Non-lysosomal glucosylceramidase inhibitors and uses thereof

Abstract

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

Description

TECHNICAL FIELD OF THEINVENTION

[0001] This application relates in part to compounds that inhibit glucosylceramidase and uses thereof.

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

[0003] Glucosylceramidase plays a key role in regulating cellular levels of these substrate molecules, glucosylceramide, which is the simplest member and biosynthetic precursor of a broad class of cell membrane lipids, glycosphingolipids (GSLs). 3,5 Dysregulation of GSL metabolism and homeostasis is a key driver of the neurological disorder Alzheimer's disease (AD). 6 , Parkinson's disease (PD) 7 , multiple sclerosis (MS) 8 , Huntington's disease (HD) 9 , amyotrophic lateral sclerosis (ALS) 10 and neuronal ceroid lipofuscinosis (Batten disease) 11Niemann-Pick disease type C (NPC), a lysosomal storage disorder 12 , mucolipidosis type IV (MLIV) 13 , and Sandhoff disease 14 and the liver disease nonalcoholic 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, inhibition of GBA2 inhibits MLIV 13 and Sandhoff disease 14 Evidence has shown that it improves lifespan and delays motor impairment in rodent models of AD. In mouse models of synucleinopathies, small molecule GBA2 inhibitors have been shown to reduce accumulation of α-synuclein aggregates in the brain. 14 Additionally, treatment with a small molecule GBA2 inhibitor reduces neuroinflammation and neurodegeneration in a mouse model of neuronal ceroid lipofuscinosis (Batten disease). 18 Reduction of GBA2 activity has also been demonstrated to reverse the clinical picture in rodent models of Gaucher disease. 19 In addition, GBA2 is involved in the regulation of inflammatory responses. 2 and studies have shown that reducing GBA2 activity reduces inflammation in cell models of cystic fibrosis (CF). 20 Increased glucosylceramide levels may contribute to the prevention of nonalcoholic steatohepatitis (NASH) 21 ,hepatitis 22 , hepatocellular carcinoma (HCC) 23 , autoimmune cholangitis 24 , and drug-induced liver injury (DILI) 25 Beneficial effects have also been demonstrated in rodent models of liver disease, including

[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), but these compounds are not selective for GBA2 and also exhibit inhibitory activity against other enzymes, including GCase, glucosylceramide synthase (GCS, EC 2.4.1.80) and intestinal α-glucosidase. 26 .

[0005] International patent application PCT / GB2003 / 003099, filed on July 17, 2003, published on January 22, 2004 as WO2004 / 007453; International patent application PCT / GB2004 / 002450, filed on June 9, 2004, published on December 23, 2004 as WO2004 / 111001; International patent application PCT / GB2004 / 002451, filed on June 9, 2004, published on December 23, 2004 as WO2004 / 111002; International patent application PCT / GB2004 / 002452, filed on January 11, 2005 as WO2004 / 111003; International patent application PCT / GB2005 / 000071, filed on and published on July 28, 2005 as WO2005 / 068426; International patent application PCT / NL2015 / 050188, filed on March 23, 2015 and published on October 1, 2015 as WO2015 / 147639; and International patent application PCT / IB2020 / 054355, filed on May 7, 2020 and published on November 19, 2020 as WO2020 / 229968, 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 the prodrugs, pharmaceutical compositions comprising the compounds or the prodrugs of the compounds, and methods for treating diseases and disorders modulated by dysregulation of the level of GBA2 activity and / or the level of glucosylceramide, and / or glycosphingolipid metabolism or homeostasis. In certain embodiments, the present invention provides compositions and methods for preventing and / or treating neurological diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis (ALS), or lysosomal storage diseases, such as Gaucher disease, Niemann-Pick disease type C, mucolipidosis type IV, and Sandhoff disease, or liver diseases, such as nonalcoholic steatohepatitis (NASH), by administering to a patient in need thereof an effective amount of one or more of the compounds described herein or a prodrug of the compounds.

[0007] In one aspect, the present invention provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof: JPEG0007674389000001.jpg6153In formula, R 1 may be H, and R 2 is CH 2 OH or R 1 is CH 2 OH, and R 2 may be H, and R 3 is (CH 2 ) n R 4 where n may be 1 or 2, and R 4are cyclohexyl, cyclohexylmethyl, phenylethyl, 4-phenylcyclohexyl, spiro[2.5]octan-6-yl, spiro[3.5]nonan-7-yl, spiro[4.5]decan-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-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-(cyclohexylcarbamoyl)piperidin-4-yl, 1-(cyclohexylcarbamothioyl)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazetidin-3-yl, 2-(thiophen-2-yl)methyl, or 2-(thiophen-3-yl)methyl, and may be one or more of F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropan-2-yl, methoxymethyl, C 1-5 Alkoxy, CHF 2 , C.F. 2 CH 3 , and / or CF 3 each optionally substituted with one to a maximum of the following substituents: R 3 are pyrrolidin-1-yl, piperidin-1-yl, 4-morpholino, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, F, Cl, C 1-6 Alkyl, cyclopropyl, propen-2-yl, OCH 3 , and / or CF 3or phenylethyl optionally substituted with one to a maximum of the following substituents: R 3 is C on the formyl group. 1-6 Alkyl, C 3-7 (1-formylpiperidin-4-yl)methyl substituted with one of cycloalkyl, phenyl, thiophen-3-yl, phenylmethyl, or cyclopentylmethyl; 1-6 Alkyl, OCH 3 , and / or CF 3 each optionally substituted with one to a maximum of the following substituents: R 3 teeth, JPEG0007674389000002.jpg16118, wherein R 5 may be selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophen-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, and may further include one or more of F, Cl, C 1-6 Alkyl, C 1-6 Alkoxy, OCF 3 , and / or CF 3 each optionally substituted with one to a maximum of However, R 1 H and R 2 CH 2 In the case of OH, 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 R 1 CH 2 OH and R 2 If H, then R 3is not phenylethyl, 3-phenylpropyl, (R)-2-phenylpropyl, or (S)-2-phenylpropyl.

[0008] In another embodiment, the present invention provides a compound of formula (Ia) or a pharma- ceutically acceptable salt thereof: JPEG0007674389000003.jpg6254In formula, R 3 is (CH 2 ) n R 4 where n may be 1 or 2, and R 4 are cyclohexyl, cyclohexylmethyl, phenylethyl, 4-phenylcyclohexyl, spiro[2.5]octan-6-yl, spiro[3.5]nonan-7-yl, spiro[4.5]decan-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-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-(cyclohexylcarbamoyl)piperidin-4-yl, 1-(cyclohexylcarbamothioyl)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazetidin-3-yl, 2-(thiophen-2-yl)methyl, or 2-(thiophen-3-yl)methyl, and may be one or more of F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropan-2-yl, methoxymethyl, C 1-5 Alkoxy, CHF 2 , C.F. 2 CH 3 , and / or CF 3 each optionally substituted with one to a maximum of the following substituents: R 3are pyrrolidin-1-yl, piperidin-1-yl, 4-morpholino, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, F, Cl, C 1-6 Alkyl, cyclopropyl, propen-2-yl, OCH 3 , and / or CF 3 or phenylethyl optionally substituted with one to a maximum of the following substituents: R 3 is C on the formyl group. 1-6 Alkyl, C 3-7 (1-formylpiperidin-4-yl)methyl substituted with one of cycloalkyl, phenyl, thiophen-3-yl, phenylmethyl, or cyclopentylmethyl; 1-6 Alkyl, OCH 3 , and / or CF 3 each optionally substituted with one to a maximum of the following substituents: R 3 teeth, JPEG0007674389000004.jpg16118, where R 5 may be selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophen-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, and may further include one or more of F, Cl, C 1-6 Alkyl, C 1-6 Alkoxy, OCF 3 , and / or CF 3 each optionally substituted with one to a maximum of However, R 3is not cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl, phenylethyl, 3-phenylpropyl, 3-(2-propoxyphenyl)propyl, 3-(3-propoxyphenyl)propyl, 3-(4-propoxyphenyl)propyl, or 4-phenylbutyl.

[0009] In another embodiment, the present invention provides a compound of formula (Ib) or a pharma- ceutically acceptable salt thereof: JPEG0007674389000005.jpg5953In formula, R 3 is (CH 2 ) n R 4 where n may be 1 or 2, and R 4 are cyclohexyl, cyclohexylmethyl, phenylethyl, 4-phenylcyclohexyl, spiro[2.5]octan-6-yl, spiro[3.5]nonan-7-yl, spiro[4.5]decan-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-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-(cyclohexylcarbamoyl)piperidin-4-yl, 1-(cyclohexylcarbamothioyl)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazetidin-3-yl, 2-(thiophen-2-yl)methyl, or 2-(thiophen-3-yl)methyl, and may be one or more of F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropan-2-yl, methoxymethyl, C 1-5 Alkoxy, CHF 2 , C.F. 2 CH 3 , and / or CF3 each optionally substituted with one to a maximum of the following substituents: R 3 are pyrrolidin-1-yl, piperidin-1-yl, 4-morpholino, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, F, Cl, C 1-6 Alkyl, cyclopropyl, propen-2-yl, OCH 3 , and / or CF 3 or phenylethyl optionally substituted with one to a maximum of the following substituents: R 3 is C on the formyl group. 1-6 Alkyl, C 3-7 (1-formylpiperidin-4-yl)methyl substituted with one of cycloalkyl, phenyl, thiophen-3-yl, phenylmethyl, or cyclopentylmethyl; 1-6 Alkyl, OCH 3 , and / or CF 3 each optionally substituted with one to a maximum of the following substituents: R 3 teeth, JPEG0007674389000006.jpg16118, wherein R 5 may be selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophen-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, and may further include one or more of F, Cl, C 1-6 Alkyl, C 1-6 Alkoxy, OCF 3 , and / or CF 3each optionally substituted with one to a maximum of However, R 3 is not phenylethyl, 3-phenylpropyl, (R)-2-phenylpropyl, or (S)-2-phenylpropyl.

[0010] In another embodiment, the present invention provides a compound of formula (Ic) or a pharma- ceutically acceptable salt thereof: JPEG0007674389000007.jpg6384In formula, R 6 and R 7 are H, F, Cl, and C. 1-6 Alkyl, OCH 3 , phenyl, cyclopropyl, vinyl, methoxymethyl, 2-fluoropropan-2-yl, CHF 2 , C.F. 2 CH 3 , and / or CF 3 where R 6 and R 7 is other than H. In certain embodiments, at least one of R 6 may be H, and R 7 CF 3 , 2-fluoropropan-2-yl, CHF 2 , C.F. 2 CH 3 , isopropyl, or tert-butyl. 6 CF 3 , 2-fluoropropan-2-yl, CHF 2 , C.F. 2 CH 3 , isopropyl, or tert-butyl, and R 7 may be H.

[0011] In another embodiment, the present invention provides a compound of formula (Id) or a pharma- ceutically acceptable salt thereof: JPEG0007674389000008.jpg7091In formula, R 6 and R 7 are H, F, Cl, and C. 1-6 Alkyl, OCH3 , phenyl, cyclopropyl, vinyl, methoxymethyl, 2-fluoropropan-2-yl, CHF 2 , C.F. 2 CH 3 , and / or CF 3 where R 6 and R 7 At least one of is other than H.

[0012] In another embodiment, the present invention provides a compound of formula (Ie) or a pharma- ceutically acceptable salt thereof: JPEG0007674389000009.jpg6890In formula, R 8 , R 9 , and R 10 are pyrrolidin-1-yl, piperidin-1-yl, 4-morpholino, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, H, F, Cl, C 1-6 Alkyl, cyclopropyl, propen-2-yl, OCH 3 , and / or CF 3 where R 8 , R 9 , and R 10 is other than H. In certain embodiments, at least one of R 8 , R 9 , and R 10 may be independently selected from the group consisting of H, F, Cl, tetrahydro-2H-pyran-4-yl, 4-morpholino, pyrrolidin-1-yl, and piperidin-1-yl, with the proviso that R 6 , R 9 and R 10 At least one of is other than H.

[0013] In another embodiment, the present invention provides a compound of formula (If) or a pharma- ceutically acceptable salt thereof: JPEG0007674389000010.jpg6295In formula, R 8 , R 9 , and R 10 are H, F, Cl, and C. 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropan-2-yl, methoxymethyl, C 1-5 Alkoxy and / or CF 3 with the proviso 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.

[0014] In another embodiment, the present invention provides a compound of formula (Ig) or a pharma- ceutically acceptable salt thereof: JPEG0007674389000011.jpg68104In formula, R 8 , R 9 , and R 10 are H, F, Cl, and C. 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropan-2-yl, methoxymethyl, C 1-5 Alkoxy and / or CF 3 In some embodiments, R 8 , R 9 , and R 10 H, F, and CF 3 may be independently selected from the group consisting of:

[0015] In another embodiment, the present invention provides a compound of formula (Ih) or a pharma- ceutically acceptable salt thereof: JPEG0007674389000012.jpg6492In formula, R 11 is C 1-6 Alkyl, C 3-7 cycloalkyl, phenyl, thiophen-3-yl, phenylmethyl, or cyclopentylmethyl; 1-6 Alkyl, OCH 3 , and / or CF 3 Each is optionally substituted with from one to a maximum of the following substituents:

[0016] In another embodiment, the present invention provides a compound of formula (Ii) or a pharma- ceutically acceptable salt thereof: JPEG0007674389000013.jpg6188In formula, R 12 may be selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophen-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, or phenylcarbonyl, and may further include one or more of F, Cl, C 1-6 Alkyl, C 1-6 Alkoxy, OCF 3 , and / or CF 3 In one embodiment, R 12 may 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.

[0017] In another embodiment, the present invention provides a compound of formula (Ij) or a pharma- ceutically acceptable salt thereof: JPEG0007674389000014.jpg6285In formula, R 12 may be selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophen-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, or phenylcarbonyl, and may further include one or more of F, Cl, C 1-6 Alkyl, C 1-6 Alkoxy, OCF 3 , and / or CF 3 In one embodiment, R 12 may 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.

[0018] In another embodiment, the present invention provides a compound of formula (Ik) or a pharma- ceutically acceptable salt thereof: JPEG0007674389000015.jpg6086In formula, R 12 may be selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophen-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, or phenylcarbonyl, and may further include one or more of F, Cl, C 1-6 Alkyl, C 1-6 Alkoxy, OCF 3 , and / or CF 3 In one embodiment, R 12may 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.

[0019] In another embodiment, the present invention provides a compound of formula (Il) or a pharma- ceutically acceptable salt thereof: JPEG0007674389000016.jpg6184In formula, R 12 may be selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophen-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, or phenylcarbonyl, and may further include one or more of F, Cl, C 1-6 Alkyl, C 1-6 Alkoxy, OCF 3 , and / or CF 3 In one embodiment, R 12 may 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.

[0020] In another embodiment, the present invention provides a compound of formula (Im) or a pharma- ceutically acceptable salt thereof. JPEG0007674389000017.jpg6480In formula, R 6 and R 7 are H, F, Cl, and C. 1-6 Alkyl, OCH 3, phenyl, cyclopropyl, vinyl, methoxymethyl, 2-fluoropropan-2-yl, CHF 2 , C.F. 2 CH 3 , and / or CF 3 In some embodiments, R 6 may be H, and R 7 CF 3 , 2-fluoropropan-2-yl, CHF 2 , C.F. 2 CH 3 , isopropyl, or tert-butyl. 6 CF3, 2-fluoropropan-2-yl, CHF 2 , C.F. 2 CH 3 , isopropyl, or tert-butyl, and R 7 may be H.

[0021] In another embodiment, the present invention provides a compound of formula (In) or a pharma- ceutically acceptable salt thereof. JPEG0007674389000018.jpg6891In formula, R 6 and R 7 are H, F, Cl, and C. 1-6 Alkyl, OCH 3 , phenyl, cyclopropyl, vinyl, methoxymethyl, 2-fluoropropan-2-yl, CHF 2 , C.F. 2 CH 3 , and / or CF 3 may be independently selected from the group consisting of:

[0022] In another embodiment, the present invention provides a compound of formula (Io) or a pharma- ceutically acceptable salt thereof: JPEG0007674389000019.jpg6886In formula, R 8 , R 9 , and R 10are pyrrolidin-1-yl, piperidin-1-yl, 4-morpholino, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, H, F, Cl, C 1-6 Alkyl, cyclopropyl, propen-2-yl, OCH 3 , and / or CF 3 with the proviso that the compound is not (2S,3R,4R,5S)-2-(hydroxymethyl)-1-phenethylpiperidine-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. 8 , R 9 , and R 10 may be independently selected from the group consisting of H, F, Cl, tetrahydro-2H-pyran-4-yl, 4-morpholino, pyrrolidin-1-yl, and piperidin-1-yl, with the proviso that R 8 , R 9 , and R 10 At least one of is other than H.

[0023] In another embodiment, the present invention provides a compound of formula (Ip) or a pharma- ceutically acceptable salt thereof: JPEG0007674389000020.jpg6094In formula, R 8 , R 9 , and R 10 are H, F, Cl, and C. 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropan-2-yl, methoxymethyl, C 1-5 Alkoxy and / or CF 3 where R8 , R 9 , and R 10 At least one of is other than H.

[0024] In another embodiment, the present invention provides a compound of formula (Iq) or a pharma- ceutically acceptable salt thereof. JPEG0007674389000021.jpg68104In formula, R 8 , R 9 , and R 10 are H, F, Cl, and C. 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropan-2-yl, methoxymethyl, C 1-5 Alkoxy and / or CF 3 In some embodiments, R 8 , R 9 , and R 10 H, F, and CF 3 may be independently selected from the group consisting of:

[0025] In another embodiment, the present invention provides a compound of formula (Ir) or a pharma- ceutically acceptable salt thereof: JPEG0007674389000022.jpg6193In formula, R 11 is C 1-6 Alkyl, C 3-7 cycloalkyl, phenyl, thiophen-3-yl, phenylmethyl, or cyclopentylmethyl; 1-6 Alkyl, OCH 3 , and / or CF 3 Each is optionally substituted with from one to a maximum of the following substituents:

[0026] In another embodiment, the present invention provides a compound of formula (Is) or a pharma- ceutically acceptable salt thereof: JPEG0007674389000023.jpg5984In formula, R 12may be selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophen-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, or phenylcarbonyl, and may further include one or more of F, Cl, C 1-6 Alkyl, C 1-6 Alkoxyl, OCF 3 , and / or CF 3 In one embodiment, R 12 may 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.

[0027] In another embodiment, the present invention provides a compound of formula (It) or a pharma- ceutically acceptable salt thereof: JPEG0007674389000024.jpg6284In formula, R 12 may be selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophen-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, or phenylcarbonyl, and may further include one or more of F, Cl, C 1-6 Alkyl, C 1-6 Alkoxyl, OCF 3 , and / or CF 3 In one embodiment, R 12may 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.

