Non-lysosomal glucosylceramide inhibitors and uses thereof

Abstract

The present invention provides compounds for inhibiting glucosylceramidase, prodrugs of the compounds, and pharmaceutical compositions comprising the compounds or the prodrugs of the compounds.

Description

Technical Field

[0001] The present invention relates in part to compounds that inhibit glucosylceramidase and their uses. Background Art

[0002] Glucosylceramidases are a group of enzymes that catalyze the hydrolytic cleavage of the β-glucosidic bond of the glycosphingolipid glucosylceramide (GlcCer, also known as glucocerebroside) to produce D-glucose and ceramide. In humans, three different enzymes with glucosylceramidase activity exist: lysosomal β-glucocerebrosidase (GCase or GBA1, EC 3.2.1.45), non-lysosomal β-glucocerebrosidase (GBA2, EC 3.2.1.45), and cytosolic β-glucocerebrosidase (GBA3, EC 3.2.1.21). GCase is a lysosomal enzyme encoded by the GBA gene; homozygous loss-of-function mutations in GBA cause the lysosomal storage disorder Gaucher disease, characterized by the pathological accumulation of glucosylceramide within lysosomes. 1 GBA2 is a membrane-associated protein localized to the cytoplasmic side of the endoplasmic reticulum (ER) and Golgi membranes and is expressed at high levels in the central nervous system (CNS). 2,3 GBA3 is a cytoplasmic enzyme expressed primarily in the liver. 3,4

[0003] Glucosylceramidase plays an important role in regulating the cellular levels of its substrate molecule, glucosylceramide, the simplest member and biosynthetic precursor of a widespread class of cell membrane lipids, glycosphingolipids (GSLs). 3,5 Dysregulation of GSL metabolism and homeostasis is implicated in a wide range of diseases, including the neurological disorders Alzheimer's disease (AD), 6 Parkinson's disease (PD) 7 、 7 Multiple sclerosis (MS), 8 Huntington's disease (HD), 9 Amyotrophic lateral sclerosis (ALS), 10 and neuronal ceroid lipofuscinosis (Patton disease); 11 Lysosomal storage disease Niemann-Pick disease type C (NPC), 12 Mucolipidosis type IV (MLIV), 13 and Sandhoff disease; 14 and liver disease non-alcoholic fatty liver disease (NAFLD) 15 and nonalcoholic steatohepatitis (NASH). 15 Small molecule GBA2 inhibitors have been shown to extend lifespan and improve motor coordination in rodent models of NPC. 16,17 Similarly, there is evidence that GBA2 inhibition can prolong MLIV 13and Sandhoff disease 14 In rodent models of synucleinopathy, small molecule GBA2 inhibitors have been shown to reduce the accumulation of α-synuclein aggregates in the brain. 14 Furthermore, treatment with a small-molecule GBA2 inhibitor reduced neuroinflammation and neurodegeneration in a mouse model of neuronal ceroid lipofuscinosis (Patton disease). 18 In a rodent model of Gaucher disease, reduction of GBA2 activity has also been shown to rescue the clinical phenotype. 19 In addition, studies have shown that GBA2 is involved in regulating inflammatory responses. 2 Furthermore, reduction of GBA2 activity reduced inflammation in a cystic fibrosis (CF) cell model. 20 Increased glucosylceramide levels have also shown beneficial effects in rodent models of liver disease, including nonalcoholic steatohepatitis (NASH), 21 hepatitis, 22 Hepatocellular carcinoma (HCC), 23 Autoimmune cholangitis, 24 and drug-induced liver injury (DILI). 25

[0004] The enzymatic activity of GBA2 can be pharmacologically blocked by the iminosugars (2R,3R,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol (NB-DNJ, Miglustat) and (2R,3R,4R,5S)-1-(5-((3R,5R,7R)-adamantan-1-ylmethoxy)pentyl)-2-(hydroxymethyl)piperidine-3,4,5-triol (AMP-DNM, Genz-529648); however, these compounds are not selective for GBA2 as they also exhibit inhibitory activity against other enzymes, including Gcase, glucosylceramide synthase (GCS, EC2.4.1.80), and intestinal α-glucosidase. 26

[0005] International patent applications PCT / GB 2003 / 003099, filed on July 17, 2003, published as WO 2004 / 007453 on January 22, 2004; PCT / GB 2004 / 002450, filed on June 9, 2004, published as WO 2004 / 111001 on December 23, 2004; PCT / GB 2004 / 002451, filed on June 9, 2004, published as WO 2004 / 111002 on December 23, 2004; PCT / GB 2005 / 000071, filed on January 11, 2005, published as WO 2004 / 000071 on July 28, 2005 2005 / 068426; PCT / NL2015 / 050188, filed on March 23, 2015, published as WO 2015 / 147639 on October 1, 2015; PCT / IB2020 / 054355, filed on May 7, 2020, published as WO 2020 / 229968 on November 19, 2020, relate to small molecule inhibitors of GBA2. Summary of the Invention

[0006] The present invention provides, in part, compounds for inhibiting non-lysosomal glucosylceramidase (GBA2), prodrugs of the compounds, uses of the compounds and prodrugs, pharmaceutical compositions comprising the compounds or prodrugs of the compounds, and methods for treating diseases and conditions regulated by GBA2 activity levels, and / or glucosylceramide levels, and / or glycosphingolipid metabolism or homeostasis. In some embodiments, the present 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, mucolipidosis type IV, and Sandhoff disease, or liver diseases, including non-alcoholic steatohepatitis (NASH), by administering to a patient in need thereof an effective amount of one or more compounds or prodrugs of the compounds described herein.

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

[0008]

[0009] Among them, R 1 Can be H and R 2 It can be CH2OH; or R 1 It can be CH2OH and R 2 can be H; and

[0010] R 3 It can be (CH2) n R4 , where n can be 1 or 2, and R 4 It can be cyclohexyl, cyclohexylmethyl, phenethyl, 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-dihydrobenzene 1-(cyclohexylmethylsulfonyl)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazetidin-3-yl, 2-(thiophen-2-yl)methyl, or 2-(thiazol-3-yl)methyl, each optionally substituted with F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoroprop-2-yl, methoxymethyl, C 1-5 One or more substituents of alkoxy, CHF2, CF2CH3, and / or CF3 are substituted by one to the maximum number; or

[0011] R 3 It can be phenethyl, pyrrolidin-1-yl, piperidin-1-yl, 4-morpholinyl, 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 substituents of alkyl, cyclopropyl, propen-2-yl, OCH3, and / or CF3 are substituted by one to the maximum number; or

[0012] R 3 It may be (1-formylpiperidin-4-yl)methyl, substituted on the formyl group by one of the following: C 1-6 Alkyl, C 3-7 Cycloalkyl, phenyl, thien-3-yl, benzyl, or cyclopentylmethyl, each optionally substituted with F, C 1-6 One or more substituents in alkyl, OCH3, and / or CF3 are substituted by one to the maximum number; or

[0013] R 3 Can be Among them, R5 may be selected from the group comprising: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thien-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 substituted with one or more F, Cl, C 1-6 alkyl, C 1-6 alkoxy, OCF3, and / or CF3substituents, up to the maximum number,

[0014] provided that R 1 is H and R 2 is CH2OH, then R 3 is not cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl, phenethyl, 3-phenylpropyl, 3-(2-propoxyphenyl)propyl, 3-(3-propoxyphenyl)propyl, 3-(4-propoxyphenyl)propyl, or 4-phenylbutyl; and

[0015] provided that R 1 is CH2OH and R 2 is H, then R 3 is not phenethyl, 3-phenylpropyl, (R)-2-phenylpropyl, or (S)-2-phenylpropyl.

[0016] In alternative embodiments, the present application provides a compound represented by Formula (la) or a pharmaceutically acceptable salt thereof:

[0017]

[0018] wherein R 3 may be (CH2) n R 4 wherein n can be 1 or 2, and R 4It can be cyclohexyl, cyclohexylmethyl, phenethyl, 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-dihydro benzo[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-(cyclohexylcarboxamido)piperidin-4-yl, 1-(cyclohexylmethylsulfamido)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazetidin-3-yl, 2-(thiophen-2-yl)methyl, or 2-(thiazol-3-yl)methyl, each optionally substituted with F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoroprop-2-yl, methoxymethyl, C 1-5 One or more substituents of alkoxy, CHF2, CF2CH3, and / or CF3 are substituted by one to the maximum number; or

[0019] R 3 It can be phenethyl, pyrrolidin-1-yl, piperidin-1-yl, 4-morpholinyl, 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 substituents of alkyl, cyclopropyl, propen-2-yl, OCH3, and / or CF3 are substituted by one to the maximum number; or

[0020] R 3 It may be (1-formylpiperidin-4-yl)methyl, substituted on the formyl group by one of the following: C 1-6 Alkyl, C 3-7 Cycloalkyl, phenyl, thien-3-yl, benzyl, or cyclopentylmethyl, each optionally substituted with F, C 1-6 One or more substituents in alkyl, OCH3, and / or CF3 are substituted by one to the maximum number; or

[0021] R 3 may be Among them, R 5can be selected from the group consisting of: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thien-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 substituted with F, Cl, C 1-6 Alkyl, C 1-6 One or more substituents in alkoxy, OCF3, and / or CF3 are substituted from one to the maximum number,

[0022] The condition is R 3 Not cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl, phenylethyl, 3-phenylpropyl, 3-(2-propoxyphenyl)propyl, 3-(3-propoxyphenyl)propyl, 3-(4-propoxyphenyl)propyl, or 4-phenylbutyl.

[0023] In an alternative embodiment, the present invention provides a compound represented by formula (Ib) or a pharmaceutically acceptable salt thereof:

[0024]

[0025] Among them, R 3 It can be (CH2) n R 4 , where n can be 1 or 2, and R 4 The cyclohexyl group may be cyclohexyl, cyclohexylmethyl, phenethyl, 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-dihydrobenzene 1-(cyclohexylcarboxamido)piperidin-4-yl, 1-(cyclohexylmethylsulfamido)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazetidin-3-yl, 2-(thiophen-2-yl)methyl, or 2-(thiazol-3-yl)methyl, each optionally substituted with F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoroprop-2-yl, methoxymethyl, C 1-5 One or more substituents of alkoxy, CHF2, CF2CH3, and / or CF3 are substituted by one to the maximum number; or

[0026] R3 It can be phenethyl, pyrrolidin-1-yl, piperidin-1-yl, 4-morpholinyl, 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; or

[0027] R 3 It may be (1-formylpiperidin-4-yl)methyl, substituted on the formyl group by one of the following: C 1-6 Alkyl, C 3-7 Cycloalkyl, phenyl, thien-3-yl, benzyl, or cyclopentylmethyl, each optionally substituted with F, C 1-6 One or more substituents in alkyl, OCH3, and / or CF3 are substituted by one to the maximum number; or

[0028] R 3 Can be Among them, R 5 can be selected from the group consisting of: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thien-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, phenylcarbonyl, thiazol-2-yl, benzo[d]oxazol-2-yl, benzo[d]thiazol-2-yl, each optionally substituted with F, Cl, C 1-6 Alkyl, C 1-6 One or more substituents in alkoxy, OCF3, and / or CF3 are substituted from one to the maximum number,

[0029] The condition is R 3 Not phenylethyl, 3-phenylpropyl, (R)-2-phenylpropyl, or (S)-2-phenylpropyl.

[0030] In an alternative embodiment, the present invention provides a compound represented by formula (Ic) or a pharmaceutically acceptable salt thereof:

[0031]

[0032] Among them, R 6 and R 7 Can be independently selected from the group consisting of: H, F, Cl, C 1-6 alkyl, OCH3, phenyl, cyclopropyl, vinyl, methoxymethyl, 2-fluoroprop-2-yl, CHF2, CF2CH3, and / or CF3, provided that R 6 and R7 In some embodiments, at least one of R 6 Can be H, and R 7 Can be CF3, 2-fluoroprop-2-yl, CHF2, CF2CH3, isopropyl, or tert-butyl. In some embodiments, R 6 It can be CF3, 2-fluoroprop-2-yl, CHF2, CF2CH3, isopropyl, or tert-butyl, and R 7 It can be H.

[0033] In an alternative embodiment, the present invention provides a compound represented by formula (Id) or a pharmaceutically acceptable salt thereof:

[0034]

[0035] Among them, R 6 and R 7 Can be independently selected from the group consisting of: H, F, Cl, C 1-6 alkyl, OCH3, phenyl, cyclopropyl, vinyl, methoxymethyl, 2-fluoroprop-2-yl, CHF2, CF2CH3, and / or CF3, provided that R 6 and R 7 At least one of them is not H.

[0036] In an alternative embodiment, the present invention provides a compound represented by formula (Ie) or a pharmaceutically acceptable salt thereof:

[0037]

[0038] Among them, R 8 、R 9 and R 10 Can be independently selected from the group consisting of: pyrrolidin-1-yl, piperidin-1-yl, 4-morpholinyl, 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, provided that R 8 、R 9 and R 10 In some embodiments, at least one of R 8 、R 9 and R 10can be independently selected from the group consisting of: H, F, Cl, tetrahydro-2H-pyran-4-yl, 4-morpholinyl, pyrrolidin-1-yl, and piperidin-1-yl, provided that R 8 、R 9 and R 10 At least one of them is not H.

[0039] In an alternative embodiment, the present invention provides a compound represented by formula (If) or a pharmaceutically acceptable salt thereof:

[0040]

[0041] Among them, R 8 、R 9 and R 10 Can be independently selected from the group consisting of: H, F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoroprop-2-yl, methoxymethyl, C 1-5 alkoxy, and / or CF3, provided that the compound is not (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(4-phenylbutyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(3-(2-propoxyphenyl)propyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(3-(3-propoxyphenyl)propyl)piperidine-3,4,5-triol, or (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(3-(4-propoxyphenyl)propyl)piperidine-3,4,5-triol.

[0042] In an alternative embodiment, the present invention provides a compound represented by formula (Ig) or a pharmaceutically acceptable salt thereof:

[0043]

[0044] Among them, R 8 、R 9 and R 10 Can be independently selected from the group consisting of: H, F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoroprop-2-yl, methoxymethyl, C 1-5 Alkoxy, and / or CF3. In some embodiments, R 8 、R 9 and R 10 Independently selected from the group consisting of: H, F and CF3.

[0045] In an alternative embodiment, the present invention provides a compound represented by formula (Ih) or a pharmaceutically acceptable salt thereof:

[0046]

[0047] Among them, R 11 Can be selected from the group consisting of: C 1-6 Alkyl, C 3-7 Cycloalkyl, phenyl, thien-3-yl, benzyl, or cyclopentylmethyl, each optionally substituted with F, C 1-6 One or more substituents in the alkyl group, OCH3, and / or CF3 are substituted from one to the maximum number.

[0048] In an alternative embodiment, the present invention provides a compound represented by formula (Ii) or a pharmaceutically acceptable salt thereof:

[0049]

[0050] Among them, R 12 can be selected from the group consisting of: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thien-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, or phenylcarbonyl, each optionally substituted with F, Cl, C 1-6 Alkyl, C 1-6 One or more substituents in alkoxy, OCF3, and / or CF3 replace one to the maximum number. In some embodiments, R 12 It can be selected from the group consisting of: 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)thiazol-2-yl.

[0051] In an alternative embodiment, the present invention provides a compound represented by formula (Ij) or a pharmaceutically acceptable salt thereof:

[0052]

[0053] Among them, R 12 can be selected from the group consisting of: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thien-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, or phenylcarbonyl, each optionally substituted with F, Cl, C 1-6 Alkyl, C 1-6 One or more substituents in alkoxy, OCF3, and / or CF3 replace one to the maximum number. In some embodiments, R 12It can be selected from the group consisting of: 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)thiazol-2-yl.

[0054] In an alternative embodiment, the present invention provides a compound represented by formula (Ik) or a pharmaceutically acceptable salt thereof:

[0055]

[0056] Among them, R 12 can be selected from the group consisting of: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thien-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, or phenylcarbonyl, each optionally substituted with F, Cl, C 1-6 Alkyl, C 1-6 One or more substituents in alkoxy, OCF3, and / or CF3 replace one to the maximum number. In some embodiments, R 12 It can be selected from the group consisting of: 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)thiazol-2-yl.

[0057] In an alternative embodiment, the present invention provides a compound represented by formula (I1) or a pharmaceutically acceptable salt thereof:

[0058]

[0059] Among them, R 12 can be selected from the group consisting of: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thien-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, or phenylcarbonyl, each optionally substituted with F, Cl, C 1-6 Alkyl, C 1-6 One or more substituents in alkoxy, OCF3, and / or CF3 replace one to the maximum number. In some embodiments, R 12It can be selected from the group consisting of: 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)thiazol-2-yl.

[0060] In an alternative embodiment, the present invention provides a compound represented by formula (Im) or a pharmaceutically acceptable salt thereof:

[0061]

[0062] Among them, R 6 and R 7 Can be independently selected from the group consisting of: H, F, Cl, C 1-6 alkyl, OCH3, phenyl, cyclopropyl, vinyl, methoxymethyl, 2-fluoroprop-2-yl, CHF2, CF2CH3, and / or CF3. In some embodiments, R 6 Can be H, and R 7 Can be CF3, 2-fluoroprop-2-yl, CHF2, CF2CH3, isopropyl, or tert-butyl. In some embodiments, R 6 It can be CF3, 2-fluoroprop-2-yl, CHF2, CF2CH3, isopropyl, or tert-butyl, and R 7 It can be H.

[0063] In an alternative embodiment, the present invention provides a compound represented by formula (In) or a pharmaceutically acceptable salt thereof:

[0064]

[0065] Among them, R 6 and R 7 Can be independently selected from the group consisting of: H, F, Cl, C 1-6 Alkyl, OCH3, phenyl, cyclopropyl, vinyl, methoxymethyl, 2-fluoroprop-2-yl, CHF2, CF2CH3, and / or CF3.

[0066] In an alternative embodiment, the present invention provides a compound represented by formula (Io) or a pharmaceutically acceptable salt thereof:

[0067]

[0068] Among them, R 8 、R 9 and R 10Can be independently selected from the group consisting of: pyrrolidin-1-yl, piperidin-1-yl, 4-morpholinyl, 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, provided that the compound is not (2S,3R,4R,5S)-2-(hydroxymethyl)-1-phenylethylpiperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-((R)-2-phenylpropyl)piperidine-3,4,5-triol, or (2S,3R,4R,5S)-2-(hydroxymethyl)-1-((S)-2-phenylpropyl)piperidine-3,4,5-triol. In some embodiments, R 8 、R 9 and R 10 can be independently selected from the group consisting of: H, F, Cl, tetrahydro-2H-pyran-4-yl, 4-morpholinyl, pyrrolidin-1-yl, and piperidin-1-yl, provided that R 8 、R 9 and R 10 At least one of them is not H.

[0069] In an alternative embodiment, the present invention provides a compound represented by formula (Ip) or a pharmaceutically acceptable salt thereof:

[0070]

[0071] Among them, R 8 、R 9 and R 10 Can be independently selected from the group consisting of: H, F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoroprop-2-yl, methoxymethyl, C 1-5 Alkoxy, and / or CF3, provided that R 8 、R 9 and R 10 At least one of them is not H.

[0072] In an alternative embodiment, the present invention provides a compound represented by formula (Iq) or a pharmaceutically acceptable salt thereof:

[0073]

[0074] where R 8 、R 9 and R 10Can be independently selected from the group consisting of: H, F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoroprop-2-yl, methoxymethyl, C 1-5 In some embodiments, R 8 、R 9 and R 10 can be independently selected from the group consisting of: H, F and CF3.

[0075] In an alternative embodiment, the present invention provides a compound represented by formula (Ir) or a pharmaceutically acceptable complex thereof:

[0076]

[0077] Among them, R 11 Can be selected from the group consisting of: C 1-6 Alkyl, C 3-7 Cycloalkyl, phenyl, thien-3-yl, benzyl, or cyclopentylmethyl, each optionally substituted with F, C 1-6 One or more substituents in the alkyl group, OCH3, and / or CF3 are substituted from one to the maximum number.

[0078] In an alternative embodiment, the present invention provides a compound represented by formula (Is) or a pharmaceutically acceptable salt thereof:

[0079]

[0080] Among them, R 12 can be selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thien-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, or phenylcarbonyl, each optionally substituted with F, Cl, C 1-6 Alkyl, C 1-6 One or more substituents in alkoxy, OCF3, and / or CF3 replace one to the maximum number. In some embodiments, R 12 It can be selected from the group consisting of: 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)thiazol-2-yl.

[0081] In an alternative embodiment, the present invention provides a compound represented by formula (It) or a pharmaceutically acceptable salt thereof:

[0082]

[0083] Among them, R 12 can be selected from the group consisting of: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thien-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, or phenylcarbonyl, each optionally substituted with F, Cl, C 1-6 Alkyl, C 1-6 One or more substituents in alkoxy, OCF3, and / or CF3 replace one to the maximum number. In some embodiments, R 12 It can be selected from the group consisting of: 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)thiazol-2-yl.

[0084] In an alternative embodiment, the present invention provides a compound represented by formula (Iu) or a pharmaceutically acceptable salt thereof:

[0085]

[0086] Among them, R 12 can be selected from the group consisting of: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thien-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, or phenylcarbonyl, each optionally substituted with F, Cl, C 1-6 Alkyl, C 1-6 One or more substituents in alkoxy, OCF3, and / or CF3 replace one to the maximum number. In some embodiments, R 12 It can be selected from the group consisting of: 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)thiazol-2-yl.

[0087] In an alternative embodiment, the present invention provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof:

[0088]

[0089] Among them, R 12 can be selected from the group consisting of: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thien-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, or phenylcarbonyl, each optionally substituted with F, Cl, C1-6 Alkyl, C 1-6 One or more substituents in alkoxy, OCF3, and / or CF3 replace one to the maximum number. In some embodiments, R 12 It can be selected from the group consisting of: 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)thiazol-2-yl.

[0090] In alternative embodiments, the compound may be a prodrug; the compound may inhibit non-lysosomal glucosylceramidase (GBA2); the compound may inhibit GBA2 (eg, mammalian GBA2); the compound may inhibit wild-type GBA2; or the compound may inhibit mutant GBA2.

[0091] In alternative embodiments, compounds according to Formula (I)-(Ia)-(Ib)-(Ic)-(Id)-(Ie)-(If)-(Ig)-(Ih)-(Ii)-(Ij)-(Ik)-(Il)-(Im)-(In)-(Io)-(Ip)-(Iq)-(Ir)-(Is)-(It)-(Iu)-(Iv) may exhibit enhanced selectivity and / or permeability.

[0092] In alternative embodiments, compounds according to Formula (Ic), Formula (Ie), Formula (Ig), Formula (Im), Formula (Io), or Formula (Iq) may exhibit enhanced selectivity and / or permeability.

[0093] In alternative embodiments, compounds according to Formula (Ic), Formula (Ie), Formula (Ig), Formula (Im), Formula (Io), or Formula (Iq) may exhibit enhanced selectivity.

[0094] In alternative embodiments, the compounds according to Formula (Ic), Formula (Ie), Formula (Ig), Formula (Im), Formula (Io), or Formula (Iq) can achieve higher brain concentrations when administered in vivo.

[0095] In an alternative aspect, the present invention provides a pharmaceutical composition comprising a compound according to the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0096] In alternative aspects, the present invention provides a method of inhibiting GBA2 in a subject in need thereof, or a method of treating a nervous system disease, a lysosomal storage disease, or a liver disease in a subject in need thereof, by administering to the subject an effective amount of a compound of formula (I) as described herein, including any one or more of formulas (Ia)-(Iv), or a pharmaceutically acceptable salt thereof. The neurological disease may be, but is 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, 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), DeGelis-Sotas disease, diffuse neurofibrillary tangles with calcifications, Down syndrome, Duchenne muscular dystrophy (DMD), epilepsy, essential tremor (ET), familial British dementia, familial Danish dementia dementia), fibromyalgia, frontotemporal dementia linked to chromosome 17 with Parkinsonism (FTDP-17), Friedreich's ataxia, Gerstmann-Straussler-Scheinker disease, glaucoma, Guadeloupean parkinsonism, Guillain-Barré syndrome, Hallervorden-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 (including DM1 and DM2), neuronal ceroid lipofuscinosis (including types 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10), neuropathy (including peripheral neuropathy) neuropathy, autonomic neuropathy, neuritis, and diabetic neuropathy), oculopharyngeal muscular dystrophy, pain, pallidoponigral degeneration, Guam Parkinsonism-dementia complex, Pick's disease (PiD), postencephalitic parkinsonism (PEP), primary lateral sclerosis (PLS), prion diseases (including Creutzfeldt-Jakob disease (CJD), variant Creutzfeldt-Jakob disease (vCJD), fatal familial insomnia, and kuru), progressive subcortical gliosis, progressive supranuclear palsy (PSP), Richardson's syndrome (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, dementia with entanglement, tardive dyskinesia, Tourette syndrome (TS), vascular dementia, or Wilson disease.

