl)phenyl)acetaldehyde as a white solid (370 mg, 35%). 1 H NMR (400MHz, CDCl3) δ9.80 (t, J = 1.2Hz, 1H), 7.30-7.25 (m, 2H), 3.91 (s, 2H).

[0559] HOAc (0.10 mL, 1.75 mmol) was added to a stirred solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (260 mg, 0.62 mmol) and 2-(2,6-difluoro-4-(trifluoromethyl)phenyl)acetaldehyde (278 mg, 1.24 mmol) in anhydrous DCM (10 mL), and the mixture was stirred for 30 min. NaBH3CN (264 mg, 1.24 mmol) was added, and the resulting mixture was stirred at room temperature for 18 h. The reaction was quenched at 0 °C with a saturated aqueous solution of NaHCO3. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to obtain (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(2,6-difluoro-4-(trifluoromethyl)phenethyl)-2-methylpiperidine, a white solid (349 mg, 90%). 1H NMR (400MHz, CDCl3) δ7.42-7.26(m,15H),7.16(d,J=6.4Hz,2H),4.98(t,J= 11.5Hz,2H),4.85(d,J=11.0Hz,1H),4.73(d,J=2.5Hz,2H),4.61(d,J=10.8 Hz,1H),3.66-3.57(m,1H),3.52(t,J=9.0Hz,1H),3.2-3.12(m,1H),3.05(t ,J=8.9Hz,1H),2.94-2.75(m,4H),2.50-2.34(m,2H),1.19(d,J=6.1Hz,3H).

[0560] At -78°C and N2, a solution of BCl3 (1 M DCM solution, 1.80 mL, 1.80 mmol) was added to a stirred solution of the above substance (185 mg, 0.30 mmol) in anhydrous DCM (10 mL). The mixture was stirred at 0°C for 2 h, then quenched with anhydrous MeOH (1 mL). The mixture was stirred at ambient temperature for 10 min. The solvent was removed under vacuum, and the residue was dissolved in a 1 M NH3 MeOH solution (10 mL) and stirred for another 10 min, then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-1-(2,6-difluoro-4-(trifluoromethyl)phenethyl)-2-methylpiperidin-3,4,5-triol, as a white solid (62 mg, 58%). 1 H NMR (400MHz, CD3OD) δ7.39-7.30(m,2H),3.53-3.44(m,1H),3.13(t,J=9.0Hz,1H),3.07(dd,J=11.1, 5.0Hz,1H),3.01-2.76(m,5H),2.36(t,J=10.8Hz,1H),2.33-2.24(m,1H),1.19(d,J=6.1Hz,3H); ESI MS m / z 356.12[M+H] + .

[0561] Example 56

[0562] (2R,3R,4R,5S)-1-(2,6-difluoro-4-(pyrrolidone-1-yl)phenethyl)-2-methylpiperidine-3,4,5-triol

[0563]

[0564] (E&Z)-5-bromo-1,3-difluoro-2-(2-methoxyvinyl)benzene (0.506 g, 2.00 mmol), pyrrolidine (0.32 g, 4.6 mmol), and KO t A mixture of Bu (0.45 g, 4.0 mmol), BINAP (0.18 g, 0.30 mmol), and Pd2(dba)3 (0.092 g, 0.10 mmol) was bubbled with Ar in anhydrous toluene (15 mL) for 10 min, followed by stirring at 85 °C for 16 h. The reaction mixture was cooled to room temperature and diluted with a saturated aqueous solution of NaHCO3 (30 mL). After extraction with EtOAc (2 × 30 mL), 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 rapid chromatography (EtOAc / hexane, 1:12 to 1:9) to give (E&Z)-1-(3,5-difluoro-4-(2-methoxyvinyl)phenyl)piperidine as a pale yellow oil (0.29 g, 61%, a mixture of trans and cis isomers). ESI MS m / z 240.115 [M+H] + .

[0565] To a THF (20 mL) solution of the above substance (0.29 g, 1.2 mmol), an aqueous HCl solution (3.5 N, 20 mL) was added, and the mixture was refluxed and stirred for 4 hours. The reaction mixture was cooled to room temperature and diluted with a saturated NaHCO3 aqueous solution (50 mL). After extraction with EtOAc (2 × 30 mL), 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 rapid chromatography (EtOAc / hexane, 1:9 to 1:6) to give 2-(2,6-difluoro-4-(pyrrolidine-1-yl)phenyl)acetaldehyde as a pale yellow oil (0.17 g, 62%). 1 H NMR (400MHz, CDCl3) δ9.68 (p, J = 1.5Hz, 1H), 6.14-6.02 (m, 2H), 3.61 (s, 2H), 3.28-3.18 (m, 4H), 2.06-1.94 (m, 4H); ESI MSm / z226.104 [M+H] + .

[0566] Under N2, a mixture of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.20 g, 0.48 mmol), 2-(2,6-difluoro-4-(pyrrolidone-1-yl)phenyl)acetaldehyde (0.15 g, 0.67 mmol), and NaBH(OAc)3 (0.20 g, 0.94 mmol) in DCM (10 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 solution (20 mL) and extracted with DCM (3 × 20 mL). 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 rapid chromatography (EtOAc / hexane, 1:8 to 1:5) to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(2,6-difluoro-4-(pyrrolidine-1-yl)phenethyl)-2-methylpiperidine as a white solid (0.25 g, 83%). ESI MS m / z 627.331 [M+H] + .

[0567] At -78°C and N2, BCl3 (1.0 M DCM solution, 2.0 mL, 2.0 mmol) was added to an anhydrous DCM solution (8 mL) of the above substance (0.25 g, 0.40 mmol), and the mixture was stirred at 0°C for 3 hours. The reaction mixture was cooled at -78°C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with 1 M NH3 MeOH solution and purified by rapid column chromatography on silica gel (1 M NH3 MeOH / DCM solution, 1:6) to give (2R,3R,4R,5S)-1-(2,6-difluoro-4-(pyrrolidine-1-yl)phenethyl)-2-methylpiperidin-3,4,5-triol, as a white solid (0.121 g, 85%). 1 H NMR (400MHz, DMSO-d6) δ6.37-6.03(m,2H),4.93-4.59(m,3H),3.30-3.11(m,5H),2.90(td,J=8.9,4.4Hz,1H),2.83(dd,J=1 0.9,4.9Hz,1H),2.75-2.53(m,5H),2.19(t,J=10.6Hz,1H),2.14-2.08(m,1H),2.01-1.87(m,4H),1.07(d,J=6.1Hz,3H); ESI MS m / z 357.201[M+H] + .

[0568] Example 57

[0569] (2R,3R,4R,5S)-1-(2,6-difluoro-4-(piperidin-1-yl)phenethyl)-2-methylpiperidin-3,4,5-triol

[0570]

[0571] At 0°C, KO was added to an anhydrous DMF (35 mL) solution of (methoxymethyl)triphenylphosphonium chloride (5.14 g, 15.0 mmol). t Bu (1.70 g, 15.0 mmol) and 4-bromo-2,6-difluorobenzaldehyde (2.21 g, 10.0 mmol) were mixed and stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 solution (200 mL) and then extracted with EtOAc (3 × 50 mL). The combined extracts were washed with brine (2 × 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 rapid chromatography (EtOAc / hexane, 1:19 to 1:9) to give (E&Z)-5-bromo-1,3-difluoro-2-(2-methoxyvinyl)benzene as a pale yellow solid (2.30 g, 92%, a mixture of trans and cis isomers).

[0572] The above substances (0.506 g, 2.00 mmol), piperidine (0.34 g, 4.0 mmol), and KO were added. t A mixture of Bu (0.45 g, 4.0 mmol), BINAP (0.18 g, 0.30 mmol), and Pd2(dba)3 (0.092 g, 0.10 mmol) was bubbled with Ar in anhydrous toluene (15 mL) for 10 min, followed by stirring at 85 °C for 16 h. The reaction mixture was cooled to room temperature and diluted with a saturated aqueous solution of NaHCO3 (30 mL). After extraction with EtOAc (2 × 30 mL), 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 rapid chromatography (EtOAc / hexane, 1:16 to 1:9) to give (E&Z)-1-(3,5-difluoro-4-(2-methoxyvinyl)phenyl)piperidine as a pale yellow oil (0.30 g, 59%, a mixture of trans and cis isomers). ESI MS m / z 254.136 [M+H] + .