[0028] In another embodiment, the present invention provides a compound of formula (Iu) or a pharma- ceutically acceptable salt thereof. JPEG0007674389000025.jpg6184In formula, R 12 may be selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophen-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, or phenylcarbonyl, and may further include one or more of F, Cl, C 1-6 Alkyl, C 1-6 Alkoxyl, OCF 3 , and / or CF 3 In one embodiment, R 12 may 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.

[0029] In another embodiment, the present invention provides a compound of formula (Iv) or a pharma- ceutically acceptable salt thereof. JPEG0007674389000026.jpg6284In formula, R 12may be selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophen-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, or phenylcarbonyl, and may further include one or more of F, Cl, C 1-6 Alkyl, C 1-6 Alkoxyl, OCF 3 , and / or CF 3 In one embodiment, R 12 may 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.

[0030] In another embodiment, the compound may be a prodrug, the compound may inhibit non-lysosomal glucosylceramidase (GBA2), the compound may inhibit GBA2 (e.g., mammalian GBA2), the compound may inhibit wild-type GBA2, or the compound may inhibit mutant GBA2.

[0031] In another embodiment, the 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), or (Iv) may exhibit enhanced selectivity and / or permeability.

[0032] In another embodiment, the compounds according to Formula (Ic), Formula (Ie), Formula (Ig), Formula (Im), Formula (Io), or Formula (Iq) may exhibit enhanced selectivity and / or permeability.

[0033] In another embodiment, the compounds according to Formula (Ic), (Ie), (Ig), (Im), (Io), or (Iq) may exhibit enhanced selectivity.

[0034] In another embodiment, 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.

[0035] In another aspect, the present invention provides a pharmaceutical composition comprising a compound according to the invention, or a pharma- ceutically acceptable salt thereof, in combination with a pharma- ceutically acceptable carrier.

[0036] In another aspect, the present invention provides a method of inhibiting GBA2 in a subject in need thereof or treating a neurological disease, or a lysosomal storage disease, or a hepatic disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I), including any one or more of formulae (Ia)-(Iv) as described herein, or a pharma- ceutically acceptable salt thereof, including, but not limited to, Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), addiction, anxiety, argyrophilic grain dementia, ataxia-telangiectasia (AT), attention-deficit / hyperactivity disorder (ADHD), autism spectrum disorder (ASD), Becker muscular dystrophy (BMD), bipolar disorder (BD), bruit disease, cerebellar ataxia, Schwartz-Hall disease, and Schwartz-Hall disease. Corr-Marie-Tooth disease (CMT), chronic fatigue syndrome, corticobasal degeneration (CBD), dementia pugilistica, dementia with Lewy bodies (DLB), Dejerine-Sottas disease, diffuse neurofibrillary tangles with calcifications, 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, Gerstmann-Sträussler-Scheinker disease, glaucoma, Guadeloupe Parkinsonism, Guillain-Barré syndrome, Hallervorden-Spatz disease (neurodegenerative disease 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 (DM1 and DM 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, Pallidopontinenigra degeneration, Parkinson-Dementia Complex of Guam, Pick's Disease (PiD), Postencephalitic Parkinsonism (PEP), PrimaryThe condition may be progressive lateral sclerosis (PLS), prion disease (CJD), variant Creutzfeldt-Jakob disease (vCJD), fatal familial insomnia, and kuru), progressive transcortical 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, fibrillary tangle-predominant dementia, Tourette's syndrome (TS), vascular dementia, or Wilson's disease.

[0037] 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.

[0038] The liver disease may be, but is not limited to, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), Alagille syndrome, alcohol-related liver disease, alpha-1 antitrypsin deficiency, autoimmune hepatitis, autoimmune cholangitis, benign liver tumors, biliary atresia, cirrhosis, Crigler-Najjar syndrome, drug-induced liver injury (DILI), galactosemia, Gilbert syndrome, hemochromatosis, hepatic encephalopathy, hepatocellular carcinoma (HCC), hepatocellular, intrahepatic cholestasis of pregnancy (ICP), lysosomal acid lipase deficiency (LAL-D), liver cyst, liver cancer, neonatal jaundice, primary sclerosing cholangitis (PBC), primary biliary cholangitis (PSC), Reye's syndrome, glycogen storage disease type I, or viral hepatitis (including types A, B, C, D, and E).

[0039] In another embodiment, the present invention provides a method of treating a neurological disorder 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 pharma- ceutically acceptable salt thereof.

[0040] In another embodiment, the administration can reduce the level of GBA2 enzyme activity in the subject. In another embodiment, the administration can modulate the level of glucosylceramide and / or glycosphingolipids in the subject. In another embodiment, the administration can increase the level of glucosylceramide in the subject. In another embodiment, the administration can increase the level of ganglioside GM1 in the subject. In another embodiment, the administration can modulate the level of ceramide and / or sphingosine and / or sphingosine-1-phosphate (S1P) in the subject. The subject may be a human.

[0041] In another aspect, the present invention provides the use of an effective amount of a compound of formula (I), including any one or more of formulae (Ia)-(Iv) as described herein, or a pharma- ceutically acceptable salt thereof, in the preparation of a medicament, which may be for inhibiting GBA2, treating a condition modulated by GBA2, or treating a neurological disease, or a lysosomal storage disease, or a liver disease.

[0042] This summary does not necessarily describe all features of the invention.

[0043] The present invention provides, in part, compounds and uses thereof for inhibiting non-lysosomal glucosylceramidase (GBA2).

[0044] "Non-lysosomal glucosylceramidase" or "GBA2" refers to a non-lysosomal membrane-bound enzyme (EC 3.2.1.45) located on the cytoplasmic side of the ER and Golgi membranes that has glucosylceramidase activity that catalyzes the hydrolytic cleavage of the β-glucosidic linkage 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, the GBA2 can be a mammalian GBA2, such as rat, mouse, or human GBA2. The GBA2 can be wild-type GBA2 or a mutant GBA2. In some embodiments, the GBA2 may be a wild-type mammalian GBA2, such as rat, mouse, or human wild-type GBA2. In some embodiments, the GBA2 may be a mutant mammalian GBA2, such as rat, mouse, or human mutant GBA2. In some embodiments, the GBA2 may have a sequence set forth in any one of the following accession numbers: Q9HCG7, Q69ZF3, D3DRP2, Q5TCV6, Q96A51, Q96LY1, Q96SJ2, Q9H2L8, Q5M868, or O16581. In other embodiments, the GBA2 may have an alternative splicing isoform sequence set forth in any one of the following accession numbers: Q9HCG7-1, Q9HCG7-2, Q9HCG7-3.In another embodiment, the GBA2 has 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_01 In another embodiment, the human GBA2 may have the sequence set forth in any one of XP_016870426.1, XP_016870427.1, XP_016870428.1, XP_016870429.1, XP_016870430.1, XP_016870431.1, XP_016870432.1, XP_016870433.1, XP_016870434.1, or XP_016870435.1. 1 0 2 0 3 0 4 0 5 0 6 0 mgtqdpgnmg tgvpaseqis cakedpqvyc peetggtkdv qvtdcksped srppketdcc 7 0 8 0 9 0 10 0 11 0 12 0 npedsgqlmv syegkamgyq vppfgwricl aheftekrkp fqannvslsn mikhigmglr 13 0 14 0 15 0 16 0 17 0 18 0 ylqwwyrkth vekktpfidm insvplrqiy gcplggiggg titrgwrgqf crwqlnpgmy 19 0 20 0 twenty one0 22 0 23 0 24 0 qhrtviadqf tvclrregqt vyqqvlsler psvlrswnwg lcgyfafyha lyprawtvyq 25 0 26 0 27 0 28 0 29 0 30 0 lpgqnvtltc rqitpilphd yqdsslpvgv fvwdvenegd ealdvsimfs mrnglgggdd 31 0 32 0 33 0 34 0 35 0 36 0 apgglwnepf clersgetvr glllhhptlp npytmavaar vtaattvthi tafdpdstgq 37 0 38 0 39 0 40 0 41 0 42 0 qvwqdllqdg qldsptgqst ptqkgvgiag avcvssklrp rgqcrlefsl awdmprimfg 43 0 44 0 45 0 46 0 47 0 48 0 akgqvhyrry trffgqdgda apalshyalc ryaeweeris awqspvlddr slpawyksal 49 0 50 0 51 0 52 0 530 54 0 fnelyfladg gtvwlevled slpeelgrnm chlrptlrdy grfgylegqe yrmyntydvh 55 0 56 0 57 0 58 0 59 0 60 0 fyasfaliml wpklelslqy dmalatlred ltrrrylmsg vmapvkrrnv iphdigdpdd 61 0 62 0 63 0 64 0 65 0 66 0 epwlrvnayl ihdtadwkdl nlkfvlqvyr dyyltgdqnf lkdmwpvcla vmesemkfdk 67 0 68 0 69 0 70 0 71 0 72 0 dhdgliengg yadqtydgwv ttgpsaycgg lwlaavavmv qmaalcgaqd iqdkfssils 73 0 74 0 75 0 76 0 77 0 78 0 rgqeayerll wngryynyds ssrpqsrsvm sdqcagqwfl kacglgegdt evfptqhvvr 79 0 80 0 81 0 82 0 83 0 84 0 alqtifelnv qafaggamga vngmqphgvp dkssvqsdev wvgvvyglaa tmiqegltwe 85 0 86 0 87 0 88 0 89 0 90 0 gfqtaegcyr tvwerlglaf qtpeaycqqr vfrslaymrp lsiwamqlal qqqqhkkasw 91 0 92 0 pkvkqgtglr tgpmfgpkea manlspe (SEQ ID NO: 1)

[0045] In another embodiment, the human GBA2 can have the nucleic acid sequence of a nucleic acid molecule encoding the sequence set forth in SEQ ID NO:1.

[0046] In certain embodiments, one or more compounds of the invention can inhibit the activity of GBA2, for example, the ability to inhibit the cleavage of glucose from glucosylceramide or the ability to inhibit the cleavage of glucose from an appropriate substrate molecule, such as 4-methylumbelliferone-β-D glucopyranoside. By "inhibit", "inhibition", or "inhibiting" is meant a reduction in GBA2 of anywhere from about 10% to about 90%, or anywhere from about 30% to about 60%, or greater 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 should be understood that the inhibition does not require complete inhibition. In certain embodiments, the inhibition may be temporary, e.g., for a period of 5 minutes to 60 minutes, 1 hour to 5 hours, 1 hour to 12 hours, 1 hour to 24 hours, 24 hours to 48 hours, 1 day to 2 days, 1 day to 5 days, 1 day to 7 days, 1 day to 14 days, 1 day to 28 days, or any particular 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 ... The inhibition period may be 0.5 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 may be localized. For example, one or more compounds of the present invention may inhibit GBA2 in a specific cellular compartment, for example, in the endoplasmic reticulum (ER) or Golgi apparatus (Gogi); or one or more compounds of the present invention may inhibit GBA2 in a specific tissue type, for example, in the brain or liver.

[0047] In some embodiments, one or more compounds of the present invention may specifically bind to GBA2. In other embodiments, one or more compounds of the present invention may specifically bind to the active site of GBA2. In some embodiments, one or more compounds of the present invention that specifically bind to the active site of GBA2 may also inhibit the activity of GBA2. In other embodiments, one or more compounds of the present invention may specifically bind to human non-lysosomal glucosylceramidase (GBA2) over human lysosomal glucosylceramidase (GCase) and / or human cytosolic glucosylceramidase (GBA3). In other embodiments, one or more compounds of the present invention may specifically bind to human non-lysosomal glucosylceramidase (GBA2) over human glucosylceramide synthase (GCS). In other embodiments, one or more compounds of the present invention may specifically bind to human non-lysosomal glucosylceramidase (GBA2) over intestinal alpha glucosidase. The intestinal alpha-glucosidase can be sucrase-isomaltase or maltase-glucoamylase. By "specifically binds" is meant a compound that binds to GBA2 but does not substantially bind to other molecules in the sample, such as lactase, sucrase, maltase, isomaltase, sucrase-isomaltase, glucoamylase, maltase-glucoamylase, glucosylceramide synthase, alpha-glucosidase II, ER alpha-glucosidase, intestinal alpha-glucosidase, glycogen phosphorylase, acid alpha-glucosidase, beta-hexosaminidase, O-GlcNAcase, GCase, or GBA3. By "substantially no binding" is meant a binding specificity in the range of about 5 to about 100,000 times, or about 10 to about 100,000 times, or about 100 to about 100,000 times, or about 1000 to about 100,000 times, or at least about 5 times, 10 times, 20 times, 50 times, 100 times, 200 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, or any value within or near the above ranges. "Binding specificity" refers to the ratio of the corresponding binding constants, i.e., Ki (他の分子) / Ki(GBA2) , or the corresponding IC 50 The ratio of IC 50(他の分子) / I C 50(GBA2) Examples of compounds that exhibit enhanced binding specificity include, but are not limited to, the compounds of Examples 4, 8, 12, 13, 14, 15, 16, 20, 21, 22, 23, 24, 25, 27, 28, 29, 31, 32, 311, 312, or 314. In certain embodiments, one or more compounds of the invention may exhibit enhanced binding specificity or enhanced selectivity as 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). In certain embodiments, "enhanced specificity" or "enhanced selectivity" refers to an increase in 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%, e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or 100% or more, or an increase in a range of 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 about 100-fold to about 100,000-fold. "Increase" refers to an increase in the range of about 1000-fold to about 100,000-fold, or at least about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 100-fold, 150-fold, 200-fold, 250-fold, 350-fold, 400-fold, 450-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, 100,000-fold, or any value within or near the above ranges.

[0048] In another embodiment, one or more compounds of the present invention may specifically bind to human non-lysosomal glucosylceramidase (GBA2) rather than rat intestinal alpha-glucosidase. The rat intestinal alpha-glucosidase may be sucrase-isomaltase or maltase-glucoamylase. In some embodiments, one or more compounds of the present invention may not substantially inhibit rat intestinal alpha-glucosidase, as compared to a suitable reference compound, such as (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 one embodiment, "does not substantially inhibit" refers to a percent inhibition of less than about 30% in the assay described below for inhibition of rat intestinal glucosidase. In one embodiment, "does not substantially inhibit" refers to a percent inhibition of less than about 20% in the assay described below for inhibition of rat intestinal glucosidase. In one embodiment, "does not substantially inhibit" refers to a percent inhibition of less than about 10% in the assay described below for inhibition of rat intestinal glucosidase.

[0049] In some embodiments, one or more compounds of the present invention can inhibit the cleavage of glucose from glucosylceramide by GBA2. In some embodiments, one or more compounds of the present invention can inhibit the aggregation of alpha-synuclein protein and / or inhibit the formation of Lewy bodies. "Inhibit", "inhibition", or "inhibiting" refers to any value between about 10% and about 90%, or any value between about 30% and about 60%, or a greater than 100% decrease, or about 1-fold, 2-fold, 5-fold, 10-fold, or more decrease, compared to a reference sample or compound, or compared to wild-type GBA2. It should be understood that the inhibition does not require complete inhibition. In some embodiments, the inhibition can be temporary.

[0050] In certain embodiments, one or more compounds of the invention can reduce inflammation in the CNS. In certain embodiments, one or more compounds of the invention can reduce alpha-synuclein protein aggregation and / or Lewy body formation. By "reducing" or "reducing" is meant any value between about 5% and 90%, or any value between about 30% and about 60%, or greater than about 100% reduction, or about 1-fold, 2-fold, 5-fold, 10-fold, 15-fold, 25-fold, 50-fold, 100-fold, or greater reduction, as compared to a reference sample or compound.

[0051] In some embodiments, one or more compounds of the present invention can increase glucosylceramide levels. In some embodiments, one or more compounds of the present invention can increase glycosphingolipid levels. In some embodiments, one or more compounds of the present invention can increase GM1 ganglioside levels. "Increasing" or "enhancing" or "increasing" refers to 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, compared to a reference sample. In some embodiments, one or more compounds of the present invention can increase glucosylceramide levels and / or glycosphingolipid levels and / or GM1 ganglioside levels in the brain.

[0052] In certain embodiments, one or more compounds of the invention can increase GCase activity levels and / or GCase protein levels in vivo and can be effective in treating conditions requiring or responsive to enhanced GCase activity. In certain embodiments, one or more compounds of the invention can increase GCase activity levels and / or GCase protein levels in vivo, particularly via interaction with GBA2, and can be effective in treating conditions requiring or responsive to enhanced GCase activity. By "increasing" or "enhancing" or "increasing" is meant any value between about 5% and about 100%, for example, about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or greater than 100% increase, or about 1-fold, 2-fold, 5-fold, 10-fold, 15-fold, 25-fold, 50-fold, 100-fold or greater increase, as compared to a reference sample or compound, or as compared to a wild-type or mutant GCase.

[0053] In certain embodiments, one or more compounds of the present invention may exhibit enhanced permeability. Permeability may 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). Effective permeability (P eff ) or apparent transmittance (P app Suitable techniques for measuring P are reviewed, for example, by Vope in The AAPS Journal, 2010, 12(4), 670-678. In certain embodiments, one or more compounds of the present invention are eff Or P appIn some embodiments, the compound exhibiting enhanced permeability can exhibit greater oral absorption. In some embodiments, the compound exhibiting enhanced permeability can exhibit greater brain penetration when administered in vivo. In some embodiments, the compound exhibiting enhanced permeability can achieve a higher brain concentration when administered in vivo. In some embodiments, the compound exhibiting enhanced permeability can exhibit a higher brain / plasma concentration ratio when administered in vivo. In one embodiment, "enhanced permeability" refers to the P measured relative 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 In one embodiment, "enhanced permeability" refers to 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 greater than 100% increase in P. ... app In an appropriate assay to measure app In one embodiment, "enhanced permeability" refers to a P value (i.e., a value greater than 0) measured using an in vitro cell monolayer. app In an appropriate assay to measure -6 P exceeding cm / s app In another embodiment, "enhanced permeability" refers to a p value using an in vitro cell monolayer. app In an appropriate assay to measure -6 cm / s~40×10 -6P in the cm / s range app In one embodiment, "high brain concentration" refers to a concentration of a compound in the brain that is higher than that of 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). When administered in vivo, this refers to any value between about 10% and about 100%, or any integer value between about 10% and about 100%, for example, about a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or greater than 100% increase in measured brain concentration.

[0054] The "reference compound" or "control" may be a carbohydrate mimetic iminosugar, i.e., a GBA2 inhibitor, as described in the literature. 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) 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). 26 .