[0097] The lysosomal storage disease can be, but is 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), cerebrotendinous xanthomatosis, Fabry disease, Farber disease, GM1 gangliosidosis, Krabbe disease, metachromatic leukodystrophy (MLD), multiple sulfatase deficiency, Pompe disease, Sandhoff disease, or Tay-Sachs disease.

[0098] The liver disease may be 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 tumor, biliary atresia, cirrhosis, Crigler-Najjar syndrome, drug-induced liver injury (DILI), galactosemia, Gilbert's syndrome, hemochromatosis, hepatic encephalopathy, hepatocellular carcinoma (HCC), intrahepatic cholestasis of pregnancy (ICP), lysosomal acid lipase deficiency (LAL-D), liver cyst, 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).

[0099] In an alternative embodiment, the present invention provides a method for treating a nervous system disease in a subject in need thereof, by administering to the subject an effective amount of any one or more compounds of Formula (Ic), Formula (Ie), Formula (Ig), Formula (Im), Formula (Io), or Formula (Iq) as described herein, or a pharmaceutically acceptable salt thereof.

[0100] In alternative embodiments, the administration can reduce the level of GBA2 enzymatic activity in a subject. In alternative embodiments, the administration can modulate the level of glucosylceramide and / or glycosphingolipids in a subject. In alternative embodiments, the administration can increase the level of glucosylceramide in a subject. In alternative embodiments, the administration can increase the level of ganglioside GM1 in a subject. In alternative embodiments, the administration can modulate the level of ceramide and / or sphingosine and / or sphingosine-1-phosphate (S1P) in a subject. The subject can be human.

[0101] In an alternative aspect, the present invention provides the use of an effective amount of a compound of formula (I), including any one or more of formulas (Ia)-(Iv), or a pharmaceutically acceptable salt thereof, as described herein, for the preparation of a medicament. The medicament can be used to inhibit GBA2, treat conditions regulated by GBA2, or treat neurological diseases, lysosomal storage diseases, or liver diseases.

[0102] This summary does not necessarily describe all features of the invention. DETAILED DESCRIPTION

[0103] Detailed description

[0104] The present invention provides, in part, compounds for inhibiting non-lysosomal glucosylceramidase (GBA2) and their uses.

[0105] "Non-lysosomal glucosylceramidase" or "GBA 2" refers to a non-lysosomal membrane-associated enzyme (EC 3.2.1.45) with glucosylceramidase activity located on the cytoplasmic side of the ER and Golgi membranes that catalyzes the hydrolytic cleavage of the β-glucosidic bond of the glycolipid glucosylceramide. Alternative names for GBA2 include: NLGase, glucosylceramidase β2, β-glucocerebrosidase 2, β-glucosidase 2, glucosylceramidase 2, bile acid β-glucosidase, "glucosidase, β-(bile acid) 2", KIAA1605, DKFZp762K054, SPG46, and AD035. In some embodiments, GBA2 can be mammalian GBA2, such as rat, mouse, or human GBA2. GBA2 can be wild-type GBA2 or a mutant GBA2. In some embodiments, GBA2 can be wild-type mammalian GBA2, such as rat, mouse, or human wild-type GBA2. In some embodiments, GBA2 can be a mutant mammalian GBA2, such as a rat, mouse, or human mutant GBA2. In some embodiments, GBA2 can have a sequence as set forth in any of the following accession numbers: Q9HCG7, Q69ZF3, D3DRP2, Q5TCV6, Q96A51, Q96LY1, Q96SJ2, Q9H2L8, Q5M868, or O16581. In alternative embodiments, GBA2 can have an alternative splice isoform sequence as set forth in any of the following accession numbers: Q9HCG7-1, Q9HCG7-2, or Q9HCG7-3. In alternative embodiments, GBA2 may be encoded by the sequence set forth 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_006716872.1, XP_011516275.1, XP_016870426.1, XP_016870427.1, XP_016870428.1, 0430.1, XP_016870431.1, XP_016870432.1, XP_016870433.1,

[0106] In an alternative embodiment, human GBA2 may have the sequence listed below:

[0107]

[0108]

[0109] In an alternative embodiment, human GBA2 may have a nucleic acid sequence encoding a nucleic acid molecule having the sequence shown in SEQ ID NO:1.

[0110] In some embodiments, one or more compounds according to the present invention can inhibit the activity of GBA2, for example, inhibiting the ability to cleave glucose from glucosylceramide or inhibiting the ability to cleave glucose from a suitable substrate molecule, for example, 4-methylumbelliferyl-β-D-glucopyranoside. "Inhibit," "inhibition," or "inhibiting" means that the activity of GBA2 is reduced by any value between about 10% and about 90%, or by any value between about 30% and about 60%, or by more than about 100%, or by about 1-fold, 2-fold, 5-fold, 10-fold, or more, compared to a reference sample or compound, or compared to wild-type GBA2. It should be understood that inhibition does not require complete inhibition. In some embodiments, the inhibition can be temporary, e.g., lasting from 5 minutes to 60 minutes, from 1 hour to 5 hours, from 1 hour to 12 hours, from 1 hour to 24 hours, from 24 hours to 48 hours, from 1 day to 2 days, from 1 day to 5 days, from 1 day to 7 days, from 1 day to 14 days, from 1 day to 28 days, or any specific time within any of these ranges, e.g., 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, 9 hours, 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 can be local. For example, one or more compounds according to the invention can inhibit GBA2 in a specific cellular compartment, such as the endoplasmic reticulum (ER) or the Golgi apparatus; or one or more compounds according to the invention can inhibit GBA2 in a specific tissue type, such as the brain or liver.

[0111] In some embodiments, one or more compounds according to the present invention may specifically bind to GBA2. In alternative embodiments, one or more compounds according to the present invention may specifically bind to the active site of GBA2. In some embodiments, one or more compounds according to the present invention that specifically bind to the active site of GBA2 may also inhibit the activity of GBA2. In alternative embodiments, one or more compounds according to the present invention may specifically bind to human non-lysosomal glucosylceramidase (GBA2) but not human lysosomal glucosylceramidase (GCase) and / or human cytosolic glucosylceramidase (GBA3). In alternative embodiments, one or more compounds according to the present invention may specifically bind to human non-lysosomal glucosylceramidase (GBA2) but not human glucosylceramide synthase (GCS). In alternative embodiments, one or more compounds according to the present invention may specifically bind to human non-lysosomal glucosylceramidase (GBA2) but not intestinal α-glucosidase, where the intestinal α-glucosidase may be sucrase-isomaltase or maltase-glucoamylase. "Specifically binds" means that the compound binds to GBA2 in a sample but does not substantially bind to other molecules, such as lactase, sucrase, maltase, isomaltase, sucrase-isomaltase, glucoamylase, maltase-glucoamylase, glucosylceramide synthase, α-glucosidase II, ER α-glucosidase, intestinal α-glucosidase, glycogen phosphorylase, acid α-glucosidase, β-hexosaminidase, acetylglucosaminase (O-GlcNAcase), GCase, or GBA3. By "substantially no binding" is meant a binding specificity within the range of about 5-fold to about 100,000-fold, or about 10-fold to about 100,000-fold, or within the range of about 100-fold to about 100,000-fold, or within the range of about 1000-fold to about 100,000-fold, or at least about 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 200-fold, 500-fold, 1000-fold, 1500-fold, 2000-fold, 2500-fold, 3000-fold, 3500-fold, 4000-fold, 4500-fold, 5000-fold, 6000-fold, 7000-fold, 10,000-fold, 25,000-fold, 50,000-fold, 75,000-fold, or any value within or around said range, wherein "binding specificity" refers to the ratio of the respective binding constants, i.e., Ki (其他分子) / Ki (GBA2) , or respective IC 50 The ratio, IC 50(其他分子) / IC 50(GBA2)Examples of compounds that exhibit enhanced binding specificity include, but are not limited to, compounds of Examples 4, 8, 12, 13, 14, 15, 16, 20, 21, 22, 23, 24, 25, 27, 28, 29, 31, 32, 311, 312, 313, or 314. In some embodiments, one or more compounds according to the present invention may exhibit enhanced binding specificity or enhanced selectivity compared to a suitable reference compound, for example, (2R,3R,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol (NB-DNJ, miglustat) or (2R,3R,4R,5S)-1-(5-((3R,5R,7R)-adamantan-1-ylmethoxy)pentyl)-2-(hydroxymethyl)piperidine-3,4,5-triol (AMP-DNM, Genz-529648). In some embodiments, "enhanced binding specificity" or "enhanced selectivity" refers to an increase in the measured binding specificity (as defined above) by any value between about 10% and about 100%, or any integer value between about 10% and about 100%, for example, about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, or an increase by about 1-fold to about 100,000-fold, or about 5-fold to about 100,000-fold, or about 10-fold to about 100,000-fold, or within the range of about 100-fold to about 100,000-fold, or .... times, 30 times, 40 times, 50 times, 10 times, 20 times, 30 times, 40 times, 50 times, 100 times, 150 times, 200 times, 250 times, 300 times, 350 times, 400 times, 450 times, 500 times, 1000 times, 1500 times, 2000 times, 2500 times, 3000 times, 3500 times, 4000 times, 4500 times, 5000 times, 6000 times, 7000 times, 10,000 times, 25,000 times, 50,000 times, 75,000 times, 100,000 times, or any value within or near said range, or more.

[0112] In alternative embodiments, one or more compounds according to the application can specifically bind to human non-lysosomal glucosylceramidase (GBA 2) and not to rat intestinal alpha-glucosidase, where the rat intestinal alpha-glucosidase can be sucrose-isomaltase or maltase-glucamylase. In some embodiments, one or more compounds according to the application can substantially not inhibit rat intestinal alpha-glucosidase as compared to a suitable reference compound, e.g., (2R,3R,4R,5S)-1- butyl-2-(hydroxymethyl)piperidine-3,4,5-triol (NB-DNJ, miglustat) or (2R,3R,4R,5S)-1- (5-((3R,5R,7R)-adamantan-1-ylmethoxy)pentyl)-2-(hydroxymethyl)piperidine-3,4,5-triol (AMP-DNM, Genz-529648). In some embodiments, "substantially not inhibit" means less than about 30% inhibition in the assay described below for inhibition of rat intestinal glucosidase. In some embodiments, "substantially not inhibit" means less than about 20% inhibition in the assay described below for inhibition of rat intestinal glucosidase. In some embodiments, "substantially not inhibit" means less than about 10% inhibition in the assay described below for inhibition of rat intestinal glucosidase.

[0113] In some embodiments, one or more compounds of the application can inhibit GBA2 cleavage of glucosylceramide to glucose. In some embodiments, one or more compounds of the application can inhibit alpha-synuclein aggregation and / or inhibit Lewy body formation. "Inhibit," "inhibition," or "inhibiting" means a reduction of between about 10% to about 90% or any value in between, or between about 30% to about 60% or any value in between, or more than about 100%, or a reduction of about 1-fold, 2-fold, 5-fold, 10-fold, or more, as compared to a reference sample or compound, or as compared to wild-type GBA2. It will be understood that inhibition need not be complete. In some embodiments, inhibition can be temporary.

[0114] In some embodiments, one or more compounds of the application can decrease inflammation in the CNS. In some embodiments, one or more compounds of the application can decrease alpha-synuclein aggregation and / or Lewy body formation. "Decreasing" or "decrease" means a reduction of between about 5% to about 90% or any value in between, or between about 30% to about 60% or any value in between, or more than about 100%, or a reduction of about 1-fold, 2-fold, 5-fold, 10-fold, 15-fold, 25-fold, 50-fold, 100-fold, or more, as compared to a reference sample or compound.

[0115] In some embodiments, one or more compounds of the present invention may increase glucosylceramide levels. In some embodiments, one or more compounds of the present invention may increase glycosphingolipid levels. In some embodiments, one or more compounds of the present invention may increase GM1 ganglioside levels. "Elevating" or "enhancing" or "increasing" means an increase of any value between about 5% and about 90%, or any value between about 30% and about 60%, or more than about 100%, or an increase of about 1-fold, 2-fold, 5-fold, 10-fold, 15-fold, 25-fold, 50-fold, 100-fold or more, as compared to a reference sample. In some embodiments, one or more compounds according to the present invention may increase glucosylceramide levels and / or glycosphingolipid levels and / or GM1 ganglioside levels in the brain.

[0116] 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 be effective in treating conditions requiring or responsive to increased GCase activity. In some embodiments, one or more compounds of the present invention can increase GCase activity levels and / or GCase protein levels in vivo specifically by interacting with GBA2 and can be effective in treating conditions requiring or responsive to increased GCase activity. "Elevating" or "enhancing" or "increasing" refers to an increase of about 5% to about 100%, for example, about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, or an increase of about 1-fold, 2-fold, 5-fold, 10-fold, 15-fold, 25-fold, 50-fold, 100-fold, or more, compared to a reference sample or compound, or compared to wild-type or mutant GCase.

[0117] In some embodiments, one or more compounds according to the present 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 ) are reviewed, for example, by Volpe in AAPS Journal, 2010, 12(4), 670-678. In some embodiments, when the eff or P appOne or more of the compounds according to the present invention may exhibit enhanced permeability when tested in one or more of these assays. In some embodiments, compounds exhibiting enhanced permeability may exhibit greater oral absorption. In some embodiments, compounds exhibiting enhanced permeability may exhibit greater brain penetrance when administered in vivo. In some embodiments, compounds exhibiting enhanced permeability may achieve higher brain concentrations when administered in vivo. In some embodiments, compounds exhibiting enhanced permeability may exhibit higher brain / plasma concentration ratios when administered in vivo. In some embodiments, "enhanced permeability" means that the measured permeability is compared to a suitable reference compound such as, for example, (2R,3R,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol (NB-DNJ, miglustat) or (2R,3R,4R,5S)-1-(5-((3R,5R,7R)-adamantan-1-ylmethoxy)pentyl)-2-(hydroxymethyl)piperidine-3,4,5-triol (AMP-DNM, Genz-529648). eff or P app Any value between about 10% and about 100%, 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-fold, 2-fold, 3-fold or more. In some embodiments, "enhanced permeability" means that the permeability of the cell is measured using an in vitro cell monolayer. app Measurable P in a suitable test app In some embodiments, "enhanced permeability" means that the permeability of the cell membrane is increased when the permeability is measured using an in vitro cell monolayer. app P in the appropriate test app Values ​​greater than 2x 10 -6 In alternative embodiments, "enhanced permeability" means the permeability measured using an in vitro cell monolayer. app Suitable assays for P app Value is 2x10 -6 cm / s to 40x 10 -6In some embodiments, "higher brain concentration" refers to a higher brain concentration when the compound is administered in vivo compared to a suitable reference compound such as, for example, (2R,3R,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol (NB-DNJ, miglustat) or (2R,3R,4R,5S)-1-(5-((3R,5R,7R)-adamantan-1-ylmethoxy)pentyl)-2-(hydroxymethyl)piperidine-3,4,5-triol. The measured brain concentration is increased by any value between about 10% and about 100%, 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 by about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, or 50-fold, or more, compared to AMP-DNM (Genz-529648).

[0118] A "reference compound" or "control" can be a carbohydrate mimetic iminosugar described in the literature as a GBA2 inhibitor. Examples of reference compounds or controls that are GBA2 inhibitors include, but are not limited to, (2R,3R,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol (NB-DNJ, miglustat), (2R,3R,4R,5S)-1-(5-((3R,5R,7R)-adamantan-1-ylmethoxy)pentyl)-2-(hydroxymethyl)piperidine-3,4,5-triol (AMP-DNM, Genz-529648). 26

[0119] In some embodiments, the present invention provides compounds generally described by Formula (I), including any one or more of Formulas (Ia)-(Iv), and salts, prodrugs, and enantiomeric forms thereof:

[0120]

[0121] As shown in formula (I): R 1 Can be H and R 2 It can be CH2OH; R 1 It can be CH2OH and R 2 can be H; and

[0122] R 3 It can be (CH2) n R 4 , where n is 1 or 2, and R 4may be cyclohexyl, cyclohexylmethyl, phenethyl, 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[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-(cyclohexylcarboxamido)piperidin-4-yl, 1-(cyclohexylsulfamoyl)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazetidin-3-yl, 2-(thiophen-2-yl)methyl, or 2-(thiazol-3-yl)methyl, each optionally substituted with one to the maximum number of F, Cl, C 1-6 alkyl, cyclopropyl, ethenyl, 2-fluoroprop-2-yl, methoxymethyl, C 1-5 alkyl, cyclopropyl, ethenyl, 2-fluoroprop-2-yl, methoxymethyl, C

[0123] R 3 may be phenethyl, substituted with pyrrolidin-1-yl, piperidin-1-yl, 4-morpholinyl, 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, ethenyl, 2-fluoroprop-2-yl, methoxymethyl, C

[0124] R 3 may be (1-formylpiperidin-4-yl)methyl, substituted on the formyl group with one of C 1-6 alkyl, C 3-7 cycloalkyl, phenyl, thiophen-3-yl, benzyl, or cyclopentylmethyl, each optionally substituted with one to the maximum number of F, Cl, C 1-6 alkyl, OCH3, and / or CF3; or

[0125] R 3 may be wherein R 5can be selected from the group consisting of: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thien-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 substituted with F, Cl, C 1-6 Alkyl, C 1-6 One or more substituents in alkoxy, OCF3, and / or CF3 are substituted from one to the maximum number,

[0126] The condition is that when R 1 is H and R 2 When it is CH2OH, then R 3 is not cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl, phenylethyl, 3-phenylpropyl, 3-(2-propoxyphenyl)propyl, 3-(3-propoxyphenyl)propyl, 3-(4-propoxyphenyl)propyl, or 4-phenylbutyl; and

[0127] The condition is that when R 1 is CH2OH and R 2 When it is H, then R 3 Not phenylethyl, 3-phenylpropyl, (R)-2-phenylpropyl, or (S)-2-phenylpropyl.

[0128] In some embodiments, as shown in formula (I), R 1 Can be H, and R 2 Can be CH2OH. In some embodiments, R 1 It can be CH2OH, and R 2 It can be H.

[0129] In some embodiments, as shown in formula (I), R 3 It can be (CH2) n R 4 , where n is 1 or 2, and R 4The cyclohexyl group may be cyclohexyl, cyclohexylmethyl, phenethyl, 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-dihydrobenzene 1-(cyclohexylmethylsulfonyl)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazetidin-3-yl, 2-(thiophen-2-yl)methyl, or 2-(thiophen-3-yl)methyl, each optionally substituted with F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoroprop-2-yl, methoxymethyl, C 1-5 One or more substituents of alkoxy, CHF2, CF2CH3, and / or CF3 are substituted by one to the maximum number; or R 3 It can be phenethyl, pyrrolidin-1-yl, piperidin-1-yl, 4-morpholinyl, 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 substituents in alkyl, cyclopropyl, propen-2-yl, OCH3, and / or CF3 are substituted by one to the maximum number; or R 3 It may be (1-formylpiperidin-4-yl)methyl, substituted on the formyl group by one of the following: C 1-6 Alkyl, C 3-7 Cycloalkyl, phenyl, thien-3-yl, benzyl, or cyclopentylmethyl, each optionally substituted with F, C 1-6 One or more substituents of alkyl, OCH3, and / or CF3 are substituted from one to the maximum number; or R 3 Can be where R 5 can be selected from the group consisting of: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thien-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 substituted with F, Cl, C1-6 Alkyl, C 1-6 One or more substituents in alkoxy, OCF3, and / or CF3 replace one to the maximum number, provided that when R 1 is H and R 2 is CH2OH, then R 3 is not cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl, phenylethyl, 3-phenylpropyl, 3-(2-propoxyphenyl)propyl, 3-(3-propoxyphenyl)propyl, 3-(4-propoxyphenyl)propyl, or 4-phenylbutyl; provided that when R 1 is CH2OH and R 2 is H, then R 3 Not phenylethyl, 3-phenylpropyl, (R)-2-phenylpropyl, or (S)-2-phenylpropyl.

[0130] In some embodiments, R 3 It can be (CH2) n R 4 , where n is 1 or 2, and R 4 It can be cyclohexyl, cyclohexylmethyl, phenethyl, 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-dihydrobenzene 1-(cyclohexylmethylsulfonyl)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazetidin-3-yl, 2-(thiophen-2-yl)methyl, or 2-(thiophen-3-yl)methyl, each optionally substituted with F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoroprop-2-yl, methoxymethyl, C 1-5 One or more substituents in alkoxy, CHF2, CF2CH3, and / or CF3 replace one to the maximum number, provided that when R 1 is H and R 2 When it is CH2OH, then R 3 is not cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl, 3-phenylpropyl, 3-(2-propoxyphenyl)propyl, 3-(3-propoxyphenyl)propyl, 3-(4-propoxyphenyl)propyl, or 4-phenylbutyl; provided that when R1 is CH2OH and R 2 is H, then R 3 Not 3-phenylpropyl, (R)-2-phenylpropyl, or (S)-2-phenylpropyl.

[0131] In some embodiments, R 3 It can be phenethyl, pyrrolidin-1-yl, piperidin-1-yl, 4-morpholinyl, 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 substituents in alkyl, cyclopropyl, propen-2-yl, OCH3, and / or CF3 are substituted by one to the maximum number, provided that R 3 Not phenethyl.

[0132] In some embodiments, R 3 It may be (1-formylpiperidin-4-yl)methyl, substituted on the formyl group by one of the following: C 1-6 Alkyl, C 3-7 Cycloalkyl, phenyl, thien-3-yl, benzyl, or cyclopentylmethyl, each optionally substituted with F, C 1-6 Alkyl, OCH3, and / or CF 3中 One or more substituents replace one to the maximum number.

[0133] In some embodiments, R 3 Can be Among them, R 5 can be selected from the group consisting of: phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thien-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 substituted with F, Cl, C 1-6 Alkyl, C 1-6 One or more substituents in the alkoxy group, OCF3, and / or CF3 are substituted from one to the maximum number.

[0134] In some embodiments, R 1 It can be H; R 2 It can be CH2OH; R 3 It can be (CH2) n R 4 , where n can be 1, and R 4It can be cyclohexyl or 1-phenylpiperidin-4-yl, each optionally substituted with F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoroprop-2-yl, methoxymethyl, C 1-5 One or more substituents in alkoxy, CHF2, CF2CH3, and / or CF3 are substituted from one to the maximum number, provided that R 3 Not cyclohexylmethyl.

[0135] In some embodiments, R 1 It can be CH2OH; R 2 It can be H; R 3 It can be (CH2) n R 4 , where n can be 1, and R 4 It can be cyclohexyl or 1-phenylpiperidin-4-yl, each optionally substituted with F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoroprop-2-yl, methoxymethyl, C 1-5 One or more substituents of alkoxy, CHF2, CF2CH3, and / or CF3 are substituted from one to the maximum number.

[0136] In some embodiments, R 1 It can be H; R 2 may be CH2OH; and R 3It may be (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-(trifluoromethyl)cyclohexyl)methyl, ((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl cyclohexyl)methyl, ((1s,4S)-4-(2-fluoropropyl-2-yl)cyclohexyl)methyl, ((1r,4R)-4-(2-fluoropropyl-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]nonan-7-yl)methyl, (spiro[4.5]dec-8-yl)methyl, 2-(4,4-difluorocyclohexyl)ethyl, 2-((1s,4S)-4-(trifluoromethyl)cyclohexyl)ethyl, 2-((1r,4R)-4-(trifluoromethyl)cyclohexyl)ethyl, 2-(adamantan-1-yl)ethyl, 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-morpholinylphenethyl, 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-(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- 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-pivaloylpiperidin-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 -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)pyridin-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-(cyclohexylcarboxamido)piperidin-4-yl)methyl, (1-(cyclohexylmethylsulfamido)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 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 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)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 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, ((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-(3,5-dimethyl-1H-pyrazol-4-yl)-2,6-difluorophenethyl Phenethyl, ((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)pyrimidin-5-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.