[0573] To a THF (20 mL) solution of the above substance (0.30 g, 1.2 mmol), an aqueous HCl solution (2.5 N, 20 mL) was added, and the mixture was refluxed and stirred for 4 hours. The reaction mixture was cooled to room temperature and diluted with a saturated NaHCO3 aqueous solution (50 mL). After extraction with EtOAc (2 × 30 mL), 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 rapid chromatography (EtOAc / hexane, 1:12 to 1:8) to give 2-(2,6-difluoro-4-(piperidin-1-yl)phenyl)acetaldehyde as a pale yellow oil (0.21 g, 74%). 1 H NMR (400MHz, CDCl3) δ9.69 (p, J = 1.4Hz, 1H), 6.47-6.36 (m, 2H), 3.63 (q, J = 1.4Hz, 2H), 3.21-3.14 (m, 4H), 1.72-1.55 (m, 6H); ESI MS m / z 240.120 [M+H] + .

[0574] Under N2, a mixture of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.25 g, 0.60 mmol), 2-(2,6-difluoro-4-(piperidin-1-yl)phenyl)acetaldehyde (0.12 g, 0.50 mmol), and NaBH(OAc)3 (0.18 g, 0.85 mmol) in DCM (10 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO3 solution (20 mL) and extracted with DCM (3 × 20 mL). 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 rapid chromatography (EtOAc / hexane, 1:12 to 1:8) to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(2,6-difluoro-4-(piperidin-1-yl)phenethyl)-2-methylpiperidine as a white solid (0.179 g, 56%). ESI MS m / z 641.351 [M+H] + .

[0575] BCl3 (1.0 M, 1.5 mL, 1.5 mmol in DCM) was added to an anhydrous DCM (8 mL) solution of the above substance (0.13 g, 0.20 mmol) at -78 °C and N2, and the mixture was stirred at 0 °C for 3 h. The reaction mixture was cooled to -78 °C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with a solution of 1 M NH3 in MeOH and subjected to rapid chromatography on silica gel (1 M NH3 in MeOH / DCM, 1:6) to give (2R,3R,4R,5S)-1-(2,6-difluoro-4-(piperidin-1-yl)phenethyl)-2-methylpiperidin-3,4,5-triol, as a white solid (0.070 g, 94%). 1 H NMR(400MHz, DMSO-d6)δ6.60-6.51(m,2H),4.71-4.65(m,3H),3.24(ddd,J=14.3,11.2,6.5Hz,1H),3.17-3.12 (m,4H),2.94-2.78(m,2H),2.72-2.51(m,5H),2.23-2.06(m,2H),1.60-1.50(m,6H),1.06(d,J=6.1Hz,3H); ESI MS m / z 371.215[M+H] + .

[0576] Example 58

[0577] (2R,3R,4R,5S)-1-(2,6-difluoro-4-morpholinophenethyl)-2-methylpiperidine-3,4,5-triol

[0578]

[0579] (E&Z)-5-bromo-1,3-difluoro-2-(2-methoxyvinyl)benzene (0.506 g, 2.00 mmol), morpholine (0.35 g, 4.0 mmol), and KO tA mixture of Bu (0.45 g, 4.0 mmol), BINAP (0.18 g, 0.30 mmol), and Pd2(dba)3 (0.092 g, 0.10 mmol) was bubbled with Ar in anhydrous toluene (15 mL) for 10 min, followed by stirring at 85 °C for 16 h. The reaction mixture was cooled to room temperature and diluted with a saturated aqueous solution of NaHCO3 (30 mL). After extraction with EtOAc (2 × 30 mL), 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 rapid chromatography (EtOAc / hexane, 1:9 to 1:6) to give (E&Z)-4-(3,5-difluoro-4-(2-methoxyvinyl)phenyl)morpholine as a pale yellow oil (0.25 g, 49%, a mixture of trans and cis isomers). ESI MS m / z 256.110 [M+H] + .

[0580] Synthesis of 2-(2,6-difluoro-4-morpholinophenyl)acetaldehyde (34B)

[0581] To a mixed THF (15 mL) solution of the above substances (0.25 g, 0.98 mmol), an aqueous HCl solution (3.5 N, 15 mL) was added, and the mixture was refluxed and stirred for 4 hours. The reaction mixture was cooled to room temperature and diluted with a saturated NaHCO3 aqueous solution (50 mL). After extraction with EtOAc (2 × 30 mL), 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 rapid chromatography (EtOAc / hexane, 1:6 to 1:4) to give 2-(2,6-difluoro-4-morpholinophenyl)acetaldehyde as a pale yellow oil (0.12 g, 51%). 1 H NMR(400MHz, CDCl3)δ9.70(s,1H),6.51-6.29(m,2H),3.88-3.79(m,4H),3.66(s,2H),3.16-3.11(m,4H); ESI MS m / z242.094[M+H] + .

[0582] Under N2, a mixture of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.19 g, 0.46 mmol), 2-(2,6-difluoro-4-morpholinophenyl)acetaldehyde (0.12 g, 0.50 mmol), and NaBH(OAc)3 (0.23 g, 1.1 mmol) was stirred in DCM (10 mL) at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 solution (20 mL) and extracted with DCM (3 × 20 mL). 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 rapid chromatography (EtOAc / hexane, 1:4 to 1:3) to give 4-(3,5-difluoro-4-(2-((2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidin-1-yl)ethyl)phenyl)morpholine as a white solid (0.26 g, 88%). ESI MS m / z 643.329 [M+H] + .

[0583] At -78°C and N2, BCl3 (1.0 M DCM solution, 2.0 mL, 2.0 mmol) was added to an anhydrous DCM solution (8 mL) of the above substance (0.26 g, 0.40 mmol), and the mixture was stirred at 0°C for 3 hours. The reaction mixture was cooled to -78°C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with 1 M NH3 MeOH solution and purified by rapid column chromatography on silica gel (1 M NH3 MeOH solution / DCM, 1:6) to give (2R,3R,4R,5S)-1-(2,6-difluoro-4-morpholinophenylethyl)-2-methylpiperidine-3,4,5-triol, as a white solid (0.124 g, 83%). 1 H NMR (400MHz, DMSO-d6) δ6.82-6.46(m,2H),4.86-4.41(m,3H),3.69(dd,J=6.0,3.8Hz,4H),3.29-3.19(m,1H),3.11(dd,J=6.0,3.8Hz,4H),2.8 9(td,J=8.8,4.3Hz,1H),2.83(dd,J=10.9,4.9Hz,1H),2.73-2.54(m,5H),2.18(t,J=10.6Hz,1H),2.14-2.07(m,1H),1.06(d,J=6.1Hz,3H); ESI MS m / z 373.195[M+H] + .

[0584] Example 59

[0585] (2R,3R,4R,5S)-1-(4-butoxy-2,6-difluorophenylethyl)-2-methylpiperidine-3,4,5-triol

[0586]

[0587] A mixture of 3,5-difluorophenol (2.60 g, 20.0 mmol), 1-bromobutane (4.00 g, 29.2 mmol), and K₂CO₃ (5.00 g, 36.3 mmol) was stirred in DMF (25 mL) at 80 °C for 2 hours, and then cooled to room temperature. The mixture was diluted with water (50 mL) and extracted with hexane (2 × 50 mL). The combined extracts were washed with brine (2 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography (hexane) on silica gel to give 1-butoxy-3,5-difluorobenzene as a clear, colorless liquid (3.50 g, 94%). 1 H NMR (400MHz, CDCl3) δ6.45-6.34(m,3H),3.92(t,J=6.5Hz,2H),1.80-1.71(m,2H),1.55-1.41(m,2H),0.98(t,J=7.4Hz,3H).

[0588] At -78°C and N2, a mixed THF / hexane (20 mL / 10 mL) solution of freshly prepared LDA (22.0 mmol) was added to an anhydrous THF (20 mL) solution of the above substance (3.50 g, 18.8 mmol), and the mixture was stirred at -78°C for 1 hour. Anhydrous DMF (2.92 g, 40.0 mmol) was added, and the mixture was stirred at -78°C for 30 minutes, then at 0°C for 1 hour. A dilute aqueous HCl solution (0.5 N, 50 mL) was added, and the mixture was extracted with EtOAc (2 × 50 mL). The combined extracts were washed with brine (2 × 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 rapid chromatography (EtOAc / hexane, 1:20) to give 4-butoxy-2,6-difluorobenzaldehyde as a white solid (3.8 g, 94%). 1 H NMR (500MHz, CDCl3) δ10.18 (s, 1H), 6.52-6.42 (m, 2H), 4.00 (t, J = 6.5Hz, 2H), 1.83-1.73 (m, 2H), 1.52-1.42 (m, 2H), 0.97 (t, J = 7.4Hz, 3H).