[0055] In certain 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. As described in formula (I), R 1 may be H, and R 2 is CH 2OH or R 1 is CH 2 OH, and R 2 may be H, and R 3 is (CH 2 ) n R 4 where n may be 1 or 2, and R 4 are cyclohexyl, cyclohexylmethyl, phenylethyl, 4-phenylcyclohexyl, spiro[2.5]octan-6-yl, spiro[3.5]nonan-7-yl, spiro[4.5]decan-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-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-(cyclohexylcarbamoyl)piperidin-4-yl, 1-(cyclohexylcarbamothioyl)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazetidin-3-yl, 2-(thiophen-2-yl)methyl, or 2-(thiophen-3-yl)methyl, and may be one or more of F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropan-2-yl, methoxymethyl, C 1-5 Alkoxy, CHF 2 , C.F. 2 CH 3 , and / or CF 3 each optionally substituted with one to a maximum of the following substituents: R 3are pyrrolidin-1-yl, piperidin-1-yl, 4-morpholino, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, F, Cl, C 1-6 Alkyl, cyclopropyl, propen-2-yl, OCH 3 , and / or CF 3 or phenylethyl optionally substituted with one to a maximum of the following substituents: 3 is C on the formyl group. 1-6 Alkyl, C 3-7 (1-formylpiperidin-4-yl)methyl substituted with one of cycloalkyl, phenyl, thiophen-3-yl, phenylmethyl, or cyclopentylmethyl; 1-6 Alkyl, OCH 3 , and / or CF 3 or R 3 teeth, JPEG0007674389000028.jpg16118, where R 5 may be selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophen-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, and may further include one or more of F, Cl, C 1-6 Alkyl, C 1-6 Alkoxy, OCF 3 , and / or CF 3 each optionally substituted with one to a maximum of the following substituents: 1 H and R 2 CH 2 In the case of OH, R3 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 R 1 CH 2 OH and R 2 If H, then R 3 is not phenylethyl, 3-phenylpropyl, (R)-2-phenylpropyl, or (S)-2-phenylpropyl.

[0056] In one embodiment, R 1 may be H, as described in formula (I), and R 2 is CH 2 In some embodiments, R 1 is CH 2 OH, and R 2 may be H.

[0057] In one embodiment, R 3 is represented by the formula (I), 2 ) n R 4 where n may be 1 or 2, and R 4are cyclohexyl, cyclohexylmethyl, phenylethyl, 4-phenylcyclohexyl, spiro[2.5]octan-6-yl, spiro[3.5]nonan-7-yl, spiro[4.5]decan-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-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-(cyclohexylcarbamoyl)piperidin-4-yl, 1-(cyclohexylcarbamothioyl)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazetidin-3-yl, 2-(thiophen-2-yl)methyl, or 2-(thiophen-3-yl)methyl, and may be one or more of F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropan-2-yl, methoxymethyl, C 1-5 Alkoxy, CHF 2 , C.F. 2 CH 3 , and / or CF 3 or R 3 are pyrrolidin-1-yl, piperidin-1-yl, 4-morpholino, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, F, Cl, C 1-6 Alkyl, cyclopropyl, propen-2-yl, OCH 3 , and / or CF 3or phenylethyl optionally substituted with one to a maximum of the following substituents: 3 is C on the formyl group. 1-6 Alkyl, C 3-7 (1-formylpiperidin-4-yl)methyl substituted with one of cycloalkyl, phenyl, thiophen-3-yl, phenylmethyl, or cyclopentylmethyl; 1-6 Alkyl, OCH 3 , and / or CF 3 each optionally substituted with one to a maximum of the following substituents: R 3 teeth, JPEG0007674389000029.jpg16118, where R 5 may be selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophen-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, and may further include one or more of F, Cl, C 1-6 Alkyl, C 1-6 Alkoxy, OCF 3 , and / or CF 3 each optionally substituted with one to a maximum of the following substituents: 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 R 1 CH 2 OH and R 2 If H, then R 3 is not phenylethyl, 3-phenylpropyl, (R)-2-phenylpropyl, or (S)-2-phenylpropyl.

[0058] In one embodiment, R3 is (CH 2 ) n R 4 where n may be 1 or 2, and R 4 are cyclohexyl, cyclohexylmethyl, phenylethyl, 4-phenylcyclohexyl, spiro[2.5]octan-6-yl, spiro[3.5]nonan-7-yl, spiro[4.5]decan-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-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-(cyclohexylcarbamoyl)piperidin-4-yl, 1-(cyclohexylcarbamothioyl)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazetidin-3-yl, 2-(thiophen-2-yl)methyl, or 2-(thiophen-3-yl)methyl, and may be one or more of F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropan-2-yl, methoxymethyl, C 1-5 Alkoxy, CHF 2 , C.F. 2 CH 3 , and / or CF 3 each optionally substituted with one to a maximum of the following substituents: 1 H and R 2 CH 2 In the case of OH, 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; and R 1 CH2 OH and R 2 If H, then R 3 is not 3-phenylpropyl, (R)-2-phenylpropyl, or (S)-2-phenylpropyl.

[0059] In one embodiment, R 3 are pyrrolidin-1-yl, piperidin-1-yl, 4-morpholino, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, F, Cl, C 1-6 Alkyl, cyclopropyl, propen-2-yl, OCH 3 , and / or CF 3 with the proviso that R 3 is not phenylethyl.

[0060] In one embodiment, R 3 is C on the formyl group. 1-6 Alkyl, C 3-7 (1-formylpiperidin-4-yl)methyl substituted with one of cycloalkyl, phenyl, thiophen-3-yl, phenylmethyl, or cyclopentylmethyl; 1-6 Alkyl, OCH 3 , and / or CF 3 Each is optionally substituted with from one to a maximum of the following substituents:

[0061] In one embodiment, R 3 teeth, JPEG0007674389000030.jpg16118, where R 5may be selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophen-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, and may further include one or more of F, Cl, C 1-6 Alkyl, C 1-6 Alkoxy, OCF 3 , and / or CF 3 Each is optionally substituted with from one to a maximum of the following substituents:

[0062] In one embodiment, R 1 may be H, R 2 is CH 2 OH, R 3 is (CH 2 ) n R 4 where n may be 1 or 2, and R 4 is one or more of F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropan-2-yl, methoxymethyl, C 1-5 Alkoxy, CHF 2 , C.F. 2 CH 3 , and / or CF 3 cyclohexyl or 1-phenylpiperidin-4-yl, each optionally substituted with one to a maximum number of substituents of 2 is not cyclohexylmethyl.

[0063] In one embodiment, R 1 is CH 2 OH, R 2 may be H, R 3 is (CH 2 ) n R 4 where n may be 1 or 2, and R 4 is one or more of F, Cl, C 1-6Alkyl, cyclopropyl, vinyl, 2-fluoropropan-2-yl, methoxymethyl, C 1-5 Alkoxy, CHF 2 , C.F. 2 CH 3 , and / or CF 3 and the like. It may be cyclohexyl or 1-phenylpiperidin-4-yl, each optionally substituted with from one to a maximum number of substituents selected from the group consisting of:

[0064] In one embodiment, R 1 may be H, R 2 is CH 2 OH, R 3are (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 cyclohexyl)methyl, ((1s,4S)-4-(trifluoromethyl)cyclohexyl)methyl, ((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl, ((1s,4S)-4-(2-fluoropropan-2-yl)cyclohexyl)methyl, ((1r,4R)-4-(2-fluoropropan-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]octan-6-yl)methyl, (spiro[3.5]nonan-7-yl)methyl, (spiro[4.5]decan-8-yl)methyl, 2-(4,4-difluorocyclohexyl)ethyl, 2-((1s,4S)-4-(trifluoromethyl)cyclohexyl 2-((1r,4R)-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-morpholinophenethyl, 4-butoxy-2,6-difluorophenethyl, 4-(cyclopropylmethyl)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-methylbutanoyl)piperidin-4-yl)methyl 1-(3,3-dimethylbutanoyl)piperidin-4-yl)methyl, (1-(2-cyclopentylacetyl)piperidin-4-yl)methyl, (1-(cyclopropanecarbonyl)piperidin-4-yl)methyl, (1-(cyclobutanecarbonyl)piperidin-4-yl)methyl, (1-(cyclopentanecarbonyl)piperidin-4-yl)methyl, (1-(cyclohexanecarbonyl)piperidine- 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-carbo (1-(cyclohexyl)piperidin-4-yl)methyl, ((5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-8-yl)methyl, (1,2,3,4-tetrahydronaphthalen-2-yl)methyl, (2,3-dihydro-1H-inden-2-yl)methyl, 2,6-difluoro-4-(tetrahydro-2H-pyran-4)-yl)phenethyl, (1-(pyridin-3-yl)piperidin-4-yl)methyl, (1-(cyclohexylcarbamoyl)piperidin-4-yl)methyl, (1-(cyclohexylcarbamothioyl)piperidin-4-yl)methyl, (1-((1S,2R)-2-(trifluoromethyl)cyclohexyl)azetidin-3-yl)methyl,((R)-1-phenylpyrrolidin-3-yl)methyl, ((R)-1-(o-tolyl)pyrrolidin-3-yl)methyl, ((R)-1-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl, ((S)-1-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl, (R)-1-(2-fluorophenyl)pyrrolidin-3-yl)methyl, (R)-1-(3-fluorophenyl)pyrrolidin-3-yl)methyl, ((R)-1-(2-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)methyl, ((R)-1-(6-(trifluoromethyl)phenyl)pyrrolidin-3-yl (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)pyridin-3-yl)pyrrolidin-3-yl)methyl, (R)-1-(thiophene-3-yl)pyrrolidin-3-yl)methyl, ((R)-1-(benzo[d]thiazol-4-yl)pyrrolidin-3-yl)methyl, (S)-(1-(4-(trifluoromethyl)benzoyl)pyrrolidin-3-yl)methyl, ((R)-1-(o-tolyl)piperidin-3-yl)methyl, ((R)-1-(2-(trifluoromethyl)benzoyl)pyrrolidin-3-yl)methyl, -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-pi (R)-1-(4-(trifluoromethyl)thiazol-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-4-yl)-2,6-difluorophenethyl, ((R)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl, ((R)-1-(5-isopropylthiazol-2-yl)piperidin-3-yl)methyl, -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, The aryl group may be ((S)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl, ((S)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl, ((S)-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl, or ((S)-1-(4-(trifluoromethyl)thiazol)-2-yl)piperidin-3-yl)methyl.

[0065] In one embodiment, R 1 is CH 2 OH, R 2 may be H, R 3are 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, ((1s,4S)-4-(2-fluoropropan-2-yl)cyclohexyl)methyl, ((1r,4R)-4-(2-fluoropropan-2-yl)cyclohexyl)methyl, ((trans)-3-(trifluoromethyl)cyclohexyl)methyl, ((cis)-3-(trifluoromethyl)cyclohexyl)methyl, ((1s,4S)-4-methoxycyclohexyl)methyl, ((1r,4R)-4-methoxycyclohex cyclohexyl)methyl, (4-(methoxymethyl)cyclohexyl)methyl, ((1s,4S)-4-cyclopropylcyclohexyl)methyl, ((1r,4R)-4-cyclopropylcyclohexyl)methyl, (4-phenylcyclohexyl)methyl, (spiro[2.5]octan-6-yl)methyl, (spiro[3.5]nonan-7-yl)methyl, (spiro[4.5]decan-8-yl)methyl, 2-cyclohexylethyl, 2-(4,4-difluorocyclohexyl)ethyl, 2-((1s,4S)-4-(trifluoromethyl)cyclohexyl)ethyl, 2-((1r,4R)-4-(trifluoromethyl)cyclohexyl)ethyl, 2-(adamantan-1-yl)ethyl, 3- Cyclohexylpropyl, 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 fluoromethyl)phenethyl, 2,6-difluoro-4-(pyrrolidin-1-yl)phenethyl, 2,6-difluoro-4-(piperidin-1-yl)phenethyl, 2,6-difluoro-4-morpholinophenethyl, 4-butoxy-2,6-difluorophenethyl, 4-(cyclopropylmethoxy)-2,6-difluorophenethyl, 4-((tetrahydrofuran-3-yl)oxy)phenethyl, 4-((tetrahydro-2H) -pyran-3-yl)oxy)phenethyl, 4-((tetrahydro-2H-pyran-4-yl)oxy)phenethyl, 4-phenoxyphenethyl, 4-((tetrahydrofuran-3-yl)methoxy)phenethyl, 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-dihydro benzo[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-methylbutanoyl)piperidin-4-yl)methyl, (1-(3,3-difluoroethyl)piperidin-4-yl)methyl, methylbutanoyl)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)piperidine-4- yl)methyl, ((5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-8-yl)methyl, (1,2,3,4-tetrahydronaphthalen-2-yl)methyl, (2,3-dihydro-1H-inden-2-yl)methyl, 2,6-difluoro-4-(tetrahydro-2H-pyran-4)-yl)phenethyl, (1-(pyridin-3-yl)piperidin-4-yl)methyl, (1-(cyclohexylcarbamoyl)piperidin-4-yl)methyl, (1-(cyclohexylcarbamothioyl)piperidin-4-yl)methyl, (1-((1S,2R)-2-(trifluoromethyl)cyclohexyl)azetidin-3-yl)methyl,((R)-1-phenylpyrrolidin-3-yl)methyl, ((R)-1-(o-tolyl)pyrrolidin-3-yl)methyl, ((R)-1-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl, ((S)-1-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl, (R)-1-(2-fluorophenyl)pyrrolidin-3-yl)methyl, (R)-1-(3-fluorophenyl)pyrrolidin-3-yl)methyl, ((R)-1-(2-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)methyl, ((R )-1-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl, ((R)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl, ((R)-1-(4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl, ((R)-1-(pyridin-3-yl)pyrrolidin-3-yl)methyl, ((R)-1-(4-methylpyridin-3-yl)pyrrolidin-3-yl)methyl, ((R)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl ethyl, ((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)pyrrolidine -3-yl)methyl, ((R)-1-(o-tolyl)piperidin-3-yl)methyl, ((R)-1-(2-fluorophenyl)piperidin-3-yl)methyl, ((R)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl, ((R)-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl, ((R)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl, 3-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 1-(4-(trifluoromethyl)pyridin-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)- It may be 1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl, 4-butoxyphenethyl, ((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.

[0066] In one embodiment, R 1 may be H, R 2 is CH 2 OH, R 3 may be 2-fluorophenethyl, 3-fluorophenethyl, 4-fluorophenethyl, 2,6-difluorophenethyl, 3-(trifluoromethyl)phenethyl, 4-(trifluoromethyl)phenethyl, (R)-2-phenylpropyl, (S)-2-phenylpropyl, 2-(pyridin-2-yl)ethyl, 2-(thiophen-2-yl)ethyl, or 2-(thiophen-3-yl)ethyl.

[0067] In one embodiment, R 1 is CH 2 OH, R 2 may be H, R 3are cyclohexylmethyl, ((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl, ((1s,4S)-4-(2-fluoropropan-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-(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)pyridin-2-yl)pyrrolidin-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl, ((R)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl, ((R)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl, ((S)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidine-3-yl)methyl,

[0046] In one embodiment, the aryl group may be ((1S)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-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.

[0068] In certain embodiments of the present invention, compounds according to formula (I) include those listed in Table 1. Table 1 JPEG0007674389000031.jpg185147JPEG0007674389000032.jpg185147JPEG0007674389000033.jpg185147JPEG0007674389000034.jpg185147JPEG0007674389000035.jpg185147JPEG0007674389000036.jpg185147JPEG0007674389000037.jpg185146JPEG0007674389000038.jpg185146JPEG0007674389000039.jpg185147JPEG0007674389000040.jpg185147JPEG0007674389000041.jpg185147JPEG0007674389000042.jpg185147JPEG0007674389000043.jpg185147JPEG0007674389000044.jpg197147JPEG0007674389000045.jpg197147JPEG0007674389000046.jpg203147JPEG0007674389000047.jpg185147JPEG0007674389000048.jpg185147JPEG0007674389000049.jpg191147JPEG0007674389000050.jpg185147JPEG0007674389000051.jpg203147JPEG0007674389000052.jpg185146JPEG0007674389000053.jpg185147JPEG0007674389000054.jpg185147JPEG0007674389000055.jpg185147JPEG0007674389000056.jpg191147JPEG0007674389000057.jpg191147JPEG0007674389000058.jpg185147JPEG0007674389000059.jpg191147JPEG0007674389000060.jpg185147JPEG0007674389000061.jpg185147JPEG0007674389000062.jpg185147JPEG0007674389000063.jpg185147JPEG0007674389000064.jpg185147JPEG0007674389000065.jpg185147JPE G0007674389000066.jpg186147JPEG0007674389000067.jpg185147JPEG000767438900 0068.jpg203146JPEG0007674389000069.jpg197146JPEG0007674389000070.jpg1851 47JPEG0007674389000071.jpg185147JPEG0007674389000072.jpg185146JPEG0007674 389000073.jpg191147JPEG0007674389000074.jpg185146JPEG0007674389000075.jp g203146JPEG0007674389000076.jpg185147JPEG0007674389000077.jpg185147JPEG00 07674389000078.jpg185147JPEG0007674389000079.jpg185147JPEG00076743890000 80.jpg191147JPEG0007674389000081.jpg191147JPEG0007674389000082.jpg185146.

[0069] As will be appreciated by those of skill in the art, formula (I) above can alternatively be represented as follows: JPEG0007674389000083.jpg5972

[0070] In another embodiment of the invention, one or more compounds in Table 2 are specifically excluded from the compounds set forth in any of Formula (I) or Formulas (Ia)-(Iv). Table 2 JPEG0007674389000084.jpg185147JPEG0007674389000085.jpg209146

[0071] As used herein, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. For example, "a compound" refers to one or more of such compounds, and "the enzyme" includes not only the specific enzyme but also other family member equivalents known to those of skill in the art.

[0072] Throughout this application, the term "compound" or "compounds" refers to the compounds discussed herein, including precursors and derivatives of the compounds, including acyl protected derivatives, and pharma- ceutically acceptable salts of the compounds, precursors, and derivatives. The invention also includes prodrugs of the compounds, pharmaceutical compositions comprising the compounds and a pharma- ceutically acceptable carrier, and pharmaceutical compositions comprising the prodrugs of the compounds and a pharma- ceutically acceptable carrier.

[0073] The compounds of the present invention may contain one or more additional asymmetric centers other than those specified in formula (I), including any one or more of formulae (Ia)-(Iv), and therefore may occur as single enantiomers, diastereomeric mixtures, and individual diastereomers. Such additional asymmetric centers may exist depending on the nature of the various substituents in the molecule. Each such additional asymmetric center independently produces two optical isomers, and all such possible optical isomers and diastereomers in mixtures, as well as pure or partially purified compounds, are intended to be included within the scope of the present invention. Any formula, structure, or name of a compound described herein that does not specify a specific stereochemistry for an additional asymmetric center is intended to encompass all of the isomers present and any mixtures thereof in any proportion as described above. When the stereochemistry of an additional asymmetric center is specified, the present invention is intended to encompass that specific isomer in pure form or as part of a mixture with other isomers in any proportion.