[0137] In some embodiments, R 1 It can be CH2OH; R 2 It can be H; and R 3It may 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-(trifluoromethyl)cyclohexyl)methyl, ((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl cyclohexyl)methyl, ((1s,4S)-4-(2-fluoropropyl-2-yl)cyclohexyl)methyl, ((1r,4R)-4-(2-fluoropropyl-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]octane-6- 1-(trifluoromethyl)cyclohexyl)ethyl, 2-(adamantan-1-yl)ethyl, 3-cyclohexylpropyl, 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 ethyl, 4-chloro-2-fluorophenethyl, 5-chloro-2-chlorophenethyl, 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-morpholinylphenethyl, 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, 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-(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-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-pivaloylpiperidin-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)pyridin-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-cyclohexylcarboxamido)piperidin-4-yl)methyl, (1-(cyclohexylmethylsulfamido)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-( methyl, (R)-1-(2-(trifluoromethyl)pyridin-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)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 phenethyl, 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, ((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-(3,5-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) methyl, ((1s,4R)-4-(difluoromethyl)cyclohexyl)methyl, ((1r,4S)-4-(difluoromethyl)cyclohexyl)methyl, ((1s,4R)-4-(1,1-difluoroethyl)cyclohexyl)methyl, or ((1r,4S)-4-(1,1-difluoroethyl)cyclohexyl)methyl.

[0138] In some embodiments, R 1 It can be H; R 2 may be CH2OH; and R 3 It can be 2-fluorophenethyl, 3-fluorophenethyl, 4-fluorophenethyl, 2,6-difluorophenethyl, 3-(trifluoromethyl)phenethyl, 4-(trifluoroethyl)phenethyl, (R)-2-phenylpropyl, (S)-2-phenylpropyl, 2-(pyridin-2-yl)ethyl, 2-(thiophen-2-yl)ethyl, or 2-(thiophen-3-yl)ethyl.

[0139] In some embodiments, R 1 It can be CH2OH; R 2 can be OH; and R 3It may be cyclohexylmethyl, ((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl, ((1s,4S)-4-(2-fluoropropyl-2-yl)cyclohexyl)methyl), (2,3-dihydro-1H-inden-2-yl)methyl, 2-cyclohexylethyl, 3-cyclohexylpropyl, 2-fluorophenethyl, 3-chloro-2-fluorophenethyl, 2-([1,1'-biphenyl]-4-yl)ethyl, 2,6-difluoro-4-(1H-inden-2-yl)methyl. -(tetrahydro-2H-pyran-4-yl)phenethyl, 4-butoxyphenethyl, 4-butoxy-2,6-difluorophenethyl, (1-(4-fluorophenyl)piperidin-4-yl)methyl, ((R)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl, ((R-)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl, ((S)-1-(3-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl ((S)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl, ((R)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl), (R)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl, ((S)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl 1-difluoroethyl)cyclohexyl)methyl, ((1r,4S)-4-(1,1-difluoroethyl)cyclohexyl)methyl, or ((1r,4S)-4-(1,1-difluoroethyl)cyclohexyl)methyl.

[0140] In particular embodiments of the present invention, the compounds according to formula (I) include the compounds described in Table 1.

[0141] Table 1

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184] As understood by those skilled in the art, the above formula (I) can also be expressed as follows:

[0185]

[0186] In alternative embodiments of the present invention, one or more compounds in Table 2 are specifically excluded from compounds described in Formula (I) or any one or more of Formulas (Ia)-(Iv).

[0187] Table 2

[0188]

[0189]

[0190]

[0191] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, "a compound" refers to one or more such compounds, and "an enzyme" includes the specific enzyme as well as other family members and equivalents thereof known to those skilled in the art.

[0192] Throughout the present invention, it is intended that the term "compound" or "compounds" refers to the compounds discussed herein and includes precursors and derivatives of the compounds, including acyl-protected derivatives, and pharmaceutically acceptable salts of the compounds, precursors, and derivatives. The present invention also includes prodrugs of the compounds, pharmaceutical compositions comprising the compounds and a pharmaceutically acceptable carrier, and pharmaceutical compositions comprising the prodrugs of the compounds and a pharmaceutically acceptable carrier.

[0193] The compounds of the present application can contain one or more additional asymmetric centers; include any one or more of Formulae (la)-(Iv), in addition to those indicated in Formula (I), and can therefore exist as single enantiomers, diastereomeric mixtures and as individual diastereomers. Such additional asymmetric centers can exist, depending on the nature of the various substituents on the molecule. Each such additional asymmetric center will independently produce two optical isomers and it is intended that all such possible optical isomers and diastereomers are encompassed within the scope of the present application. Any formula, structure or name of a particular stereochemistry described in this specification that does not specify a particular stereochemistry for an additional asymmetric center is intended to encompass all possible stereochemistry at that center. Where stereochemistry is specified for an additional asymmetric center, the present application is intended to encompass both the specified stereochemistry in pure form or as part of a mixture of that other isomer in any ratio.

[0194] "Alkyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and including, for example, 1-10 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, and which is attached to the rest of the molecule by a single bond. In an alternative embodiment, an alkyl can contain 1 to 8 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. In an alternative embodiment, an alkyl can contain 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5, or 6 carbon atoms. In an alternative embodiment, an alkyl can contain 1 to 5 carbon atoms, such as 1, 2, 3, 4, or 5 carbon atoms. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted by one or more substituents as described herein. It is understood that a substituent can be present on any carbon of the alkyl group unless otherwise specifically stated in the specification.

[0195] "Cycloalkyl" refers to a stable monovalent monocyclic, bicyclic or tricyclic hydrocarbon radical, which is saturated, having, for example, 3-15 carbon atoms, and which is attached to the rest of the molecule by a single bond. In an alternative embodiment, a cycloalkyl can contain 3 to 6 carbon atoms, such as 3, 4, 5, or 6 carbon atoms. Unless stated otherwise specifically in the specification, the term "cycloalkyl" is meant to include optionally substituted cycloalkyl groups as described herein.

[0196] "Alkoxy" refers to a radical of the formula -OR a where each R a is independently a C 1-10 alkyl or C 1-6 alkyl or C 1-5 alkyl as described herein. An alkoxy group can be optionally substituted as described herein.

[0197] "Optional" or "optionally" means that the event of the subsequently described situation may or may not occur, and the description includes instances where the event or situation occurs one or more times and instances where it does not occur. For example, "optionally substituted alkyl" means that the alkyl group may or may not be substituted, and the description includes substituted alkyl and unsubstituted alkyl, and the alkyl group may be substituted one or more times. Examples of optionally substituted alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, and the like. Examples of suitable optional substituents include, but are not limited to, H, F, Cl, CH , OH, OCH , CF , CHF , CH F, and CN.

[0198] Treatment indications

[0199] The present invention provides, in part, methods for treating conditions that are directly or indirectly regulated by the GBA2 enzyme or the level of GBA2 activity, e.g., conditions that benefit from inhibiting the GBA2 enzyme or by reducing the level of GBA2 enzyme activity. Such conditions 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, mucolipidosis type IV, and Sandhoff disease, and liver diseases such as non-alcoholic steatohepatitis (NASH). Thus, one or more compounds of the present invention can be used to treat subjects who are at risk of developing or have been diagnosed with various neurological or other diseases. As used herein, the term "treating" can include treatment, prevention, and / or amelioration.

[0200] In alternative embodiments, one or more compounds of the present invention may also be used to treat diseases or conditions associated with a deficiency or overexpression of GBA2 or an accumulation or depletion of glucosylceramide, or any disease or condition responsive to glycosidase inhibitor therapy or glycosidase inhibition therapy. Such diseases and conditions 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, mucolipidosis type IV, and Sandhoff disease, and liver diseases such as non-alcoholic steatohepatitis (NASH). Such diseases and conditions may also include diseases or conditions associated with accumulation or deficiency of the enzyme glucosylceramide synthase, or disorders of glycosylsphingolipid metabolism and / or balance. Also included are methods of protecting or treating target cells expressing GBA2, the disorders of which may lead to disease or pathology.

[0201] In alternative embodiments, the present invention provides methods for reducing the level of GBA2 enzyme activity in animal subjects, such as veterinary and human subjects. This reduction in GBA2 activity levels can be used to prevent or treat neurological or 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, mucolipidosis type IV, and Sandhoff disease); and prevent or treat liver diseases (e.g., non-alcoholic steatohepatitis (NASH)).

[0202] In alternative embodiments, the present invention provides methods of inhibiting the GBA2 enzyme in animal subjects, such as veterinary and human subjects.

[0203] In alternative embodiments, the present invention provides methods for reducing CNS inflammation in animal subjects, such as veterinary and human subjects. Disease states of interest may include neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis (ALS), in which neuroinflammation is involved in disease pathogenesis. In some embodiments, compounds according to the present invention can be used to prevent, treat, or ameliorate neuroinflammation by reducing the level of GBA2 enzyme activity, thereby providing therapeutic benefit.

[0204] In alternative embodiments, the present invention provides methods for inhibiting α-synuclein aggregation, or inhibiting Lewy body formation, in animal subjects, such as veterinary and human subjects. Disease states of interest may include Parkinson's disease (PD) and related neurodegenerative synucleinopathies, in which abnormal aggregation of α-synuclein is implicated in disease pathogenesis. In some embodiments, compounds according to the present invention can be used to block the aggregation of α-synuclein by reducing the level of GBA2 enzyme activity, thereby providing therapeutic benefit.

[0205] Neurological diseases that can be treated with the compounds of the application 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, argyrophilic grain dementia, ataxia-telangiectasia (A-T), attention deficit / hyperactivity disorder (ADHD), autism spectrum disorder (ASD), Becker muscular dystrophy (BMD), bipolar disorder (BD), Batten disease, cerebellar ataxia, Charcot-Marie-Tooth disease (CMT), chronic fatigue syndrome, corticobasal degeneration (CBD), dementia pugilistica, dementia with Lewy bodies (DLB), Dejerine- Sottas disease, diffuse neurofibrillary tangle with calcification, Down syndrome, Duchenne muscular dystrophy (DMD), epilepsy, essential tremor (ET), familial British dementia, familial Danish dementia, fibromyalgia, frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), Friedreich's ataxia, Gastaut-Schaefer disease, glaucoma, Guadeloupean parkinsonism, Guillain-Barre syndrome, Hallervorden-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 (including types DM1 and DM2), neuronal ceroid lipofuscinosis (including types 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10), neuropathy (including peripheral neuropathy, autonomic neuropathy, neuritis, and diabetic neuropathy), oculopharyngeal muscular dystrophy, pain, pallido-ponto-nigral degeneration, Parkinsonism-dementia complex of Guam, Pick's disease (PiD), postencephalitic parkinsonism (PEP), primary lateral sclerosis (PLS), prion diseases (including Creutzfeldt-Jakob disease (CJD), variant Creutzfeldt-Jakob disease (vCJD), fatal familial insomnia, and kuru), progressive subcortical gliosis, progressive supranuclear palsy (PSP), Richardson's 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, tangle only dementia, tardive dyskinesia, Tourette syndrome (TS), vascular dementia, and Wilson's disease.

[0206] Lysosomal storage diseases that can be treated with the compounds of the present invention may 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), cerebrotendinous xanthomatosis, Fabry disease, Farber disease, GM1 gangliosidosis, Krabbe disease, metachromatic leukodystrophy (MLD), multiple sulfatase deficiency, Pompe disease, Sandhoff disease, or Tay-Sachs disease.

[0207] Liver diseases that can be treated with the compounds of the present invention include, but are not limited to, 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's 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, glycogen storage disease type I, or viral hepatitis (including types A, B, C, D, and E).

[0208] In some embodiments, the compounds according to the present invention are useful in treating diseases in which modulation of GBA2 enzyme activity levels is implicated, or any of the conditions described herein.

[0209] Other conditions that may be treated using one or more compounds according to the present invention are those conditions that are triggered, influenced, or in any other way related to the level of GBA2 enzyme activity. It is expected that one or more compounds of the present invention may be used to treat such conditions and in particular, but not limited to, Parkinson's disease, neuronal ceroid lipofuscinosis (Patton disease), Gaucher disease, Niemann-Pick disease type C, mucolipidosis type IV, and Sandhoff disease.

[0210] Pharmaceutical and veterinary compositions, dosages and administration

[0211] Pharmaceutical compositions comprising compounds according to the present invention or for use according to the present invention are considered to be within the scope of the present invention. In some embodiments, pharmaceutical compositions are provided comprising an effective amount of a compound of formula (I), including any one or more of formulas (Ia)-(Iv).

[0212] Compounds of formula (I), including any one or more of formulas (Ia)-(Iv), and pharmaceutically acceptable salts, enantiomers, solvates, or derivatives thereof, may be useful because they may have pharmacological activity in animals, including humans. In some embodiments, one or more compounds according to the present invention may be stable in plasma when administered to a subject, such as a human.

[0213] Generally, the compounds according to the present invention can be administered to a subject in need thereof, or by contacting a cell or sample, for example, with a pharmaceutical composition comprising a therapeutically effective amount of a compound according to formula (I), including any one or more of formulas (Ia)-(Iv).

[0214] In some embodiments, the compounds according to the present invention, or used according to the present invention, may be provided in combination with any other active agent or pharmaceutical composition, wherein such combination therapy is useful for inhibiting GBA2 activity levels, for example, to treat neurological diseases, or lysosomal storage diseases, or liver diseases, or any of the conditions described herein. In some embodiments, the compounds according to the present invention, or used according to the present invention, may be provided in combination with one or more agents useful for preventing or treating Parkinson's disease. Examples of such agents may include, but are not limited to:

[0215] Levodopa (L-DOPA);

[0216] Peripheral dopa decarboxylase inhibitors (DDCIs), such as carbidopa

[0217] Carbidopa / levodopa combination

[0218] Carbidopa / levodopa / entacapone combination

[0219] Amantadine

[0220] Dopamine antagonists, such as bromocriptine Pergolide Pramipexole Ropinirole Piribedil Cabergoline Apomorphine Rotigotine (AY-27,110), (DAR-0100), Epicryptine (β-dihydroergocryptine), N-propylnorapomorphine (NPA), quinagolide (EMD-49,980), (PNU-95,666), Padruno, Aplindo, etc.;

[0221] Monoamine oxidase-B (MAO-B) inhibitors, such as selegiline Rasagiline ( AGN 1135), safinamide, etc.;

[0222] Anticholinergics, such as benztropine ), diphenhydramine Orphenadrine Benhexyphenidyl ( benzhexol, trihex), etc.

[0223] Catechol-O-methyltransferase (COMT) inhibitors, such as entacapone Tolcapone Niticapine, nebicapone, etc.

[0224] Adenosine A2A receptor antagonists, such as istradefylline (KW-6002), preladenant, fipamezole (JP-1730), SCH-420814, BIIA-014, and LuAA4707;

[0225] Metabotropic glutamate receptor 5 (mgluR5) modulators, such as dipraglurant;

[0226] AMPA receptor antagonists, such as perampanel wait;

[0227] Anticonvulsants, such as zonisamide wait;

[0228] Nicotinic acetylcholine receptor (nAChR) agonists, such as nicotine, ABT-418, WAY-317, 538 (SEN-12333), EVP-6124, MEM 3454, nefiracetam, etc.

[0229] Acetylcholinesterase inhibitors (AChEIs), such as (donepezil), (rivastigmine), (Razadyne Galantamine), (tacrine), huperzine A, phenylserine, Debio-9902SR (ZT-1SR), zanapezil (TAK0147), ganstigmine, NP7557, etc.;

[0230] Atypical antipsychotics, such as clozapine; or

[0231] Modafinil Provigil).

[0232] It should be understood that the combination of the compound according to the present invention or used according to the present invention with a medicament useful for treating Parkinson's disease is not limited to the examples described herein, but may include a combination with any medicament useful for treating Parkinson's disease. The combination of the compound according to the present invention or used according to the present invention with other medicaments useful for treating Parkinson's disease may be administered alone or in combination. Administration of one medicament may be before, simultaneously with, or after administration of the other medicament.

[0233] In some embodiments, the compounds according to the present invention or for use according to the present invention may be provided in combination with one or more agents for preventing or treating Gaucher disease. Examples of such agents may include, but are not limited to:

[0234] Recombinant human GCase enzyme replacement therapy, such as imigranase Velaglucerase alfa Taliglucerase alfa wait;

[0235] Glucosylceramide synthase inhibitors, such as EXEL-0346, Genz-123346, (Genz-112638) etc.

[0236] Bisphosphonates, such as zoledronate Alendronate sodium Etidronate Clodronate Tiludronate Pamidronate Neridronate Olapadronate, ibandronate Risedronate wait;

[0237] Antiepileptic drugs, such as ( Carbamazepine), (ethosuximide), (non-bamate), (Tiagabine), (Levetiracetam), (lamotrigine), (pregabalin), (gabapentin), (phenytoin), (topiramate), (oxcarbazepine), ( Valproate, valproic acid), (Zonisamide), (diazepam), (lorazepam) (clonazepam), (perampanel), Oxtellar (oxcarbazepine), etc.; or

[0238] Gene therapy

[0239] It should be understood that the combination of the compound according to the present invention, or used according to the present invention, and a pharmaceutical agent useful for treating Gaucher disease is not limited to the examples described herein, but may include combinations with any pharmaceutical agent useful for treating Gaucher disease. The combination of the compound according to the present invention, or used according to the present invention, and other pharmaceutical agents useful for treating Gaucher disease may be administered alone or in combination. Administration of one pharmaceutical agent may be before, simultaneously with, or after administration of the other pharmaceutical agent.

[0240] In alternative embodiments, the compound according to the present invention can be provided as a "prodrug" or as a protected form, which releases the compound after being administered to a subject. For example, the compound can carry a blocking group that splits in body fluids, for example, in the bloodstream, by hydrolysis, thereby releasing the active compound or being oxidized or reduced to release the compound in body fluids. Accordingly, "prodrug" means a compound that can be converted into the bioactive compound of the present invention under physiological conditions or by solvolysis. Therefore, the term "prodrug" refers to a metabolic precursor of a pharmaceutically acceptable compound of the present invention. When administered to a subject in need, the prodrug can be inactive, but can be converted into the active compound of the present invention in vivo. 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 often provide the advantages of solubility, tissue compatibility or delayed release in a subject.

[0241] The term "prodrug" is also meant to include any covalently bonded carrier that releases the active compound of the invention in vivo when such prodrug is administered to a subject. Prodrugs of the compounds of the invention can be prepared by modifying functional groups present in the compounds of the invention, using modification methods that cleave to the parent compound of the invention during routine manipulation or in vivo. Prodrugs include compounds of the invention in which a hydroxyl, amino, or sulfhydryl group is attached to any group that, when the prodrug of the compounds of the invention is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol functional groups and acetamide, formamide, and benzamide derivatives of amine functional groups in one or more compounds of the invention.

[0242] Discussions of prodrugs can be found in "Smith and Williams' Introduction to the Principles of Drug Design," HJ Smith, Wright, Second Edition, London (1988); Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam); The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31, (Academic Press, 1996); A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pgs 113191 (Harwood Academic Publishers, 1991); Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14; or in Bioreversible Carriers in Drug Design. Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0243] Suitable prodrug forms of one or more compounds of the present invention may include embodiments wherein one or more OH groups as shown in formula (I), including any one or more of formulas (Ia)-(Iv), may be protected as OC(O)R, wherein R may optionally be replaced by C 1-6 Alkyl substitution. In these cases, the ester group can be hydrolyzed in vivo (e.g., in body fluids), releasing the OH group and releasing the active compound. Preferred prodrug embodiments of the present invention may include compounds of formula (I), including any one or more of formulas (Ia)-(Iv), wherein one or more OH groups can be protected with acetate, such as OC(O)CH3.

[0244] According to the present invention, or the compound used according to the present invention, it can be provided alone or in the presence of liposomes, nanoparticles, adjuvants or any pharmaceutically acceptable carriers, diluents or excipients in combination with other compounds to be suitable for being applied to a subject (e.g., mammal, such as people, cattle, sheep, etc.). If desired, the treatment with the compound according to the present invention can be combined with more traditional and existing therapies for the treatment indications described in the present invention. The compound according to the present invention can be provided for a long time or intermittently. " Chronic " administration refers to the administration of the compound in a continuous mode opposite to the acute mode, so that the initial therapeutic effect (activity) is maintained over an extended period of time. " Intermittent " administration is not a treatment that is continuously performed without interruption, but is essentially cyclical. These terms, such as " administration (administration) ", " administerable (administrable) " or " administering (administering) " used in the present invention should be understood as meaning that the subject in need of treatment provides the compound of the present invention.

[0245] A "pharmaceutically acceptable carrier, diluent or excipient" may include, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved, for example, by the U.S. Food and Drug Administration or other governmental agency for use in humans or veterinary medicine.

[0246] The compounds of the present invention can be administered in the form of a pharmaceutically acceptable salt. In this case, the pharmaceutical composition according to the present invention may comprise a salt of such a compound, preferably a physiologically acceptable salt, which is known in the art. In some embodiments, the term "pharmaceutically acceptable salt" as used herein refers to an active ingredient comprising a compound of formula I, including any one or more of formulas (Ia)-(Iv), used in its salt form, particularly wherein the salt form imparts improved pharmacokinetic properties to the active ingredient compared to the free form or other previously disclosed salt forms of the active ingredient.

[0247] "Pharmaceutically acceptable salts" can include acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable. These salts can be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0248] "Pharmaceutically acceptable base addition salts" refers to those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable. These salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases can include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts can be ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases can include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Particularly preferred organic bases can be isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and a salt of caffeine.

[0249] Thus, the term "pharmaceutically acceptable salt" includes all acceptable salts, including but not limited to acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, methanesulfonate, borate, methylbromide, bromide, methylnitrite, calcium edetate, methylsulfate, camphorsulfonate, mucate, carbonate, naphthylsulfonate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisulphonate,

[0014] Examples of the present invention include, for example, benzoic acid salts ...

[0250] The pharmaceutically acceptable salts of the compounds of this invention can be used as dosages that change solubility or hydrolysis characteristics, or can be used in sustained-release or prodrug formulations. In addition, the pharmaceutically acceptable salts of the compounds of this invention can include salts formed by cations (e.g., sodium, potassium, aluminum, calcium, lithium, magnesium, zinc) and bases (e.g., ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)methylamine, and tetramethylammonium hydroxide).

[0251] Pharmaceutical preparations can generally include one or more acceptable carriers for the mode of administration of the preparation, which can be injection, inhalation, topical administration, lavage or other modes suitable for the selected treatment. Suitable carriers can be those known in the art for such modes of administration.

[0252] Suitable pharmaceutical compositions can be prepared by methods known in the art, and their mode of administration and dosage are determined by technicians. For parenteral administration, the compound can be dissolved in sterile water or saline or in a pharmaceutically acceptable carrier for the administration of non-water-soluble compounds, such as those for vitamin K. For enteral administration, the compound can be administered in tablets, capsules or dissolved in liquid form. Tablets or capsules can be enteric-coated, or in sustained-release formulations. Many suitable preparations are known, including polymers or protein microparticles, ointments, gels, hydrogels or solutions encapsulating the compound to be released, which can be applied topically or locally. Sustained-release patches or implants can be used to provide release over an extended period of time. Many technical descriptions known to those skilled in the art are in Remington: The Science & Practice of Pharmacy by Alfonso Gennaro, 20 th Ed., Williams & Wilkins, (2000). Preparations for parenteral administration can, for example, contain excipients, polyalkylene glycols such as polyethylene glycol, oils of plant origin, or hydrogenated naphthalenes. Biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers can be used to control the release of the compound. Other potentially useful parenteral delivery systems for regulating the compound can include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Preparations for inhalation can contain excipients, such as lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate, and deoxycholate, or can be oily solutions for use in the form of nasal drops or as a gel.

[0253] The compounds or pharmaceutical compositions according to the present invention can be administered orally or non-orally, such as intramuscularly, intraperitoneally, intravenously, intracisternal injection or infusion, subcutaneously, transdermally or transmucosally. In some embodiments, the compounds or pharmaceutical compositions according to the present invention or used herein can be administered by means of medical devices or appliances such as implants, grafts, prostheses, stents, etc. Implants can be designed to contain and release these compounds or compositions. An example is an implant made of a polymer material suitable for releasing the compound over a period of time. The compound can be administered alone or as a mixture with a pharmaceutically acceptable carrier, such as solid preparations such as tablets, capsules, granules, powders, etc.; liquid preparations such as syrups, injections, etc.; injections, drops, suppositories, vaginal suppositories. In some embodiments, the compounds or pharmaceutical compositions according to the present invention or used herein can be administered by inhalation spray, nasal, vaginal, rectal, sublingual or topical routes, and can be formulated alone or together into suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles suitable for each route of administration.