[0589] At 0°C, KO was added to an anhydrous DMF (30 mL) solution of (methoxymethyl)triphenylphosphonium chloride (2.30 g, 6.50 mmol). t Bu (0.729 g, 6.50 mmol) and 4-butoxy-2,6-difluorobenzaldehyde (1.15 g, 5.37 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with saturated NaHCO3 aqueous solution (50 mL) and extracted with EtOAc (2 × 40 mL). The combined extracts were washed with brine (2 × 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 rapid chromatography (EtOAc / hexane, 1:30 to 1:9) to give a clear liquid. The clear liquid was dissolved in a mixture of THF (25 mL) and HCl aqueous solution (2.5 N, 25 mL). After stirring under reflux for 2 h, the mixture was cooled and diluted with ice water (50 mL). After extraction with EtOAc (2 × 40 mL), the combined extracts were washed with saturated NaHCO3 aqueous solution (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 rapid chromatography (EtOAc / hexane, 1:20 to 1:9) to give 2-(4-butoxy-2,6-difluorophenyl)acetaldehyde as a colorless oil (0.20 g, 16%, step 2). 1 H NMR(500MHz, CDCl3)δ9.71(p,J=1.3Hz,1H),6.44-6.39(m,2H),3.91(t,J=6.5Hz ,2H),3.69(s,2H),1.80-1.69(m,2H),1.50-1.43(m,2H),0.97(t,J=7.4Hz,3H).

[0590] Under N2, a mixture of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.25 g, 0.60 mmol), 2-(4-butoxy-2,6-difluorophenyl)acetaldehyde (0.20 g, 0.88 mmol), and NaBH(OAc)3 (0.32 g, 1.5 mmol) was stirred in DCM (15 mL) at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 solution (20 mL) and extracted with DCM (3 × 15 mL). 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 rapid chromatography (EtOAc / hexane, 1:20 to 1:8) to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(4-butoxy-2,6-difluorophenylethyl)-2-methylpiperidine as a colorless oil (0.31 g, 82%). ESIMS m / z 630.335 [M+H] + .

[0591] The mixture of the above-mentioned substance (0.230 g, 0.365 mmol) and Pd(OH)₂ / C (20% by weight Pd, 0.080 g, 0.15 mmol) and 5 drops of concentrated HCl in MeOH solution (20 mL) was stirred overnight under H₂ and one atmosphere. The mixture was filtered through a diatomaceous earth filter cake, the filtrate was collected and concentrated to dryness. The residue was neutralized with 1 M NH₃ in MeOH solution and purified by rapid chromatography (1 M NH₃ / MeOH / DCM, 1:6) on silica gel to give (2R,3R,4R,5S)-1-(4-butoxy-2,6-difluorophenylethyl)-2-methylpiperidin-3,4,5-triol (0.115 g, 88%) as a white solid. 1 H NMR (400MHz, CD3OD) δ6.59-6.44(m,2H),3.94(t,J=6.4Hz,2H),3.52-3.45(m,1 H),3.11(t,J=9.0Hz,1H),3.03(dd,J=11.2,4.9Hz,1H),2.91(t,J=9.1Hz,1H), 2.86-2.65(m,4H),2.36(t,J=10.8Hz,1H),2.28(dq,J=9.1,6.1Hz,1H),1.81-1 .67(m,2H),1.58-1.39(m,2H),1.21(d,J=6.1Hz,3H),0.98(t,J=7.4Hz,3H); ESI m / z 360.201[M+H] + .

[0592] Example 60

[0593] (2R,3R,4R,5S)-1-(4-(cyclopropylmethoxy)-2,6-difluorophenylethyl)-2-methylpiperidine-3,4,5-triol

[0594]

[0595] A mixture of 3,5-difluorophenol (1.80 g, 13.8 mmol), (bromomethyl)cyclopropane (2.00 g, 14.8 mmol), and K₂CO₃ (3.00 g, 21.7 mmol) was stirred in DMF (20 mL) at 80 °C for 16 hours, and then cooled to room temperature. The mixture was diluted with water (50 mL) and extracted with hexane (2 × 50 mL). The combined extracts were washed with brine (2 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography (hexane) on silica gel to give 1-(cyclopropylmethoxy)-3,5-difluorobenzene as a clear, colorless liquid (2.30 g, 90%).

[0596] At -78°C and N2, a freshly prepared THF / hexane (20 mL / 10 mL) mixture of LDA (14.0 mmol) was added to an anhydrous THF (20 mL) solution of the above substance (2.30 g, 12.5 mmol) at N2. The mixture was stirred at -78°C for 1 h and then at 0°C for 1 h. A dilute aqueous HCl solution (0.5 N, 50 mL) was added, and the mixture was extracted with EtOAc (2 × 50 mL). The combined extracts were washed with brine (2 × 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 rapid chromatography (EtOAc / hexane, 1:10) to give 4-(cyclopropylmethoxy)-2,6-difluorobenzaldehyde as a white solid (2.35 g, 90%). 1 H NMR (400MHz, CDCl3) δ10.18 (s, 1H), 6.63-6.39 (m, 2H), 3.85 (d, J = 7.0Hz, 2H), 1.37-1.08 (m, 1H), 0.73-0.59 (m, 2H), 0.39-0.35 (m, 2H).

[0597] At 0°C, KO was added to an anhydrous DMF (20 mL) solution of (methoxymethyl)triphenylphosphonium chloride (2.40 g, 7.00 mmol). tBu (0.841 g, 7.50 mmol) and 4-(cyclopropylmethoxy)-2,6-difluorobenzaldehyde (1.00 g, 4.71 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with saturated NaHCO3 aqueous solution (50 mL) and extracted with EtOAc (2 × 40 mL). The combined extracts were washed with brine (2 × 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 rapid chromatography (EtOAc / hexane, 1:30 to 1:9) to give a clear liquid. The clear liquid was dissolved in a mixture of THF (25 mL) and HCl aqueous solution (3.5 N, 25 mL). After stirring under reflux for 4 hours, the mixture was cooled and diluted with ice water (50 mL). After extraction with EtOAc (2 × 40 mL), the combined extracts were washed with saturated NaHCO3 aqueous solution (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 rapid chromatography (EtOAc / hexane, 1:12 to 1:7) to give 2-(4-(cyclopropylmethoxy)-2,6-difluorophenyl)acetaldehyde as a colorless oil (0.43 g, 40%, step 2). 1 H NMR(400MHz, CDCl3)δ9.71(p,J=1.3Hz,1H),6.62-6.36(m,2H),3.77(d,J=6.9Hz,2 H), 3.68 (q, J = 1.3Hz, 2H), 1.32-1.18 (m, 1H), 0.71-0.58 (m, 2H), 0.40-0.28 (m, 2H).

[0598] Under N2, a mixture of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.22 g, 0.53 mmol), 2-(4-(cyclopropylmethoxy)-2,6-difluorophenyl)acetaldehyde (0.20 g, 0.88 mmol), and NaBH(OAc)3 (0.30 g, 1.4 mmol) was stirred in DCM (10 mL) at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 solution (20 mL) and extracted with DCM (3 × 15 mL). 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 rapid chromatography (EtOAc / hexane, 1:10 to 1:7) to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-1-(4-(cyclopropylmethoxy)-2,6-difluorophenylethyl)-2-methylpiperidine as a colorless oil (0.315 g, 95%). ESI MS m / z 628.322 [M+H] + .

[0599] The mixture of the above-mentioned substance (0.31 g, 0.50 mmol), Pd(OH)₂ / C (20% by weight Pd, 0.080 g, 0.15 mmol), and 6 drops of concentrated HCl in MeOH solution (25 mL) was stirred overnight under hydrogen atmosphere at one atmosphere. The mixture was filtered through a diatomaceous earth filter cake, and the filtrate was collected and concentrated to dryness. The residue was neutralized with 1 M NH₃ in MeOH solution and purified by rapid column chromatography (1 M NH₃ MeOH / DCM, 1:6) on silica gel to give (2R,3R,4R,5S)-1-(4-(cyclopropylmethoxy)-2,6-difluorophenylethyl)-2-methylpiperidin-3,4,5-triol (0.157 g, 88%) as a white solid. 1 H NMR (400MHz, CD3OD) δ6.59-6.46(m,2H),3.78(d,J=6.9Hz,2H),3.49(ddd,J= 10.5,9.0,4.9Hz,1H),3.11(t,J=9.0Hz,1H),3.03(dd,J=11.1,4.9Hz,1H),2 .91(t,J=9.1Hz,1H),2.87-2.66(m,4H),2.36(t,J=10.9Hz,1H),2.27(dt,J= 9.1,6.1Hz,1H),1.27-1.12(m,4H),0.67-0.55(m,2H),0.40-0.28(m,2H);ESI m / z 358.183[M+H] + .