[0074] "Alkyl" refers to a straight or branched hydrocarbon chain group composed solely of carbon and hydrogen atoms and containing no unsaturation, e.g., 1-10 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, attached to the remainder of the molecule by a single bond. In another embodiment, an alkyl group can contain 1-8 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. In another embodiment, an alkyl group can contain 1-6 carbon atoms, e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. In another embodiment, an alkyl group can contain 1-5 carbon atoms, e.g., 1, 2, 3, 4, or 5 carbon atoms. Unless specifically stated herein, an alkyl group may be optionally substituted with one or more substituents as described herein. It is understood that unless specifically stated herein, said substitution may occur at any carbon of the alkyl group.

[0075] "Cycloalkyl" refers to a stable monovalent monocyclic, bicyclic, or tricyclic hydrocarbon group composed solely of carbon and hydrogen atoms, e.g., having 3 to 15 carbon atoms, that is saturated and attached to the remainder of the molecule by a single bond. In another embodiment, a cycloalkyl group can contain 3 to 6 carbon atoms, e.g., 3, 4, 5, or 6 carbon atoms. Unless specifically stated herein, the term "cycloalkyl" is intended to include cycloalkyl groups, which may be optionally substituted as described herein.

[0076] "Alkoxy" means a group of the formula -OR a In the formula, R a is independently C as described herein. 1-10 Alkyl or C 1-6 Alkyl or C 1-5 An alkoxy group may be optionally substituted as described herein.

[0077] "Optional" or "may" means that the subsequently described event or circumstance may or may not occur, and that the description includes the occurrence of the event or circumstance one or more times or none at all. For example, "optionally substituted alkyl" means that the alkyl group may or may not be substituted, and that the description includes both substituted alkyl groups and alkyl groups that have no substituents, and that 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 3 , O.H., O.C.H. 3 , C.F. 3 , CHF 2 , C.H. 2 F, and CN. Treatment indications

[0078] The present invention provides, in part, methods of treating conditions that are directly or indirectly regulated by the GBA2 enzyme or GBA2 enzyme activity levels, such as conditions that would benefit from inhibiting the GBA2 enzyme or reducing the GBA2 enzyme activity levels. 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), lysosomal storage diseases, such as Gaucher disease, Niemann-Pick disease type C, mucolipidosis type IV, and Sandhoff disease, and liver diseases, such as nonalcoholic steatohepatitis (NASH). Thus, one or more compounds of the present invention may be used to treat subjects at risk of developing, or who have already been diagnosed with, various neurological or other diseases. The term "treating" as used herein may include treatment, prevention, and / or amelioration.

[0079] In another embodiment, one or more compounds of the present invention may also be useful for treating diseases or disorders associated with deficiency or overexpression of GBA2, or accumulation or depletion of glycosylceramide, or any disease or disorder that responds to glycosidase inhibitor therapy or glycosidase inhibitor therapy. Such diseases and disorders may include, but are not limited to, neurological diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis (ALS), 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 disorders may also include diseases or disorders associated with accumulation or deficiency of the enzyme glucosylceramide synthase, or dysregulation of glycosphingolipid metabolism and / or homeostasis. Also included are methods of protecting or treating target cells expressing GBA2, the dysregulation of which may result in a disease or pathology.

[0080] In another embodiment, the present invention provides a method for reducing the level of GBA2 enzyme activity in an animal subject, e.g., livestock and human subjects, which may be useful for preventing or treating neurological or neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis (ALS)), providing a neuroprotective effect, preventing damage to dopaminergic neurons, preventing or treating lysosomal storage diseases (e.g., Gaucher disease, Niemann-Pick disease type C, mucolipidosis type IV, and Sandhoff disease), and preventing or treating liver diseases (e.g., nonalcoholic steatohepatitis (NASH)).

[0081] In another embodiment, the invention provides methods of inhibiting the GBA2 enzyme in animal subjects, including livestock and human subjects.

[0082] In another embodiment, the present invention provides a method for reducing CNS inflammation in animal subjects, such as livestock and human subjects.Disease conditions of interest may include neurodegenerative diseases whose etiology is related to neuroinflammation, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis (ALS).In some embodiments, the compounds of the present invention can be used to prevent, treat, or ameliorate neuroinflammation by reducing GBA2 enzyme activity levels, thereby providing therapeutic benefits.

[0083] In another embodiment, the present invention provides a method for inhibiting the aggregation of alpha-synuclein protein or inhibiting the formation of Lewy bodies in animal subjects, e.g., livestock and human subjects. Disease conditions of interest may include Parkinson's disease (PD) and related neurodegenerative synucleinopathies, whose etiology is linked to abnormal aggregation of alpha-synuclein protein. In an embodiment, the compounds of the present invention can be used to reduce GBA2 enzyme activity levels, thereby blocking the abnormal aggregation of alpha-synuclein protein, thereby providing a therapeutic benefit.

[0084] Neurological disorders that may be treated by the compounds of the present invention 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 (AT), attention-deficit / hyperactivity disorder (ADHD), autism spectrum disorder (ASD), Becker muscular dystrophy (BMD), bipolar disorder (BD), bruit 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 tangles with calcification, Down's 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, Gerstmann-Sträussler-Scheinker disease, glaucoma, Guadeloupe parkinsonism, Guillain-Barré syndrome, Hallervorden-Spatz syndrome (neurodegenerative disease 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, autonomic neuropathy, neuritis, and diabetic neuropathy), oculopharyngeal muscular dystrophy, pain, pallidopontineral degeneration, Parkinson-Dementia Complex of Guam, Pick's disease (PiD), postencephalitic parkinsonism (PEP), primary lateral sclerosis (PLS), prion diseases (Creutzfeldt-Jakob disease (CJD), variant Creutzfeldt-Jakob disease (VJD), and variant Creutzfeldt-Jakob disease (VJD)). disease (vCJD), fatal familial insomnia, and kuru), progressive transcortical gliosis, progressive supranuclear palsy (PSP), Richardson's syndrome, schizophrenia, seizures, spinal cord disorders, spinal muscular atrophy (SMA), spinocerebellar ataxias (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, fibrillary tangle-predominant dementia, tardive dyskinesia, Tourette's syndrome (TS), vascular dementia, or Wilson's disease.

[0085] Lysosomal storage diseases that may be treated by the compounds of the 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.

[0086] Liver diseases that may be treated by the compounds of the invention may 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 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 sclerosing cholangitis (PBC), primary biliary cholangitis (PSC), Reye's syndrome, glycogen storage disease type I, or viral hepatitis (including types A, B, C, D, and E).

[0087] In certain embodiments, the compounds of the present invention may be useful in the treatment of disorders in which modulation of GBA2 enzyme activity levels is implicated, or any of the conditions described herein.

[0088] Other conditions that may be treated using one or more compounds of the present invention are conditions that are induced, affected, or in any other way correlated with the level of GBA2 enzyme activity. It is expected that one or more compounds of the present invention may be useful in treating such conditions, particularly, but not limited to, Parkinson's disease, neuronal ceroid lipofuscinosis (Batten disease), Gaucher disease, Niemann-Pick disease type C, mucolipidosis type IV, and Sandhoff disease. Pharmaceutical & Veterinary Compositions, Dosages, and Administration

[0089] Pharmaceutical compositions comprising a compound of the invention or for use according to the invention are considered within the scope of the invention. In one embodiment, a pharmaceutical composition is provided that comprises an effective amount of a compound of formula (I), including any one or more of formulae (Ia)-(Iv).

[0090] Compounds of formula (I), including any one or more of formulae (Ia)-(Iv), and pharma- ceutically acceptable salts, enantiomers, solvates, or derivatives thereof, may be useful because they may have pharmacological activity in animals, including humans. In certain embodiments, one or more compounds according to the invention may be stable in plasma when administered to a subject, such as a human.

[0091] Generally, the compounds of the invention can be administered to a subject in need thereof, for example, by contacting a cell or sample with a pharmaceutical composition comprising a therapeutically effective amount of a compound according to formula (I), including any one or more of formulae (Ia)-(Iv).

[0092] In some embodiments, the compounds of the present invention or used in accordance with the present invention may be provided in combination with any other active agent or pharmaceutical composition, and such combination therapy may be useful for inhibiting GBA2 activity levels to treat, for example, neurological disorders, or lysosomal storage diseases, or liver diseases, or any of the conditions described herein. In some embodiments, the compounds of the present invention or used in accordance with the present invention may be provided in combination with one or more agents useful for the prevention or treatment of Parkinson's disease. Examples of such agents may include, but are not limited to, the following: Levodopa (L-DOPA), Peripheral DOPA decarboxylase inhibitors (DDCIs), e.g., carbidopa (Lodosyn®, Carbidopa / levodopa combination (Kinson®, Sinemet®, Parcopa®, Atamet®) Carbidopa / levodopa / entacapone combination (Stalevo®, Amantadine (Symmetrel®), dopamine antagonists, for example bromocriptine (Cycloset®, Parlodel®), pergolide (Permax®), pramipexole (Mirapexin®, Sifrol®, Mirapex®), ropinirole (Ronirol®, Adartrel®, Requip®), piribedil (Trivastal Retard®, Trastal®, Trivastan®, Clarium®, Pronoran®), cabergoline (Cabaser®, Dostinex®), apomorphine (Ixense®, Spontane®, Uprima®, Apokyn®, Lisuride® (Dopergin®, Proclacam®, Revanil®, rotigotine (Neupro®), (registered trademark), Ciladopa (registered trademark) (AY-27,110), Dihydrexidine (registered trademark) (DAR-0100), Dinapsoline (registered trademark), Doxanthrine (registered trademark), Epicryptine (β-dihydroergocryptine), Nn-propylnorapomorphine (NPA), quinagolide (Norprolac (registered trademark), Roxindole (registered trademark) (EMD-49,980), Sumanirole (registered trademark) (PNU-95,666), Pardoprunox, Aprindore, etc., Monoamine oxidase B (MAO-B) inhibitors, such as selegiline (Anipryl®, L-deprenyl®, Eldepryl®, Emsam®, Zelapar®), rasagiline (Azilect®, AGN 1135), safinamide, etc. Anticholinergic drugs, such as benzatropine (Benztropine, Cogentin®), diphenhydramine (Benadryl®, Dimedrol®, Daedalon®, Nytol®), orphenadrine (Norflex®, Mephenamin®, Disipal®, Banflex®, Flexon®, Biorphen®, Brocasipal®, Dolan®, Norgesic®, OrfenAce®, trihexyphenidyl (Artane®, Apo-Trihex®, Parkin®, Pacitane®, Benzhexaol, Trihex, etc., Catechol-O-methyltransferase (COMT) inhibitors, such as entacapone (COMTan®), tolcapone (Tasmar®), nitecapone, nebicapone, etc. Adenosine A 2A Receptor antagonists, such as istradefylline (KW-6002), preladenant, fipamezole (JP-1730), SCH-420814, BIIA-014, Lu AA4707, etc. Metabotropic glutamate receptor 5 (mgluR5) modulators, such as dipragnant, AMPA receptor antagonists, such as perampanel (Fycompa®), Anticonvulsants, such as zonisamide (Tremode®), Nicotinic acetylcholine receptor (nAChR) agonists, such as nicotine, ABT-418, WAY-317,538 (SEN-12333), EVP-6124, MEM 3454, nefiracetam, etc. Acetylcholinesterase inhibitors (AChEIs), such as Aricept® (Donepezil), Exelon® (Rivastigmine), Razadyne® (Razadyne ER®, Reminyl®, Nivalin®, galantamine), Cognex® (tacrine), Huperzine A, Phenserine, Debio-9902 SR (ZT-1 SR), Zanapezil (TAK0147), Ganstigmine, NP7557, etc. atypical antipsychotics, such as clozapine, or Modafinil (Alertec®, Modavigil®, Provigil®).

[0093] It should be understood that the combination of the compound according to or used according to the invention with an agent useful for treating Parkinson's disease is not limited to the examples described herein and may include any combination with an agent useful for treating Parkinson's disease. The combination of the compound according to or used according to the invention with another agent useful for treating Parkinson's disease may be administered separately or together. The administration of one agent may be prior to, simultaneous with, or subsequent to the administration of the other agent.

[0094] In one embodiment, a compound according to or for use in accordance with the present invention may be provided in combination with one or more agents useful in the prevention or treatment of Gaucher's disease. Examples of such agents may include, but are not limited to: Combination human GCase enzyme replacement therapy, e.g., imiglucerase (Cerezyme®), velaglucerase alfa (VPRIV®), taliglucerase alfa (Elelyso®), etc. Glucosylceramide synthase inhibitors, such as EXEL-0346, Genz-123346, Eliglustat® (Genz-112638), etc. Bisphosphonates, such as zoledronate (Zometa®, Zomera®, Aclasta®, Reclast®), sodium alendronate (Fosamax®), etidronate (Didronel®), clodronate (Bonefos®, Loron®), tiludronate (Skelid®), pamidronate (APD®, Aredia®), neridronate (Nerixia®, olpadronate, ibandronate (Boniva®), risedronate (Actonel®), etc. Antiepileptic drugs, such as Tegretol® (Carbatrol®, carbamazepine), Zarontin® (ethosuximide), Felbato® (felbamate), Gabitril® (tiagabine), Keppra® (levetiracetam), Lamictal® (lamotrigine), Lyrica® (pregabalin), Neurontin® (gabapentin), Dilantin® (rituximide), Trademark) (phenytoin), Topamax® (topiramate), Trileptal® (oxcarbazepine), Depakene® (Depakote®, valproate, valproic acid), Zonegran® (zonisamide), Valium® (diazepam), Ativan® (lorazepam), Klonopin® (clonazepam), Fycompa® (perampanel), Oxtellar XR® (oxcarbazepine), and the like; Gene therapy.

[0095] It is to be understood that combinations of compounds according to or for use in accordance with the present invention with agents useful for the treatment of Gaucher's disease are not limited to the examples described herein and may include combinations with any agent useful for the treatment of Gaucher's disease. Combinations of compounds according to or for use in accordance with the present invention with other agents useful for the treatment of Gaucher's disease may be administered separately or together. Administration of one agent may be prior to, simultaneous with, or subsequent to administration of the other agent.

[0096] In another embodiment, the compounds of the invention may be provided in a "prodrug" or protected form that releases the compound after administration to a subject. For example, the compounds may carry a protecting group that is cleaved by hydrolysis in a body fluid, e.g., the bloodstream, thereby releasing the active compound, or that is oxidized or reduced in a body fluid to release the compound. Thus, a "prodrug" is intended to indicate a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound of the invention. Thus, the term "prodrug" refers to a metabolic precursor of a compound of the invention that is pharma- ceutically acceptable. A prodrug may be inactive when administered to a subject in need thereof, but can be converted in vivo to an active compound of the invention. A prodrug is typically rapidly transformed in vivo, e.g., by hydrolysis in the blood, to yield the parent compound of the invention. In many cases, a prodrug compound offers advantages of solubility, tissue compatibility, or delayed release in a subject.

[0097] The term "prodrug" is also intended to include any covalently bonded carrier that releases an active compound of the invention in vivo when such prodrug is administered to a subject. Prodrugs of the compounds of the invention may be prepared by modifying functional groups present in the compounds of the invention such that the modifications are cleaved from the parent compound either in routine manipulation or in vivo. Prodrugs include compounds of the invention in which a hydroxy, amino or mercapto group is bonded to any group that will cleave to form a free hydroxy, free amino or free mercapto group, respectively, when a prodrug of the compound of the invention is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetates, formates, benzoic acid derivatives of alcohols and acetamides, formamides, and benzamide derivatives of amine functional groups in one or more compounds of the invention.

[0098] A discussion 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 113 191 (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, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0099] Suitable prodrug forms of one or more of the compounds of the invention include those in which one or more OH groups according to formula (I), including any one or more of formulae (Ia) to (Iv), may be protected as OC(O)R, where R is an optionally substituted C 1-6 In these cases, the ester group can be hydrolyzed in vivo (e.g., in body fluids) to liberate the OH group and release the active compound. Preferred prodrug embodiments of the invention include those in which one or more of the OH groups are acetate salts, e.g., OC(O)CH 3The compound may include a compound of formula (I) comprising any one or more of formulae (Ia) to (Iv), which may be protected by:

[0100] The compounds of the present invention or compounds used according to the present invention may be provided in a form suitable for administration to a subject, such as a mammal, for example a human, cow, sheep, etc., alone or in combination with other compounds, in the presence of liposomes, nanoparticles, adjuvants, or any pharma- ceutically acceptable carrier, diluent, or excipient. If desired, treatment with the compounds of the present invention can be combined with traditional, existing therapies for the therapeutic indications described herein. The compounds of the present invention may be provided chronically or intermittently. "Chronic" administration refers to administration of the compound in a continuous manner as opposed to an acute manner, such that the initial therapeutic effect (activity) is maintained over an extended period of time. "Intermittent" administration is not continuous without interruption, but rather is a treatment that is cyclic in nature. It should be understood that the terms "administration," "administerable," or "administering," as used herein, refer to providing the compounds of the present invention to a subject in need of treatment.

[0101] A "pharmaceutical 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, stabilizing, isotonic agent, solvent, or emulsifying agent approved by the U.S. Food and Drug Administration or other government agency as acceptable for use in humans or domestic animals.

[0102] The compounds of the present invention may be administered in the form of pharma- ceutical acceptable salts.In such cases, the pharmaceutical compositions according to the present invention may contain salts of such compounds, preferably physiologically acceptable salts, as known in the art.In one embodiment, the term "pharma-ceutical acceptable salts" as used herein means active ingredients, including compounds of formula (I), including any one or more of formulas (Ia)-(Iv), used in the form of salts, and in particular, the salt forms provide the active ingredients with improved pharmacokinetic properties compared to the free form or other previously disclosed salt forms of the active ingredients.

[0103] "Pharmaceutically acceptable salts" may include both acid and base addition salts. "Pharmaceutically acceptable acid addition salts" refers to salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which may be formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (e.g., acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.).

[0104] "Pharmaceutically acceptable base addition salt" refers to a salt that may retain biological effectiveness and properties that are not biologically or otherwise undesirable. These salts may be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases may include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts may be ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases may 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, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Particularly preferred organic bases may be isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0105] Thus, the term "pharmaceutical acceptable salt" includes acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methyl bromide, bromide, methyl nitrite, calcium edetate, methyl sulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, es ... This includes all acceptable salts, including, but not limited to, anthrate, fumarate, phosphate / diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycolylarsanilate, sulfate, hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, theoclate, iodide, tosylate, isethionate, triethyodide, lactate, panoate, valerate, and the like.