[0254] The compounds of the present invention can be used to treat animals, including mice, rats, horses, cattle, sheep, dogs, cats and monkeys. However, the compounds of the present invention can also be used in other organisms, such as avian species (e.g., chickens). One or more compounds of the present invention can also be effectively used in humans. The term "subject" or "patient" as it may be considered herein alternatively is intended to refer to an animal, preferably a mammal, most preferably a human, that has been the subject of treatment, observation or experiment. However, one or more compounds, methods and pharmaceutical compositions of the present invention can be used to treat animals. Accordingly, as used herein, a "subject" can be a human, 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.

[0255] An "effective amount" of a compound according to the present invention may include a therapeutically effective amount or a prophylactically effective amount. A "therapeutically effective amount" refers to an amount effective, at the dosage and for the time period necessary, to achieve the desired therapeutic outcome, such as inhibition of GBA2, reduction in GBA2 enzyme activity levels, inhibition of α-synuclein aggregation, or any of the conditions described herein. The therapeutically effective amount of a compound may vary depending on factors such as the individual's disease state, age, sex, and weight, as well as the compound's ability to elicit a desired response in the individual. Dosage regimens may be adjusted to provide the optimal therapeutic response. A therapeutically effective amount may also be an amount in which any toxic or deleterious effects of the compound are outweighed by the therapeutic benefits. A "prophylactically effective amount" may refer to an amount effective, at the dosage and for the time period necessary, to achieve the desired prophylactic outcome, such as inhibition of GBA2, reduction in GBA2 enzyme activity levels, inhibition of α-synuclein aggregation, or any of the conditions described herein. Generally, a prophylactic dose may be administered to a subject prior to or at an earlier stage of disease, such that the prophylactically effective amount may be less than the therapeutically effective amount. Suitable ranges for a therapeutically or prophylactically effective amount of a compound may 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.

[0256] In alternative embodiments, in the treatment or prevention of conditions that may require inhibition of GBA2 activity, suitable dosage levels may generally be about 0.01-500 mg / kg of subject body weight / day, and may be administered in single or multiple doses. In some embodiments, dosage levels may be from about 0.1 to about 250 mg / kg / day per day. It should be understood that the specific dosage level and frequency of administration for any particular patient may 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, body weight, general health, sex, diet, route and timing of administration, rate of excretion, drug combination, severity of the particular condition, and the patient being treated.

[0257] It should be noted that dosage values ​​may vary with the severity of the condition to be alleviated. For any particular subject, the specific dosage regimen may be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition. The dosage ranges described herein are exemplary only and do not limit the dosage range that may be selected by a medical practitioner. The amount of active compound in the composition may vary according to factors such as the subject's disease state, age, sex, and weight. The dosage regimen may be adjusted to provide the optimal therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased depending on the urgency of the therapeutic situation. It may be advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Generally, the compounds of the present invention should be used without causing substantial toxicity, and as described herein, one or more compounds may exhibit a suitable safety profile for therapeutic use. The toxicity of the compounds of the present invention can be determined using standard techniques, for example, by testing in cell cultures or experimental animals and determining the therapeutic index, i.e., the ratio between the LD50 (the dose lethal to 50% of the population) and the LD100 (the dose lethal to 100% of the population). However, in some circumstances, such as in severe disease conditions, it may be necessary to administer a substantial excess of the composition.

[0258] In compounds of formula (I), including any one or more of formulas (Ia)-(Iv), the atoms may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched with a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is intended to include all suitable isotopic variants of the compounds of formula (I), including any one or more of formulas (Ia)-(Ik). For example, different isotopic forms of hydrogen (H) include protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H). Protium is the predominant hydrogen isotope found in nature. Enrichment with deuterium can provide certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements, or can provide compounds useful as standards for characterizing biological samples. Isotopically enriched compounds within Formula (I), including any one or more of Formulas (Ia)-(Iv), can be prepared by conventional techniques well known to those skilled in the art or by processes analogous to those described in the schemes and examples herein, using appropriate isotopically enriched reagents and / or intermediates.

[0259] Other Uses

[0260] In alternative embodiments, one or more compounds of the present invention can be used to study the physiological effects of GBA2 at the cellular and organismal levels. In some embodiments, one or more compounds can be used to develop animal models for studying diseases or conditions that may be associated with GBA2 deficiency, GBA2 overexpression, glucosylceramide accumulation, glucosylceramide depletion, glycosphingolipid accumulation, or glycosphingolipid depletion, as well as for studying treatments for diseases and conditions that may be associated with GBA2 deficiency or overexpression, or glucosylceramide accumulation or depletion, or glycosphingolipid accumulation or depletion. 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, amyotrophic lateral sclerosis (ALS), and neuronal ceroid lipofuscinosis (Patton disease); lysosomal storage diseases, including Gaucher disease, Niemann-Pick disease type C, mucolipidosis type IV, and Sandhoff disease; or liver diseases, including non-alcoholic steatohepatitis (NASH).

[0261] The effectiveness of a compound in treating pathologies associated with a lysosomal storage disease (e.g., Gaucher disease, Niemann-Pick disease type C, mucolipidosis type IV, or Sandhoff disease) can be demonstrated using standard techniques, for example, by testing the compound's ability to prevent, treat, or ameliorate disease symptoms in established cellular and / or transgenic animal disease models. 13,14,16,17,27

[0262] Various alternative embodiments and examples of the present invention are described herein. These embodiments and examples are illustrative and should not be construed as limiting the scope of the invention.

[0263] Example

[0264] The following examples are intended to illustrate embodiments of the present invention and are not intended to be construed in a limiting sense.

[0265] abbreviation

[0266] DCM = dichloromethane

[0267] DIPEA = diisopropylethylamine

[0268] DMA = dimethylacetamide

[0269] DMF=N,N-dimethylformamide

[0270] EtOH = ethanol

[0271] HOAc = acetic acid

[0272] MeOH = methanol

[0273] RT = Room temperature

[0274] TFA = 2,2,2-trifluoroacetic acid

[0275] Example 1

[0276] (2R,3R,4R,5S)-1-(2-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol

[0277]

[0278] To a solution of (2R,3R,4R,5S)-3,4,5-tri(benzyloxy)-2-((benzyloxy)methyl)piperidine (100 mg, 0.19 mmol) and 1-(2-bromoethyl)-2-fluorobenzene (194 mg, 0.95 mmol) in DMF (5 mL) in a sealed tube was added K2CO3(210 mg, 1.52 mmol). The mixture was stirred at 80 °C for 18 h and cooled to room temperature. The reaction mixture was poured into ice water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give (2R,3R,4R,5S)-3,4,5-tri(benzyloxy)-2-((benzyloxy)methyl)-1-(2-fluorophenethyl)piperidine as a white solid (63 mg, 51 %). ESI MS m / z 646.32 [M+H] + .

[0279] To a solution of the above (63 mg, 0.098 mmol) in EtOH (10 mL) was added Pd(OH)2 / C (20 wt.%, 8.6 mg, 0.012 mmol) and 6 N HCl (0.1 mL). The mixture was treated with hydrogen gas (1 atm) for 18 h. The catalyst was removed by filtration through celite and the solvent was evaporated under reduced pressure. The residue was dissolved in 1 M NH3in 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)-1-(2-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol as a white solid (21 mg, 75 %). 1HNMR(400MHz,CD3OD)δ7.29(td,J=7.6,1.8Hz,1H),7.23(tdd,J=7.4,5.2,1.8Hz,1H),7 .10(td,J=7.5,1.2Hz,1H),7.05(ddd,J=9.7,8.2,1.2Hz,1H),3.96(dd,J=11.9,2.5Hz, 1H),3.88(dd,J=11.9,3.1Hz,1H),3.51(ddd,J=10.4,9.0,4.9Hz,1H),3.37(t,J=12Hz, 1H),3.18(t,J=9.0Hz,1H),3.09(dd,J=11.1,4.9Hz,1H),3.05-2.81(m,4H),2.43(t,J=

[0280] 10.8Hz, 1H), 2.30 (dt, J=9.5, 2.9Hz, 1H); ESI MS m / z 286.14[M+H] + .

[0281] Example 2

[0282] (2R,3R,4R,5S)-1-(3-Fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol

[0283]

[0284] To a solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine (100 mg, 0.19 mmol) and 1-(2-bromoethyl)-3-fluorobenzene (194 mg, 0.95 mmol) in DMF (5 mL) in a sealed tube was added KCO (210 mg, 1.52 mmol). The mixture was stirred at 80 ° C for 18 h and cooled to room 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 NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(3-fluorophenethyl)piperidine as a white solid (71 mg, 58%). ESI MS m / z 646.32 [M+H] + .

[0285] To a solution of the above-mentioned substance (71 mg, 0.11 mmol) in EtOH (10 mL) was added Pd (OH) / C (20 wt.%, 8.6 mg, 0.012 mmol) and 6N HCl (0.1 mL). The mixture was treated with hydrogen (1 atm) for 18 h. The catalyst was removed by filtration through diatomaceous earth and the solvent was evaporated under reduced pressure. The residue was dissolved in 1M NH3 in MeOH (10 mL) and stirred for another 10 minutes, then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to obtain (2R, 3R, 4R, 5S) -1- (3-fluorophenethyl) -2- (hydroxymethyl) piperidine -3,4,5- triol as a white solid (22 mg, 70%). 1 H NMR (400MHz, CD3OD) δ7.29(td,J=7.9,6.1Hz,1H),7.05(dt,J=7.6,1.2Hz,1H),7.00(dt,J=10 .1,2.1Hz,1H),6.95-6.87(m,1H),3.96(dd,J=12.0,2.5Hz,1H),3.86(dd,J=12.0,3.2Hz,1H), 3.51(ddd,J=10.4,9.0,4.9Hz,1H),3.34(t,J=12Hz,1H),3.18(t,J=9.0Hz,1H),3.09(dd,J=1 1.2, 4.9Hz, 1H), 3.05-2.74 (m, 4H), 2.38 (t, J = 10.8Hz, 1H), 2.29 (dt, J = 9.5, 2.9Hz, 1H); ESIMS m / z 286.14[M+H] + .

[0286] Example 3

[0287] (2R,3R,4R,5S)-1-(4-Fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol

[0288]

[0289] To a solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine (100 mg, 0.19 mmol) and 1-(2-bromoethyl)-4-fluorobenzene (194 mg, 0.95 mmol) in DMF (5 mL) in a sealed tube was added KCO (210 mg, 1.52 mmol). The mixture was stirred at 80 ° C for 18 h and cooled to room temperature. The reaction mixture was poured into ice water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layer was washed with water (2×20 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(4-fluorophenethyl)piperidine as a white solid (70 mg, 57%). ESI MS m / z 646.32 [M+H] + .

[0290] To a solution of the above-mentioned substance (70 mg, 0.11 mmol) in EtOH (10 mL) was added Pd (OH) / C (20 wt.%, 8.6 mg, 0.012 mmol) and 6N HCl (0.1 mL). The mixture was treated with hydrogen (1 atm) for 18 h. The catalyst was removed by filtration through diatomaceous earth and the solvent was evaporated under reduced pressure. The residue was dissolved in 1M NH3 in MeOH (10 mL) and stirred for another 10 minutes, then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to obtain (2R, 3R, 4R, 5S) -1- (4- fluorophenethyl) -2- (hydroxymethyl) piperidine -3,4,5- triol as a white solid (16 mg, 51%). 1 H NMR (400MHz, CD3OD) δ7.29-7.19(m,2H),7.05-6.97(m,2H),3.95(dd,J=11.9,2.5Hz,1H),3.85(dd,J=11.9,3.1Hz,1H),3.51(ddd,J=10.4,9.0,4.9Hz,1 H),3.34(t,J=12Hz,1H),3.17(t,J=9.0Hz,1H),3.09(dd,J=11.1,4.9Hz,1H) ,3.05-2.72(m,4H),2.37(t,J=10.8Hz,1H),2.28(dt,J=9.5,2.9Hz,1H); ESI MS m / z 286.14[M+H] + .

[0291] Example 4

[0292] (2R,3R,4R,5S)-1-(2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol

[0293]

[0294] A mixture of (2R, 3R, 4R, 5S) -3, 4, 5-tris (benzyloxy) -2- (benzyloxy) methyl) piperidine (0.30 g, 0.57 mmol), 2- (2-bromoethyl) -1, 3-difluorobenzene (0.40 g, 1.8 mmol) and DIPEA (0.35 g, 2.7 mmol) in anhydrous DMF (5 mL) in a sealed tube was stirred at 85 ° C for 16 h. The reaction mixture was cooled to room temperature and diluted with saturated aqueous NaHCO3 (20 mL). After extraction with EtOAc (3 × 20 mL), the combined extracts were washed with brine (2 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:6 to 1:3) to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(2,6-difluorophenethyl)piperidine as a light yellow oil (0.10 g, 26%). ESI MS m / z 664.364 [M+H] + .

[0295] At -78 ° C and N2, to anhydrous DCM (3mL) solution of the above-mentioned substance (0.10 g, 0.15 mmol) was added BCl3 (concentration in DCM was 1.0 M, 1.5 mL, 1.5 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 1M NH3 in MeOH and purified by flash chromatography (1M NH3 in 1:4 MeOH / DCM) on silica gel to obtain (2R, 3R, 4R, 5S) -1- (2,6- difluorophenethyl) -2- (hydroxymethyl) piperidine -3,4,5- triol as a white solid (0.040 g, 87%). 1H NMR (500MHz, DMSO-d6) δ7.33-7.24(m,1H),7.10-7.00(m,2H),4.72-.67(m,3H),4.15(dd,J=6.1,4.2Hz,1H),3.76-3.71(m,1H),3.54-3.48( m,1H),3.26-3.18(m,1H),3.05-2.99(m,1H),2.96-2.82(m,3H),2.80-2.68(m,3H),2.20(t,J=10.6Hz,1H),2.06(dt,J=9.3,2.9Hz,1H); ESI MS m / z 304.129[M+H] + .

[0296] Example 5

[0297] (2R,3R,4R,5S)-2-(Hydroxymethyl)-1-(3-(trifluoromethyl)phenethyl)piperidine-3,4,5-triol

[0298]

[0299] To a solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine (100 mg, 0.19 mmol) and 1-(2-bromoethyl)-3-(trifluoromethyl)benzene (240 mg, 0.95 mmol) in DMF (5 mL) in a sealed tube was added KCO (210 mg, 1.52 mmol). The mixture was stirred at 80°C for 18 h and cooled to room temperature. The reaction mixture was poured into ice water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(3-(trifluoromethyl)phenethyl)piperidine as a white solid (70 mg, 53%). ESI MS m / z 696.33 [M+H] + .

[0300] To a stirred solution of the above material (70 mg, 0.10 mmol) in anhydrous DCM (5 mL) was added BCI3(concentration 1 M in DCM, 1.0 mL, 1.0 mmol) at -78 °C under N2. The mixture was stirred at 0 °C for 2 h, then quenched with anhydrous MeOH (1 mL). The mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, the residue was dissolved in 1 M NH3in 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-(hydroxymethyl)-1-(3-(trifluoromethyl)phenethyl)piperidine-3,4,5-triol as a white solid (21 mg, 63%). 1 H NMR (400 MHz, CD3OD) δ 7.59 - 7.44 (m, 4H), 3.97 (dd, J = 11.9, 2.5 Hz, 1H), 3.86 (dd, J = 11.9, 3.1 Hz, 1H), 3.52 (ddd, J = 10.4, 9.0, 4.9 Hz, 1H), 3.34 (t, J = 12 Hz, 1H), 3.19 (t, J = 9.0 Hz, 1H), 3.13 (dd, J = 11.1, 4.9 Hz, 1H), 3.09 - 2.84 (m, 4H), 2.42 (t, J = 10.8 Hz, 1H), 2.34 (dt, J = 9.5, 2.9 Hz, 1H); ESI MS m / z 336.14 [M+H] + .

[0301] Example 6

[0302] (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(4-(trifluoromethyl)phenethyl)piperidine-3,4,5-triol

[0303]

[0304] To a solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-(benzyloxy)methyl)piperidine (100 mg, 0.19 mmol) and 1-(2-bromoethyl)-4-(trifluoromethyl)benzene (193 mg, 0.76 mmol) in DMF (8 mL) in a sealed tube was added DIPEA (0.35 mL, 1.9 mmol). The mixture was stirred at 80 ° C for 18 h and cooled to room 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 flash chromatography on silica gel to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(4-(trifluoromethyl)phenethyl)piperidine as a white solid (76 mg, 61%).

[0305] To a solution of the above substance (70 mg, 0.1 mmol) in anhydrous DCM (2 mL) was added BCl 3 (1.0 mL, 1 M in DCM, 1.0 mmol) at -78 ° C under Ar. The mixture was stirred at -78 ° C for 2 h and at 0 ° C for 2 h; MeOH (20 mL) was added. The mixture was stirred at 0 ° C for another 2 h and evaporated to dryness on a rotary evaporator. The residue was purified by flash chromatography on silica gel using 10% MeOH and 2% NH 3 in DCM to give phenyl (2R, 3R, 4R, 5S) -2- (hydroxymethyl) -1- (4- (trifluoromethyl) phenethyl) piperidine -3,4,5- triol as a white foam (26 mg, 70%). 1 H NMR (400MHz, CD3OD) δ7.58(d,J=8.0Hz,2H),7.44(d,J=8.0Hz,2H),3.97(dd,J=12.0,2.5Hz,1H),3.85(dd,J=12.0,3.3Hz,1H),3.51(ddd,J= ESI MS m / z 336.1[M+H] + .

[0306] Examples 7 and 8

[0307] (2R,3R,4R,5S)-2-(Hydroxymethyl)-1-((R)-2-phenylpropyl)piperidine-3,4,5-triol and (2R,3R,4R,5S)-2-(Hydroxymethyl)-1-((S)-2-phenylpropyl)piperidine-3,4,5-triol

[0308]

[0309] To a solution of 2-phenylpropanal (78 mg, 0.57 mmol), (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine (200 mg, 0.38 mmol) and HOAc (three drops) in anhydrous MeOH (10 mL) was added NaBHCN (38 mg, 95%, 0.57 mmol) under Ar. The mixture was stirred at room temperature for 18 h, saturated aqueous NaHCO (30 mL) was added, and the mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were dried over anhydrous NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel using 30% EtOAc in hexane to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(2-phenylpropyl)piperidine (the ratio of the two isomers was 1:3) (207 mg, 85%).

[0310] To a solution of the above substance (155 mg, 0.24 mmol, the ratio of the two isomers is 1:3) in anhydrous DCM (2 mL) was added BCl 3 (3.0 mL, 1 M in DCM, 3.0 mmol) at -78 ° C under Ar. The mixture was stirred at -78 ° C for 2 h and at 0 ° C for 2 h; MeOH (20 mL) was added. The mixture was stirred at 0 ° C for another 2 h and evaporated to dryness on a rotary evaporator. The residue was purified by flash chromatography on silica gel using 10% MeOH and 2% NH 3 in DCM to give phenyl (2R, 3R, 4R, 5S) -2- (hydroxymethyl) -1- ((R) -2-phenylpropyl) piperidine -3,4,5- triol as a white foam (14.5 mg, 87%). 1HNMR(400MHz,CD3OD)δ7.32-7.22(m,4H),7.19(t,J=7.1Hz,1H),3.94-3.61(m,2H),3.48(td,J=9.8,4.7Hz,1H),3 .36-3.32(m,1H),3.27-2.86(m,4H),2.49(t,J=8.7Hz,1H),2.10(q,J=10.2,9.5Hz,2H),1.29(d,J=5.6Hz,3H); ESI MS m / z 282.2[M+H] + (2R,3R,4R,5S)-2-(hydroxymethyl)-1-((S)-2-phenylpropyl)piperidine-3,4,5-triol was also isolated as a white foam (34 mg, 67%). 1 H NMR (400MHz, CD3OD) δ7.68-6.63(m,5H),3.82(d,J=11.7Hz,1H),3.68(dd,J=11.9,3.0Hz,1H),3.37-3.28(m,1 ESI MS m / z 282.2[M+H] + Each compound was isolated as a diastereomer with the stereochemistry of the phenylpropyl group randomly assigned.

[0311] Example 9

[0312] (2R,3R,4R,5S)-2-(Hydroxymethyl)-1-(2-(pyridin-2-yl)ethyl)piperidine-3,4,5-triol

[0313]

[0314] To a stirred solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2- ((benzyloxy)methyl)piperidine (300 mg, 0.57 mmol) and 2-(2- bromoethyl)pyridine (900 mg, 4.86 mmol) in DMF (15 mL) in a sealed tube was added K2CO3(1000 mg, 7.24 mmol). The mixture was stirred at 80 °C for 18 h and cooled to room temperature. The reaction mixture was poured into ice water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), separated, dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give 2-(2-((2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2- ((benzyloxy)methyl)piperidin-l-yl)ethyl)pyridine as a white solid (340 mg, 95%). ESI MS m / z 629.34 [M+H] + .

[0315] To a stirred solution of the above material (183 mg, 0.29 mmol) in dry DCM (5 mL) at -78 °C under N2was added BCl3(concentration 1 M in DCM, 2.1 mL, 2.1 mmol). The mixture was stirred at 0 °C for 2 h, then quenched with dry MeOH (1 mL). The mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, the residue was dissolved in 1 M NH3in 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-(hydroxymethyl)-l-(2-(pyridin-2- yl)ethyl)piperidine-3,4,5-triol as a white solid (63 mg, 81%). 1 H NMR (400 MHz, CD3OD) δ 8.51 - 8.45 (m, 1H), 7.81 (td, J = 7.7, 1.8 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.35 - 7.24 (m, 1H), 4.07 - 3.92 (m, 2H), 3.59 (ddd, J = 10.5, 8.9, 4.8 Hz, 1H), 3.54 - 3.40 (m, 2H), 3.32 - 3.19 (m, 3H), 3.13 (t, J = 7.6 Hz, 2H), 2.71 - 2.57 (m, 2H); ESIMS m / z 269.15 [M+H] + .

[0316] Example 10

[0317] (2R,3R,4R,5S)-2-(Hydroxymethyl)-1-(2-(thien-2-yl)ethyl)piperidine-3,4,5-triol

[0318]

[0319] To a solution of 2-(thiophen-2-yl)acetaldehyde (80 mg, 0.63 mmol), (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine (221 mg, 0.42 mmol) and HOAc (three drops) in anhydrous MeOH (10 mL) was added NaBHCN (50 mg, 95%, 0.62 mmol) under Ar. The mixture was stirred at room temperature for 18 h, saturated aqueous NaHCO (30 mL) was added, and the mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were dried over anhydrous NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel using 30% EtOAc in hexanes to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(2-(thiophen-2-yl)ethyl)piperidine (175 mg, 66%).

[0320] At -78 ° C, under Ar, to anhydrous DCM (2mL) solution of the above-mentioned substance (175mg, 0.27mmol) was added BCl (3.0mL, the concentration in DCM was 1M, 3.0mmol). The mixture was stirred at -78 ° C for 2h and at 0 ° C for 2h, then MeOH (20mL) was added. The mixture was stirred for another 2h at 0 ° C and evaporated to dryness on a rotary evaporator. The residue was purified by flash chromatography on silica gel using a DCM solution of 10% MeOH and 2% NH to give phenyl (2R, 3R, 4R, 5S) -2- (hydroxymethyl) -1- (2- (thiophene-2-yl) ethyl) piperidine -3,4,5- triol as a white foam (63mg, 85%). 1 H NMR (400MHz, CD3OD) δ7.24 (dd, J=5.1, 1.3Hz, 1H), 7.05-6.67 (m, 2H), 3.95 (d, J=2.7Hz, 2H), 3.6 0(ddd,J=10.6,9.1,4.9Hz,1H),3.46(t,J=9.4Hz,1H),3.31-3.01(m,6H),2.88-2.44(m,2H); ESI MS m / z 274.1[M+H] + .

[0321] Example 11

[0322] (2R,3R,4R,5S)-2-(Hydroxymethyl)-1-(2-(thien-3-yl)ethyl)piperidine-3,4,5-triol

[0323]

[0324] To a solution of 2-(thiophen-3-yl)acetaldehyde (85 mg, 0.67 mmol), (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine (221 mg, 0.42 mmol) and HOAc (three drops) in anhydrous MeOH (10 mL) was added NaBHCN (50 mg, 95%, 0.63 mmol) under Ar. The mixture was stirred at room temperature for 18 h, saturated aqueous NaHCO (30 mL) was added, and the mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were dried over anhydrous NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel using 30% EtOAc in hexanes to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-(benzyloxy)methyl)-1-(2-(thiophen-3-yl)ethyl)piperidine (181 mg, 68%).