[0600] Example 61

[0601] (2R,3R,4R,5S)-2-methyl-1-(4-((tetrahydrofuran-3-yl)oxy)phenethyl)piperidine-3,4,5-triol

[0602]

[0603] DIAD (1.68 g, 8.32 mmol) was slowly added to a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (1.0 g, 5.5 mmol), PPh3 (2.18 g, 8.32 mmol), and tetrahydrofuran-3-ol (0.73 g, 8.32 mmol) in anhydrous THF (10 mL). The resulting mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure, and the crude product was purified by silica gel rapid chromatography to give ethyl 2-(4-((tetrahydrofuran-3-yl)oxy)phenyl)acetate as an oil (0.55 g, 40%). 1H NMR (400MHz, CDCl3) δ7.26-7.19(m,2H),6.87-6.82(m,2H),4.93(ddt,J=6.5,4.5,2.2Hz,1H),4.17(q,J=7.1H z,2H),4.06-3.97(m,3H),3.92(td,J=8.2,4.4Hz,1H),3.57(s,2H),2.28-2.14(m,2H),1.28(t,J=7.1Hz,3H).

[0604] At 0°C, LAH (204 mg, 5.34 mmol) was added to an anhydrous THF (10 mL) solution of the above substance (550 mg, 2.20 mmol), and the mixture was stirred at 0°C for 1 hour. The mixture was slowly quenched with saturated NaHCO3 and filtered. The solid was washed with EtOAc. The combined organic layers were washed with water (2 × 20 mL), separated, and dried with Na2SO4. After filtration, the solvent was evaporated under reduced pressure to give crude 2-(4-((tetrahydrofuran-3-yl)oxy)phenyl)ethanol as an oil (490 mg).

[0605] The solution of the above substances (310 mg, 1.49 mmol) and CBr4 (593 mg, 1.79 mmol) in DCM (10 mL) was cooled to 0 °C, and PPh3 (469 mg, 1.79 mmol) was added in portions. The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM and washed with a saturated aqueous solution of NaHCO3. The organic phase was separated and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give 3-(4-(2-bromoethyl)phenoxy)tetrahydrofuran as an oil (311 mg, 77%). 1 H NMR (400MHz, CDCl3) δ7.18-7.12(m,2H),6.87-6.81(m,2H),4.93(ddt,J=6.4,4.5,2.2Hz,1H),4.05-3. 97(m,3H),3.92(td,J=8.2,4.4Hz,1H),3.56(t,J=7.6Hz,2H),3.13(t,J=7.6Hz,2H),2.28-2.12(m,2H).

[0606] In a sealed tube, DIPEA (0.16 mL, 0.96 mmol) was added to a solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (50 mg, 0.12 mmol) and 3-(4-(2-bromoethyl)phenoxy)tetrahydrofuran (130 mg, 0.48 mmol) in DMF (5 mL). The mixture was stirred at 80 °C for 18 h and cooled to ambient temperature. The reaction mixture was poured into ice water (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL), separated, and dried over Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-(4-((tetrahydrofuran-3-yl)oxy)phenethyl)piperidine, as a white solid (39 mg, 52%). ESI MS m / z 608.32 [M+H] + .

[0607] To a solution of the above substance (35 mg, 0.058 mmol) in EtOH (10 mL), Pd(OH)₂ / C (20 wt%, 8.6 mg, 0.012 mmol) and 6N HCl (0.1 mL) were added. The mixture was treated with hydrogen (1 atm) for 18 h. The catalyst was filtered off through diatomaceous earth, and the solvent was evaporated under reduced pressure. The residue was dissolved in a 1 M NH₃ solution of MeOH (10 mL) and stirred for another 10 min, then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-2-methyl-1-(4-((tetrahydrofuran-3-yl)oxy)phenethyl)piperidine-3,4,5-triol, a white solid (14 mg, 72%). 1 H NMR (400MHz, CD3OD) δ7.20-7.13(m,2H),6.89-6.83(m,2H),5.03-4.97(m,1H),4.05-3.80(m,4H),3.63-3.52(m,1H),3.21(t,J=8.7Hz,2H),3 .13-3.00(m,2H),2.99-2.87(m,1H),2.87-2.71(m,2H),2.61-2.41(br,2H),2.31-2.18(m,1H),2.15-2.06(m,1H),1.33(d,J=6.2Hz,3H); ESI MS m / z338.19[M+H] + .

[0608] Example 62

[0609] (2R,3R,4R,5S)-2-methyl-1-(4-((tetrahydro-2H-pyran-3-yl)oxy)phenethyl)piperidine-3,4,5-triol

[0610]

[0611] To a THF (400 mL) solution of (2S,3R,4S,5S)-3,4,5-tris(benzyloxy)-2-methoxy-6-methylenetetrahydro-2H-pyran (24.4 g, 54.6 mmol) (Heterocycles, 2007, 73, C, 165-168), an aqueous HCl solution (2.5 N, 200 mL) was added, and the mixture was stirred at 50 °C for 2 hours. The reaction mixture was diluted with ice water (400 mL) and extracted with EtOAc (3 × 300 mL). The combined extracts were washed with a saturated aqueous NaHCO3 solution (500 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure at room temperature to give (2R,3R,4S)-2,3,4-tris(benzyloxy)-5-oxohexanal as a white solid. The substance was dissolved in a mixed solvent of anhydrous DCM (50 mL) and anhydrous MeOH (450 mL), and NH4OAc (75.0 g, 973 mmol), Na2SO4 (50.0 g, 352 mmol), and NaBH3CN (20.0 g, 318 mmol) were added at 0 °C and N2. After stirring at room temperature for 16 hours, the mixture was diluted with saturated NaHCO3 aqueous solution (1 L) and extracted with DCM (3 × 500 mL). 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 rapid chromatography (EtOAc / hexane, 3:7, then 1 M NH3 in MeOH solution / DCM, 1:20) to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine as a white solid (20.3 g, 89%, step 2). 1H NMR (400MHz, DMSO-d6) δ7.43-7.15(m,15H),4.86(d,J=11.2Hz,1H),4.77(d,J=11. 2Hz,1H),4.72(d,J=11.2Hz,1H),4.65(d,J=12.0Hz,1H),4.62-4.53(m,2H),3.43-3 .34(m,2H),3.14(dd,J=11.9,4.4Hz,1H),2.89(t,J=8.8Hz,1H),2.41(dd,J=9.4,6. 3Hz, 1H), 2.28 (dd, J=11.9, 9.4Hz, 1H), 2.08 (s, br., 1H), 1.05 (d, J=6.2Hz, 3H); ESI MS m / z 418.235[M+H] + .

[0612] At 0 °C, DIAD (3.40 g, 16.8 mmol) was slowly added to an anhydrous THF (30 mL) solution of ethyl 2-(4-hydroxyphenyl)acetate (2.00 g, 11.1 mmol), PPh3 (4.50 g, 17.2 mmol), and tetrahydro-2H-pyran-3-ol (1.70 g, 16.6 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure at room temperature, and the residue was purified by rapid chromatography (EtOAc / hexane, 1:7 to 1:3) on silica gel to give ethyl 2-(4-((tetrahydro-2H-pyran-3-yl)oxy)phenyl)acetate as a pale yellow oil (1.50 g, 51%).

[0613] At 0 °C and N2, LAH (0.152 g, 4.00 mmol) was added to an anhydrous THF (20 mL) solution of the above substance (0.650 g, 2.46 mmol), and the mixture was stirred at 0 °C for 1 hour. Wet sodium sulfate heptahydrate (50 g) was added to quench the reaction, and the suspension was stirred at room temperature for 30 minutes. After filtration, the solvent was evaporated to give 2-(4-((tetrahydro-2H-pyran-3-yl)oxy)phenyl)ethanol, a clear oil.

[0614] At 0 °C, PPh3 (0.84 g, 3.2 mmol) and CBr4 (1.0 g, 3.0 mmol) were added to an anhydrous DCM (30 mL) solution of the above substances, and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure, and the residue was purified on silica gel by rapid chromatography (EtOAc / hexane, 1:9 to 1:7) to give 3-(4-(2-bromoethyl)phenoxy)tetrahydro-2H-pyran as a clear oil (0.61 g, 87%, two steps). 1H NMR (500MHz, CDCl3) δ7.14-7.08(m,2H),6.92-6.80(m,2H),4.28(tt,J=7.6,3.6Hz,1H),3.95(ddd,J=11.5,3.6,1.6Hz,1H),3.80-3.72(m,1H) ,3.60-3.53(m,2H),3.52(t,J=7.7Hz,2H),3.09(t,J=7.7Hz,2H),2.14 -2.03(m,1H),1.94-1.83(m,1H),1.81-1.74(m,1H),1.68-1.59(m,1H).