[0106] The pharma- ceutically acceptable salts of the compounds of the present invention may be used as dosages to modify solubility or hydrolysis characteristics, or may be used in sustained release or prodrug formulations.The pharma- ceutically acceptable salts of the compounds of the present invention may also include those formed from cations (e.g., sodium, potassium, aluminum, calcium, lithium, magnesium, zinc) and those formed from bases (e.g., ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide).

[0107] Pharmaceutical compositions typically include one or more carriers acceptable for the administration form of the formulation, such as injection, inhalation, topical administration, irrigation, or other mode appropriate for the selected treatment. Suitable carriers may be those known in the art for use in such administration forms.

[0108] Suitable pharmaceutical compositions may be formulated by methods known to those skilled in the art, and their dosage forms and doses may be determined by the skilled artisan. For parenteral administration, the compound may be dissolved in sterile water, or saline, or in a pharma- ceutically acceptable solvent used for the administration of water-insoluble compounds (e.g., vitamin K). For enteral administration, the compound may be administered in a tablet, capsule, or may be dissolved in a liquid form. The tablet or capsule may be enteric coated or formulated for sustained release. Many suitable formulations are known, including polymer or protein microparticles, ointments, gels, hydrogels, or solutions that encapsulate the compound to be released, and may be used topically or locally to administer the compound. Sustained release patches or implants may be used to provide release over an extended period of time. Many techniques known to the skilled artisan are described in Remington: The Science & Practice of Pharmacy, 2000, by Alfonso Gennaro. thed., Williams & Wilkins, (2000). Formulations for parenteral administration may contain, for example, excipients, polyalkylene glycols, such as polyethylene glycol, vegetable oils, or hydrogenated naphthalenes. Biocompatible biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compound. Other potentially useful parenteral delivery systems for modulatory compounds may include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients, such as lactose, or may be aqueous solutions, such as polyoxyethylene-9-lauryl ether, glycocholate, and deoxycholate, or may be oily solutions administered in the form of nasal drops or as a gel.

[0109] The compound or pharmaceutical composition of the present invention may be administered orally or parenterally, for example, intramuscularly, intraperitoneally, intravenously, intracisternally, subcutaneously, transdermally, or transmucosally. In some embodiments, the compound or pharmaceutical composition according to or used in the present invention may be administered by a medical device or apparatus, for example, an implant, a graft, a prosthesis, a stent, etc. Implants intended to contain and release such compounds or compositions may be devised. An example is an implant made of a polymeric material adapted to release the compound over an extended period of time. The compound may be administered alone or in admixture with a pharma-ceutically acceptable carrier, for example, as a solid formulation (e.g., tablet, capsule, granule, powder, etc.), a liquid formulation (e.g., syrup, injection, etc.), an injection, a drop, a suppository, a vaginal suppository. In certain embodiments, the compounds or pharmaceutical compositions according to or used in the present invention may be administered by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes and may be formulated, alone or together, into suitable dosage unit formulations containing conventional non-toxic pharma- ceutically acceptable carriers, adjuvants, and solvents appropriate for each route of administration.

[0110] The compounds of the present invention can be used to treat animals, including mice, rats, horses, cows, sheep, dogs, cats, and monkeys. However, the compounds of the present invention can also be used in other organisms, such as birds (e.g., chickens). One or more compounds of the present invention can also be effective for use in humans. The term "subject" or alternatively referred to herein as "patient" is intended to refer to an animal, preferably a mammal, most preferably a human, that is the object of treatment, observation, or experiment. However, one or more compounds, methods, and pharmaceutical compositions of the present invention can be used to treat animals. Thus, as used herein, a "subject" can be a human, a non-human primate, a rat, a mouse, cows, horses, pigs, sheep, goats, dogs, cats, etc. The subject can have or be at risk for a condition that may require inhibition of GBA2 activity.

[0111] An "effective amount" of a compound of the invention may include a therapeutically effective amount or a prophylactically effective amount. A "therapeutically effective amount" refers to an amount that is effective at dosages and for periods of time necessary to achieve a desired therapeutic outcome, e.g., inhibition of GBA2, reduction of GBA2 enzyme activity levels, inhibition of alpha-synuclein protein aggregation, or any condition described herein. A therapeutically effective amount of a compound may vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual. Dosage regimens may be adjusted to provide an optimal therapeutic response. A therapeutically effective amount may also be one in which any toxic or adverse effects of the compound are outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" may refer to an amount that is effective at dosages and for periods of time necessary to achieve a desired prophylactic outcome, e.g., inhibition of GBA2, reduction of GBA2 enzyme activity levels, inhibition of alpha-synuclein protein aggregation, or any condition described herein. Typically, a prophylactic dose may be used in subjects prior to or at an early stage of disease, such that the prophylactically effective amount may be less than the therapeutically effective amount. A suitable range for a therapeutically or prophylactically effective amount of a compound may be any integer between 0.1 nM and 0.1 M, 0.1 nM and 0.05 M, 0.05 nM and 15 μM, or 0.01 nM and 10 μM.

[0112] In another embodiment, for the treatment or prevention of a condition that may require inhibition of GBA2 activity, an appropriate dosage level may generally be about 0.01 to 500 mg per kg of subject body weight per day, and may be administered in single or multiple doses. In some embodiments, the dosage level may be about 0.1 to about 250 mg / kg per day. It will be understood that the specific dosage level and frequency of administration to 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 that compound, age, body weight, general health, sex, diet, dosage form and time, excretion rate, drug combinations, the severity of the particular condition, and the patient undergoing therapy.

[0113] It should be noted that dosage values ​​may vary with the severity of the condition to be alleviated. In any particular subject, a particular dosage regimen may be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition. The dosage ranges described herein are merely exemplary and do not limit the dosage range that may be selected by a physician. The amount of active compound in the composition may vary depending on factors such as the disease state, age, sex, and weight of the subject. The dosage regimen may be adjusted to provide an optimal therapeutic response. For example, a single rapid administration may be performed, several divided doses may be administered over time, or the dose may be reduced or increased as indicated by the exigencies of the treatment situation. For ease of administration and uniformity of dosage, it may be advantageous to formulate parenteral compositions in unit dosage form. In general, the compounds of the present invention should be used without causing substantial toxicity, and as described herein, one or more compounds may exhibit a safety profile suitable for therapeutic use. The toxicity of the compounds of the present invention can be measured using standard techniques, for example, by testing in cell cultures or experimental animals, and determining the therapeutic index, i.e., the ratio between LD50 (the dose that is lethal to 50% of the population) and LD100 (the dose that is lethal to 100% of the population). However, in some circumstances, for example in severe disease conditions, it may be necessary to administer substantial excesses of the composition.

[0114] In the compounds of general formula (I) including any one or more of formulae (Ia)-(Iv), atoms may exhibit natural isotopic abundances or one or more atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from that found predominantly in nature. The present invention is intended to include all appropriate isotopic variations of the compounds of general formula (I) including any one or more of formulae (Ia)-(Iv). For example, different isotopic forms of hydrogen (H) include protium ( 1 H), deuterium ( 2 H), and tritium ( 3H). Protium is the predominant hydrogen isotope found in nature. Enrichment of deuterium can provide certain therapeutic benefits, such as increased in vivo half-life or reduced required dosage, or can provide compounds useful as standards for characterization of biological samples. Isotopically enriched compounds within the scope of general formula (I), including any one or more of formulae (Ia)-(Iv), can be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the schemes and examples herein using appropriately isotopically enriched reagents and / or intermediates. Other uses

[0115] In another embodiment, one or more compounds of the present invention may be used to study the physiological role of GBA2 at the cellular and organismal levels. In one embodiment, the one or more compounds may be useful for developing animal models for studying the treatment of diseases and disorders that may be associated with GBA2 deficiency, GBA2 overexpression, glucosylceramide accumulation, glucosylceramide depletion, glycosphingolipid accumulation, and glycosphingolipid depletion, and for studying diseases or disorders that may be associated with GBA2 deficiency or overexpression, or glucosylceramide accumulation or depletion, or glycosphingolipid accumulation or depletion. Such diseases and disorders may include, but are not limited to, lysosomal storage diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, amyotrophic lateral sclerosis (ALS), neuronal ceroid lipofuscinosis (Batten disease), Gaucher disease, Niemann-Pick disease type C, mucolipidosis type IV, and Sandhoff disease; or liver diseases including nonalcoholic steatohepatitis (NASH).

[0116] The efficacy of a compound for treating a condition associated with a lysosomal storage disease (e.g., Gaucher disease, Niemann-Pick disease type C, mucolipidosis type IV, or Sandhoff disease) can be confirmed using standard techniques, for example, by testing the ability of the compound to prevent, treat, or ameliorate symptoms of the disease in established cellular and / or transgenic animal disease models.13、14、16、17、27 .

[0117] Various alternative embodiments and examples of the present invention are described herein. These embodiments and examples are for illustrative purposes and should not be construed as limiting the scope of the present invention. EXAMPLES

[0118] The following examples are intended to illustrate embodiments of the invention and are not intended to be construed as limiting. Abbreviation DCM = dichloromethane DIPEA = diisopropylethylamine DMA = Dimethylacetamide DMF = N,N-dimethylformamide EtOH = ethanol HOAc = acetic acid MeOH = methanol RT = room temperature TFA = 2,2,2-trifluoroacetic acid Example 1 (2R,3R,4R,5S)-1-(2-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol JPEG0007674389000086.jpg4162

[0119] In a sealed tube, 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)-2-fluorobenzene (194 mg, 0.95 mmol) in DMF (5 mL) was added with K 2 CO 3 (210 mg, 1.52 mmol) was added. The mixture was stirred at 80° C. for 18 h and cooled to ambient temperature. The reaction mixture was poured into ice water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×20 mL), separated and washed with Na 2 SO4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(2-fluorophenylethyl)piperidine as a white solid (63 mg, 51%). ESI MS m / z 646.32 [M + H] + .

[0120] The above material (63 mg, 0.098 mmol) was dissolved in EtOH (10 mL) and Pd(OH) 2 HCl (20 wt%, 8.6 mg, 0.012 mmol) and 6N HCl (0.1 mL) were added. The mixture was treated with hydrogen (1 atm) for 18 h. The catalyst was removed by filtration through Celite and the solvent was evaporated under reduced pressure. The residue was diluted with 1M NH 3 After stirring for an additional 10 min, the solvent was removed in vacuo and the residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-1-(2-fluorophenyl)-2-(hydroxymethyl)piperidine-3,4,5-triol (21 mg, 75%) as a white solid. 1 H NMR (400 MHz, CD 3OD) δ 7.29 (td, J = 7.6, 1.8 Hz, 1H), 7.23 (tdd, J = 7.4, 5.2, 1.8 Hz, 1H), 7.10 (td, J = 7.5, 1.2 Hz, 1H), 7.05 (ddd, J = 9.7, 8.2, 1.2 Hz, 1H), 3.96 (dd, J = 11.9, 2.5 Hz, 1H), 3.88 (dd, J = 11.9, 3.1 Hz, 1H), 3.51 (ddd, J = 10.4, 9.0, 4.9 Hz, 1H), 3.37 (t, J = 12 Hz, 1H), 3.18 (t, J = 9.0 ESI MS m / z 286.14 [M+H] + . Example 2 (2R,3R,4R,5S)-1-(3-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol JPEG0007674389000087.jpg4166

[0121] In a sealed tube, 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) was added with K 2 CO 3 (210 mg, 1.52 mmol) was added. The mixture was stirred at 80° C. for 18 h and cooled to ambient temperature. The reaction mixture was poured into ice water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×20 mL), separated and washed with Na 2 SO 4After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(3-fluorophenylethyl)piperidine as a white solid (71 mg, 58%). ESI MS m / z 646.32 [M + H] + .

[0122] The above material (71 mg, 0.11 mmol) was dissolved in EtOH (10 mL) and Pd(OH) 2 HCl (20% by weight, 8.6 mg, 0.012 mmol) and 6N HCl (0.1 mL) were added. The mixture was treated with hydrogen (1 atm) for 18 h. The catalyst was removed by filtration through Celite and the solvent was evaporated under reduced pressure. The residue was diluted with 1M NH 3 After stirring for an additional 10 min, the solvent was removed in vacuo and the residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-1-(3-fluorophenyl)-2-(hydroxymethyl)piperidine-3,4,5-triol (22 mg, 70%) as a white solid. 1 H NMR (400 MHz, CD 3OD) δ 7.29 (td, J = 7.9, 6.1 Hz, 1H), 7.05 (dt, J = 7.6, 1.2 Hz, 1H), 7.00 (dt, J = 10.1, 2.1 Hz, 1H), 6.95-6.87 (m, 1H), 3.96 (dd, J = 12.0, 2.5 Hz, 1H), 3.86 (dd, J = 12.0, 3.2 Hz, 1H), 3.51 (ddd, J = 10.4, 9.0, 4.9 Hz, 1H), 3.34 (t, J = 12 Hz, 1H), 3.18 (t, J = 9.0 Hz, 1H), 3.09 (dd, J = ESI MS m / z 286.14 [M + H] + . Example 3 (2R,3R,4R,5S)-1-(4-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol JPEG0007674389000088.jpg4368

[0123] In a sealed tube, 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) was added with K 2 CO 3 (210 mg, 1.52 mmol) was added. The mixture was stirred at 80° C. for 18 h and cooled to ambient temperature. The reaction mixture was poured into ice water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×20 mL), separated and washed with Na 2 SO 4After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(4-fluorophenylethyl)piperidine as a white solid (70 mg, 57%). ESI MS m / z 646.32 [M + H] + .

[0124] The above material (70 mg, 0.11 mmol) was dissolved in EtOH (10 mL) and Pd(OH) 2 HCl (20 wt%, 8.6 mg, 0.012 mmol) and 6N HCl (0.1 mL) were added. The mixture was treated with hydrogen (1 atm) for 18 h. The catalyst was removed by filtration through Celite and the solvent was evaporated under reduced pressure. The residue was diluted with 1M NH 3 After stirring for an additional 10 min, the solvent was removed in vacuo and the residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-1-(4-fluorophenyl)-2-(hydroxymethyl)piperidine-3,4,5-triol (16 mg, 51%) as a white solid. 1 H NMR (400 MHz, CD 3 OD) δ 7.29-7.19 (m, 2H), 7.05-6.97 (m, 2H), 3.95 (dd, J = 11.9, 2.5 Hz, 1H), 3.85 (dd, J = 11.9, 3.1 Hz, 1H), 3.51 (ddd, J = 10.4, 9.0, 4.9 Hz, 1H), 3.34 (t, J = 12 Hz, 1H), 3.17 (t, J = 9.0 Hz, 1H), 3.09 (dd, J = 11.1, 4.9 Hz, 1H), 3.05-2.72 (m, 4H), 2.37 (t, J = 10.8 Hz, 1H), 2.28 (dt, J = 9.5, 2.9 Hz, 1H); ESI MS m / z 286.14 [M + H] + . Example 4 (2R,3R,4R,5S)-1-(2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol JPEG0007674389000089.jpg3960

[0125] In a sealed tube, 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) was stirred at 85° C. for 16 h. The reaction mixture was cooled to room temperature and NaHCO 3 After dilution with saturated aqueous solution (20 mL), the combined extracts were washed with brine (2×30 mL) and diluted with anhydrous Na 2 SO 4 The solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography (EtOAc / hexanes, 1:6 to 1:3) to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(2,6-difluorophenoxy)piperidine as a pale yellow oil (0.10 g, 26%). ESI MS m / z 664.364 [M + H] + .

[0126] -78°C and N 2 To a solution of the above material (0.10 g, 0.15 mmol) in anhydrous DCM (3 mL), 3 (1.0M in DCM, 1.5 mL, 1.5 mmol) was added 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 purified with 1M NH 3 The mixture was neutralized with a solution of MeOH (1M NH 3Purification on silica gel with MeOH / DCM (1:4) afforded (2R,3R,4R,5S)-1-(2,6-difluorophenoxy)-2-(hydroxymethyl)piperidine-3,4,5-triol as a white solid (0.040 g, 87%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.33-7.24 (m, 1H), 7.10-7.00 (m, 2H), 4.72-.67 (m, 3H), 4.15 (dd, J = 6.1, 4.2 Hz, 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 = 10.6 Hz, 1H), 2.06 (dt, J = 9.3, 2.9 Hz, 1H); ESI MS m / z 304.129 [M + H] + . Example 5 2R,3R,4R,5S)-2-(hydroxymethyl)-1-(3-(trifluoromethyl)phenethyl)piperidine-3,4,5-triol JPEG0007674389000090.jpg4177

[0127] In a sealed tube, 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) was added with K 2 CO 3 (210 mg, 1.52 mmol) was added. The mixture was stirred at 80° C. for 18 h and cooled to ambient temperature. The reaction mixture was poured into ice water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×20 mL), separated and washed with Na 2 SO 4After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel flash chromatography 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] + .

[0128] To a stirred solution of the above material (70 mg, 0.10 mmol) in anhydrous DCM (5 mL) was added BCl 3 (1M in DCM, 1.0 mL, 1.0 mmol) was incubated at -78 °C and N 2 The mixture was stirred at 0° C. for 2 h and quenched with anhydrous MeOH (1 mL). The mixture was stirred at ambient temperature for 10 min. The solvent was removed in vacuo and the residue was washed with 1M NH 3 After stirring for an additional 10 min, the solvent was removed in vacuo and 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, CD 3 OD) 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] + . Example 6 (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(4-(trifluoromethyl)phenethyl)piperidine-3,4,5-triol JPEG0007674389000091.jpg4274

[0129] 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) was added IPEA (0.35 mL, 1.9 mmol) in a sealed tube. The mixture was stirred at 80° C. for 18 h and cooled to ambient temperature. The reaction mixture was poured into ice water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×20 mL), separated and concentrated with NaCl. 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel flash chromatography 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%).

[0130] A solution of the above material (70 mg, 0.1 mmol) in anhydrous DCM (2 mL) at -78 °C and Ar was added with BCl 3 (1M in DCM, 1.0 mmol) was added. The mixture was stirred at -78 for 2 h and at 0° C. for 2 h. MeOH (20 mL) was added. The mixture was stirred at 0° C. for an additional 2 h and rotary evaporated to dryness. The residue was washed with 10% MeOH and 2% NH 3 Purification on silica gel by flash chromatography using a solution of 1:1 in DCM afforded 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 (400 MHz, CD 3OD) δ 7.58 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 3.97 (dd, J = 12.0, 2.5 Hz, 1H), 3.85 (dd, J = 12.0, 3.3 Hz, 1H), 3.51 (ddd, J = 10.4, 9.0, 4.9 Hz, 1H), 3.36-3.33 (m, 1H), 3.18 (t, J = 9.0 Hz, 1H), 3.10-2.71 (m, 5H), 2.38 (t, J = 10.8 Hz, 1H), 2.30 (dt, J = 9.5, 2.9 Hz, 1H); ESI MS m / z 336.1 [M+H] + . Examples 7 and 8 (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 JPEG0007674389000092.jpg44141

[0131] 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 (3 drops) in anhydrous MeOH (10 mL) was added to NaBH 3 CN (38 mg, 95%, 0.57 mmol) was added. The mixture was stirred at room temperature for 18 h and then cooled to 0° C. with NaHCO 3 Saturated aqueous solution (30 mL) was added and the mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with anhydrous Na 2 SO 4After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography with 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%).