[0325] At -78 ° C, under Ar, to anhydrous DCM (2mL) solution of the above-mentioned substance (181mg, 0.28mmol) was added BCl (6.0mL, the concentration in DCM is 1M, 6.0mmol). The mixture was stirred at -78 ° C for 2h and at 0 ° C for 2h, MeOH (20mL) was added. The mixture was stirred for another 2 hours at 0 ° C and evaporated to dryness on a rotary evaporator. The residue was purified by flash chromatography on silica gel using a DCM solution of 10% MeOH and 2% NH to give phenyl (2R, 3R, 4R, 5S) -2- (hydroxymethyl) -1- (2- (thiophene-3-yl) ethyl) piperidine -3,4,5- triol as white foam (23mg, 29%). 1H NMR (400MHz, CD3OD) δ7.34(dd,J=5.0,2.9Hz,1H),7.11(d,J=2.9Hz,1H),7.02(d,J=4.8Hz,1H),3.92(qd,J=12.2,2.8Hz,2H),3.55(td,J=9.9,4.8Hz,1H ),3.39(t,J=9.5Hz,1H),3.22(t,J=9.1Hz,1H),3.15-3.05(m,2H),3.01-2. 94(m,1H),2.90-2.85(m,2H),2.42(t,J=10.9Hz,1H),2.37-2.29(m,1H);ESI MS m / z274.3[M+H] + .

[0326] Example 12

[0327] (2S,3R,4R,5S)-1-(Cyclohexylmethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol

[0328]

[0329] Under Ar, a mixture of (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine (0.20 g, 0.38 mmol), (bromomethyl)cyclohexane (0.18 g, 1.0 mmol) and DIPEA (0.20 g, 1.6 mmol) in anhydrous DMF (5 mL) in a sealed tube was stirred at 85 ° C for 16 h. The reaction mixture was cooled at room temperature and diluted with saturated aqueous NaHCO3 (20 mL). After extraction with EtOAc (2×30 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 flash chromatography on silica gel (EtOAc / hexanes, 1:12 to 1:7) to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(cyclohexylmethyl)piperidine as a light yellow oil (0.17 g, 71%).

[0330] To a solution of the above substance (0.17 g, 0.27 mmol) in anhydrous DCM (8 mL) was added BCl at -78 ° C and Ar (1.0 M in DCM, 2.0 mL, 2.0 mmol), and the mixture was stirred at 0 ° C for 3 h. The reaction mixture was cooled at -78 ° C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with 1 M NH in MeOH and purified by flash chromatography (0.5 M NH in 1:5 MeOH / DCM) on silica gel to give (2S, 3R, 4R, 5S) -1- (cyclohexylmethyl) -2- (hydroxymethyl) piperidine -3,4,5- triol as a white solid (0.059 g, 83%). 1 H NMR(400MHz,DMSO-d6)δ4.73(d,J=4.6Hz,1H),4.64(d,J=4.2Hz,1H),4.60(d ,J=5.1Hz,1H),4.06(t,J=5.0Hz,1H),3.65-3.56(m,2H),3.44-3.38(m,1H),3 .30-3.20(m,1H),3.11-3.02(m,1H),2.81-2.72(m,1H),2.58-2.30(m,4H),1. 75-1.55(m,5H),1.46-1.33(m,1H),1.24-1.05(m,3H),0.85-0.70(m,2H); ESI m / z 260.187[M+H] + .

[0331] Example 13

[0332] (2S,3R,4R,5S)-2-(Hydroxymethyl)-1-(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol

[0333]

[0334] To a stirred solution of (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-(benzyloxy)methyl)piperidine (400 mg, 0.76 mmol) and (1r,4r)-4-(trifluoromethyl)cyclohexanecarboxaldehyde (274 mg, 1.52 mmol) in anhydrous DCM (10 mL) was added HOAc (0.2 mL) and the mixture was stirred for 30 minutes. NaBH(OAc)3 (340 mg, 1.60 mmol) was added and the resulting mixture was stirred at room temperature for 18 h. The reaction was quenched with NaHCO3 solution 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 flash chromatography on silica gel to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(((1r,4S)-4-(trifluoromethyl)cyclohexyl)-methyl)piperidine as an oil (375 mg, 72%). ESIMS m / z 688.35 [M+H] + .

[0335] At -78 ° C, under N2, a BCl3 solution (1M in DCM, 1.75 mL, 1.75 mmol) was added to a stirred solution of the above substance (240 mg, 0.35 mmol) in anhydrous DCM (5 mL). The mixture was stirred at 0 ° C for 4 h and then quenched with anhydrous MeOH (1 mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum, and the residue was dissolved in 1M NH3 in MeOH (10 mL) and stirred for another 10 minutes, and then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to obtain (2S, 3R, 4R, 5S) -2- (hydroxymethyl-1- (((1r, 4S) -4- (trifluoromethyl) cyclohexyl) methyl) piperidine-3,4,5-triol as a white solid (78 mg, 68%). 1 H NMR (400MHz, CD3OD) δ3.88-3.77(m,2H),3.69(dd,J=9.3,5.5Hz,1H),3.55-3.46(m,1H),3.39-3.34(m,1H),2.99(q,J=5.5Hz,1H),2.72(ddd,J =12.6,5.4,1.0Hz,1H),2.64-2.46(m,3H),2.15-2.02(m,1H),2.02-1. 89(m,4H),1.56-1.44(m,1H),1.40-1.24(m,2H),1.04-0.85(m,2H); ESI MS m / z 328.17[M+H] + .

[0336] Example 14

[0337] (2S,3R,4R,5S)-1-(((1s,4S)-4-(2-fluoropropan-2-yl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol

[0338]

[0339] Under Ar, a mixture of (2S, 3R, 4R, 5S) -3, 4, 5- tris (benzyloxy) -2- ( (benzyloxy) methyl) piperidine (0.25 g, 0.50 mmol), cis -4- (2-fluoropropan-2-yl) cyclohexanecarbaldehyde (0.12 g, 0.70 mmol) and NaBH (OAc) (0.21 g, 1.0 mmol) in DCM (15 mL) was stirred at room temperature for 3 days. The reaction mixture was diluted with saturated aqueous NaHCO (10 mL) and extracted with DCM (3 × 15 mL). The combined extracts were dried over anhydrous NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:7 to 1:5) to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(((1s,4R)-4-(2-fluoropropan-2-yl)cyclohexyl)methyl)piperidine as a light yellow oil (0.31 g, 91%).

[0340] A mixture of the above (0.31 g, 0.45 mmol), Pd(OH)2 / C (20% mass percent, 0.10 g, 0.19 mmol) and 6 drops of concentrated HC1 in MeOH (20 mL) was stirred under hydrogen at one atmosphere overnight. The mixture was filtered through a pad of celite, and the filtrate was collected and concentrated to dryness. The residue was dissolved in anhydrous pyridine (3 mL) at 0 °C, to which Ac2O (0.5 mL) was added. The mixture was stirred at room temperature for 16 h, and diluted with saturated aqueous NaHC03solution (20 mL). After extraction with EtOAc (2 x 20 mL), the combined extracts were dried over anhydrous Na2S04. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1 :4 to 1 :3) to give a clear oil. The clear oil was treated with 1 M NH3in MeOH (5 mL) at room temperature for 16 h. After concentration under reduced pressure, the residue was purified by flash chromatography on silica gel (0.5 M NH3MeOH / DCM, 1 :5) to give (2S,3R,4R,5S)-1-(((1s,4R)-4-(2-fluoroprop-2-yl)cyclohexyl)methyl)-2- (hydroxymethyl)piperidine-3,4,5-triol (0.057 g, 39% over three steps) as a white solid. 1 HNMR (400 MHz, CD3OD) δ 3.86-3.78 (m, 2H), 3.69 (dd, J = 9.3, 5.5 Hz, 1H), 3.55-3.43 (m, 1H), 3.35 (t, J = 8.9 Hz, 1H), 3.04-2.96 (m, 1H), 2.84-2.68 (m, 2H), 2.68-2.52 (m, 2H), 1.91-1.68 (m, 3H), 1.66-1.38 (m, 5H), 1.27 (d, J = 21.8 Hz, 6H), 1.26-1.10 (m, 2H); ESI MS m / z 320.233 [M+H] + .

[0341] Example 15

[0342] (2S,3R,4R,5S)-1-((2,3-dihydro-1H-inden-2-yl)methyl)-2-(hydroxymethyl)piperidine- 3,4,5-triol

[0343]

[0344] To a stirred solution of (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine (130 mg, 0.23 mmol) and 2,3-dihydro-1H-indene-2-carbaldehyde (40 mg, 0.27 mmol) in anhydrous DCM (5 mL) was added HOAc (0.1 mL) and stirred for 30 minutes. NaBH(OAc)3 (73 mg, 0.35 mmol) was added, and the resulting mixture was stirred at room temperature for 18 hours. The reaction was quenched with NaHCO3 solution 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 flash chromatography on silica gel to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-((2,3-dihydro-1H-inden-2-yl)methyl)piperidine as an oil (90 mg, 60%). ESI MS m / z 654.35 [M+H] + .

[0345] To a stirred solution of the above substance (90 mg, 0.14 mmol) in anhydrous DCM (5 mL) was added a BCl solution (1 M in DCM, 0.69 mL, 0.69 mmol) at -78 ° C and N2. The mixture was stirred at 0 ° C for 4 h and then quenched with anhydrous MeOH (1 mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum and the residue was dissolved in 1M NH3 in MeOH (10 mL) and stirred for another 10 minutes, and then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2S, 3R, 4R, 5S) -1- ((2,3-dihydro-1H-inden-2-yl) methyl) -2- (hydroxymethyl) piperidine-3,4,5-triol as a white solid (23 mg, 56%) 1 H NMR (400MHz, CD3OD) δ7.20-7.14(m,2H),7.11-7.06(m,2H),3.91-3.80(m,2H),3.76-3.7 0(m,1H),3.59-3.51(m,1H),3.42-3.34(m,1H),3.10-2.97(m,3H),2.85-2.60(m,7H);ESI MS m / z 294.17[M+H] + .

[0346] Example 16

[0347] (2S,3R,4R,5S)-1-(2-cyclohexylethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol

[0348]

[0349] Under Ar, a mixture of (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine (0.20 g, 0.38 mmol), (2-bromoethyl)cyclohexane (0.19 g, 1.0 mmol) and DIPEA (0.20 g, 1.6 mmol) in anhydrous DMF (5 mL) in a sealed tube was stirred at 85 ° C for 16 h. The reaction mixture was cooled at room temperature and diluted with saturated aqueous NaHCO3 (20 mL). After extraction with EtOAc (2×30 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 flash chromatography on silica gel (EtOAc / hexanes, 1:12 to 1:7) to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(2-cyclohexylethyl)piperidine as a light yellow oil (0.17 g, 71%).

[0350] To anhydrous DCM (8mL) solution of the above-mentioned substance (0.17g, 0.27mmol) was added BCl at -78°C and Ar (1.0M in DCM, 2.0mL, 2.0mmol), and the mixture was stirred at 0°C for 3h. The reaction mixture was cooled at -78°C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with 1M NH in MeOH and purified by flash chromatography (0.5M NH in 1:5 MeOH / DCM) on silica gel to give (2S, 3R, 4R, 5S) -1- (2-cyclohexylethyl) -2- (hydroxymethyl) piperidine -3,4,5- triol as a white solid (0.054g, 74%). 1 H NMR (400MHz, DMSO-d6) δ4.71(d,J=4.8Hz,1H),4.65(d,J=4.2Hz,1H),4.61(d,J= 5.1Hz,1H),4.09(s,br.,1H),3.67-3.55(m,2H),3.47-3.36(m,1H),3.31-3.21(m ,1H),3.12-3.06(m,1H),2.85-2.76(m,1H),2.72-2.62(m,1H),2.61-2.43(m,2H) ,2.42-2.32(m,1H),1.75-1.54(m,5H),1.35-1.04(m,6H),0.93-0.80(m,2H);ESI MS m / z 274.202[M+H] + .

[0351] Example 17

[0352] (2S,3R,4R,5S)-1-(3-cyclohexylpropyl)-2-(hydroxymethyl)piperidine-3,4,5-triol

[0353]

[0354] Under Ar, a mixture of (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine (0.20 g, 0.38 mmol), (3-bromopropyl)cyclohexane (0.21 g, 1.0 mmol) and DIPEA (0.20 g, 1.6 mmol) in anhydrous DMF (5 mL) in a sealed tube was stirred at 85 ° C for 16 h. The reaction mixture was cooled at room temperature and diluted with saturated aqueous NaHCO3 (20 mL). After extraction with EtOAc (2×30 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 flash chromatography on silica gel (EtOAc / hexane, 1:12 to 1:7) to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(3-cyclohexylpropyl)piperidine as a light yellow oil (0.25 g, 100%).

[0355] To anhydrous DCM (8mL) solution of the above-mentioned substance (0.25g, 0.38mmol) was added BCl at -78°C and Ar (1.0M in DCM, 3.0mL, 3.0mmol), and the mixture was stirred at 0°C for 3h. The reaction mixture was cooled at -78°C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with 1M NH in MeOH and purified by flash chromatography (0.5M NH in 1:5 MeOH / DCM) on silica gel to give (2S, 3R, 4R, 5S) -1- (3-cyclohexylpropyl) -2- (hydroxymethyl) piperidine -3,4,5- triol as a white solid (0.095g, 87%). 1H NMR(400MHz,DMSO-d6)δ4.81-4.61(m,3H),4.09(s,br.,1H),3.69-3.56(m,2H),3.48-3.36(m,1H),3.32-3.23(m,1H),3.15-3.0 4(m,1H),2.90-2.77(m,1H),2.63-2.32(m,4H),1.70-1.54(m,5H),1.44-1.32(m,2H),1.25-1.08(m,6H),0.91-0.78(m,2H); ESI MS m / z 288.218[M+H] + .

[0356] Example 18

[0357] (2S,3R,4R,5S)-1-(2-Fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol

[0358]

[0359] A solution of (2S, 3R, 4R, 5S) -3, 4, 5-tris (benzyloxy) -2- ( (benzyloxy) methyl) piperidine (7.50 g, 14.3 mmol) (J. Am. Chem. Soc. 2017, 139, 14192-14197), 1- (2-bromoethyl) -2-fluorobenzene (4.14 g, 20.4 mmol) (Tetrahedron Asymmetry, 2001, 12, 4, 585-596), tetrabutylammonium iodide (Bu4NI) (0.450 g, 1.22 mmol) and K2CO3 (4.14 g, 30.0 mmol) in anhydrous DMF (40 mL) was stirred at 100 ° C for 16 h. The reaction mixture was cooled at room temperature and diluted with water (300 mL). After extraction with Et2O (2 x 100 mL), the combined extracts were washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:10 to 1:5) to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(2-fluorophenethyl)piperidine as a light yellow oil (3.60 g, 39%); ESI MS m / z 646.327 [M+H] + .

[0360] To a solution of the above material (3.60 g, 5.57 mmol) in anhydrous DCM (40 mL) was added BC13(concentration 1.0 M in DCM, 33 mL, 33 mmol) at -78 °C under N2and the mixture was stirred at 0 °C for 3 h. The reaction mixture was cooled at -78 °C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with 1 M NH3in MeOH and purified by flash chromatography on silica gel (1 M NH3in MeOH / DCM, 1 :5) to give (2S,3R,4R,5S)-1-(2-fluorophenethyl)-2- (hydroxymethyl)piperidine-3,4,5-triol as a white solid (1.48 g, 93%). 1 HNMR (400 MHz, CD3OD) δ 7.26 (td, J = 7.5, 1.8 Hz, 1H), 7.22-7.16 (m, 1H), 7.07 (td, J = 7.5, 1.2 Hz, 1H), 7.04-6.99 (m, 1H), 3.94-3.75 (m, 2H), 3.67 (dd, J = 8.8, 5.2 Hz, 1H), 3.53 (ddd, J = 9.5, 8.0, 4.9 Hz, 1H), 3.38 (t, J = 8.5 Hz, 1H), 3.12-2.97 (m, 2H), 2.95-2.77 (m, 4H), 2.63 (dd, J = 12.4, 9.5 Hz, 1H); ESI MS m / z 286.139 [M+H] + .

[0361] Example 19

[0362] (2S,3R,4R,5S)-1-(3-chloro-2-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol

[0363]

[0364] A mixture of (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine (0.35 g, 0.67 mmol), 2-(3-chloro-2-fluorophenyl)acetaldehyde (0.14 g, 0.81 mmol) and NaBH(OAc) (0.20 g, 0.94 mmol) in DCM (10 mL) was stirred at room temperature for 16 h under Ar. The reaction mixture was diluted with saturated aqueous NaHCO (10 mL) and extracted with DCM (3 × 15 mL). The combined extracts were dried over anhydrous NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:9 to 1:6) to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(3-chloro-2-fluorophenethyl)piperidine as a light yellow oil (0.43 g, 94%).

[0365] To a solution of the above substance (0.43 g, 0.63 mmol) in anhydrous DCM (10 mL) was added BCl at -78 ° C and Ar (1.0 M in DCM, 4.0 mL, 4.0 mmol), and the mixture was stirred at 0 ° C for 3 h. The reaction mixture was cooled at -78 ° C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with 1 M NH in MeOH and purified by flash chromatography (0.5 M NH in 1:5 MeOH / DCM) on silica gel to give (2S, 3R, 4R, 5S) -1- (3-chloro-2-fluorophenethyl) -2- (hydroxymethyl) piperidine -3,4,5- triol as a white solid (0.15 g, 74%). 1 HNMR(400MHz,DMSO-d6)δ7.42-7.36(m,1H),7.31-7.25(m,1H),7.16-7.10(m,1H),4. 71(d,J=4.9Hz,1H),4.67(d,J=4.1Hz,1H),4.65(d,J=5.2Hz,1H),4.17(t,J=5.0Hz,1 H),3.72-3.56(m,2H),3.40-3.30(m,1H),3.30-3.20(m,1H),3.12-3.04(m,1H),2.98 -2.92(m,1H),2.87-2.81(m,1H),2.80-2.67(m,4H),2.44(dd,J=11.9,9.4Hz,1H); ESI MS m / z 320.109[M+H] + .

[0366] Example 20

[0367] (2S,3R,4R,5S)-1-(2-([1,1'-biphenyl]-4-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol

[0368]

[0369] Under Ar, a mixture of (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine (0.20 g, 0.38 mmol), 4-(2-bromoethyl)-1,1'-biphenyl (0.25 g, 0.96 mmol) and DIPEA (0.20 g, 1.6 mmol) in anhydrous DMF (5 mL) in a sealed tube was stirred at 85 ° C for 16 h. The reaction mixture was cooled at room temperature and diluted with saturated aqueous NaHCO3 (20 mL). After extraction with EtOAc (2×30 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 flash chromatography on silica gel (EtOAc / hexanes, 1:12 to 1:7) to give (2S,3R,4R,5S)-1-(2-([1,1'-biphenyl]-4-yl)ethyl)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine as a light yellow oil (0.18 g, 67%).

[0370] To a solution of the above substance (0.18 g, 0.26 mmol) in anhydrous DCM (8 mL) was added BCl at -78 ° C and Ar (1.0 M in DCM, 2.0 mL, 2.0 mmol), and the mixture was stirred at 0 ° C for 3 h. The reaction mixture was cooled at -78 ° C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with 1 M NH in MeOH and purified by flash chromatography (0.5 M NH in 1:5 MeOH / DCM) on silica gel to give (2S, 3R, 4R, 5S) -1- (2- ([1,1'-biphenyl] -4- base) ethyl) -2- (hydroxymethyl) piperidine -3,4,5- triol as a white solid (0.031 g, 35%). 1H NMR(400MHz,DMSO-d6)δ7.69-7.61(m,2H),7.60-7.52(m,2H),7.50-7.40(m,2H),7.37-7.27(m,3H),4.48-4.60(m,3H),4.19(s,br.,1H), ESI MS m / z 344.185[M+H] + .

[0371] Example 21

[0372] (2S,3R,4R,5S)-1-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol

[0373]

[0374] A mixture of (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine (0.20 g, 0.38 mmol), 2-(4-(3,6-dihydro-2H-pyran-4-yl)-2,6-difluorophenyl)acetaldehyde (0.12 g, 0.50 mmol) and NaBH(OAc) (0.15 g, 0.71 mmol) in DCM (10 mL) was stirred at room temperature for 16 h under Ar. The reaction mixture was diluted with saturated aqueous NaHCO (10 mL) and extracted with DCM (3 x 15 mL). The combined extracts were dried over anhydrous NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:6 to 1:4) to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(4-(3,6-dihydro-2H-pyran-4-yl)-2,6-difluorophenethyl)piperidine as a light yellow oil (0.27 g, 75%).

[0375] Under hydrogen at 1 atmosphere, a mixture of the above substance (0.27 g, 0.36 mmol), Pd(OH)2 / C (20% Pd by mass, 0.070 g, 0.13 mmol) and 5 drops of concentrated HCl in MeOH (20 mL) was stirred overnight. The mixture was filtered through a celite filter cake, and the filtrate was collected and concentrated to dryness. The residue was neutralized with 1M NH3 in MeOH and purified by flash chromatography on silica gel (0.5M NH3MeOH / DCM, 1:5) to obtain (2S,3R,4R,5S)-1-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol (0.12 g, 86%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ6.98-6.92 (m, 2H), 4.71 (d, J = 4.8Hz, 1H), 4.69-4. 62(m,2H),4.14(t,J=4.9Hz,1H),3.97-3.82(m,2H),3.72-3.51(m,2H),3.3 9(td,J=11.5,2.8Hz,2H),3.40-3.30(m,1H),3.30-3.20(m,1H),3.12-3.0 3(m,1H),2.98-2.56(m,7H),2.42(t,J=10.6Hz,1H),1.81-1.42(m,4H);ESI MS m / z 388.193[M+H] + .

[0376] Example 22

[0377] (2S,3R,4R,5S)-1-(4-Butoxyphenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol

[0378]

[0379] A mixture of (2S,3R,4R,5S)-3,4,5-tri(benzyloxy)-2-((benzyloxy)methyl)piperidine (0.20 g, 0.38 mmol), 2-(4-butoxyphenyl)acetaldehyde (0.12 g, 0.62 mmol) and NaBH(OAc)3(0.15 g, 0.71 mmol) in DCM (10 mL) was stirred at room temperature under Ar for 3 days. The reaction mixture was diluted with saturated aqueous NaHCO3solution (10 mL) and extracted with DCM (3 x 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 flash chromatography on silica gel (EtOAc / hexanes, 1 :9 to 1 :6) to give (2S,3R,4R,5S)-3,4,5-tri(benzyloxy)-2-((benzyloxy)methyl)-1-(4-butoxyphenethyl)piperidine as a pale yellow oil (0.23 g, 86%).

[0380] A mixture of the above material (0.23 g, 0.33 mmol), Pd(OH)2 / C (20% mass percentage, 0.10 g, 0.19 mmol) and 5 drops of concentrated HCI in MeOH (20 mL) was stirred under hydrogen at one atmosphere overnight. The mixture was filtered through a pad of celite and the filtrate was collected and concentrated to dryness. The residue was neutralized with 1 M NH3in MeOH and purified by flash chromatography on silica gel (0.5 M NH3

[0381] MeOH / DCM, 1 :5) to give (2S,3R,4R,5S)-1-(4-butoxyphenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol (0.051 g, 46%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.16 - 7.01 (m, 2H), 6.90 - 6.73 (m, 2H), 4.87 - 4.51 (m, 3H), 4.14 (s, br.1H), 3.91 (t, J = 6.5 Hz, 2H), 3.70 - 3.57 (m, 2H), 3.45 - 3.35 (m, 1H), 3.34 - 3.24 (m, 1H), 3.14 - 3.06 (m, 1H), 2.93 - 2.83 (m, 2H), 2.73 - 2.55 (m, 4H), 2.50 - 2.39 (m, 1H), 1.71 - 1.62 (m, 2H), 1.49 - 1.33 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H); ESI MS m / z 340.212 [M+H] + .

[0382] Example 23

[0383] (2S,3R,4R,5S)-1-(4-Butoxy-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol

[0384]

[0385] Under N2, a mixture of (2S, 3R, 4R, 5S) -3, 4, 5- tris (benzyloxy) -2- ( (benzyloxy) methyl) piperidine (1.20 g, 2.29 mmol), 2- (4- butoxy -2, 6- difluorophenyl) acetaldehyde (0.68 g, 3.0 mmol) and NaBH (OAc) 3 (0.85 g, 4.0 mmol) in DCM (30 mL) was stirred at room temperature for 3 days. The reaction mixture was diluted with saturated aqueous NaHCO 3 (30 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 by flash chromatography on silica gel (EtOAc / hexane, 1:12 to 1:7) to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(4-butoxy-2,6-difluorophenethyl)piperidine as a light yellow oil (1.3 g, 77%). ESI MS m / z 736.3689 [M+H] + .