[0615] A mixture of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (0.10 g, 0.24 mmol), 3-(4-(2-bromoethyl)phenoxy)tetrahydro-2H-pyran (0.20 g, 0.70 mmol), and DIPEA (0.20 g, 2.3 mmol) was stirred in anhydrous DMF (5 mL) at 85 °C for 16 hours. The reaction mixture was cooled to room temperature and diluted with a saturated aqueous solution of NaHCO3 (20 mL). After extraction with EtOAc (3 × 20 mL), the combined extracts were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by rapid chromatography (EtOAc / hexane, 1:7 to 1:3) to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-(4-((tetrahydro-2H-pyran-3-yl)oxy)phenethyl)piperidine as a pale yellow oil (0.11 g, 74%); ESI MS m / z 622.342 [M+H] + .

[0616] The mixture of the above substance (0.10 g, 0.16 mmol) and Pd(OH)₂ / C (20% by weight Pd, 0.075 g, 0.14 mmol) and two drops of concentrated HCl in MeOH (20 mL) was stirred overnight under hydrogen at one atmosphere. The mixture was filtered through a diatomaceous earth filter cake, the filtrate was collected and concentrated to dryness. The residue was neutralized with 1 M NH₃ in MeOH solution and purified on silica gel by rapid chromatography (1 M NH₃ MeOH / DCM, 1:8) to give (2R,3R,4R,5S)-2-methyl-1-(4-((tetrahydro-2H-pyran-3-yl)oxy)phenethyl)piperidine-3,4,5-triol (0.042 g, 75%) as a white foam. 1H NMR(400MHz,DMSO-d6)δ7.08(d,J=8.5Hz,2H),6.85(d,J=8.5Hz,2H),4.71-4.64(m,3H), 4.29(tt,J=7.0,3.5Hz,1H),3.82-3.76(m,1H),3.66-3.58(m,1H),3.53-3.39(m,2H),3. 28-3.16(m,1H),2.93-3.84(m,2H),2.79-2.65(m,2H),2.64-2.54(m,3H),2.15-1.96(m, 3H),1.78-1.71(m,1H),1.68-1.60(m,1H),1.55-1.47(m,1H),1.09(d,J=6.1Hz,3H); ESI MS m / z 352.207[M+H] + .

[0617] Example 63

[0618] (2R,3R,4R,5S)-2-methyl-1-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenethyl)piperidine-3,4,5-triol

[0619]

[0620] DIAD (3.36 g, 16.6 mmol) was slowly added to a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (2.0 g, 11.1 mmol), PPh3 (4.36 g, 16.6 mmol), and tetrahydro-2H-pyran-4-ol (1.70 g, 16.6 mmol) in anhydrous THF (20 mL). The resulting mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure, and the crude substance was purified by silica gel rapid chromatography to give ethyl 2-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)acetate as an oil (1.45 g, 54%). 1 HNMR (400MHz, CDCl3) δ7.25-7.17(m,2H),6.97-6.85(m,2H),4.48(tt,J=7.8,3.8Hz,1H),4.17(q,J=7.1Hz,2H),4.00(ddd ,J=11.7,6.1,3.8Hz,2H),3.64-3.55(m,4H),2.08-1.96(m,2H),1.81(dtd,J=12.4,8.1,3.8Hz,2H),1.28(t,J=7.1Hz,3H).

[0621] At 0°C, LAH (431 mg, 11.4 mmol) was added to an anhydrous THF (20 mL) solution of the above substance (1.0 g, 3.79 mmol), and the mixture was stirred at 0°C for 1 hour. The mixture was slowly quenched with a saturated aqueous solution of Na₂SO₄ and filtered. The solid was washed with EtOAc. The combined organic layers were washed with water (2 × 20 mL), separated, and dried with Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure to give crude 2-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)ethanol as an oil (890 mg, 100%).

[0622] The solution of the above substances (540 mg, 2.43 mmol) and CBr4 (967 mg, 2.92 mmol) in DCM (20 mL) was cooled to 0 °C, and PPh3 (766 mg, 2.92 mmol) was added in portions. The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM and washed with a saturated aqueous solution of NaHCO3. The organic phase was separated and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by rapid chromatography on silica gel to give 4-(4-(2-bromoethyl)phenoxy)tetrahydro-2H-pyran as an oil (568 mg, 82%). 1 H NMR (400MHz, CDCl3) δ7.17-7.09(m,2H),6.94-6.84(m,2H),4.48(tt,J=7.8,3.9Hz,1H),4.01(ddd,J=10.7,6. 0,3.8Hz,2H),3.67-3.45(m,4H),3.12(t,J=7.6Hz,2H),2.08-1.97(m,2H),1.81(dtd,J=12.4,8.1,3.8Hz,2H).

[0623] In a sealed tube, DIPEA (0.16 mL, 0.96 mmol) was added to a solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methylpiperidine (50 mg, 0.12 mmol) and 4-(4-(2-bromoethyl)phenoxy)tetrahydro-2H-pyran (136 mg, 0.48 mmol) in DMF (5 mL). The mixture was stirred at 80 °C for 18 h and cooled to ambient temperature. The reaction mixture was poured into ice water (30 mL) and extracted with EtOAc (3 × 20 mL)....

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: （I） in, R 1 is H and R 2 is CH3, CH2F or CHF2; or R 1 is CH3 or CH2F and R 2 is H; and R 3 Yes (CH2) n R 4 , where n is 1 or 2, and R 4 is cyclohexyl, cyclohexylmethyl, phenylethyl, 4-phenylcyclohexyl, spiro[2.5]oct-6-yl, spiro[3.5]non-7-yl, spiro[4.5]dec-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]dec-8-yl, 1,2,3,4-tetrahydronaphthalen-2-yl, 2,3-dihydro-1H-inden-2-yl, (adamantyl)methyl, (pyridin-2-yl)methyl, (benzo[d][1,3]dioxol-5-yl)methyl, (2,3-dihydrobenzo[d][1,3]dioxol-5-yl)methyl [b][1,4]dioxin-6-yl)methyl, ([1,1'-biphenyl]-4-yl)methyl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, 1-(pyridin-3-yl)piperidin-4-yl, 1-(cyclohexylcarbamoyl)piperidin-4-yl, 1-(cyclohexylthiocarbamoyl)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazetidin-3-yl, 2-(thiophen-2-yl)methyl, or 2-(thiophen-3-yl)methyl, each of which is optionally replaced by F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropan-2-yl, methoxymethyl, C 1-6 One or more substitutions of alkoxy and / or CF3; or R 3 is phenylethyl, which is optionally substituted with pyrrolidin-1-yl, piperidin-1-yl, 4-morpholino, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, F, Cl, C 1-6 Alkyl, cyclopropyl, propen-2-yl, OCH3 and / or CF3 are substituted by one or more of the following; or R 3 is (1-formylpiperidin-4-yl)methyl, substituted on the formyl group by any of the following groups: C 1-6 Alkyl, C 3-7 cycloalkyl, phenyl, thien-3-yl, phenylmethyl or cyclopentylmethyl, each of which is optionally substituted with F, C 1-6 Alkyl, OCH3 and / or CF3 are substituted by one or more thereof; or R 3 yes , , or , where R 5 selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thien-3-yl, benzo[d]thiazol-4-yl, phenylcarbonyl, thiazol-2-yl, benzo[d]oxazol-2-yl and benzo[d]thiazol-2-yl, each of which is optionally substituted with F, Cl, C 1-6 Alkyl, C 1-6 One or more of alkoxy, OCF3 and / or CF3 are substituted.