[0132] A solution of the above material (155 mg, 0.24 mmol, 1:3 ratio of two isomers) in anhydrous DCM (2 mL) was added with BCl 3 (3.0 mL, 1M in DCM, 3.0 mmol) was added. The mixture was stirred at -78 for 2 h and at 0° C. for 2 h. MeOH (20 mL) was added. The mixture was stirred at 0° C. for an additional 2 h and rotary evaporated to dryness. The residue was washed with 10% MeOH and 2% NH 3 Purification on silica gel by flash chromatography using a solution of 1:1 in DCM afforded phenyl(2R,3R,4R,5S)-2-(hydroxymethyl)-1-((R)-2-phenylpropyl)piperidine-3,4,5-triol as a white foam (14.5 mg, 87%). 1 H NMR (400 MHz, CD 3 OD) δ 7.32-7.22 (m, 4H), 7.19 (t, J = 7.1 Hz, 1H), 3.94-3.61 (m, 2H), 3.48 (td, J = 9.8, 4.7 Hz, 1H), 3.36 -3.32 (m, 1H), 3.27-2.86 (m, 4H), 2.49 (t, J = 8.7 Hz, 1H), 2.10 (q, J = 10.2, 9.5 Hz, 2H), 1.29 (d, J = 5.6 Hz, 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 (400 MHz, CD 3OD) δ 7.68-6.63 (m, 5H), 3.82 (d, J = 11.7 Hz, 1H), 3.68 (dd, J = 11.9, 3.0 Hz, 1H), 3.37-3.28 (m, 1H), 3.27-2.94 (m, 5H), 2.66-2.43 (m, 1H), 2.24-2.11 (m, 1H), 2.03 (t, J = 10.9 Hz, 1H), 1.24 (d, J = 6.2 Hz, 3H); ESI MS m / z 282.2 [M + H] + Each compound was isolated as a single diastereomer with random assignment of stereochemistry at the phenylpropyl group. Example 9 (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(2-(pyridin-2-yl)ethyl)piperidine-3,4,5-triol JPEG0007674389000093.jpg4658

[0133] In a sealed tube, a 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) was added with K 2 CO 3 (1000 mg, 7.24 mmol) was added. The mixture was stirred at 80° C. for 18 h and cooled to ambient temperature. The reaction mixture was poured into ice water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×20 mL), separated and diluted with Na 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography to give 2-(2-((2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidin-1-yl)ethyl)pyridine as a white solid (340 mg, 95%). ESI MS m / z 629.34 [M + H] + .

[0134] To a stirred solution of the above material (183 mg, 0.29 mmol) in anhydrous DCM (5 mL) was added BCl 3 (1M in DCM, 2.1 mL, 2.1 mmol) at -78 °C and N 2 The mixture was stirred at 0° C. for 2 h and quenched with anhydrous MeOH (1 mL). The mixture was stirred at ambient temperature for 10 min. The solvent was removed in vacuo and the residue was washed with 1M NH 3 The residue was purified by silica gel chromatography to give (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(2-(pyridin-2-yl)ethyl)piperidine-3,4,5-triol as a white solid (63 mg, 81%). 1 H NMR (400 MHz, CD 3 OD) 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); ESI MS m / z 269.15 [M+H] + . Example 10 (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(2-(thiophen-2-yl)ethyl)piperidine-3,4,5-triol JPEG0007674389000094.jpg4060

[0135] 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 (3 drops) in anhydrous MeOH (10 mL) was added with NaBH 3 CN (50 mg, 95%, 0.62 mmol) was added. The mixture was stirred at room temperature for 18 h and then cooled to 0° C. with NaHCO 3 Saturated aqueous solution (30 mL) was added and the mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with anhydrous Na 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography with 30% EtOAc in hexane to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(2-(thiophen-2-yl)ethyl)piperidine (175 mg, 66%).

[0136] A solution of the above material (175 mg, 0.27 mmol) in anhydrous DCM (2 mL) at -78 °C and Ar was added with BCl 3 (3.0 mL, 1M in DCM, 3.0 mmol) was added. The mixture was stirred at -78 for 2 h and at 0° C. for 2 h, after which MeOH (20 mL) was added. The mixture was stirred at 0° C. for an additional 2 h and rotary evaporated to dryness. The residue was purified by distillation with 10% MeOH and 2% NH 3 Purification on silica gel by flash chromatography using a solution of 1:1 in DCM afforded phenyl(2R,3R,4R,5S)-2-(hydroxymethyl)-1-(2-(thiophen-2-yl)ethyl)piperidine-3,4,5-triol as a white foam (63 mg, 85%). 1 H NMR (400 MHz, CD 3OD) δ 7.24 (dd, J = 5.1, 1.3 Hz, 1H), 7.05-6.67 (m, 2H), 3.95 (d, J = 2.7 Hz, 2H), 3.60 (ddd, J = 10.6, 9.1, 4.9 Hz, 1H), 3.46 (t, J = 9.4 Hz, 1H), 3.31-3.01 (m, 6H), 2.88-2.44 (m, 2H); ESI MS m / z 274.1 [M + H] + . Example 11 (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(2-(thiophen-3-yl)ethyl)piperidine-3,4,5-triol JPEG0007674389000095.jpg4260

[0137] 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 (3 drops) in anhydrous MeOH (10 mL) was added with NaBH 3 CN (50 mg, 95%, 0.63 mmol) was added. The mixture was stirred at room temperature for 18 h and then cooled to 0° C. with NaHCO 3 Saturated aqueous solution (30 mL) was added and the mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with anhydrous Na 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography with 30% EtOAc in hexane to give (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(2-(thiophen-3-yl)ethyl)piperidine (181 mg, 68%).

[0138] A solution of the above material (181 mg, 0.28 mmol) in anhydrous DCM (2 mL) at -78 °C and Ar was added with BCl 3(6.0 mL, 1M in DCM, 6.0 mmol) was added. The mixture was stirred at -78 for 2 h, stirred at 0° C. for 2 h, and MeOH (20 mL) was added. The mixture was stirred at 0° C. for an additional 2 h, rotary evaporated to dryness. The residue was purified by distillation with 10% MeOH and 2% NH 3 Purification on silica gel by flash chromatography using a solution of 1:1 in DCM afforded phenyl(2R,3R,4R,5S)-2-(hydroxymethyl)-1-(2-(thiophen-3-yl)ethyl)piperidine-3,4,5-triol as a white foam (23 mg, 29%). 1 H NMR (400 MHz, CD 3 OD) δ 7.34 (dd, J = 5.0, 2.9 Hz, 1H), 7.11 (d, J = 2.9 Hz, 1H), 7.02 (d, J = 4.8 Hz, 1H), 3.92 (qd, J = 12.2, 2.8 Hz, 2H), 3.55 (td, J = 9.9, 4.8 Hz, 1H), 3.39 (t, J = 9.5 Hz, 1H), 3.22 (t, J = 9.1 Hz, 1H), 3.15-3.05 (m, 2H), 3.01-2.94 (m, 1H), 2.90-2.85 (m, 2H), 2.42 (t, J = 10.9 Hz, 1H), 2.37-2.29 (m, 1H); ESI MS m / z 274.3 [M + H] + . Example 12 (2S,3R,4R,5S)-1-(Cyclohexylmethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol JPEG0007674389000096.jpg3953

[0139] In a sealed tube and 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) was stirred at 85 °C for 16 h. The reaction mixture was cooled to RT and NaHCO 3 After dilution with saturated aqueous solution (20 mL), the combined extracts were washed with brine (2×20 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography (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 pale yellow oil (0.17 g, 71%).

[0140] A solution of the above material (0.17 g, 0.27 mmol) in anhydrous DCM (8 mL) at -78 °C and Ar was added with BCl 3 (1.0M in DCM, 2.0 mL, 2.0 mmol) was added 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 purified with 1M NH 3 Neutralized with a solution of MeOH (0.5 M NH 3 Purification on silica gel with MeOH / DCM (1:5) afforded (2S,3R,4R,5S)-1-(cyclohexylmethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol as a white solid (0.059 g, 83%). 1 H NMR (400 MHz, DMSO-d 6) δ 4.73 (d, J = 4.6 Hz, 1H), 4.64 (d, J = 4.2 Hz, 1H), 4.60 (d, J = 5.1 Hz, 1H), 4.06 (t, J = 5.0 Hz, 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 MS m / z 260.187 [M + H] + . Example 13 (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol JPEG0007674389000097.jpg3771

[0141] 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)cyclohexanecarbaldehyde (274 mg, 1.52 mmol) in anhydrous DCM (10 mL) was added HOAc (0.2 mL) and the mixture was stirred for 30 min. 3 (340 mg, 1.60 mmol) was added and the resulting mixture was stirred at RT for 18 h. The reaction was quenched with NaHCO 3 The mixture was quenched with a solution of 100 ml of EtOAc (3×20 mL). The mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×10 mL), separated and washed with Na 2 SO 4After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography 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%). ESI MS m / z 688.35 [M + H] + .

[0142] To a stirred solution of the above material (240 mg, 0.35 mmol) in anhydrous DCM (5 mL) was added BCl 3 The solution (1M in DCM, 1.75 mL, 1.75 mmol) was incubated at -78 °C and N 2 The mixture was stirred at 0° C. for 4 h and quenched with anhydrous MeOH (1 mL). The mixture was stirred at RT for 10 min. The solvent was removed in vacuo and the residue was washed with 1M NH 3 in MeOH (10 mL) and stirred for an additional 10 min, after which the solvent was removed in vacuo. The residue was purified by silica gel chromatography to give (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 (400 MHz, CD 3 OD) δ 3.88-3.77 (m, 2H), 3.69 (dd, J = 9.3, 5.5 Hz, 1H), 3.55-3.46 (m, 1H), 3.39 -3.34 (m, 1H), 2.99 (q, J = 5.5 Hz, 1H), 2.72 (ddd, J = 12.6, 5.4, 1.0 Hz, 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] + . Example 14 (2S,3R,4R,5S)-1-(((1s,4S)-4-(2-fluoropropan-2-yl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol JPEG0007674389000098.jpg4166

[0143] 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 (0.21 g, 1.0 mmol) in DCM (15 mL) was stirred at RT under Ar for 3 days. The reaction mixture was cooled to room temperature and cooled to room temperature. 3 The mixture was diluted with saturated aqueous solution (10 mL) and extracted with DCM (3×15 mL). The combined extracts were washed with anhydrous Na 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography (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 pale yellow oil (0.31 g, 91%).

[0144] The above material (0.31 g, 0.45 mmol), Pd(OH) 2 A mixture of 1 / C (20% Pd by weight, 0.10 g, 0.19 mmol) and 6 drops of concentrated HCl in MeOH (20 mL) was stirred under 1 atm pressure overnight. The mixture was filtered through a cake 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 was added Ac 2 O (0.5 mL) was added. The mixture was stirred at RT for 16 h and then diluted with NaHCO 3 The mixture was diluted with saturated aqueous solution (20 mL). After extraction with EtOAc (2×20 mL), the combined extracts were washed with anhydrous Na 2 SO4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography (EtOAc / Hexanes, 1:4 to 1:3) to give a clear oil. The clear oil was purified with 1M NH 3 The mixture was treated with a solution of 0.5M NH 3 Purification on silica gel with MeOH / DCM (1:5) afforded (2S,3R,4R,5S)-1-(((1s,4R)-4-(2-fluoropropan-2-yl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol as a white solid (0.057 g, 39%, 3 steps). 1 H NMR (400 MHz, CD 3 OD) 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); m / z 320.233 [M+H] + . Example 15 (2S,3R,4R,5S)-1-((2,3-dihydro-1H-inden-2-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol JPEG0007674389000099.jpg4366

[0145] 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 min. NaBH(OAc) 3 (73 mg, 0.35 mmol) was added and the resulting mixture was stirred at RT for 18 h. The reaction was quenched with NaHCO 3 The mixture was quenched with EtOAc (3×20 mL). The mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×10 mL), separated and washed with Na 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-((2,3-dihydro-1H-indan-2-yl)methyl)piperidine as an oil (90 mg, 60%). ESI MS m / z 654.35 [M + H] + .

[0146] To a stirred solution of the above material (90 mg, 0.14 mmol) in anhydrous DCM (5 mL) was added BCl 3 The solution (1M in DCM, 0.69 mL, 0.69 mmol) was incubated at -78 °C and N 2 The mixture was stirred at 0° C. for 4 h and quenched with anhydrous MeOH (1 mL). The mixture was stirred at RT for 10 min. The solvent was removed in vacuo and the residue was washed with 1M NH 3 The residue was purified by silica gel chromatography to give (2S,3R,4R,5S)-1-((2,3-dihydro-1H-indan-2-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol as a white solid (23 mg, 56%). 1 H NMR (400 MHz, CD 3OD) δ 7.20-7.14 (m, 2H), 7.11-7.06 (m, 2H), 3.91-3.80 (m, 2H), 3.76-3.70 (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] + . Example 16 (2S,3R,4R,5S)-1-(2-cyclohexylethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol JPEG0007674389000100.jpg4259

[0147] 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) was stirred in a sealed tube at 85° C. for 16 h under Ar. The reaction mixture was cooled to RT and added NaHCO 3 After dilution with saturated aqueous solution (20 mL), the combined extracts were washed with brine (2×20 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography (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 pale yellow oil (0.17 g, 71%).

[0148] A solution of the above material (0.17 g, 0.27 mmol) in anhydrous DCM (8 mL) at -78 °C and Ar was added with BCl 3(1.0M in DCM, 2.0 mL, 2.0 mmol) was added 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 purified with 1M NH 3 Neutralized with a solution of MeOH (0.5M NH 3 Purification on silica gel with MeOH / DCM (1:5) afforded (2S,3R,4R,5S)-1-(2-cyclohexylethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol as a white solid (0.054 g, 74%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 4.71 (d, J = 4.8 Hz, 1H), 4.65 (d, J = 4.2 Hz, 1H), 4.61 (d, J = 5.1 Hz, 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] + . Example 17 (2S,3R,4R,5S)-1-(3-cyclohexylpropyl)-2-(hydroxymethyl)piperidine-3,4,5-triol JPEG0007674389000101.jpg3866

[0149] 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) was stirred in a sealed tube at 85° C. for 16 h under Ar. The reaction mixture was cooled to RT and added NaHCO 3 After dilution with saturated aqueous solution (20 mL), the combined extracts were washed with brine (2×20 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography (EtOAc / hexanes, 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 pale yellow oil (0.25 g, 100%).

[0150] A solution of the above material (0.25 g, 0.38 mmol) in anhydrous DCM (8 mL) at -78 °C and Ar was added with BCl 3 (1.0M in DCM, 3.0 mL, 3.0 mmol) was added 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 purified with 1M NH 3 Neutralized with a solution of MeOH (0.5M NH 3 Purification on silica gel with MeOH / DCM (1:5) afforded (2S,3R,4R,5S)-1-(3-cyclohexylpropyl)-2-(hydroxymethyl)piperidine-3,4,5-triol as a white solid (0.095 g, 87%). 1 H NMR (400 MHz, DMSO-d 6) δ 4.81-4.61 (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), 3.15-3.04 (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] + . Example 18 (2S,3R,4R,5S)-1-(2-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol JPEG0007674389000102.jpg4359

[0151] (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 (Bu 4 NI) (0.450 g, 1.22 mmol), and K 2 CO 3 A mixture of (4.14 g, 30.0 mmol) in anhydrous DMF (40 mL) was stirred at 100° C. for 16 h. The reaction mixture was cooled to RT and diluted with water (300 mL). 2 After extraction with 2×100 mL of HO (2×100 mL), the combined extracts were washed with brine (3×100 mL) and diluted with anhydrous Na 2 SO 4After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography (EtOAc / hexanes, 1:10 to 1:5) to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(2-fluorophenyl)piperidine as a pale yellow oil (3.60 g, 39%).

[0152] -78°C and N 2 To a solution of the above material (3.60 g, 5.57 mmol) in anhydrous DCM (40 mL) was added BCl 3 (1.0M in DCM, 33 mL, 33 mmol) was added 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 purified with 1M NH 3 The mixture was neutralized with a solution of MeOH (1M NH 3 Purification on silica gel with MeOH / DCM (1:5) afforded (2S,3R,4R,5S)-1-(2-fluorophenyl)-2-(hydroxymethyl)piperidine-3,4,5-triol as a white solid (1.48 g, 93%). 1 H NMR (400 MHz, CD 3 OD) 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] + . Example 19 (2S,3R,4R,5S)-1-(3-chloro-2-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol JPEG0007674389000103.jpg4066

[0153] (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) were added under Ar. 3 A mixture of (0.20 g, 0.94 mmol) in DCM (10 mL) was stirred at RT for 16 h. The reaction mixture was diluted with NaHCO 3 The mixture was diluted with saturated aqueous solution (10 mL) and extracted with DCM (3×15 mL). The combined extracts were washed with anhydrous Na 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography (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-fluorophenyl)piperidine as a pale yellow oil (0.43 g, 94%).

[0154] To a solution of the above material (0.43 g, 0.63 mmol) in anhydrous DCM (10 mL) at -78 °C and Ar, 3 (1.0M in DCM, 4.0 mL, 4.0 mmol) was added 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 purified with 1M NH 3 Neutralized with a solution of MeOH (0.5M NH 3 Purification on silica gel with MeOH / DCM (1:5) afforded (2S,3R,4R,5S)-1-(3-chloro-2-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol as a white solid (0.15 g, 74%). 1H NMR (400 MHz, DMSO-d 6 ) δ 7.42-7.36 (m, 1H), 7.31-7.25 (m, 1H), 7.16-7.10 (m, 1H), 4.71 (d, J = 4.9 Hz, 1H), 4.67 (d, J = 4.1 Hz, 1H), 4.65 (d, J = 5.2 Hz, 1H), 4.17 (t, J = 5.0 Hz, 1H), 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, 9.4 Hz, 1H); ESI MS m / z 320.109 [M + H] + . Example 20 (2S,3R,4R,5S)-1-(2-([1,1'-biphenyl]-4-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol JPEG0007674389000104.jpg4876

[0155] 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) was stirred in a sealed tube at 85° C. for 16 h under Ar. The reaction mixture was cooled to RT and added NaHCO 3 After dilution with saturated aqueous solution (20 mL), the combined extracts were washed with brine (2×20 mL) and diluted with anhydrous Na 2 SO 4After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography (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 pale yellow oil (0.18 g, 67%).