[0386] A mixture of the above substance (1.30 g, 1.76 mmol), Pd(OH)2 / C (20% Pd by mass, 0.25 g, 0.47 mmol) and concentrated HCl (0.5 mL) in MeOH (80 mL) was stirred overnight under hydrogen at 1 atmosphere. The mixture was filtered through a celite filter cake, and the filtrate was collected and concentrated to dryness. The residue was neutralized with 1M NH3 in MeOH and then purified on silica gel by flash column chromatography (0.5M NH3MeOH / DCM, 1:4) to give (2S,3R,4R,5S)-1-(4-butoxy-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol (0.58 g, 88%) as a white solid. 1H NMR(400MHz,CD3OD)δ6.53-6.47(m,2H),3.94(t,J=6.4Hz,2H),3.88-3.75(m,2H), 3.63(dd,J=8.9,5.3Hz,1H),3.50(ddd,J=9.5,8.1,5.0Hz,1H),3.36(t,J=8.5Hz,1 H),3.06-2.90(m,2H),2.88(dd,J=12.4,5.0Hz,1H),2.83-2.74(m,3H),2.61(dd,J =12.4,9.5Hz,1H),1.80-1.68(m,2H),1.54-1.44(m,2H),0.98(t,J=7.4Hz,3H); ESI MS m / z376.1604[M+H] + .

[0387] Example 24

[0388] (2S,3R,4R,5S)-1-((1-(4-Fluorophenyl)piperidin-4-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol

[0389]

[0390] To a stirred solution of (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine (600 mg, 1.06 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (272 mg, 1.28 mmol) in anhydrous DCM (10 mL) was added HOAc (0.2 mL) and the mixture was stirred for 30 minutes. NaBH(OAc)3 (337 mg, 1.59 mmol) was added and the resulting mixture was stirred at room temperature for 18 h. The reaction was quenched with NaHCO3 solution 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 flash chromatography on silica gel to give tert-butyl 4-(((2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidin-1-yl)methyl)piperidine-1-carboxylate as an oil (740 mg, 97%). ESI MS m / z 721.42 [M+H] + .

[0391] TFA (3 mL) was cooled to 0°C and added to the above substance (740 mg, 1.03 mmol) in DCM (6 mL). The mixture was stirred at 0°C for 10 minutes and then at room temperature for 2 hours. TFA and DCM were removed under vacuum. The residue was dissolved in EtOAc (50 mL) and washed with NaHCO3 solution (2×20 mL), then washed with water, separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the crude product (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(piperidin-4-ylmethyl)piperidine was used directly in the next step without further purification (624 mg, 98%). ESI MS m / z 621.37 [M+H] + .

[0392] To a stirred solution of the above material (228 mg, 0.37 mmol) and 4-bromofluorobenzene (128 mg, 0.74 mmol) in toluene (10 mL) was added Pd2(dba)3 (34 mg, 0.037 mmol) and RuPhos (35 mg, 0.074 mmol), followed by the addition of Cs2CO3 (361 mg, 1.11 mmol) under argon. The mixture was stirred at 100°C for 18 h, followed by the addition of water at 0°C. The mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (2 x 10 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-((1-(4-fluorophenyl)piperidin-4-yl)methyl)piperidine as an oil (208 mg, 79%). ESI MS m / z 715.39 [M+H] + .

[0393] To a stirred solution of the above substance (110 mg, 0.15 mmol) in anhydrous DCM (5 mL) was added BCl solution (1 M in DCM, 0.75 mL, 0.75 mmol) under N2 at -78 ° C. The mixture was stirred at 0 ° C for 4 h and then quenched with anhydrous MeOH (1 mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum, and the residue was dissolved in 1M NH3 in MeOH (10 mL) and stirred for another 10 minutes, and then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to obtain (2S, 3R, 4R, 5S) -1- ((1- (4-fluorophenyl) piperidin-4-yl) methyl) -2- (hydroxymethyl) piperidine-3,4,5-triol as a white solid (25 mg, 47%). 1H NMR(400MHz,CD3OD)δ7.04-6.93(m,4H),3.91-3.80(m,2H),3.74-3.69(m,1H),3.60-3.49(m,3H),3.41-3.3 4(m,1H),3.06-2.99(m,1H),2.80-2.56(m,6H),1.97-1.84(m,2H),1.72-1.58(m,1H),1.41-1.26(m,2H); ESI MS m / z 355.20[M+H] + .

[0394] Example 25

[0395] (2S,3R,4R,5S)-2-(Hydroxymethyl)-1-(((R)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol

[0396]

[0397] To (2S, 3R, 4R, 5S) -3,4,5- tris (benzyloxy) -2- ( (benzyloxy) methyl) piperidine (0.78g, 1.5mmol) in DCM (20mL) solution, (S) -3- formyl pyrrolidine -1- carboxylic acid tert-butyl ester (0.45g, 2.25mmol) and HOAc (0.5mL) were added. After stirring at room temperature for 10 minutes, NaBH (OAc) was added (0.5g, 2.5mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and then diluted with DCM (25mL). The organic matter was saturated with NaHCO aqueous solution, salt water washing, anhydrous NaSO dried and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 3:7) to give (R)-tert-butyl 3-(((2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate as an oil (1.0 g, 94%). 1H NMR (400 MHz, CDC13) δ 7.40 - 7.27 (m, 20H), 4.88 (d, J = 11.0 Hz, 1H), 4.82 (d, J = 11.1 Hz, 1H), 4.74 (d, J = 11.4 Hz, 1H), 4.71 - 4.62 (m, 3H), 4.54 (d, J = 12.1 Hz, 1H), 4.50 (d, J = 12.4 Hz, 1H), 3.73 (dd, J = 10.2, 2.5 Hz, 1H), 3.67 (td, J = 6.8, 5.8, 3.6 Hz, 1H), 3.59 - 3.42 (m, 3H), 3.39 - 3.25 (m, 3H), 3.04 - 2.89 (m, 1H), 2.87 - 2.79 (m, 1H), 2.76 - 2.63 (m, 1H), 2.61 - 2.52 (m, 2H), 2.37 - 2.25 (m, 1H), 1.88 - 1.80 (bs, 1H), 1.60 - 1.54 (m, 2H), 1.50 (s, 9H); ESI MS m / z 707.404 [M+H] + .

[0398] The above material (1.0 g, 1.45 mmol) was dissolved in 3:7 TFA:DCM (16 mL) at 0 °C and stirred for 30 min. The reaction mixture was heated to room temperature for 2 h, then concentrated to dryness. Diluted with EtOAc (30 mL) and the organics were washed with saturated NaHC03(2 x 50 mL), dried over anhydrous Na2S04, and concentrated to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-((S)-pyrrolidin-3- ylmethyl)piperidine as an oil (0.8 g, 90%). 1HNMR (400 MHz, CDC13) δ 7.40 - 7.26 (m, 20H), 4.88 (d, J = 10.9 Hz, 1H), 4.83 (d, J = 10.9 Hz, 1H), 4.76 - 4.62 (m, 4H), 4.56 - 4.49 (m, 3H), 3.85 (dd, J = 10.1, 7.1 Hz, 1H), 3.73 (dd, J = 10.2, 2.6 Hz, 1H), 3.70 - 3.63 (m, 1H), 3.59 - 3.47 (m, 2H), 3.34 (td, J = 6.6, 6.2, 2.7 Hz, 1H), 3.06 - 2.91 (m, 3H), 2.90 - 2.83 (m, 1H), 2.80 - 2.44 (m, 4H), 2.31 (tt, J = 13.9, 6.1 Hz, 1H), 1.84 (dtd, J = 13.2, 8.0, 5.6 Hz, 1H), 1.42 (dq, J = 13.8, 7.2 Hz, 1H); ESI MS m / z 607.350 [M+H] + .

[0399] To a solution of the above material (0.19 g, 0.31 mmol) and 2-chloro-3- (trifluoromethyl)pyridine (0.11 g, 0.62 mmol) in anhydrous DMF (5 mL) was added K2CO3(0.12 g, 0.93 mmol) and the reaction mixture was heated at 120 °C overnight. The reaction mixture was partitioned between EtOAc (50 mL) and water; the organics were separated and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 2:8) to give 3-(trifluoromethyl)-2-((R)-3-(((2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2- ((benzyloxy)methyl)piperidin-l-yl)methyl)pyrrolidin-l-yl)pyridine as an oil (0.1 g, 43%). 1HNMR(400MHz, CDCl3)δ8.32(dd,J=4.7,1.7Hz,1H),7.81(dd,J=7.8,1.8Hz,1H),7.41-7.27(m,20H),6.66(dd,J=7.8,4.7Hz,1H),4.89(d, J=10.9Hz,1H),4.84(d,J=10.9Hz,1H),4.75(d,J=11.5Hz,1H),4.70(s,2H),4.68-4.62(m,1H),4.58-4.49(m,2H),3.88(dd,J=10.2,7.1Hz ,1H),3.74(dd,J=10.4,2.8Hz,1H),3.72-3.49(m,6H),3.40-3.31(m,2H),2.88(dt,J=11.9,5.8Hz,1H),2.78(dd,J=12.8,8.4Hz,1H),2.6 7(dd,J=12.7,6.6Hz,1H),2.64-2.53(m,1H),2.40(dq,J=14.6,7.3Hz,1H),1.97(dq,J=11.7,5.8Hz,1H),1.63(dq,J=12.3,8.0Hz,1H); ESI MS m / z752.362[M+H] + .

[0400] At -78 ℃, under Ar, to DCM (8mL) solution of above-mentioned substance (0.1g, 0.13mmol), add BCl (concentration in DCM is 1.0M, 0.8mL, 0.8mmol), and the mixture is stirred for 3h, and bath temperature reaches 0 ℃ simultaneously.Then the mixture is cooled at -78 ℃, and MeOH (3mL) is added carefully. After stirring at room temperature for 30 minutes, the mixture is concentrated under reduced pressure. With gained residue 1M NH MeOH solution (2 × 5mL) neutralize and concentrate again under reduced pressure. The residue was purified by flash chromatography on silica gel (MeOH / DCM, 1:9) to give (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol (0.031 g, 60.9%) as a white solid. 1H NMR (400MHz, CD3OD) δ8.25 (dd, J=4.8, 1.8Hz, 1H), 7.87 (dd, J=7.8, 1.8Hz, 1H), 6.73 (dd, J=7.8 ,4.7Hz,1H),3.91-3.82(m,2H),3.71(dd,J=9.3,5.5Hz,1H),3.68-3.61(m,3H),3.53(ddd,J=10 .0,8.5,5.2Hz,1H),3.44-3.35(m,2H),3.06(p,J=6.1,5.7Hz,1H),2.90-2.73(m,3H),2.68-2.6 0(m,1H),2.53(h,J=7.6Hz,1H),2.10(dq,J=11.9,6.1Hz,1H),1.71(dq,J=12.1,7.9Hz,1H); ESI MS m / z 392.176[M+H] + .

[0401] Example 26

[0402] (2S,3R,4R,5S)-2-(Hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol

[0403]

[0404] To a stirred solution of (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-((S)-pyrrolidin-3-ylmethyl)piperidine (0.14 g, 0.23 mmol) and 2-bromo-4-(trifluoromethyl)thiazole (0.1 g, 0.46 mmol) in DMA (5 mL) was added CsCO (0.22 g, 0.69 mmol) under Ar. The mixture was stirred at 80°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give 4-(trifluoromethyl)-2-((S)-3-(((2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidin-1-yl)methyl)pyrrolidin-1-yl)thiazole as an oil (0.11 g, 63%). 1HNMR (400MHz, CDCl3) δ7.39-7.27(m,20H),6.90(d,J=1.2Hz,1H),4.89(d,J=10.9Hz,1H),4.83(d,J=10. 9Hz,1H),4.75(d,J=11.5Hz,1H),4.70-4.68(m,2H),4.64(d,J=11.5Hz,1H),4.57-4.48(m,2H),3.87(dd, J=10.2,7.3Hz,1H),3.77-3.64(m,2H),3.60-3.42(m,5H),3.34-3.27(m,1H),3.16(dd,J=10.1,6.5Hz,1 H),2.84(dd,J=12.2,5.4Hz,1H),2.76-2.46(m,4H),2.09-1.98(m,1H),1.72(dq,J=12.7,7.5Hz,1H); ESI MS m / z 758.321[M+H] + .

[0405] At -78 ℃, under Ar, to DCM (5ml) solution of the above-mentioned substance (0.11g, 0.15mmol), add BCl (concentration in DCM is 1.0M, 0.75ml, 0.75mmol), and the mixture is stirred for 3h, and the bath temperature reaches 0 ℃ simultaneously.Then the mixture is cooled at -78 ℃, and MeOH (3mL) is carefully added. After stirring at room temperature for 30 minutes, the mixture is concentrated under reduced pressure. The gained residue is neutralized with 1M NH MeOH solution (2 × 5mL) and concentrated under reduced pressure again. The residue was purified by flash chromatography on silica gel (MeOH / DCM, 1:9) to give (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-)4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol (0.04 g, 67%) as a white solid. 1HNMR(400MHz,CD3OD)δ7.14(s,1H),3.90-3.82(m,2H),3.71(dd,J=9.3,5.5Hz,1 H),3.65-3.44(m,4H),3.37(dd,J=8.9,6.7Hz,1H),3.28(dd,J=10.1,6.4Hz,1H) ,3.06(q,J=5.7Hz,1H),2.88-2.80(m,2H),2.76(dd,J=12.7,8.5Hz,1H),2.71-2 .61(m,2H),2.20(dtd,J=12.2,6.9,4.9Hz,1H),1.86(dq,J=12.4,7.6Hz,1H); ESI m / z 398.132[M+H] + .

[0406] Example 27

[0407] (2S,3R,4R,5S)-2-(Hydroxymethyl)-1-(((S)-1-)(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol

[0408]

[0409] To a stirred solution of (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-((R)-pyrrolidin-3-ylmethyl)piperidine (210 mg, 0.35 mmol) and 2-chloro-3-(trifluoromethyl)pyridine (127 mg, 0.70 mmol) in DMF (5 mL) was added DIPEA (0.24 mL, 1.39 mmol). The mixture was stirred at 100°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (2 x 10 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give 3-(trifluoromethyl)-2-((S)-3-(((2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidin-1-yl)methyl)pyrrolidin-1-yl)pyridine as an oil (100 mg, 38%). ESI MS m / z 752.36 [M+H] + .

[0410] To a stirred solution of the above substance (95 mg, 0.13 mmol) in anhydrous DCM (5 mL) was added a BCl solution (1 M in DCM, 0.63 mL, 0.63 mmol) under N2 at -78°C. The mixture was stirred at 0°C for 4 h and then quenched with anhydrous MeOH (1 mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum, and the residue was dissolved in 1M NH3 in MeOH (10 mL) and stirred for another 10 minutes, then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2S, 3R, 4R, 5S)-2-(hydroxymethyl)-1-(((S)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol as a white solid (30 mg, 59%). 1 HNMR (400MHz, CD3OD) δ8.26 (dd, J=4.9, 1.8Hz, 1H), 7.87 (dd, J=7.8, 1.9Hz, 1H), 6. 73(dd,J=7.8,4.7Hz,1H),3.90-3.82(m,2H),3.76-3.59(m,4H),3.58-3.49(m,1H), 3.44-3.34(m,2H),3.11-3.03(m,1H),2.90(dd,J=12.8,6.8Hz,1H),2.83-2.76(m,1 H),2.73-2.61(m,2H),2.60-2.48(m,1H),2.15-2.04(m,1H),1.80-1.67(m,1H); ESI MS m / z 392.17[M+H] + .

[0411] Example 28

[0412] (2S,3R,4R,5S)-2-(Hydroxymethyl)-1-(((S)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol

[0413]

[0414] To a stirred solution of (2S,3R,4R,5S)-3,4,5-tri(benzyloxy)-2- ((benzyloxy)methyl)piperidine (1.42 g, 2.71 mmol) and (R)-3-formylpyrrolidine-1- carboxylic acid tert-butyl ester (0.60 g, 3.01 mmol) in dry DCM (20 mL) was added HOAc (0.2 mL) and the mixture was stirred for 30 min, then NaBH(OAc)3 (745 mg, 3.51 mmol) was added and the resulting mixture was stirred at room temperature for 18 h. The reaction was quenched with NaHCO3 solution at 0 °C. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (2 x 10 mL), separated and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give (S)-3-(((2S,3R,4R,5S)-3,4,5-tri(benzyloxy)-2-((benzyloxy)methyl)piperidin-1- yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester as an oil (1.51 g, 79%). ESI MS m / z 707.41 [M+H] + .

[0415] TFA (7 mL) was cooled to 0 °C and added to the above material (1.51 g, 2.13 mmol) in DCM (20 mL). The mixture was stirred at 0 °C for 10 min, then at room temperature for 2 h. TFA and DCM were removed under vacuum. The residue was dissolved in EtOAc (80 mL) and washed with NaHCO3 solution (2 x 20 mL), then with water, separated, dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel to give (2S,3R,4R,5S)-3,4,5-tri(benzyloxy)-2-((benzyloxy)methyl)-1-((R)- pyrrolidin-3-ylmethyl)piperidine as an oil (886 mg, 68%). ESI MS m / z 607.35 [M+H] + .

[0416] To a stirred solution of the above material (210 mg, 0.35 mmol) and 2-bromo-4-(trifluoromethyl)thiazole (162 mg, 0.70 mmol) in DMA (5 mL) was added CsCO (457 mg, 2.40 mmol). The mixture was stirred at 80°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (2 x 10 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel to give 4-(trifluoromethyl)-2-((S)-3-(((2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidin-1-yl)methyl)pyrrolidin-1-yl)thiazole as an oil (161 mg, 61%). ESI MS m / z 758.32[M+H] + .

[0417] To a stirred solution of the above substance (150 mg, 0.35 mmol) in anhydrous DCM (5 mL) was added a BCl solution (1 M in DCM, 1.0 mL, 1.0 mmol) under N2 at -78°C. The mixture was stirred at 0°C for 4 h and then quenched with anhydrous MeOH (1 mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum, and the residue was dissolved in 1M NH3 in MeOH (10 mL) and stirred for another 10 minutes, then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to give (2S, 3R, 4R, 5S)-2-(hydroxymethyl)-1-(((S)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol as a white solid (50 mg, 63%). 1 HNMR(400MHz,CD3OD)δ7.15-7.13(m,1H),3.90-3.82(m,2H),3.74-3.67(m,1H),3.65-3.43(m,4H),3.40-3.3 4(m,1H),3.31-3.23(m,1H),3.09-3.02(m,1H),2.94-2.60(m,5H),2.25-2.14(m,1H),1.94-1.80(m,1H); ESI MS m / z 398.13[M+H] + .

[0418] Example 29

[0419] (2S,3R,4R,5S)-2-(Hydroxymethyl)-1-(((R)-1-)(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0420]

[0421] To (2S, 3R, 4R, 5S) -3,4,5- tris (benzyloxy) -2- ( (benzyloxy) methyl) piperidine (0.8g, 1.5mmol) in DCM (30mL) solution, (S) -3- formyl piperidine -1- carboxylic acid tert-butyl ester (0.42g, 2.0mmol) and HOAc (0.5mL) were added. After stirring at room temperature for 10 minutes, NaBH (OAc) was added (0.48g, 2.26mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and then diluted with DCM (25mL). The organic matter was saturated with NaHCO aqueous solution, salt water washing, anhydrous NaSO dried and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 3:7) to give (R)-tert-butyl 3-(((2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidin-1-yl)methyl)piperidine-2-carboxylate as an oil (1.0 g, 94%). 1 HNMR (400MHz, CDCl3) δ7.38-7.27(m,20H),4.88(d,J=11.1Hz,1H),4.82(d,J=11.1Hz,1H),4.75(d,J= 11.5Hz,1H),4.71-4.63(m,3H),4.57-4.49(m,2H),3.99-3.87(m,2H),3.85(dd,J=10.1,6.9Hz,1H),3. 75-3.68(m,2H),3.63-3.48(m,2H),3.31-3.25(m,1H),2.89-2.77(m,2H),2.66-2.51(m,3H),2.44(dd ,J=13.0,5.6Hz,1H),1.73-1.57(m,3H),1.46(s,9H),1.45-1.33(m,1H),1.07(q,J=10.1Hz,1H); ESIMS m / z721.421[M+H] + .

[0422] The above substance (1.0 g, 1.4 mmol) was dissolved in 3:7 TFA: DCM (16 mL) solution at 0 ° C and stirred for 30 minutes. The reaction mixture was heated to room temperature for 2 hours and then concentrated to dryness. It was diluted with EtOAc (30 mL) and the organic matter was washed with saturated NaHCO aqueous solution (2 × 50 mL), dried over anhydrous Na SO and concentrated to give (2S, 3R, 4R, 5S) -3, 4, 5- tris (benzyloxy) -2- ((benzyloxy) methyl) -1- ((S) -piperidin-3-ylmethyl) piperidine as an oil (0.8 g, 92%). 1 HNMR (400MHz, CDCl3) δ7.85 (bs, 1H), 7.39-7.27 (m, 20H), 4.85 (d, J = 11.0Hz, 1H), 4.81 (d, J = 10.9Hz, 1H), 4.72-4.61 (m, 4H),4.56-4.45(m,2H),3.85(dd,J=10.3,7.6Hz,1H),3.70(dd,J=10.3,2.6Hz,1H),3.63(dd,J=9.2,5.7Hz,1H),3.57-3 .46(m,2H),3.42(dd,J=12.7,3.7Hz,1H),3.34-3.21(m,2H),2.92(dd,J=11.9,5.3Hz,1H),2.72(ddt,J=16.3,11.7,5.2 Hz,1H),2.65-2.49(m,3H),2.41(dd,J=13.1,10.6Hz,1H),2.05-1.93(m,1H),1.83-1.69(m,3H),1.11-0.96(m,1H); ESI MS m / z 621.362[M+H] + .

[0423] To a solution of the above material (0.155 g, 0.25 mmol) and 2-chloro-3-(trifluoromethyl)pyridine (0.09 g, 0.5 mmol) in anhydrous DMF (6 mL) was added KCO (0.1 g, 0.75 mmol) and the reaction mixture was heated at 120° C. overnight. The reaction mixture was partitioned between EtOAc (50 mL) and water, and the organics were separated and dried over anhydrous NaSO. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 2:8) to give 3-(trifluoromethyl)-2-((R)-3-(((2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)pyridine as an oil (0.1 g, 52.2%). 1HNMR (400MHz, CDCl3) δ8.42 (dd, J=4.8, 1.8Hz, 1H), 7.85 (dd, J=7.8, 2.0Hz, 1H), 7.37-7.27 (m, 20H), 6.95 (dd, J=7 .8,4.7Hz,1H),4.85(d,J=10.9Hz,1H),4.81(d,J=10.9Hz,1H),4.73(d,J=11.4Hz,1H),4.69-4.59(m,3H),4.56-4. 47(m,2H),3.85(dd,J=10.1,6.8Hz,1H),3.77-3.63(m,3H),3.62-3.45(m,3H),3.25(td,J=6.4,2.5Hz,1H),3.02-2 .87(m,2H),2.65-2.54(m,2H),2.54-2.45(m,2H),1.90(q,J=5.3Hz,1H),1.84-1.58(m,3H),1.14-1.01(m,1H); ESI MS m / z 766.378[M+H] + .

[0424] To a solution of the above material (0.1 g, 0.13 mmol) in DCM (6 ml) was added BCl₃ (1.0 M in DCM, 0.65 ml, 0.65 mmol) at -78°C under Ar, and the mixture was stirred for 3 h while the bath temperature reached 0°C. The mixture was then cooled to -78°C and MeOH (3 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 1M NH₃ in MeOH (2×5 mL) and concentrated again under reduced pressure. The residue was purified by flash chromatography on silica gel (MeOH / DCM, 1:9) to give (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-)3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol (0.033 g, 62%) as a white solid. 1HNMR(400MHz,CD3OD)δ8.43(dd,J=4.9,1.8Hz,1H),7.98(dd,J=7.8,1.9Hz,1H),7.13-7.07(m,1H) ,3.89-3.82(m,2H),3.74-3.69(m,1H),3.66(dd,J=9.4,5.6Hz,1H),3.53-3.46(m,2H),3.37(d,J=1 .9Hz,1H),2.99-2.92(m,2H),2.80(dd,J=12.2,5.4Hz,1H),2.68(dd,J=13.2,5.3Hz,1H),2.63-2.5 0(m,3H),1.93(dt,J=9.6,4.8Hz,1H),1.88-1.76(m,2H),1.76-1.63(m,1H),1.21-1.10(m,1H); ESI MS m / z 406.189[M+H] + .