2. A compound of formula (I) or a pharmaceutically acceptable salt thereof: （I） in: R 1 It is H; R 2 is CH3 or CH2F; and R 3 is cyclohexylmethyl, (4,4-dimethylcyclohexyl)methyl, (4,4-difluorocyclohexyl)methyl, (4,4-dichlorocyclohexyl)methyl, (4-ethylcyclohexyl)methyl, ((1s,4S)-4-vinylcyclohexyl)methyl, ((1s,4S)-4-isopropylcyclohexyl)methyl, ((1r,4R)-4-isopropylcyclohexyl)methyl, (4-(tert-butyl)cyclohexyl)methyl, ((1s,4S)-4-(trifluoromethyl)cyclohexyl)methyl, ((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl, ((1s,4S)-4-(2-fluoroprop-2-yl)cyclohexyl)methyl, ((1r,4R)-4-(2-fluoroprop-2-yl)cyclohexyl)methyl, ((trans) -3-(trifluoromethyl)cyclohexyl)methyl, ((cis)-3-(trifluoromethyl)cyclohexyl)methyl, ((1s,4S)-4-methoxycyclohexyl)methyl, ((1r,4R)-4-methoxycyclohexyl)methyl, (4-(methoxymethyl)cyclohexyl)methyl, ((1s,4S)-4-cyclopropylcyclohexyl)methyl, ((1r,4R)-4-cyclopropylcyclohexyl)methyl, (4-phenylcyclohexyl)methyl, (spiro[2.5]oct-6-yl)methyl, (spiro[3.5]non-7-yl)methyl, (spiro[4.5]dec-8-yl)methyl, 2-cyclohexylethyl, 2-(4,4-difluorocyclohexyl)ethyl, 2-((1s,4S)-4-(trifluoromethyl)cyclohexyl)ethyl, 2 -((1r,4R)-4-(trifluoromethyl)cyclohexyl)ethyl, 2-(adamantan-1-yl)ethyl, 3-cyclohexylpropyl, phenethyl, 2-methylphenethyl, 2-methoxyphenethyl, 2-fluorophenethyl, 2-chlorophenethyl, 2,3-difluorophenethyl, 2,4-difluorophenethyl, 2,5-difluorophenethyl, 3,4-difluorophenethyl, 2-fluoro-4-methoxyphenethyl, 3-chloro-2-fluorophenethyl, 4-chloro-2-fluorophenethyl, 5-chloro-2-fluorophenethyl, 2,6-difluorophenethyl, 3-chloro-2,6-difluorophenethyl, 2,6-difluoro-4-(prop-1-en-2-yl)phenethyl, 2,6-difluoro-4-isopropylphenethyl, 2,6-difluoro-3-isopropylphenethyl, 4 -cyclopropyl-2,6-difluorophenethyl, 2,6-difluoro-4-(trifluoromethyl)phenethyl, 2,6-difluoro-4-(pyrrolidin-1-yl)phenethyl, 2,6-difluoro-4-(piperidin-1-yl)phenethyl, 2,6-difluoro-4-morpholinophenethyl, 4-butoxy-2,6-difluorophenethyl, 4-(cyclopropylmethoxy)-2,6-difluorophenethyl, 4-((tetrahydrofuran-3-yl)oxy)phenethyl, 4-((tetrahydro-2H-pyran-3-yl)oxy)phenethyl, 4-((tetrahydro-2H-pyran-4-yl)oxy)phenethyl, 4-phenoxyphenethyl, 4-((tetrahydrofuran-3-yl)methoxy)phenethyl, (R)-2-phenylpropyl, (S)-2-phenylpropyl,2-([1,1'-biphenyl]-4-yl)ethyl, 2-(3,5-difluoro-[1,1'-biphenyl]-4-yl)ethyl, 2-(benzo[d][1,3]dioxol-5-yl)ethyl, 2-(6-fluorobenzo[d][1,3]dioxol-5-yl)ethyl, 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl, 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl, 2-(thiophen-2-yl)ethyl, 2-(thiophen-3-yl)ethyl, 2-(pyridin-2-yl)ethyl, 3-phenylpropyl, 3-(2-fluorophenyl)propyl, 3-(4-fluorophenyl)propyl phenyl)propyl, 3-(thien-2-yl)propyl, 3-(thien-3-yl)propyl, (1-phenylpiperidin-4-yl)methyl, (1-(2-fluorophenyl)piperidin-4-yl)methyl, (1-(3-fluorophenyl)piperidin-4-yl)methyl, (1-(4-fluorophenyl)piperidin-4-yl)methyl, (1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)methyl, (4-methyl-1-phenylpiperidin-4-yl)methyl, (4-fluoro-1-phenylpiperidin-4-yl)methyl, 2-(1-phenylpiperidin-4-yl)ethyl, (1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl, (1-isobutyrylpiperidin-4-yl)methyl, (1-neobutylpiperidin-4-yl)methyl pentanoylpiperidin-4-yl)methyl, (1-butanoylpiperidin-4-yl)methyl, (1-(3-methylbutanoyl)piperidin-4-yl)methyl, (1-(3,3-dimethylbutanoyl)piperidin-4-yl)methyl, (1-(2-cyclopentylacetyl)piperidin-4-yl)methyl, (1-(cyclopropanecarbonyl)piperidin-4-yl)methyl, (1-(cyclobutanecarbonyl)piperidin-4-yl)methyl, (1-(cyclopentanecarbonyl)piperidin-4-yl)methyl, (1-(cyclohexanecarbonyl)piperidin-4-yl)methyl, (1-((1s,4s)-4-(tert-butyl)cyclohexanecarbonyl)piperidin-4-yl)methyl, (1-((1r,4r)-4-(tert-butyl)cyclohexanecarbonyl)piperidin-4-yl)methyl methyl, (1-(4-(trifluoromethyl)cyclohexanecarbonyl)piperidin-4-yl)methyl, (1-(4-(trifluoromethyl)cyclohexanecarbonyl)piperidin-4-yl)methyl, (1-benzoylpiperidin-4-yl)methyl, (1-(3-(trifluoromethyl)benzoyl)piperidin-4-yl)methyl, (1-(2-phenylacetyl)piperidin-4-yl)methyl, (1-(thiophene-3-carbonyl)piperidin-4-yl)methyl, ((5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]dec-8-yl)methyl, (1,2,3,4-tetrahydronaphthalen-2-yl)methyl, (2,3-dihydro-1H-inden-2-yl)methyl, 2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenethyl, (1-(pyridin-3-yl)piperidin-4-yl)methyl, (1-(cyclohexylcarbamoyl)piperidin-4-yl)methyl, (1-(cyclohexylthiocarbamoyl)piperidin-4-yl)methyl, (1-((1S,2R)-2-(trifluoromethyl)cyclohexyl)azetidin-3-yl)methyl, ((R)-1-phenylpyrrolidin-3-yl)methyl, ((R)-1-(o-tolyl)pyrrolidin-3-yl)methyl, ((R)-1-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl, ((S)-1-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl, (R)-1-(2-fluorophenyl pyrrolidin-3-yl)methyl, (R)-1-(3-fluorophenyl)pyrrolidin-3-yl)methyl, (R)-1-(2-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)methyl, (R)-1-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl, (R)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl, (R)-1-(4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl, (R)-1-(pyridin-3-yl)pyrrolidin-3-yl)methyl, (R)-1-(4-methylpyridin-3-yl)pyrrolidin-3-yl)methyl, (R)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl )pyrrolidin-3-yl)methyl, ((R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl, ((R)-1-(2-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl, ((R)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl, ((R)-1-(thiophen-3-yl)pyrrolidin-3-yl)methyl, ((R)-1-(benzo[d]thiazol-4-yl)pyrrolidin-3-yl)methyl, (S)-(1-(4-(trifluoromethyl)benzoyl)pyrrolidin-3-yl)methyl, ((R)-1-(o-tolyl)piperidin-3-yl)methyl, ((R)-1-(2-fluorophenyl)piperidin-3-yl)methyl methyl, ((R)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl, ((R)-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl, ((R)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl, 3-fluorophenethyl, 4-fluorophenethyl, 3,4-dichlorophenethyl, 3-(trifluoromethyl)phenethyl, 4-(trifluoromethyl)phenethyl, ((R)-1-(Benzo[d]thiazol-2-yl)pyrrolidin-3-yl)methyl, ((R)-1-(2-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl, 4-(3,5-dimethylisoxazol-4-yl)-2,6-difluorophenethyl, 4-(3,4-dichlorophenethyl5-dimethyl-1H-pyrazol-4-yl)-2,6-difluorophenethyl, ((R)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl, ((R)-1-(Benzo[d]oxazol-2-yl)pyrrolidin-3-yl)methyl, ((R)-1-(5-isopropylthiazol-2-yl)piperidin-3-yl)methyl, ((R)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl, ((R)-1-(Benzo[d]thiazol-2-yl)piperidin-3-yl)methyl, ((R)-1-(Benzo[d]thiazol-4-yl)piperidin-3-yl)methyl, ((S)- 1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl, ((S)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl, ((S)-1-(6-(trifluoromethyl)pyridin-2-yl) piperidin-3-yl)methyl, or ((S)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that: The R 3 It is ((1s,4S)-(4-(tert-butyl)cyclohexyl)methyl, ((1r,4R)-(4-(tert-butyl)cyclohexyl)methyl.