[0156] A solution of the above material (0.18 g, 0.26 mmol) in anhydrous DCM (8 mL) at -78 °C and Ar was added with BCl 3 (1.0M in DCM, 2.0 mL, 2.0 mmol) was added 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 purified with 1M NH 3 Neutralized with a solution of MeOH (0.5M NH 3 Purification on silica gel with eluent: MeOH / DCM, 1:5) afforded (2S,3R,4R,5S)-1-(2-([1,1'-biphenyl]-4-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol as a white solid (0.031 g, 35%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.69-7.61 (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), 3.73-3.59 (m, 2H), 3.47-3.39 (m, 1H), .3.35-3.23 (m, 1H), 3.16-3.05 (m, 1H), 3.04-2.89 (m, 2H), 2.85-2.67 (m, 4H), 2.53-2.44 (m, 1H); ESI MS m / z 344.185 [M + H]. Example 21 (2S,3R,4R,5S)-1-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol JPEG0007674389000105.jpg5279

[0157] (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) were added under Ar. 3 A mixture of (0.15 g, 0.71 mmol) in DCM (10 mL) was stirred at RT for 16 h. The reaction mixture was added NaHCO 3 The mixture was diluted with saturated aqueous solution (10 mL) and extracted with DCM (3×15 mL). The combined extracts were washed with anhydrous Na 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography (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-difluorophenylethyl)piperidine as a pale yellow oil (0.27 g, 75%).

[0158] The above material (0.27 g, 0.36 mmol), Pd(OH) 2 A mixture of 1M NH 2 O (20% Pd by weight, 0.070 g, 0.13 mmol) and 5 drops of concentrated HCl in MeOH (20 mL) was stirred overnight under 1 atm pressure. The mixture was filtered through a cake of Celite, and the filtrate was collected and concentrated to dryness. The residue was dissolved in 1M NH 3 Neutralized with a solution of MeOH (0.5M NH 3Purification on silica gel with MeOH / DCM (1:5) gave (2S,3R,4R,5S)-1-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol as a white solid (0.12 g, 86%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.98-6.92 (m, 2H), 4.71 (d, J = 4.8 Hz, 1H), 4.69-4.62 (m, 2H), 4.14 (t, J = 4.9 Hz, 1H), 3.97-3.82 (m, 2H), 3.72-3.51 (m, 2H), 3.39 (td, J = 11.5, 2.8 Hz, 2H), 3.40-3.30 (m, 1H), 3.30-3.20 (m, 1H), 3.12-3.03 (m, 1H), 2.98-2.56 (m, 7H), 2.42 (t, J = 10.6 Hz, 1H), 1.81-1.42 (m, 4H); ESI MS m / z 388.193 [M + H] + . Example 22 (2S,3R,4R,5S)-1-(4-butoxyphenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol JPEG0007674389000106.jpg4286

[0159] (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine (0.20 g, 0.38 mmol), 2-(4-butoxyphenyl)acetaldehyde (0.12 g, 0.62 mmol), and NaBH(OAc) were added under Ar. 3 A mixture of (0.15 g, 0.71 mmol) in DCM (10 mL) was stirred at RT for 3 days. The reaction mixture was diluted with NaHCO 3 The mixture was diluted with saturated aqueous solution (10 mL) and extracted with DCM (3×15 mL). The combined extracts were washed with anhydrous Na 2 SO 4After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography (EtOAc / hexanes, 1:9 to 1:6) to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(4-butoxyphenylethyl)piperidine as a pale yellow oil (0.23 g, 86%).

[0160] The above material (0.23 g, 0.33 mmol), Pd(OH) 2 A mixture of 1M NH 2 O (20% by weight Pd, 0.10 g, 0.19 mmol) and 5 drops of concentrated HCl in MeOH (20 mL) was stirred overnight under 1 atm pressure. The mixture was filtered through a cake of Celite, and the filtrate was collected and concentrated to dryness. The residue was diluted with 1M NH 3 Neutralized with a solution of MeOH (0.5M NH 3 Purification on silica gel with MeOH / DCM (1:5) afforded (2S,3R,4R,5S)-1-(4-butoxyphenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol as a white solid (0.051 g, 46%). 1 H NMR (400 MHz, DMSO-d 6 ) 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] + . Example 23 (2S,3R,4R,5S)-1-(4-butoxy-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol JPEG0007674389000107.jpg4287

[0161] N 2 (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) were added under 3 A mixture of (0.85 g, 4.0 mmol) in DCM (30 mL) was stirred at RT for 3 days. The reaction mixture was diluted with NaHCO 3 The mixture was diluted with saturated aqueous solution (30 mL) and extracted with DCM (3×20 mL). The combined extracts were washed with anhydrous Na 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography (EtOAc / hexanes, 1:12 to 1:7) to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(4-butoxy-2,6-difluorophenylethyl)piperidine as a pale yellow oil (1.3 g, 77%). ESI MS m / z 736.3689 [M + H] + .

[0162] The above material (1.30 g, 1.76 mmol), Pd(OH) 2 A mixture of 1M NH4O / C (20% by weight Pd, 0.25 g, 0.47 mmol) and concentrated HCl (0.5 mL) in MeOH (80 mL) was stirred under hydrogen and 1 atm pressure overnight. The mixture was filtered through a cake of Celite, and the filtrate was collected and concentrated to dryness. The residue was diluted with 1M NH4O / C. 3 After neutralization with MeOH solution (0.5M NH 3Purification on silica gel with MeOH / DCM (1:4) afforded (2S,3R,4R,5S)-1-(4-butoxy-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol as a white solid (0.58 g, 88%). 1 H NMR (400 MHz, CD 3 OD) δ 6.53-6.47 (m, 2H), 3.94 (t, J = 6.4 Hz, 2H), 3.88-3.75 (m, 2H), 3.63 (dd, J = 8.9, 5.3 Hz, 1H), 3.50 (ddd, J = 9.5, 8.1, 5.0 Hz, 1H), 3.36 (t, J = 8.5 Hz, 1H), 3.06-2.90 (m, 2H), 2.88 (dd, J = 12.4, 5.0 Hz, 1H), 2.83-2.74 (m, 3H), 2.61 (dd, J = 12.4, 9.5 Hz, 1H), 1.80-1.68 (m, 2H), 1.54-1.44 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H); ESI MS m / z 376.1604 [M + H] + . Example 24 (2S,3R,4R,5S)-1-((1-(4-fluorophenyl)piperidin-4-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol JPEG0007674389000108.jpg4981

[0163] 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 min. NaBH(OAc) 3 (337 mg, 1.59 mmol) was added and the resulting mixture was stirred at RT for 18 h. The reaction was quenched with NaHCO 3The mixture was quenched with a solution of 100 ml of EtOAc (3×20 mL). The mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×10 mL), separated and washed with Na 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography 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] + .

[0164] TFA (3 mL) was cooled to 0° C. and added to a solution of the previous material (740 mg, 1.03 mmol) in DCM (6 mL). The mixture was stirred at 0° C. for 10 min and then at RT for 2 h. TFA and DCM were removed under vacuum. The residue was dissolved in EtOAc (50 mL) and NaHCO 3 solution (2×20 mL), then washed with water, separated and 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the crude (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-(piperidin-4-ylmethyl)piperidine (624 mg, 98%) was used directly in the next step without further purification. ESI MS m / z 621.37 [M + H] + .

[0165] 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), Pd 2 (dba) 3 (34 mg, 0.037 mmol) and RuPhos (35 mg, 0.074 mmol) were added and the mixture was cooled to room temperature under Ar. 2 CO 3(361 mg, 1.11 mmol) was added. The mixture was stirred at 100° C. for 18 h, then water was added at 0° C. The mixture was extracted with EtOAc (2×30 mL). The combined organic layers were washed with water (2×10 mL), separated and diluted with Na 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography 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] + .

[0166] To a stirred solution of the above material (110 mg, 0.15 mmol) in anhydrous DCM (5 mL) was added BCl 3 The solution (1M in DCM, 0.75 mL, 0.75 mmol) was incubated at -78 °C and N 2 The mixture was stirred at 0° C. for 4 h and quenched with anhydrous MeOH (1 mL). The mixture was stirred at RT for 10 min. The solvent was removed in vacuo and the residue was washed with 1M NH 3 The residue was purified by silica gel chromatography to give (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%). 1 H NMR (400 MHz, CD 3OD) δ 7.04-6.93 (m, 4H), 3.91-3.80 (m, 2H), 3.74 -3.69 (m, 1H), 3.60-3.49 (m, 3H), 3.41-3.34 (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] + . Example 25 (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol JPEG0007674389000109.jpg4070

[0167] To a solution of (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine (0.78 g, 1.5 mmol) in DCM (20 mL) was added (S)-tert-butyl 3-formylpyrrolidine-1-carboxylate (0.45 g, 2.25 mmol) and HOAc (0.5 mL). After stirring at RT for 10 min, NaBH(OAc) 3 (0.5 g, 2.5 mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was concentrated and then diluted with DCM (25 mL). The organics were washed with NaHCO 3 Wash with saturated aqueous solution and brine, and then with anhydrous Na 2 SO 4 The residue was purified on silica gel by flash chromatography (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%). 1 H NMR (400 MHz, CDCl 3) 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] + .

[0168] The above material (1.0 g, 1.45 mmol) was added to a 3:7 TFA:DCM solution (16 mL) at 0° C. and stirred for 30 min. The reaction mixture was heated to RT for 2 h and concentrated to dryness. It was diluted with EtOAc (30 mL) and the organics were washed with NaHCO 3 Wash with saturated aqueous solution (2×50 mL) of anhydrous Na 2 SO 4 Drying at 40° C. and concentration afforded (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%). 1 H NMR (400 MHz, CDCl 3) δ 7.40-7.26 (m, 20H), 4.88 (d, J = 10.9 Hz, 1H), 4.83 (d, J = 10.9 H z, 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] + .

[0169] 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 dry DMF (5 mL) was diluted with K 2 CO 3 (0.12 g, 0.93 mmol) was added 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 washed with anhydrous Na 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography (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)pyrrolidin-1-yl)pyridine as an oil (0.1 g, 43%). 1 H NMR (400 MHz, CDCl 3) δ 8.32 (dd, J = 4.7, 1.7 Hz, 1H), 7.81 (dd, J = 7.8, 1.8 Hz, 1H), 7.41-7.27 (m, 20H), 6.66 (dd, J = 7.8, 4.7 Hz, 1H), 4.89 (d, J = 10.9 Hz, 1H), 4.84 (d, J = 10.9 Hz, 1H), 4.75 (d, J = 11.5 Hz, 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, 2.8 Hz, 1H), 3.72-3.49 (m, 6H), 3.40-3.31 (m, 2H), 2.88 (dt, J = 11.9, 5.8 Hz, 1H), 2.78 (dd, J = 12.8, 8.4 Hz, 1H), 2.67 (dd, J = 12.7, 6.6 Hz, 1H), 2.64-2.53 (m, 1H), 2.40 (dq, J = 14.6, 7.3 Hz, 1H), 1.97 (dq, J = 11.7, 5.8 Hz, 1H), 1.63 (dq, J = 12.3, 8.0 Hz, 1H); ESI MS m / z 752.362 [M+H] + .

[0170] A solution of the above material (0.1 g, 0.13 mmol) in DCM (8 mL) at -78 °C and Ar was added with BCl 3 (1.0M in DCM, 0.8 mL, 0.8 mmol) was added 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 RT for 30 min, the mixture was concentrated under reduced pressure. The resulting residue was diluted with 1M NH 3The mixture was neutralized with MeOH (2×5 mL) and concentrated under reduced pressure again. The residue was purified on silica gel by flash chromatography (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 as a white solid (0.031 g, 60.9%). 1 H NMR (400 MHz, CD 3 OD) δ 8.25 (dd, J = 4.8, 1.8 Hz, 1H), 7.87 (dd, J = 7.8, 1.8 Hz, 1H), 6.73 (dd, J = 7.8, 4.7 Hz, 1H), 3.91-3.82 (m, 2H), 3.71 (dd, J = 9.3, 5.5 Hz, 1H), 3.68-3.61 (m, 3H), 3.53 (ddd, J = 10.0, 8.5, 5.2 Hz, 1H), 3.44-3.35 (m, 2H), 3.06 (p, J = 6.1, 5.7 Hz, 1H), 2.90-2.73 (m, 3H), 2.68-2.60 (m, 1H), 2.53 (h, J = 7.6 Hz, 1H), 2.10 (dq, J = 11.9, 6.1 Hz, 1H), 1.71 (dq, J = 12.1, 7.9 Hz, 1H); ESI MS m / z 392.176 [M + H] + . Example 26 (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol JPEG0007674389000110.jpg4185

[0171] 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 to the solution. 2 CO 3 (0.22 g, 0.69 mmol) was added 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 (2×20 mL). The combined organic layers were washed with water (2×20 mL), separated and washed with Na 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography 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%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.39-7.27 (m, 20H), 6.90 (d, J = 1.2 Hz, 1H), 4.89 (d, J = 10.9 Hz, 1H), 4.83 (d, J = 10.9 Hz, 1H), 4.75 (d, J = 11.5 Hz, 1H), 4.70-4.68 (m, 2H), 4.64 (d, J = 11.5 Hz, 1H), 4.57-4.48 (m, 2H), 3.87 (dd, J = 10.2, 7.3 Hz, 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, 6.5 Hz, 1H), 2.84 (dd, J = 12.2, 5.4 Hz, 1H), 2.76-2.46 (m, 4H), 2.09-1.98 (m, 1H), 1.72 (dq, J = 12.7, 7.5 Hz, 1H); ESI MS m / z 758.321 [M + H]+ .

[0172] A solution of the above material (0.11 g, 0.15 mmol) in DCM (5 mL) at -78 °C and Ar was added with BCl 3 (1.0M in DCM, 0.75 mL, 0.75 mmol) was added 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 RT for 30 min, the mixture was concentrated under reduced pressure. The resulting residue was diluted with 1M NH 3 The mixture was neutralized with a solution of MeOH (2×5 mL) and concentrated under reduced pressure again. The residue was purified on silica gel by flash chromatography (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 as a white solid (0.04 g, 67%). 1 H NMR (400 MHz, CD 3 OD) δ 7.14 (s, 1H), 3.90-3.82 (m, 2H), 3.71 (dd, J = 9.3, 5.5 Hz, 1H), 3.65-3.44 (m, 4H), 3.37 (dd, J = 8.9, 6.7 Hz, 1H), 3.28 (dd, J = 10.1, 6.4 Hz, 1H), 3.06 (q, J = 5.7 Hz, 1H), 2.88-2.80 (m, 2H), 2.76 (dd, J = 12.7, 8.5 Hz, 1H), 2.71-2.61 (m, 2H), 2.20 (dtd, J = 12.2, 6.9, 4.9 Hz, 1H), 1.86 (dq, J = 12.4, 7.6 Hz, 1H); ESI MS m / z 398.132 [M + H] + . Example 27 (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol JPEG0007674389000111.jpg4070

[0173] 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 (2×30 mL). The combined organic layers were washed with water (2×10 mL), separated and concentrated with NaCl. 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography 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] + .

[0174] To a stirred solution of the above material (95 mg, 0.13 mmol) in anhydrous DCM (5 mL) was added BCl 3 The solution (1 M in DCM, 0.63 mL, 0.63 mmol) was incubated at -78 °C and N 2 The mixture was stirred at 0° C. for 4 h and quenched with anhydrous MeOH (1 mL). The mixture was stirred at RT for 10 min. The solvent was removed in vacuo and the residue was washed with 1M NH 3 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 H NMR (400 MHz, CD 3 OD) δ 8.26 (dd, J = 4.9, 1.8 Hz, 1H), 7.87 (dd, J = 7.8, 1.9 Hz, 1H), 6.73 (dd, J = 7.8, 4.7 Hz, 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, 6.8 Hz, 1H), 2.83-2.76 (m, 1H), 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] + . Example 28 (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol JPEG0007674389000112.jpg3881

[0175] To a stirred solution of (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine (1.42 g, 2.71 mmol) and (R)-tert-butyl 3-formylpyrrolidine-1-carboxylate (0.60 g, 3.01 mmol) in anhydrous DCM (20 mL) was added HOAc (0.2 mL) and the mixture was stirred for 30 min. NaBH(OAc) 3 (745 mg, 3.51 mmol) was added and the resulting mixture was stirred at RT for 18 h. The reaction was quenched with NaHCO 3 The mixture was quenched with a solution of 100 ml of EtOAc (3×20 mL). The mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×10 mL), separated and washed with Na 2 SO 4After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography to give (S)-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 (1.51 g, 79%). ESI MS m / z 707.41 [M + H] + .

[0176] TFA (7 mL) was cooled to 0° C. and added to a solution of the above material (1.51 g, 2.13 mmol) in DCM (20 mL). The mixture was stirred at 0° C. for 10 min and then at RT for 2 h. TFA and DCM were removed under vacuum. The residue was dissolved in EtOAc (80 mL) and diluted with NaHCO 3 solution (2×20 mL), then washed with water, separated and 2 SO 4 The mixture was dried at 50° C. After filtration, the solvent was evaporated under reduced pressure. The residue was purified on silica gel by flash chromatography to give (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-1-((R)-pyrrolidin-3-ylmethyl)piperidine as an oil (886 mg, 68%). ESI MS m / z 607.35 [M + H] + .

[0177] 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 Cs 2 CO 3 (457 mg, 2.40 mmol) was added. The mixture was stirred at 80° C. for 18 h, then water was added at 0° C. The mixture was extracted with EtOAc (2×30 mL). The combined organic layers were washed with water (2×10 mL), separated and diluted with Na 2 SO 4After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography 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] + .