[0425] Example 30

[0426] (2S,3R,4R,5S)-2-(Hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0427]

[0428] To a stirred solution of (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-((S)-piperidin-3-ylmethyl)piperidine (0.16 g, 0.25 mmol) and 2-bromo-4-(trifluoromethyl)thiazole (0.11 g, 0.50 mmol) in DMA (5 mL) was added CsCO (0.24 g, 0.75 mmol) under Ar. The mixture was stirred at 80°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give 4-(trifluoromethyl)-2-((R)-3-(((2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)thiazole as an oil (0.11 g, 59.5%). 1H NMR (400MHz, CDCl3) δ7.41-7.27(m,20H),6.89(d,J=1.2Hz,1H),4.89(d,J=10.8Hz,1H),4.84(d,J=10.8Hz,1H),4. 75(d,J=11.5Hz,1H),4.72-4.63(m,3H),4.58-4.50(m,2H),3.96(dt,J=13.2,4.2Hz,1H),3.87(dd,J=10.2,7.2Hz, 1H),3.81-3.69(m,3H),3.66-3.59(m,1H),3.54(q,J=9.9,9.1Hz,1H),3.31-3.24(m,1H),3.23-3.12(m,1H),2.89- 2.74(m,2H),2.68-2.52(m,3H),1.81-1.71(m,3H),1.61(qd,J=10.6,10.0,4.6Hz,1H),1.18(q,J=10.7Hz,1H); ESI MS m / z 772.331[M+H] + .

[0429] To a solution of the above material (0.11 g, 0.14 mmol) in DCM (8 ml) was added BCl₃ (1.0 M in DCM, 1.1 ml, 1.1 mmol) at -78°C under Ar, and the mixture was stirred for 3 h while the bath temperature reached 0°C. The mixture was then cooled to -78°C and MeOH (3 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 1M NH₃ in MeOH (2×5 mL) and concentrated again under reduced pressure. The residue was purified by flash chromatography on silica gel (MeOH / DCM, 1:9) to give (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol (0.049 g, 85%) as a white solid. 1HNMR(400MHz,CD3OD)δ7.17(s,1H),3.94-3.85(m,4H),3.74(dd,J=9.4,5.6Hz,1H),3 .54(ddd,J=10.2,8.6,5.2Hz,1H),3.36(d,J=9.0Hz,1H),3.20(ddd,J=13.4,10.6,3.4 Hz,1H),3.02(p,J=6.1Hz,1H),2.95(dd,J=13.0,9.3Hz,1H),2.79(dd,J=12.4,5.2Hz ,1H),2.74-2.55(m,3H),1.94-1.75(m,3H),1.70-1.58(m,1H),1.30-1.22(m,1H); ESI MS m / z412.144[M+H] + .

[0430] Example 31

[0431] (2S,3R,4R,5S)-2-(Hydroxymethyl)-1-(((S)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0432]

[0433] To (2S, 3R, 4R, 5S) -3, 4, 5- tris (benzyloxy) -2- ( (benzyloxy) methyl) piperidine (0.91g, 1.7mmol) in DCM (30mL) solution was added (R) -3- formyl piperidine -1- carboxylic acid tert-butyl ester (0.54g, 2.5mmol) and HOAc (0.5mL). After stirring at room temperature for 10 minutes, NaBH (OAc) was added (0.6g, 2.9mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and then diluted with DCM (25mL). The organic matter was washed with saturated NaHCO aqueous solution, brine, and dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 3:7) to give (S)-tert-butyl 3-(((2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidin-1-yl)methyl)piperidine-1-carboxylate as an oil (1.0 g, 81%). 1HNMR (400MHz, CDCl3) δ7.38-7.27(m,20H),4.88(d,J=11.0Hz,1H),4.83(d,J=11.0Hz,1H),4.77-4.67(m,3H),4.65 (d,J=11.5Hz,1H),4.57-4.47(m,2H),3.99-3.89(m,2H),3.85(dd,J=10.1,6.9Hz,1H),3.73(dd,J=11.1,3.6Hz,2H ),3.70(d,J=8.7Hz,1H),3.60-3.48(m,2H),3.37(tt,J=6.4,2.3Hz,1H),2.90-2.73(m,2H),2.65-2.52(m,2H),2.5 2-2.35(m,1H),1.80-1.72(bs,1H),1.68-1.58(m,2H),1.48(s,9H),1.45-1.34(m,1H),1.02(q,J=11.2Hz,1H); ESI MS m / z 721.417[M+H] + .

[0434] The above substance (1.0 g, 1.4 mmol) was dissolved in 3:7 TFA: DCM (16 mL) solution at 0 ° C and stirred for 30 minutes. The reaction mixture was heated to room temperature for 2 h and then concentrated to dryness. The organic matter was diluted with EtOAc (30 mL) and washed with saturated NaHCO (2 × 50 mL), dried over anhydrous Na SO, and concentrated to give (2S, 3R, 4R, 5S) -3, 4, 5- tris (benzyloxy) -2- ((benzyloxy) methyl) -1- ((R) -piperidin-3-ylmethyl) piperidine as an oil (0.85 g, 93%). 1HNMR (400MHz, CDCl3) δ7.89 (bs, 1H), 7.38-7.26 (m, 20H), 4.86-4.75 (m, 2H), 4.69 (d, J = 6.8Hz, 1 H),4.68-4.59(m,3H),4.51(d,J=12.1Hz,1H),4.46(d,J=12.1Hz,1H),3.83(dd,J=10.3,7.3Hz,1 H),3.72-3.66(m,1H),3.62(dd,J=9.1,5.6Hz,1H),3.55-3.41(m,2H),3.34-3.26(m,3H),2.80-2 .50(m,4H),2.48-2.34(m,2H),2.07-1.99(m,1H),1.86-1.65(m,3H),0.99(q,J=11.0Hz,1H); ESI MS m / z 621.368[M+H] + .

[0435] To a solution of the above material (0.18 g, 0.29 mmol) and 2-chloro-3-(trifluoromethyl)pyridine (0.10 g, 0.58 mmol) in anhydrous DMF (6 mL) was added KCO (0.12 g, 0.87 mmol) and the reaction mixture was heated at 120°C overnight. The reaction mixture was partitioned between EtOAc (50 mL) and water, and the organics were separated and dried over anhydrous NaSO. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 2:8) to give 3-(trifluoromethyl)-2-((S)-3-(((2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)pyridine as an oil (0.1 g, 46.8%). 1HNMR (400 MHz, CDC13) δ 8.41 (dd, J = 4.8, 1.8 Hz, 1H), 7.84 (dd, J = 7.8, 1.9 Hz, 1H), 7.38 - 7.27 (m, 20H), 6.94 (dd, J = 7.8, 4.7 Hz, 1H), 4.86 (d, J = 10.9 Hz, 1H), 4.80 (d, J = 10.9 Hz, 1H), 4.74 - 4.60 (m, 4H), 4.54 (d, J = 12.1 Hz, 1H), 4.48 (d, J = 12.2 Hz, 1H), 3.85 (dd, J = 10.2, 6.7 Hz, 1H), 3.73 (dd, J = 10.2, 2.4 Hz, 1H), 3.68 (dd, J = 9.3, 5.8 Hz, 1H), 3.65 - 3.60 (m, 1H), 3.58 - 3.43 (m, 4H), 2.95 - 2.86 (m, 1H), 2.81 - 2.73 (m, 2H), 2.63 - 2.46 (m, 2H), 2.33 (dd, J = 12.7, 8.6 Hz, 1H), 1.97 (bs, 1H), 1.81 - 1.56 (m, 3H), 1.10 - 0.97 (m, 1H); ESI MS m / z 766.37 [M+H] + .

[0436] To a solution of the above material (0.1 g, 0.13 mmol) in DCM (6 ml) was added BCl3(concentration 1.0 M in DCM, 1.0 ml, 1.0 mmol) at -78 °C under Ar and the mixture was stirred for 3 h while the bath temperature was allowed to reach 0 °C. The mixture was then cooled at -78 °C and MeOH (3 mL) was added carefully. After stirring at room temperature for 30 min, the mixture was concentrated under reduced pressure. The resulting residue was neutralized with 1 M NH3in MeOH (2 x 5 mL) and concentrated again under reduced pressure. The residue was purified by flash chromatography (MeOH / DCM, 1 :9) on silica gel to give (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol as a white solid (0.03 g, 62 %). 1HNMR(400MHz,CD3OD)δ8.44(dd,J=5.0,1.8Hz,1H),7.98(dd,J=7.8,1.9Hz,1H),7.14-7.07(m,1H),3. 92-3.80(m,2H),3.70(dd,J=9.3,5.1Hz,1H),3.64(dt,J=12.6,2.2Hz,1H),3.57-3.43(m,2H),3.38(t, J=8.7Hz,1H),3.13-3.06(m,1H),2.96(t,J=11.5Hz,1H),2.82(dd,J=13.0,5.4Hz,1H).2.78-2.43(m,4 H),2.08-1.98(m,1H),1.94-1.84(m,1H),1.83-1.76(m,1H),1.76-1.63(m,1H),1.23-1.12(m,1H); MS m / z 406.194[M+H] + .

[0437] Example 32

[0438] (2S,3R,4R,5S)-2-(Hydroxymethyl)-1-(((S)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0439]

[0440] To a stirred solution of (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-((R)-piperidin-3-ylmethyl)piperidine (0.15 g, 0.24 mmol) and 2-bromo-4-(trifluoromethyl)thiazole (0.11 g, 0.48 mmol) in DMA (5 mL) under Ar was added CsCO (0.23 g, 0.72 mmol). The mixture was stirred at 80°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give 4-(trifluoromethyl)-2-((S)-3-(((2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidin-1-yl)methyl)piperidin-1-yl)thiazole as an oil (0.12 g, 64.7%). 1H NMR (400MHz, CDCl3) δ7.43-7.27(m,20H),6.90(s,1H),4.90(d,J=10.9Hz,1H),4.84(d,J=10.9Hz,1H),4.78-4.64(m,4H),4. 55(d,J=12.2Hz,1H),4.51(d,J=12.1Hz,1H),3.96-3.80(m,3H),3.78-3.71(m,2H),3.61(ddd,J=10.2,8.7,5.6Hz,1H),3.51( t,J=9.2Hz,1H),3.44-3.38(m,1H),3.14(ddd,J=13.7,11.1,3.1Hz,1H),2.82-2.74(m,3H),2.65(dd,J=11.9,10.3Hz,1H),2. 40(dd,J=12.8,8.3Hz,1H),1.93-1.82(m,1H),1.83-1.69(m,2H),1.66-1.54(m,1H),1.14(ddd,J=18.1,10.2,5.8Hz,1H); ESI MS m / z 772.329[M+H] + .

[0441] To a solution of the above material (0.12 g, 0.15 mmol) in DCM (8 ml) was added BCl₃ (1.0 M in DCM, 1.3 mL, 1.3 mmol) at -78°C under Ar, and the mixture was stirred for 3 h while the bath temperature reached 0°C. The mixture was then cooled to -78°C, and MeOH (3 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 1M NH₃ in MeOH (2×5 mL) and concentrated again under reduced pressure. The residue was purified by flash chromatography on silica gel (MeOH / DCM, 1:9) to give (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol (0.056 g, 90%) as a white solid. 1HNMR(400MHz,CD3OD)δ7.18(s,1H),3.97-3.89(m,2H),3.88-3.85(m,2H),3.72(dd,J=9.1,5.3Hz,1H) ,3.56(ddd,J=9.3,8.2,5.5Hz,1H),3.37(t,J=8.7Hz,1H),3.16(ddd,J=12.9,11.0,3.3Hz,1H),3.05(q ,J=5.7Hz,1H),2.89(dd,J=13.0,9.8Hz,1H),2.82-2.75(m,1H),2.74-2.64(m,2H),2.56(dd,J=13.0, 8.4Hz,1H),1.99-1.85(m,2H),1.80(dt,J=13.3,3.9Hz,1H),1.70-1.58(m,1H),1.30-1.21(m,1H); ESI MS m / z 412.154[M+H] + .

[0442] Example 311

[0443] (2S,3R,4R,5S)-1-(((1s,4R)-4-(difluoromethyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol

[0444]

[0445] To a solution of cyclohexane-1,4-diyldimethanol (2.00 g, 13.9 mmol) in anhydrous DCM (60 mL) cooled at 0°C was added DIPEA (2.06 g, 16.0 mmol) and benzoyl chloride (1.97 g, 14.0 mmol) under Ar. The mixture was stirred at room temperature for 16 h and then diluted with saturated aqueous NaHCO3 (50 mL). After extraction with DCM (3 × 30 mL), the combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under vacuum, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:3 to 1:2) to give methyl (4-(hydroxymethyl)cyclohexyl)benzoate as a light yellow oil (1.51 g, 43%).

[0446] DCM (30mL) mixture of above-mentioned substance (0.950g, 3.83mmol) and DMP (2.12g, 5.0mmol) is at room temperature stirred to 1h, forms white suspension.Hexane (40mL) is added, and suspension is filtered by diatomite filter cake.Collect filtrate and concentrate under vacuum, and residue is passed through flash chromatography (EtOAc / hexane, 1:4) purifying on silica gel, obtain (4-formylcyclohexyl) methyl benzoate, be colorless oil (0.50g, 53%).

[0447] Under Ar, DAST (0.80 g, 5.0 mmol) was added to a solution of the above-mentioned substance (0.50 g, 2.0 mmol) in anhydrous DCM (10 mL) cooled at -78 ° C., and the mixture was stirred at -78 ° C for 30 minutes, then at room temperature for 5 h. The mixture was cooled at -78 ° C and quenched with a saturated NaHCO aqueous solution (20 mL). The organic layer was collected and the aqueous layer was extracted with DCM (3 × 20 mL). The combined extracts were dried with anhydrous Na SO. After filtration, the solvent was evaporated under vacuum, and the residue was purified by flash chromatography (EtOAc / hexane, 1:10) on silica gel to obtain methyl (4-(difluoromethyl)cyclohexyl)benzoate as a colorless oil (0.40 g, 75%).

[0448] A mixture of the above material (0.40 g, 1.5 mmol) and KCO (0.45 g, 0.33 mmol) in MeOH (25 mL) was stirred for 16 h. The solvent was removed under vacuum and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:2) to give (4-(difluoromethyl)cyclohexyl)methanol as a clear liquid (0.21 g, 86%).

[0449] To a solution of the above material (0.21 g, 1.3 mmol) in acetone (25 mL) cooled at 0°C was added a pre-cooled 0°C solution of CrO₃ (0.60 g, 6.0 mmol) in 2.0 M H₂SO₄ (6 mL). The mixture was stirred at 0°C for 1 h and at room temperature for 16 h. Isopropanol (5 mL) was then added, and the mixture was stirred for an additional 1 h. After concentration under vacuum, the mixture was diluted with water (50 mL) and extracted with DCM (3 x 20 mL). The combined extracts were dried over anhydrous Na₂SO₄. After filtration, the solvent was evaporated under vacuum, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:1 to 3:1) to give 4-(difluoromethyl)cyclohexanecarboxylic acid as a white solid (0.22 g, 96%). 1 H NMR showed that the solid contained a mixture of cis and trans isomers in a ratio of cis:trans = 0.32:0.68.

[0450] A mixture of 4-(difluoromethyl)cyclohexanecarboxylic acid (0.050 g, 0.28 mmol), (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine (0.147 g, 0.281 mmol) (Lahav et al. J Am Chem Soc 2017, 139, 14192-14197), HATU (0.20 g, 0.53 mmol) and DIPEA (0.11 g, 0.85 mmol) in DMF (5 mL) was stirred at room temperature for 16 h. The mixture was diluted with saturated aqueous NaHCO (20 mL) and extracted with EtOAc (3×15 mL). The combined extracts were washed with brine (2×20 mL) and dried over anhydrous NaSO. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified and separated by flash chromatography on silica gel (EtOAc / hexane, 1:5 to 1:3) to give ((1r,4S)-4-(difluoromethyl)cyclohexyl)((2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidin-1-yl)methanone (0.13 g, 68%) and ((1s,4R)-4-(difluoromethyl)cyclohexyl)((2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidin-1-yl)methanone (0.055 g, 29%), both as white solids. ESI MS m / z 684.352 [M+H] + .

[0451] To a solution of ((1r,4R)-4-(difluoromethyl)cyclohexyl)((2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidin-1-yl)methanone (0.14 g, 0.20 mmol) in anhydrous Et2O (10 mL) cooled at 0°C was added LAH (0.050 g, 1.3 mmol) under Ar, and the mixture was stirred at 0°C for 4 h. The reaction was then quenched with water and diluted with saturated aqueous NaHCO3 (20 mL). After extraction with Et2O (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 by flash chromatography on silica gel (EtOAc / hexanes, 1:12 to 1:7) to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(((1s,4R)-4-(difluoromethyl)cyclohexyl)methyl)piperidine as a colorless oil (0.10 g, 73%). ESI MS m / z 670.372 [M+H] + .

[0452] Under hydrogen (1 atm.), a mixture of the above substance (0.10 g, 0.15 mmol), Pd(OH)2 / C (20% Pd by mass, 0.050 g, 0.094 mmol) and 2 drops of concentrated HCl in MeOH (15 mL) was stirred overnight. The mixture was filtered through a celite filter cake, and the filtrate was collected and concentrated to dryness. The residue was neutralized with 1M NH3 in MeOH and purified by flash chromatography on silica gel (0.5M NH3MeOH / DCM, 1:5) to give (2S,3R,4R,5S)-1-(((1s,4R)-4-(difluoromethyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol (0.033 g, 72%) as a white solid. 1 HNMR(500MHz,CD3OD)δ5.75(td,J=57.1,5.3Hz,1H),3.90-3.79(m,2H),3.70(dd,J=9.3,5.5Hz,1H),3.55-3.48(m,1H) ,3.39-3.33(m,1H),3.04-2.99(m,1H),2.78-2.70(m,2H),2.65-2.57(m,2H),1.90-1.76(m,2H),1.64-1.46(m,8H); ESI MS m / z 310.184[M+H] + .

[0453] Example 312

[0454] (2S,3R,4R,5S)-1-(((1r,4S)-4-(difluoromethyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol

[0455]

[0456] To a solution of ((1r,4S)-4-(difluoromethyl)cyclohexyl)((2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidin-1-yl)methanone (0.25 g, 0.37 mmol) in anhydrous THF (10 mL) cooled at 0°C was added LAH (0.050 g, 1.3 mmol) under Ar, and the mixture was stirred at 0°C for 4 hours. The reaction was then quenched with water and diluted with saturated aqueous NaHCO3 (20 mL). After extraction with Et2O (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 by flash chromatography on silica gel (EtOAc / hexanes, 1:12 to 1:7) to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(((1r,4S)-4-(difluoromethyl)cyclohexyl)methyl)piperidine (0.075 g, 30%) as a colorless oil. ESI MS m / z 670.377 [M+H] + .

[0457] A mixture of the above material (0.075 g, 0.11 mmol), Pd(OH)2 / C (20% Pd by mass, 0.050 g, 0.094 mmol) and 2 drops of concentrated HCl in MeOH (20 mL) was stirred overnight under hydrogen (1 atm.). The mixture was filtered through a celite filter cake, and the filtrate was collected and concentrated to dryness. The residue was neutralized with 1 M NH3 in MeOH and purified by flash chromatography on silica gel (0.5 M NH3MeOH / DCM, 1:5) to give (2S,3R,4R,5S)-1-(((1r,4S)-4-(difluoromethyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol (0.021 g, 60%) as a white solid. 1 HNMR(400MHz,CD3OD)δ5.71(td,J=57.1,4.5Hz,1H),3.89-3.77(m,2H),3.70 (dd,J=9.2,5.4Hz,1H),3.56-3.48(m,1H),3.40-3.33(m,1H),3.03-2.96(m, 1H),2.73(dd,J=12.4,5.4Hz,1H),2.65-2.46(m,3H),2.00-1.81(m,4H),1.8 0-1.62(m,1H),1.55-1.41(m,1H),1.26-1.10(m,2H),1.00-0.82(m,2H);ESI m / z 310.183[M+H] + .

[0458] Example 313

[0459] (2S,3R,4R,5S)-1-(((1s,4R)-4-(1,1-difluoroethyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol

[0460]

[0461] To a solution of cis / trans-4-(hydroxymethyl)cyclohexanecarboxylic acid (3.20 g, 20.2 mmol) in anhydrous MeOH (50 mL) was added SOCl2 (4.8 g, 40 mmol) dropwise, and the mixture was stirred at room temperature for 4 h. The solvent was then removed under vacuum, and the residue was diluted with saturated aqueous NaHCO3 (40 mL). After extraction with DCM (3 × 40 mL), the combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under vacuum to obtain a clear liquid. The liquid was dissolved in anhydrous DMF (30 mL) and cooled at 0°C, followed by the addition of imidazole (2.72 g, 40.0 mmol) and TBDMSCl (4.52 g, 30.0 mmol). After stirring at room temperature for 16 h, the mixture was diluted with brine (100 mL) and extracted with EtOAc (3 × 40 mL). The combined extracts were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under vacuum, and the residue was purified by flash chromatography (EtOAc / hexane, 1: 9) on silica gel to obtain a colorless oil. Under Ar, the oil was dissolved in anhydrous THF (50mL), and the solution was cooled at 0°C. LAH (1.00g, 26.3mmol) was added in batches, and the mixture was stirred at 0°C for 1h. Wet sodium sulfate heptahydrate (50g) was added to quench the reaction, and the suspension was stirred for 30 minutes. After filtration, the solvent was evaporated under vacuum, and the residue was purified by flash chromatography (EtOAc / hexane, 1: 4 to 1: 2) on silica gel to obtain a mixture of cis and trans-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)methanol, which was a colorless oil (4.6 grams, 88%, 3 steps).

[0462] To a solution of the above material (2.30 g, 9.00 mmol) in anhydrous THF (40 mL) cooled at 0 °C under Ar was added MeMgCl (3.0 M in THF, 4.0 mL, 12 mmol) and the mixture was stirred at room temperature for 16 h. The mixture was quenched with ice water, diluted with saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (2 x 50 mL). The combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under vacuum and the residue was purified by flash chromatography (EtOAc / hexanes, 1 :4) on silica gel to give 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)ethanol as a colorless oil (2.40 g, 98%).

[0463] To a solution of the above material (2.40 g, 8.80 mmol) and DMP (5.60 g, 13.2 mmol) in DCM (50 mL) was stirred at room temperature for 3 h to form a white suspension. Hexanes (50 mL) was added and the suspension was filtered through a pad of celite. The filtrate was collected and concentrated under vacuum and the residue was purified by flash chromatography (EtOAc / hexanes, 1 :15 to 1 :6) on silica gel to give 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)ethanone as a colorless oil (2.11 g, 89%).

[0464] To a solution of the above material (2.40 g, 8.80 mmol) and DMP (5.60 g, 13.2 mmol) in DCM (50 mL) was stirred at room temperature for 3 h to form a white suspension. Hexanes (50 mL) was added and the suspension was filtered through a pad of celite. The filtrate was collected and concentrated under vacuum and the residue was purified by flash chromatography (EtOAc / hexanes, 1 :15 to 1 :6) on silica gel to give 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)ethanone as a colorless oil (2.11 g, 89%).

[0465] To a solution of the above material (2.11 g, 7.8 mmol) in anhydrous THF (30 mL) cooled at 0° C. under Ar was added TBAF (1.0 M in THF, 10.0 mL, 10.0 mmol), and the mixture was stirred at room temperature for 3 h. After dilution with saturated aqueous NaHCO₃ (40 mL), the mixture was extracted with EtOAc (2×30 mL), and the combined extracts were dried over anhydrous Na₂SO₄. After filtration, the solvent was evaporated under vacuum, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 2:3 to 1:1) to give 1-(4-(hydroxymethyl)cyclohexyl)ethanone as a clear liquid (1.10 g, 92%).

[0466] Under Ar, to a solution of the above-mentioned substance (1.10 g, 7.20 mmol) in anhydrous DCM (25 mL) cooled at 0° C., DMAP (0.25 g, 2.0 mmol), DIPEA (1.93 g, 15.0 mmol) and benzoyl chloride (1.40 g, 10.0 mmol) were added. The mixture was stirred at room temperature for 16 h and diluted with saturated NaHCO aqueous solution (30 mL). After extraction with DCM (3×30 mL), the combined extracts were dried over anhydrous Na SO. After filtration, the solvent was evaporated under vacuum, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:6 to 1:3) to obtain methyl (4-acetylcyclohexyl)benzoate as a light yellow oil (1.85 g, 99%).