4. A compound, wherein the compound is: (2R,3R,4R,5S)-1-(cyclohexylmethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-((4,4-dimethylcyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-((4,4-dichlorocyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-((4-ethylcyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((1s,4S)-4-vinylcyclohexyl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(((1s,4S)-4-isopropylcyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(((1r,4R)-4-isopropylcyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(((1s,4S)-4-(tert-butyl)cyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(((1r,4R)-4-(tert-butyl)cyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((1s,4S)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(((1s,4S)-4-(2-fluoropropan-2-yl)cyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(((1r,4R)-4-(2-fluoropropan-2-yl)cyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((trans)-3-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((cis)-3-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(((1s,4S)-4-methoxycyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(((1r,4R)-4-methoxycyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-((4-(methoxymethyl)cyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(((1s,4S)-4-cyclopropylcyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(((1r,4R)-4-cyclopropylcyclohexyl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-((4-phenylcyclohexyl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(spiro[2.5]octan-6-ylmethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(spiro[3.5]nonan-7-ylmethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(spiro[4.5]dec-8-ylmethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(((5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]dec-8-yl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-((1,2,3,4-tetrahydronaphthalen-2-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-1-((2,3-dihydro-1H-inden-2-yl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(2-cyclohexylethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(2-(4,4-difluorocyclohexyl)ethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(2-((1s,4S)-4-(trifluoromethyl)cyclohexyl)ethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(2-((1r,4R)-4-(trifluoromethyl)cyclohexyl)ethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-1-((2-adamantan-1-yl)ethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(3-cyclohexylpropyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-phenylethylpiperidin-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(2-methylphenethyl)piperidin-3,4,5-triol; (2R,3R,4R,5S)-1-(2-methoxyphenethyl)-2-methylpiperidin-3,4,5-triol; (2R,3R,4R,5S)-1-(2-fluorophenethyl)-2-methylpiperidin-3,4,5-triol; (2R,3R,4R,5S)-1-(2-chlorophenethyl)-2-methylpiperidin-3,4,5-triol; (2R,3R,4R,5S)-1-(2,3-difluorophenethyl)-2-methylpiperidin-3,4,5-triol; (2R,3R,4R,5S)-1-(2,4-difluorophenethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(2,5-difluorophenethyl)-2-methylpiperidin-3,4,5-triol; (2R,3R,4R,5S)-1-(3,4-difluorophenethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(2-fluoro-4-methoxyphenethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(3-chloro-2-fluorophenethyl)-2-methylpiperidin-3,4,5-triol; (2R,3R,4R,5S)-1-(4-chloro-2-fluorophenethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(5-chloro-2-fluorophenethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(2,6-difluorophenethyl)-2-methylpiperidin-3,4,5-triol; (2R,3R,4R,5S)-1-(3-chloro-2,6-difluorophenethyl)-2-methylpiperidin-3,4,5-triol; (2R,3R,4R,5S)-1-(2,6-difluoro-4-(prop-1-en-2-yl)phenethyl)-2-methylpiperidin-3,4,5-triol; (2R,3R,4R,5S)-1-(2,6-difluoro-4-isopropylphenethyl)-2-methylpiperidin-3,4,5-triol; (2R,3R,4R,5S)-1-(2,6-difluoro-3-isopropylphenethyl)-2-methylpiperidin-3,4,5-triol; (2R,3R,4R,5S)-1-(4-cyclopropyl-2,6-difluorophenethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(2,6-difluoro-4-(trifluoromethyl)phenethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(2,6-difluoro-4-(pyrrolidin-1-yl)phenethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(2,6-difluoro-4-(piperidin-1-yl)phenethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(2,6-difluoro-4-morpholinophenethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(4-Butoxy-2,6-difluorophenethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(4-(cyclopropylmethoxy)-2,6-difluorophenethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(4-((tetrahydrofuran-3-yl)oxy)phenethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(4-((tetrahydro-2H-pyran-3-yl)oxy)phenethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(4-phenoxyphenethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(4-((tetrahydrofuran-3-yl)methoxy)phenethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-((R)-2-phenylpropyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-((S)-2-phenylpropyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(2-([1,1'-biphenyl]-4-yl)ethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(2-(3,5-difluoro-[1,1'-biphenyl]-4-yl)ethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(2-(6-fluorobenzo[d][1,3]dioxol-5-yl)ethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(2-(thien-2-yl)ethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(2-(thien-3-yl)ethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(2-(pyridin-2-yl)ethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(3-phenylpropyl)piperidin-3,4,5-triol; (2R,3R,4R,5S)-1-(3-(2-fluorophenyl)propyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(3-(4-fluorophenyl)propyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(3-(thien-2-yl)propyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(3-(thien-3-yl)propyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-((1-phenylpiperidin-4-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-1-((1-(2-fluorophenyl)piperidin-4-yl)methyl)-2-methylpiperidin-3,4,5-triol; (2R,3R,4R,5S)-1-((1-(3-fluorophenyl)piperidin-4-yl)methyl)-2-methylpiperidin-3,4,5-triol; (2R,3R,4R,5S)-1-((1-(4-fluorophenyl)piperidin-4-yl)methyl)-2-methylpiperidin-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-((1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-((4-methyl-1-phenylpiperidin-4-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-1-((4-fluoro-1-phenylpiperidin-4-yl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(2-(1-phenylpiperidin-4-yl)ethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-((1-(pyridin-3-yl)piperidin-4-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)piperidine-3,4,5-triol; 2-methyl-1-(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-methylpiperidin-1-yl)methyl)piperidin-1-yl)propan-1-one; 2,2-Dimethyl-1-(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-methylpiperidin-1-yl)methyl)piperidin-1-yl)propan-1-one; 1-(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-methylpiperidin-1-yl)methyl)piperidin-1-yl)butan-1-one; 3-methyl-1-(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-methylpiperidin-1-yl)methyl)piperidin-1-yl)butan-1-one; 3,3-Dimethyl-1-(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-methylpiperidin-1-yl)methyl)piperidin-1-yl)butan-1-one; 2-Cyclopentyl-1-(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-methylpiperidin-1-yl)methyl)piperidin-1-yl)ethanone; Cyclopropyl(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-methylpiperidin-1-yl)methyl)piperidin-1-yl)methanone; Cyclobutyl(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-methylpiperidin-1-yl)methyl)piperidin-1-yl)methanone; Cyclopentyl(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-methylpiperidin-1-yl)methyl)piperidin-1-yl)methanone; Cyclohexyl(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-methylpiperidin-1-yl)methyl)piperidin-1-yl)methanone; ((1s,4S)-4-(tert-butyl)cyclohexyl)(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-methylpiperidin-1-yl)methyl)piperidin-1-yl)methanone; ((1r,4R)-4-(tert-butyl)cyclohexyl)(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-methylpiperidin-1-yl)methyl)piperidin-1-yl)methanone; (4-methoxycyclohexyl)(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-methylpiperidin-1-yl)methyl)piperidin-1-yl)methanone; (4-(Trifluoromethyl)cyclohexyl)(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-methylpiperidin-1-yl)methyl)piperidin-1-yl)methanone; Phenyl (4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-methylpiperidin-1-yl)methyl)piperidin-1-yl)methanone; (3-(Trifluoromethyl)phenyl)(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-methylpiperidin-1-yl)methyl)piperidin-1-yl)methanone; 2-phenyl-1-(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-methylpiperidin-1-yl)methyl)piperidin-1-yl)ethanone; Thiophen-3-yl(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-methylpiperidin-1-yl)methyl)piperidin-1-yl)methanone; N-cyclohexyl-4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-methylpiperidin-1-yl)methyl)piperidine-1-carboxamide; N-cyclohexyl-4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-methylpiperidin-1-yl)methyl)piperidine-1-carbothioamide; (2R,3R,4R,5S)-2-methyl-1-((1-((1S,2R)-2-(trifluoromethyl)cyclohexyl)azetidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((R)-1-phenylpyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((R)-1-(o-tolyl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((R)-1-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(((R)-1-(2-fluorophenyl)pyrrolidin-3-yl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(((R)-1-(3-fluorophenyl)pyrrolidin-3-yl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((R)-1-(2-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((R)-1-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((R)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((R)-1-(4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((R)-1-(pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((R)-1-(4-methylpyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((R)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((R)-1-(2-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((R)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((R)-1-(thiophen-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(((R)-1-(Benzo[d]thiazol-4-yl)pyrrolidin-3-yl)methyl)-2-methylpiperidine-3,4,5-triol; (4-(Trifluoromethyl)phenyl)((R)-3-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-methylpiperidin-1-yl)methyl)pyrrolidin-1-yl)methanone; (2R,3R,4R,5S)-2-methyl-1-(((S)-1-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((S)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((S)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((S)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((S)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((R)-1-(o-tolyl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(((R)-1-(2-fluorophenyl)piperidin-3-yl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((R)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((R)-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((R)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((S)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((S)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((S)-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((S)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-2-(Fluoromethyl)-1-((4-isopropylcyclohexyl)methyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-1-((4-(tert-butyl)cyclohexyl)methyl)-2-(fluoromethyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-2-(fluoromethyl)-1-(((1r,4S)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-2-(Fluoromethyl)-1-phenethylpiperidine-3,4,5-triol; (2S,3R,4R,5S)-2-(Fluoromethyl)-1-(2-fluorophenethyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-1-(2,6-difluoro-4-isopropylphenethyl)-2-(fluoromethyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-1-(2-(3,5-difluoro-[1,1'-biphenyl]-4-yl)ethyl)-2-(fluoromethyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-1-(2-(6-fluorobenzo[d][1,3]dioxol-5-yl)ethyl)-2-(fluoromethyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-1-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2-(fluoromethyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-2-(Fluoromethyl)-1-((1-phenylpiperidin-4-yl)methyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-2-(fluoromethyl)-1-((1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-2-(Difluoromethyl)-1-phenylethylpiperidine-3,4,5-triol; (2S,3R,4R,5S)-1-(2-fluorophenethyl)-2-methylpiperidin-3,4,5-triol; (2S,3R,4R,5S)-1-(4-Butoxy-2,6-difluorophenethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-2-(Fluoromethyl)-1-(2-fluorophenethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(4-butoxy-2,6-difluorophenethyl)-2-(fluoromethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(3-fluorophenethyl)-2-methylpiperidin-3,4,5-triol; (2R,3R,4R,5S)-1-(4-fluorophenethyl)-2-methylpiperidin-3,4,5-triol; (2R,3R,4R,5S)-1-(3,4-dichlorophenethyl)-2-methylpiperidin-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(3-(trifluoromethyl)phenethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(4-(trifluoromethyl)phenethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(4-(3,5-dimethylisoxazol-4-yl)-2,6-difluorophenethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-2,6-difluorophenethyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((R)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(((R)-1-(Benzo[d]oxazol-2-yl)pyrrolidin-3-yl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(((R)-1-(Benzo[d]thiazol-2-yl)pyrrolidin-3-yl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(((R)-1-(5-isopropylthiazol-2-yl)piperidin-3-yl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((R)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-methyl-1-(((R)-1-(2-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(((R)-1-(Benzo[d]thiazol-2-yl)piperidin-3-yl)methyl)-2-methylpiperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(((R)-1-(Benzo[d]thiazol-4-yl)piperidin-3-yl)methyl)-2-methylpiperidine-3,4,5-triol; Or a pharmaceutically acceptable salt of any of the foregoing compounds.

5. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

6. Use of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting GBA2.

7. Use of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for reducing GBA2 enzyme activity.

8. Use of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable form thereof in the preparation of a medicament for treating a condition modulated by GBA2.

9. The method of claim 8, wherein the disorder is Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, amyotrophic lateral sclerosis (ALS), addiction, anxiety, argyrophilic grain dementia, ataxia-telangiectasia (AT), attention-deficit / hyperactivity disorder (ADHD), autism spectrum disorder (ASD), Becker muscular dystrophy (BMD), bipolar disorder (BD), Blunt disease, cerebellar ataxia, Charcot-Marie-Tooth disease (CMT), chronic fatigue syndrome, corticobasal degeneration (CBD), dementia pugilistica, dementia with Lewy bodies (DLB), Degerin-Sottas syndrome, diffuse neurofibrillary tangles with calcifications, Down syndrome, Duchenne muscular dystrophy (DMD), epilepsy, essential tremor (ET), familial British dementia, familial Danish dementia, fibromuscular dystrophy, Friedreich's ataxia, Gerstmann-Strauss sodium disease, glaucoma, Guillain-Barré syndrome, Hallevorden-Spatz disease (neurodegeneration with brain iron accumulation type 1), insomnia, Lambert-Eaton myasthenic syndrome (LEMS), major depressive disorder (MDD), migraine, mild cognitive impairment (MCI), multi-infarct dementia, multiple system atrophy (MSA), myasthenia gravis, myotonic dystrophy, neuronal ceroid lipofuscinosis, neuropathy, oculopharyngeal muscular dystrophy, pain, globus pallidus ponto-nigral degeneration, Guam Parkinson's syndrome- Dementia syndrome, Pick's disease (PiD), primary lateral sclerosis (PLS), prion disease, progressive supracortical gliosis, progressive supranuclear palsy (PSP), Richardson syndrome, schizophrenia, seizures, spinal cord injury, spinal muscular atrophy (SMA), spinocerebellar ataxia, stroke, subacute sclerosing panencephalitis, tangled dementia, tardive dyskinesia, Tourette syndrome (TS), vascular dementia, Wilson disease, Gaucher disease, Niemann-Pick disease, mucolipidosis, cerebrotendinous xanthomatosis, Fabry disease, Farber disease, GM1 gangliosidosis, Krabbe disease, metachromatic leukodystrophy (MLD), multiple sulfatase deficiency, Pompe disease, Sandhoff disease, Tay Sachs disease, nonalcoholic fatty liver disease (NAFLD), Alagille syndrome, alcohol-related liver disease, alpha-1 antitrypsin deficiency, autoimmune hepatitis, autoimmune cholangitis, benign liver tumor, biliary atresia, cirrhosis, Crigler-Najjar syndrome, drug-induced liver injury (DILI), galactosemia, Gilbert syndrome, hemochromatosis, hepatic encephalopathy, intrahepatic cholestasis of pregnancy (ICP), lysosomal acid lipase deficiency (LAL-D), liver cysts, liver cancer, neonatal jaundice, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), Reye syndrome, glycogen storage disease type I, or viral hepatitis.

10. The use according to claim 9, wherein the disorder is Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) or multiple sclerosis.

11. The use according to claim 9, wherein the disorder is Niemann-Pick disease, Gaucher disease, mucolipidosis, neuronal ceroid lipofuscinosis, spinocerebellar ataxia, GM1 gangliosidosis or Sandhoff disease.

12. The use according to claim 8, wherein the disorder is Parkinsonism associated with chromosome 17 (FTDP-17), Guadilopa Parkinsonism or postencephalitis Parkinsonism (PEP).

13. The use according to claim 9, wherein the amyotrophic lateral sclerosis (ALS) is amyotrophic lateral sclerosis with cognitive impairment (ALSci).

14. The use according to claim 9, wherein the Niemann-Pick disease is Niemann-Pick disease type A, B or C.

15. The use according to claim 14, wherein the Niemann-Pick disease is Niemann-Pick disease type C.

16. The method of claim 9, wherein the spinocerebellar ataxia is spinocerebellar ataxia type 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 28 or 29.

17. The use according to claim 9, wherein the neuronal ceroid lipofuscinosis is neuronal ceroid lipofuscinosis type 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

18. The use according to claim 17, wherein the neuronal ceroid lipofuscinosis is neuronal ceroid lipofuscinosis type 3.

19. The use according to claim 8, wherein the disorder is non-alcoholic steatohepatitis (NASH).

20. The use according to claim 9, wherein the liver cancer is hepatocellular carcinoma (HCC).

21. The use according to claim 9, wherein the myotonic dystrophy is myotonic dystrophy of DM1 or DM2 type.

22. The use according to claim 8, wherein the disorder is peripheral neuropathy, autonomic neuropathy, neuritis or neurodystrophy.

23. The use according to claim 8, wherein the disease is Creutzfeldt-Jakob disease (CJD), variant Creutzfeldt-Jakob disease (vCJD), fatal familial insomnia or kuru.

24. The use according to claim 9, wherein the Gaucher disease is type I, II or III Gaucher disease.

25. The use according to claim 9, wherein the mucolipidosis is mucolipidosis type I, II, III, IV, VI or VII.

26. The use according to claim 9, wherein the viral hepatitis is A, B, C, D or E viral hepatitis.

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