[0467] Under Ar, DAST (5.74 g, 35.9 mmol) was added to a solution of the above substance (1.70 g, 6.53 mmol) in anhydrous DCM (15 mL), and the mixture was stirred at room temperature for 1 hour and then heated to reflux for 4 days. The mixture was cooled at -78 ° C and quenched with saturated NaHCO3 aqueous solution (50 mL). After extraction with DCM (2 × 50 mL), the combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under vacuum, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:11 to 1:9) to obtain (4- (1,1-difluoroethyl) cyclohexyl) benzoic acid methyl ester as a light yellow oil (1.45 g, 79%).

[0468] A mixture of the above material (1.45 g, 5.13 mmol) and KCO (1.5 g, 11 mmol) in MeOH (40 mL) was stirred for 16 h. The solvent was removed under vacuum and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:4 to 1:2) to give (4-(1,1-difluoroethyl)cyclohexyl)methanol as a clear liquid (0.85 g, 93%).

[0469] To a solution of the above substance (0.85 g, 4.8 mmol) in acetone (40 mL) cooled at 0°C was added a 2.0 M H2SO4 aqueous solution (10 mL) of CrO3 (1.5 g, 15 mmol) pre-cooled at 0°C. The mixture was stirred at 0°C for 1 h and at room temperature for 16 h. Isopropanol (5 mL) was then added, and the mixture was stirred for another 1 h. After concentration under vacuum, the mixture was diluted with water (50 mL) and extracted with DCM (3×30 mL). The combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under vacuum to give 4-(1,1-difluoroethyl)cyclohexanecarboxylic acid as a white solid (0.90 g, 98%). 1 H NMR showed that the solid contained a mixture of cis and trans isomers in a ratio of cis:trans = 0.35:0.65.

[0470] A mixture of 4-(1,1-difluoroethyl)cyclohexanecarboxylic acid (0.192 g, 1.00 mmol) and (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine (0.340 g, 0.649 mmol), HATU (0.46 g, 1.2 mmol) and DIPEA (0.19 g, 1.5 mmol) in DMF (10 mL) was stirred at room temperature for 16 h. The mixture was diluted with saturated aqueous NaHCO (20 mL) and extracted with EtOAc (3 x 20 mL). The combined extracts were washed with brine (2 x 20 mL) and dried over anhydrous NaSO. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified and separated by flash chromatography on silica gel (EtOAc / hexane, 1:6 to 1:4) to give ((1r,4S)-4-(1,1-difluoroethyl)cyclohexyl)((2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidin-1-yl)methanone (0.28 g, 62%) and ((1s,4R)-4-(1,1-difluoroethyl)cyclohexyl)((2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidin-1-yl)methanone (0.13 g, 29%), both as white solids.

[0471] To a solution of ((1s,4R)-4-(1,1-difluoroethyl)cyclohexyl)((2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidin-1-yl)methanone (0.13 g, 0.19 mmol) in anhydrous Et2O (15 mL) cooled at 0°C was added LAH (0.050 g, 1.3 mmol) under Ar, and the mixture was stirred at 0°C for 4 hours. The reaction was then quenched with water and diluted with saturated aqueous NaHCO3 (20 mL). After extraction with Et2O (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 by flash chromatography on silica gel (EtOAc / hexanes, 1:12 to 1:7) to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(((1s,4R)-4-(1,1-difluoroethyl)cyclohexyl)methyl)piperidine as a colorless oil (0.099 g, 76%). ESI MS m / z 684.385 [M+H] + .

[0472] Under hydrogen (1 atm.), a mixture of the above substance (0.099 g, 0.14 mmol), Pd(OH)2 / C (20% Pd by mass, 0.050 g, 0.094 mmol) and 2 drops of concentrated HCl in MeOH (20 mL) was stirred overnight. The mixture was filtered through a celite filter cake, and the filtrate was collected and concentrated to dryness. The residue was neutralized with 1M NH3 in MeOH and purified by flash chromatography on silica gel (0.5M NH3MeOH / DCM, 1:5) to obtain (2S,3R,4R,5S)-1-(((1s,4R)-4-(1,1-difluoroethyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol (0.034 g, 72%) as a white solid. 1 H NMR(400MHz, DMSO-d6)4.74(d,J=4.6Hz,1H),4.65(d,J=4.2Hz,1H),4.61(d,J= 5.1Hz,1H),4.10(t,J=5.3Hz,1H),3.69-3.58(m,2H),3.47-3.38(m,1H),3.31-3 .22(m,1H),3.14-3.04(m,1H),2.86-2.75(m,1H),2.65(dd,J=13.0,8.3Hz,1H), 2.58-2.38(m,3H),1.85-1.47(m,9H),1.47-1.32(m,2H),1.30-1.18(m,2H); ESI MS m / z 324.199[M+H]+ .

[0473] Example 314

[0474] (2S,3R,4R,5S)-1-(((1r,4S)-4-(1,1-difluoroethyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol

[0475]

[0476] To a solution of ((1r,4S)-4-(1,1-difluoroethyl)cyclohexyl)((2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidin-1-yl)methanone (0.27 g, 0.39 mmol) in anhydrous Et2O (20 mL) cooled at 0°C was added LAH (0.080 g, 2.1 mmol) under Ar, and the mixture was stirred at 0°C for 4 h. The reaction was then quenched with water and diluted with saturated aqueous NaHCO3 (20 mL). After extraction with Et2O (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 by flash chromatography on silica gel (EtOAc / hexanes, 1:12 to 1:7) to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(((1r,4S)-4-(1,1-difluoroethyl)cyclohexyl)methyl)piperidine as a colorless oil (0.23 g, 86%). ESI MS m / z 684.381 [M+H] + .

[0477] Under hydrogen (1 atm.), a mixture of the above substance (0.23 g, 0.34 mmol), Pd(OH)2 / C (20% Pd by mass, 0.080 g, 0.15 mmol) and 3 drops of concentrated HCl in MeOH (25 mL) was stirred overnight. The mixture was filtered through celite, and the filtrate was collected and concentrated to dryness. The residue was neutralized with 1M NH3 in MeOH and purified by flash chromatography on silica gel (0.5M NH3MeOH / DCM, 1:5) to give (2S,3R,4R,5S)-1-(((1r,4S)-4-(1,1-difluoroethyl)cyclohexyl)methyl)-2-(hydroxymethyl)-piperidine-3,4,5-triol (0.092 g, 85%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ4.74(d,J=4.6Hz,1H),4.64(d,J=4.2Hz,1H),4.60(d,J=5.0H z,1H),4.09(t,J=5.1Hz,1H),3.67-3.58(m,2H).3.42(dt,J=9.6,5.1Hz,1H),3.29-3. 20(m,1H),3.12-3.03(m,1H),2.82-2.74(m,1H),2.57-2.33(m,4H),1.90-1.64(m,5H) ,1.54(t,J=19.4Hz,3H),1.45-1.30(m,1H),1.19-1.04(m,2H),0.89-0.74(m,2H); ESI MS m / z 324.198[M+H] + .

[0478] As shown in Table 1, Examples 33-310 were synthesized according to procedures similar to those described in the present invention.

[0479] Biological activity

[0480] For determination of IC of GBA2 inhibition in cell lysates 50 Test of value

[0481] HEK 293T cells stably expressing GBA2 were generated as follows. Human GBA2 (GBA2 nucleotide accession number BC011363) was PCR amplified using the following primers: sense 5'-CGC AAA TGG GCG GTA GGC GTG---3' and antisense 5'-TAG TCAGCC ATG GGG CGG AGA---3') and cloned into pLenti-GIII-CMV from ABM Inc. The construct was verified by sequencing. Lentiviral particles containing the pLenti-GIII-CMV plasmid carrying GBA2 were prepared using a third-generation viral packaging mix (ABM cat#LV053-G074) for HEK293T cells and provided as a viral particle suspension. The viral suspension was used to infect HEK293T cells. Cell populations stably expressing human GBA2 were selected with puromycin for several weeks and assayed by activity assays and Western blotting.

[0482] Various concentrations of test compounds were prepared in DMSO and then diluted in a pH 5.5 buffer consisting of 100 mM citric acid, 200 mM sodium phosphate dibasic, and 1% v / v C10E6. Homogenates (0.25 mg / mL) of a stable HEK293T-overexpressing GBA2 cell line were preincubated with a GCase inhibitor (20 μM (6R,7R,8S)-8-ethyl-4-azaspiro[2.5]octan-6,7-diol) on ice for 10 minutes. The reaction consisted of 20 μL of 750 μM 4-methylumbelliferyl-β-D-glucopyranoside in 5% DMSO in the same buffer, 20 μL of GBA2 cell homogenate pretreated with (6R,7R,8S)-8-ethyl-4-azaspiro[2.5]octan-6,7-diol, and 20 μL of various concentrations of test compounds in 10% DMSO in the same buffer. The final concentrations in the reaction were 0.083 mg / mL GBA2-cell homogenate, 250 μM 4-methylumbelliferyl-β-D-pyranoside, and various concentrations of inhibitor. The inhibitor and GBA2-cell homogenate were preincubated together at 37°C for 5 minutes. The reaction was initiated by adding substrate and allowed to react at 37°C for 20 minutes to assess GBA2 activity. The reaction was terminated by adding an equal volume (60 μL) of 0.5 M NaOH, 0.3 M glycine, pH 10.5. Fluorescence was measured using a Biotek Synergy H4 microplate reader at an excitation wavelength of 365 nm and an emission wavelength of 450 nm. Incubations without enzyme or inhibitor were used to determine no enzyme activity and maximum enzyme activity, respectively. The IC was determined by fitting the data to a log [inhibitor concentration] versus response curve using GraphPad Prism. 50 IC 50 The values ​​were calculated as the inhibitor concentration required to inhibit GBA2 activity by 50%.

[0483] The compounds of the present invention tested showed an IC of GBA2 inhibition 50 The values ​​ranged from 0.1 nM to 50 μM.

[0484] Representative data of the above GBA2 inhibition test are shown in Table 3, where the symbol “***” represents IC 50 <100nM; the symbol “**” indicates 100nM <IC 50 <1μM; the symbol "*" indicates 1μM <IC 50 <25 μM.

[0485] Table 3

[0486]

[0487]

[0488] The present invention has been described with respect to one or more embodiments. However, it will be apparent to those skilled in the art that many variations and modifications may be made without departing from the scope of the invention as defined in the appended claims.

[0489] Therefore, although various embodiments of the present invention are disclosed herein, many adjustments and modifications can be made within the scope of the present invention according to the common knowledge of those skilled in the art. Such modifications include replacing any aspect of the present invention with known equivalents in order to achieve the same results in substantially the same manner. It should be understood that specific embodiments can be combined in any manner and in any number to produce additional embodiments, and unless the context otherwise indicates, any permutation and combination of embodiments should be considered to be disclosed by the description of this application. Numerical ranges include the numbers that define the ranges. The description of numerical ranges in the present invention is intended only to be used as a shorthand method of individually referring to each individual value falling within the range. Unless otherwise indicated in the present invention, each individual value is incorporated into this specification as if it were individually cited in the present invention. Unless otherwise indicated in the present invention or clearly contradicted by the context, the terms "a" and "an" and "the" and similar references used in the context of describing the present invention should be interpreted as covering both the singular and the plural. In the specification, the word "comprising" is used as an open term, essentially equivalent to the phrase "including but not limited to", and the word "comprises" has a corresponding meaning. However, it should be understood that where the words "comprising" or "comprises," or variations thereof, are used herein, variations or modifications of "consisting of" or "consists of" that exclude any element, step, or ingredient not specified, or variations or modifications of "consisting essentially of" or "consists essentially of" that limit the materials or steps specified and that do not materially affect the basic and novel characteristics of the claimed invention are also contemplated. Citation of references herein should not be construed as an admission that these references are prior art to the present invention. All publications are incorporated herein by reference as if each individual publication was specifically and individually indicated to be incorporated herein by reference and as if fully set forth herein. The present invention includes all embodiments and variations substantially as described above and with reference to the examples.

[0490] References

[0491] 1.Grabowski,GALancet 2008,372,1263-1271.

[0492] 2.Massimo,A.et al.Neurochem Res 2016,41,210-20.

[0493] 3.Woeste,MAet al.FrontMolNeurosci 2017,10,386.

[0494] 4.Hayashi,Y.et al.JBiol Chem 2007,282,30889-30900.

[0495] 5.Lahiri,S.et al.CellMolLife Sci 2007,64,2270-2284.

[0496] 6.Mutoh,T.et al.CNSNeurolDisordDrug Targets 2006,5,375-380.

[0497] 7.Kim,S.et al.ProcNatlAcadSci USA 2018,115,798-803.

[0498] 8.Halmer,R.et al.CellPhysiolBiochem 2014,34,111-118.

[0499] 9.Di Pardo,A.et al.FrontNeurosci 2017,11,698.

[0500] 10.Dodge,JCet al.ProcNatlAcadSci USA 2015,112,8100-5.

[0501] 11.Somogyi,A.et al.IntJMol Sci 2018,19,625.

[0502] 12.Zervas,M.et al.CurrBiol 2001,11,1283-7.

[0503] 13.Boudewyn,LCet al.NeurobiolDis 2017,105,257-270.

[0504] 14. Ashe, K. M. et al. PLoS One 2011, 6, e21758.

[0505] 15. Ilan, Y. Am J Physiol-Gast Liver Physiol 2016, 310, G1102-G1117.

[0506] 16. Marques, A. R. et al. PLoS One 2015, 10, e0135889.

[0507] 17. Nietupski, J. B. et al. Mol Genet Metab 2012, 105, 621-8.

[0508] 18. PCT Int. Appl. WO 2017 / 185010.

[0509] 19. Mistry, P. K. et al. Proc Natl Acad Sci USA 2014, 111, 4934-9.

[0510] 20. Loberto, N. et al. PLoS One 2014, 9, e104763.

[0511] 21. Margalit, M. et al. J Pharm Exp Ther 2006, 319, 105-110.

[0512] 22. Margalit, M. et al. Am J Physiol-Gast Liver Physiol 2005, 289, G917-G925.23. Zigmond, E. et al. Gut 2007, 56, 82-89.

[0513] 24. Zhang, W. et al. Clin & Exp Immunol 2009, 157, 359-364.

[0514] 25. Mizrahi, M. et al. J Clin Trans Hepatol 2018, 6, 127-134.

[0515] 26. Ghisaidoobe, A. T. et al. J Med Chem 2014, 57, 9096-104.

[0516] 27. Farfel-Becker, T. et al. DisModelMech 2011, 4, 746-752. SEQUENCE LISTING <110> Alecto Therapeutics <120> Non-lysosomal glucosylceramidase inhibitors and uses thereof <130> 10103-032WO1 <140> Not yet allocated <141> 2021-05-06 <150> 63 / 021,432 <151> 2020-05-07 <160> 1 <170> PatentIn version 3.5 <210> 1 <211> 926 <212> PRT <213> Homo sapiens <400> 1 Met Gly Thr Gln Asp Pro Gly Asn Met Gly Thr Gly Val Pro Ala Ser 1 5 10 15 Glu Gln Ile Ser Cys Ala Lys Glu Asp Pro Gln Val Tyr Cys Pro Glu 20 25 30 Glu Thr Gly Gly Thr Lys Asp Val Gln Val Thr Asp Cys Lys Ser Pro 35 40 45 Glu Asp Ser Arg Pro Pro Lys Glu Thr Asp Cys Cys Asn Pro Glu Asp 50 55 60 Ser Gly Gln Leu Met Val Ser Tyr Glu Gly Lys Ala Met Gly Tyr Gln 65 70 75 80 Val Pro Pro Phe Gly Trp Arg lie Cys Leu Ala His Glu Phe Thr Glu 85 90 95 Lys Arg Lys Pro Phe Gin Ala Asn Asn Val Ser Leu Ser Asn Met lie 100 105 110 Lys His lie Gly Met Gly Leu Arg Tyr Leu Gin Trp Trp Tyr Arg Lys 115 120 125 Thr His Val Glu Lys Lys Thr Pro Phe lie Asp Met lie Asn Ser Val 130 135 140 Pro Leu Arg Gin lie Tyr Gly Cys Pro Leu Gly Gly lie Gly Gly Gly 145 150 155 160 Thr lie Thr Arg Gly Trp Arg Gly Gin Phe Cys Arg Trp Gin Leu Asn 165 170 175 Pro Gly Met Tyr Gin His Arg Thr Val lie Ala Asp Gin Phe Thr Val 180 185 190 Cys Leu Arg Arg Glu Gly Gin Thr Val Tyr Gin Gin Val Leu Ser Leu 195 200 205 Glu Arg Pro Ser Val Leu Arg Ser Trp Asn Trp Gly Leu Cys Gly Tyr 210 215 220 Phe Ala Phe Tyr His Ala Leu Tyr Pro Arg Ala Trp Thr Val Tyr Gin 225 230 235 240 Leu Pro Gly Gln Asn Val Thr Leu Thr Cys Arg Gln Ile Thr Pro Ile 245 250 255 Leu Pro His Asp Tyr Gln Asp Ser Ser Leu Pro Val Gly Val Phe Val 260 265 270 Trp Asp Val Glu Asn Glu Gly Asp Glu Ala Leu Asp Val Ser Ile Met 275 280 285 Phe Ser Met Arg Asn Gly Leu Gly Gly Gly Asp Asp Ala Pro Gly Gly 290 295 300 Leu Trp Asn Glu Pro Phe Cys Leu Glu Arg Ser Gly Glu Thr Val Arg 305 310 315 320 Gly Leu Leu Leu His His Pro Thr Leu Pro Asn Pro Tyr Thr Met Ala 325 330 335 Val Ala Ala Arg Val Thr Ala Ala Thr Thr Val Thr His Ile Thr Ala 340 345 350 Phe Asp Pro Asp Ser Thr Gly Gln Gln Val Trp Gln Asp Leu Leu Gln 355 360 365 Asp Gly Gln Leu Asp Ser Pro Thr Gly Gln Ser Thr Pro Thr Gln Lys 370 375 380 Gly Val Gly Ile Ala Gly Ala Val Cys Val Ser Ser Lys Leu Arg Pro 385 390 395 400 Arg Gly Gln Cys Arg Leu Glu Phe Ser Leu Ala Trp Asp Met Pro Arg 405 410 415 Ile Met Phe Ala Lys Gly Gln Val His Tyr Arg Arg Tyr Thr Arg Phe 420 425 430 Phe Gly Gln Asp Gly Asp Ala Ala Pro Ala Leu Ser His Tyr Ala Leu 435 440 445 Cys Arg Tyr Ala Glu Trp Glu Glu Arg Ile Ser Ala Trp Gln Ser Pro 450 455 460 Val Leu Asp Asp Arg Ser Leu Pro Ala Trp Tyr Lys Ser Ala Leu Phe 465 470 475 480 Asn Glu Leu Tyr Phe Leu Ala Asp Gly Gly Thr Val Trp Leu Glu Val 485 490 495 Leu Glu Asp Ser Leu Pro Glu Glu Leu Gly Arg Asn Met Cys His Leu 500 505 510 Arg Pro Thr Leu Arg Asp Tyr Gly Arg Phe Gly Tyr Leu Glu Gly Gln 515 520 525 Glu Tyr Arg Met Tyr Asn Thr Tyr Asp Val His Phe Tyr Ala Ser Phe 530 535 540 Ala Leu Ile Met Leu Trp Pro Lys Leu Glu Leu Ser Leu Gln Tyr Asp 545 550 555 560 Met Ala Leu Ala Thr Leu Arg Glu Asp Leu Thr Arg Arg Arg Tyr Leu 565 570 575 Met Ser Gly Val Met Ala Pro Val Lys Arg Arg Asn Val Ile Pro His 580 585 590 Asp Ile Gly Asp Pro Asp Asp Glu Pro Trp Leu Arg Val Asn Ala Tyr 595 600 605 Leu Ile His Asp Thr Ala Asp Trp Lys Asp Leu Asn Leu Lys Phe Val 610 615 620 Leu Gln Val Tyr Arg Asp Tyr Tyr Leu Thr Gly Asp Gln Asn Phe Leu 625 630 635 640 Lys Asp Met Trp Pro Val Cys Leu Ala Val Met Glu Ser Glu Met Lys 645 650 655 Phe Asp Lys Asp His Asp Gly Leu Ile Glu Asn Gly Gly Tyr Ala Asp 660 665 670 Gln Thr Tyr Asp Gly Trp Val Thr Thr Gly Pro Ser Ala Tyr Cys Gly 675 680 685 Gly Leu Trp Leu Ala Ala Val Ala Val Met Val Gln Met Ala Ala Leu 690 695 700 Cys Gly Ala Gln Asp Ile Gln Asp Lys Phe Ser Ser Ile Leu Ser Arg 705 710 715 720 Gly Gln Glu Ala Tyr Glu Arg Leu Leu Trp Asn Gly Arg Tyr Tyr Asn 725 730 735 Tyr Asp Ser Ser Ser Arg Pro Gln Ser Arg Ser Val Met Ser Asp Gln 740 745 750 Cys Ala Gly Gln Trp Phe Leu Lys Ala Cys Gly Leu Gly Glu Gly Asp 755 760 765 Thr Glu Val Phe Pro Thr Gln His Val Val Arg Ala Leu Gln Thr Ile 770 775 780 Phe Glu Leu Asn Val Gln Ala Phe Ala Gly Gly Ala Met Gly Ala Val 785 790 795 800 Asn Gly Met Gln Pro His Gly Val Pro Asp Lys Ser Ser Val Gln Ser 805 810 815 Asp Glu Val Trp Val Gly Val Val Tyr Gly Leu Ala Ala Thr Met Ile 820 825 830 Gln Glu Gly Leu Thr Trp Glu Gly Phe Gln Thr Ala Glu Gly Cys Tyr 835 840 845 Arg Thr Val Trp Glu Arg Leu Gly Leu Ala Phe Gln Thr Pro Glu Ala 850 855 860 Tyr Cys Gln Gln Arg Val Phe Arg Ser Leu Ala Tyr Met Arg Pro Leu 865 870 875 880 Ser Ile Trp Ala Met Gln Leu Ala Leu Gln Gln Gln Gln His Lys Lys 885 890 895 Ala Ser Trp Pro Lys Val Lys Gln Gly Thr Gly Leu Arg Thr Gly Pro 900 905 910 Met Phe Gly Pro Lys Glu Ala Met Ala Asn Leu Ser Pro Glu 915 920 925

Claims

1. A compound, characterized in that The compound is: (2R,3R,4R,5S)-1-(2-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(3-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(4-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-1-(2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(3-(trifluoromethyl)phenethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(4-(trifluoromethyl)phenethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-(hydroxymethyl)-1-((R)-2-phenylpropyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-(hydroxymethyl)-1-((S)-2-phenylpropyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(2-(pyridin-2-yl)ethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(2-(thien-2-yl)ethyl)piperidine-3,4,5-triol; (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(2-(thien-3-yl)ethyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-1-(cyclohexylmethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-1-(((1s,4S)-4-(2-fluoropropan-2-yl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-1-((2,3-dihydro-1H-inden-2-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-1-(2-cyclohexylethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-1-(3-cyclohexylpropyl)-2-(hydroxymethyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-1-(2-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-1-(3-chloro-2-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-1-(2-([1,1′-biphenyl]-4-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-1-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-1-(4-Butoxyphenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-1-(4-Butoxy-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-1-((1-(4-fluorophenyl)piperidin-4-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-1-(((1s,4R)-4-(difluoromethyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-1-(((1r,4S)-4-(difluoromethyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-1-(((1s,4R)-4-(1,1-difluoroethyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol; (2S,3R,4R,5S)-1-(((1r,4S)-4-(1,1-difluoroethyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol; or a pharmaceutically acceptable salt of any of the foregoing compounds.

2. The compound according to claim 1, characterized in that The compounds inhibit non-lysosomal glucosylceramidase (GBA2).

3. The compound according to claim 1, characterized in that The compounds specifically bind to GBA2.

4. The compound according to claim 1, characterized in that The compounds reduce the level of GBA2 enzymatic activity.

5. The compound according to claim 2, characterized in that The GBA2 is mammalian GBA2.

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

7. Use of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 6, in the preparation of a medicament for inhibiting GBA2.

8. Use of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 6, in the preparation of a medicament for reducing GBA2 enzyme activity.

Images