[0178] To a stirred solution of the above material (150 mg, 0.35 mmol) in anhydrous DCM (5 mL) was added BCl 3 The solution (1 M in DCM, 1.0 mL, 1.0 mmol) was incubated at -78 °C and N 2 The mixture was stirred at 0° C. for 4 h and quenched with anhydrous MeOH (1 mL). The mixture was stirred at RT for 10 min. The solvent was removed in vacuo and the residue was washed with 1M NH 3 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 H NMR (400 MHz, CD 3 OD) δ 7.15-7.13 (m, 1H), 3.90-3.82 (m, 2H), 3.74-3.67 (m, 1H), 3.65-3.43 (m, 4H), 3.40-3.34 (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] + . Example 29 (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol JPEG0007674389000113.jpg4270

[0179] To a solution of (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine (0.8 g, 1.5 mmol) in DCM (30 mL) was added (S)-tert-butyl 3-formylpiperidine-1-carboxylate (0.42 g, 2.0 mmol) and HOAc (0.5 mL). After stirring at RT for 10 min, NaBH(OAc) 3 (0.48 g, 2.26 mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was concentrated and diluted with DCM (25 mL). The organics were washed with NaHCO 3 Wash with saturated aqueous solution and brine, and then with anhydrous Na 2 SO 4 The residue was purified on silica gel by flash chromatography (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-1-carboxylate as an oil (1.0 g, 94%). 1 H NMR (400 MHz, CDCl 3) δ 7.38-7.27 (m, 20H), 4.88 (d, J = 11.1 Hz, 1H), 4.82 (d, J = 11.1 Hz, 1H), 4.75 (d, J = 11.5 Hz, 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, 6.9 Hz, 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 ESI MS m / z 721.421 [M+H] + .

[0180] The above material (1.0 g, 1.4 mmol) was added to a solution of 3:7 TFA:DCM (16 mL) at 0° C. and stirred for 30 min. The reaction mixture was heated to RT for 2 h and then concentrated to dryness. It was diluted with EtOAc (30 mL) and the organics were washed with NaHCO 3 Wash with saturated aqueous solution (2×50 mL) of anhydrous Na 2 SO 4 Drying at 40° C. and concentration afforded (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 H NMR (400 MHz, CDCl 3) δ 7.85 (bs, 1H), 7.39-7.27 (m, 20H), 4.85 (d, J = 11.0 Hz, 1H), 4.81 (d, J = 10.9 Hz, 1H), 4.72-4.61 (m, 4H), 4.56-4.45 (m, 2H), 3.85 (dd, J = 10.3, 7.6 Hz, 1H), 3.70 (dd, J = 10.3, 2.6 Hz, 1H), 3.63 (dd, J = 9.2, 5.7 Hz, 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, 5.3 Hz, 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, 10.6 Hz, 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] + .

[0181] 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 dry DMF (6 mL) was diluted with K 2 CO 3 (0.1 g, 0.75 mmol) was added 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 washed with anhydrous Na 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography (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%). 1H NMR (400 MHz, CDCl 3 ) δ 8.42 (dd, J = 4.8, 1.8 Hz, 1H), 7.85 (dd, J = 7.8, 2.0 Hz, 1H), 7.37-7.27 (m, 20H), 6.95 (dd, J = 7.8, 4.7 Hz, 1H), 4.85 (d, J = 10.9 Hz, 1H), 4.81 (d, J = 10.9 Hz, 1H), 4.73 (d, J = 11.4 Hz, 1H), 4.69-4.59 (m, 3H), 4.56-4.47 (m, 2H), 3.85 (dd, J = 10.1, 6.8 Hz, 1H), 3.77-3.63 (m, 3H), 3.62-3.45 (m, 3H), 3.25 (td, J = 6.4, 2.5 Hz, 1H), 3.02-2.87 (m, 2H), 2.65-2.54 (m, 2H), 2.54-2.45 (m, 2H), 1.90 (q, J = 5.3 Hz, 1H), 1.84-1.58 (m, 3H), 1.14-1.01 (m, 1H); ESI MS m / z 766.378 [M + H] + .

[0182] A solution of the above material (0.1 g, 0.13 mmol) in DCM (6 mL) at -78 °C and Ar was added with BCl 3 (1.0M in DCM, 0.65 mL, 0.65 mmol) was added 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 RT for 30 min, the mixture was concentrated under reduced pressure. The resulting residue was diluted with 1M NH 3 The mixture was neutralized with MeOH (2×5 mL) and concentrated under reduced pressure again. The residue was purified on silica gel by flash chromatography (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 as a white solid (0.033 g, 62%). 1H NMR (400 MHz, CD 3 OD) δ 8.43 (dd, J = 4.9, 1.8 Hz, 1H), 7.98 (dd, J = 7.8, 1.9 Hz, 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, 5.6 Hz, 1H), 3.53-3.46 (m, 2H), 3.37 (d, J = 1.9 Hz, 1H), 2.99-2.92 (m, 2H), 2.80 (dd, J = 12.2, 5.4 Hz, 1H), 2.68 (dd, J = 13.2, 5.3 Hz, 1H), ESI MS m / z 406.189 [M + H] + . Example 30 (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol JPEG0007674389000114.jpg3982

[0183] 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 to the solution. 2 CO 3 (0.24 g, 0.75 mmol) was added 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 (2×20 mL). The combined organic layers were washed with water (2×20 mL), separated and washed with Na 2 SO 4After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography 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%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.41-7.27 (m, 20H), 6.89 (d, J = 1.2 Hz, 1H), 4.89 (d, J = 10.8 Hz, 1H), 4.84 (d, J = 10.8 Hz, 1H), 4.75 (d, J = 11.5 Hz, 1H), 4.72-4.63 (m, 3H), 4.58-4.50 (m, 2H), 3.96 (dt, J = 13.2, 4.2 Hz, 1H), 3.87 (dd, J = 10.2, 7.2 Hz, 1H), 3.81-3.69 (m, 3H), 3.66-3.59 (m, 1H), 3.54 (q, J = 9.9, 9.1 Hz, 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, 4.6 Hz, 1H), 1.18 (q, J = 10.7 Hz, 1H); ESI MS m / z 772.331 [M + H] + .

[0184] A solution of the above material (0.11 g, 0.14 mmol) in DCM (8 mL) at -78 °C and Ar was added with BCl 3 (1.0M in DCM, 1.1 mL, 1.1 mmol) was added and the mixture was stirred for 3 h while the bath temperature reached 0 °C. The mixture was cooled to -78 °C and MeOH (3 mL) was carefully added. After stirring at RT for 30 min, the mixture was concentrated under reduced pressure. The resulting residue was diluted with 1M NH 3The mixture was neutralized with MeOH (2×5 mL) and concentrated under reduced pressure again. The residue was purified on silica gel by flash chromatography (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 as a white solid (0.049 g, 85%). 1 H NMR (400 MHz, CD 3 OD) δ 7.17 (s, 1H), 3.94-3.85 (m, 4H), 3.74 (dd, J = 9.4, 5.6 Hz, 1H), 3.54 (ddd, J = 10.2, 8.6, 5.2 Hz, 1H), 3.36 (d, J = 9.0 Hz, 1H), 3.20 (ddd, J = 13.4, 10.6, 3.4 Hz, 1H), 3.02 (p, J = 6.1 Hz, 1H), 2.95 (dd, J = 13.0, 9.3 Hz, 1H), 2.79 (dd, J = 12.4, 5.2 Hz, 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 / z 412.144 [M + H] + . Example 31 (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol JPEG0007674389000115.jpg3969

[0185] To a solution of (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine (0.91 g, 1.7 mmol) in DCM (30 mL) was added (R)-tert-butyl 3-formylpiperidine-1-carboxylate (0.54 g, 2.5 mmol) and HOAc (0.5 mL). After stirring at RT for 10 min, NaBH(OAc) 3 (0.6 g, 2.9 mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was concentrated and then diluted with DCM (25 mL). The organics were washed with NaHCO 3 Wash with saturated aqueous solution and brine, and then with anhydrous Na 2 SO 4 The residue was purified on silica gel by flash chromatography (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%). 1 H NMR (400 MHz, CDCl 3) δ 7.38-7.27 (m, 20H), 4.88 (d, J = 11.0 Hz, 1H), 4.83 (d, J = 11.0 Hz, 1H), 4.77-4.67 (m, 3H), 4.65 (d, J = 11.5 Hz, 1H), 4.57-4.47 (m, 2H), 3.99-3.89 (m, 2H), 3.85 (dd, J = 10.1, 6.9 Hz, 1H), 3.73 (dd, J = 11.1, 3.6 Hz, 2H), 3.70 (d, J = 8.7 Hz, 1H), 3.60-3.48 (m, 2H), 3.37 (tt, J = 6.4, 2.3 Hz, 1H), 2.90-2.73 (m, 2H), 2.65-2.52 (m, 2H), 2.52-2.35 (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 = 11.2 Hz, 1H); ESI MS m / z 721.417 [M + H] + .

[0186] The above material (1.0 g, 1.4 mmol) was added to a 3:7 TFA:DCM solution (16 mL) at 0° C. and stirred for 30 min. The reaction mixture was heated at RT for 2 h and concentrated to dryness. It was diluted with EtOAc (30 mL) and the organics were washed with NaHCO 3 Wash with saturated aqueous solution (2×50 mL) of anhydrous Na 2 SO 4 Drying at 40° C. and concentration afforded (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%). 1 H NMR (400 MHz, CDCl 3) δ 7.89 (bs, 1H), 7.38-7.26 (m, 20H), 4.86-4.75 (m, 2H), 4.69 (d, J = 6.8 Hz, 1H), 4.68-4.59 (m, 3H), 4.51 (d, J = 12.1 Hz, 1H), 4.46 (d, J = 12.1 Hz, 1H), 3.83 (dd, J = 10.3, 7.3 Hz, 1H), 3.72-3.66 (m, 1H), 3.62 (dd, J = 9.1, 5.6 Hz, 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 = 11.0 Hz, 1H); ESI MS m / z 621.368 [M + H] + .

[0187] 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 dry DMF (6 mL) was diluted with K 2 CO 3 (0.12 g, 0.87 mmol) was added 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 washed with anhydrous Na 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography (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%). 1 H NMR (400 MHz, CDCl 3) 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, 1 H), 1.97 (bs, 1H), 1.81-1.56 (m, 3H), 1.10-0.97 (m, 1H); ESI MS m / z 766.37 [M + H] + .

[0188] A solution of the above material (0.1 g, 0.13 mmol) in DCM (6 mL) was added with BCl 3 (1.0M in DCM, 1.0 mL, 1.0 mmol) was added 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 RT for 30 min, the mixture was concentrated under reduced pressure. The resulting residue was diluted with 1M NH 3The mixture was neutralized with a solution of MeOH (2×5 mL) and concentrated under reduced pressure again. The residue was purified on silica gel by flash chromatography (MeOH / DCM, 1:9) 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%). 1 H NMR (400 MHz, CD 3 OD) δ 8.44 (dd, J = 5.0, 1.8 Hz, 1H), 7.98 (dd, J = 7.8, 1.9 Hz, 1H), 7.14-7.07 (m, 1H), 3.92-3.80 (m, 2H), 3.70 (dd, J = 9.3, 5.1 Hz, 1H), 3.64 (dt, J = 12.6, 2.2 Hz, 1H), 3.57-3.43 (m, 2H), 3.38 (t, J = 8.7 Hz, 1H), 3.13-3.06(m, 1H), 2.96 (t, J = 11.5 Hz, 1H), 2.82 (dd, J = 13.0, 5.4 Hz, ESI MS m / z 406.194 [M+H] + . Example 32 (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol JPEG0007674389000116.jpg4181

[0189] 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) was added to the solution. 2 CO 3 (0.23 g, 0.72 mmol) was added 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 (2×20 mL). The combined organic layers were washed with water (2×20 mL), separated and washed with Na 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography 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%). 1 H NMR (400 MHz, CDCl 3) δ 7.43-7.27 (m, 20H), 6.90 (s, 1H), 4.90 (d, J = 10.9 Hz, 1H), 4.84 (d, J = 10.9 Hz, 1H), 4.78-4.64 (m, 4H), 4.55 (d, J = 12.2 Hz, 1H), 4.51 (d, J = 12.1 Hz, 1H), 3.96-3.80 (m, 3H), 3.78-3.71 (m, 2H), 3.61 (ddd, J = 10.2, 8.7, 5.6 Hz, 1H), 3.51 (t, J = 9.2 Hz, 1H), 3.44-3.38 (m, 1H), 3.14 (ddd, J = 13.7, 11.1, 3.1 Hz, 1H), 2.82-2.74 (m, 3H), 2.65 (dd, J = 11.9, 10.3 Hz, 1H), 2.40 (dd, J = 12.8, 8.3 Hz, 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, 5.8 Hz, 1H); ESI MS m / z 772.329 [M + H] + .

[0190] A solution of the above material (0.12 g, 0.15 mmol) in DCM (8 mL) at -78 °C and Ar was added with BCl 3 (1.0M in DCM, 1.3 mL, 1.3 mmol) was added and the mixture was stirred for 3 h while the bath temperature reached 0 °C. The mixture was cooled to -78 °C and MeOH (3 mL) was carefully added. After stirring at RT for 30 min, the mixture was concentrated under reduced pressure. The resulting residue was diluted with 1M NH 3 The mixture was neutralized with MeOH (2×5 mL) and concentrated under reduced pressure again. The residue was purified on silica gel by flash chromatography (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 as a white solid (0.056 g, 90%). 1H NMR (400 MHz, CD 3 OD) δ 7.18 (s, 1H), 3.97-3.89 (m, 2H), 3.88-3.85 (m, 2H), 3.72 (dd, J = 9.1, 5.3 Hz, 1H), 3.56 (ddd, J = 9.3, 8.2, 5.5 Hz, 1H), 3.37 (t, J = 8.7 Hz, 1H), 3.16 (ddd, J = 12.9, 11.0, 3.3 Hz, 1H), 3.05 (q, J = 5.7 Hz, 1H), 2.89 (dd, J = 13.0, 9.8 Hz, 1H), 2.82-2.75 (m, 1H), 2.74-2.64 (m, 2H), 2.56 (dd, J = 13.0, 8.4 Hz, 1H), 1.99-1.85 (m, 2H), 1.80 (dt, J = 13.3, 3.9 Hz, 1H), 1.70-1.58 (m, 1H), 1.30-1.21 (m, 1H); ESI MS m / z 412.154 [M+H] + . Example 311 (2S,3R,4R,5S)-1-(((1s,4R)-4-(difluoromethyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol JPEG0007674389000117.jpg4366

[0191] To a solution of cyclohexane-1,4-dinyldimethanol (2.00 g, 13.9 mmol) in anhydrous DCM (60 mL) cooled to 0° C., DIPEA (2.06 g, 16.0 mmol) and benzoyl chloride (1.97 g, 14.0 mmol) were added under Ar. The mixture was stirred at RT for 16 h, then NaHCO 3 The mixture was diluted with saturated aqueous solution (50 mL). After extraction with DCM (3×30 mL), the combined extracts were washed with anhydrous Na 2 SO 4After filtration, the solvent was evaporated in vacuo and the residue was purified on silica gel by flash chromatography (EtOAc / hexanes, 1:3 to 1:2) to give methyl (4-(hydroxymethyl)cyclohexyl)benzoate as a pale yellow oil (1.51 g, 43%).

[0192] A mixture of the above material (0.950 g, 3.83 mmol) and DMP (2.12 g, 5.0 mmol) in DCM (30 mL) was stirred at RT for 1 h to form a white suspension. Hexanes (40 mL) were added and the suspension was filtered through a cake of Celite. The filtrate was collected and concentrated in vacuo, and the residue was purified on silica gel by flash chromatography (EtOAc / Hexanes, 1:4) to give methyl (4-formylcyclohexyl)benzoate as a colorless oil (0.50 g, 53%).

[0193] To a solution of the above material (0.50 g, 2.0 mmol) in anhydrous DCM (10 mL) cooled at -78°C, DAST (0.80 g, 5.0 mmol) was added under Ar, and the mixture was stirred at -78°C for 30 min and then at RT for 5 h. The mixture was cooled to -78°C and NaHCO 3 Quenched with saturated aqueous solution (20 mL). The organic layer was collected and the aqueous layer was extracted with DCM (3×20 mL). The combined extracts were washed with anhydrous Na 2 SO 4 After filtration, the solvent was evaporated in vacuo and the residue was purified on silica gel by flash chromatography (EtOAc / hexanes, 1:10) to give methyl (4-(difluoromethyl)cyclohexyl)benzoate as a colorless oil (0.40 g, 75%).

[0194] The above material (0.40 g, 1.5 mmol) and K 2 CO 3(0.45 g, 0.33 mmol) in MeOH (25 mL) was stirred for 16 h. The solvent was removed in vacuo and the residue was purified on silica gel by flash chromatography (EtOAc / hexanes, 1:2) to give (4-(difluoromethyl)cyclohexyl)methanol as a clear liquid (0.21 g, 86%).

[0195] The above material (0.21 g, 1.3 mmol) was cooled to 0°C and dissolved in acetone (25 mL) of CrO 3 (0.60 g 6.0 mmol) of 2.0MH 2 SO 4 Aqueous solution (6 mL) was added. The mixture was stirred at 0° C. for 1 h and then at RT for 16 h. Isopropanol (5 mL) was then added and the mixture was stirred for another 1 h. After concentration in vacuum, the mixture was diluted with water (50 mL) and extracted with DCM (3×20 mL). The combined extracts were washed with anhydrous Na 2 SO 4 After filtration, the solvent was evaporated in vacuo and the residue was purified on silica gel by flash chromatography (EtOAc / Hexanes, 1:1 to 3:1) to give 4-(difluoromethyl)cyclohexanecarboxylic acid as a white solid (0.22 g, 96%). 1 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.

[0196] 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 RT for 16 h. The mixture was cooled to RT with NaHCO 3The mixture was diluted with saturated aqueous solution (20 mL) and extracted with EtOAc (3×15 mL). The combined extracts were washed with brine (2×20 mL) and anhydrous Na 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified and separated on silica gel by flash chromatography (EtOAc / hexanes, 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] + .

[0197] ((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) was cooled to 0 °C and diluted with anhydrous Et 2 To the O solution (10 mL) 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 quenched with water and NaHCO 3 Dilute with saturated aqueous solution (20 mL). 2 After extraction with 2×30 mL of HO (3×30 mL), the combined extracts were washed with anhydrous Na 2 SO 4After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography (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] + .

[0198] The above material (0.10 g, 0.15 mmol), Pd(OH) 2 A mixture of 1M NH 2 + C (20% by weight Pd, 0.050 g, 0.094 mmol) and 2 drops of concentrated HCl in MeOH (15 mL) was stirred under hydrogen and 1 atm overnight. The mixture was filtered through a cake of Celite, and the filtrate was collected and concentrated to dryness. The residue was diluted with 1M NH 3 Neutralized with a solution of MeOH (0.5M NH 3 Purification on silica gel with MeOH / DCM (1:5) to give (2S,3R,4R,5S)-1-(((1s,4R)-4-(difluoromethyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol as a white solid (0.033 g, 72%). 1 H NMR (500 MHz, CD 3 OD) δ 5.75 (td, J = 57.1, 5.3 Hz, 1H), 3.90-3.79 (m, 2H), 3.70 (dd, J = 9.3, 5.5 Hz, 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] + . Example 312 (2S,3R,4R,5S)-1-(((1r,4S)-4-(difluoromethyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol JPEG0007674389000118.jpg4368

[0199] 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 to 0° C., LAH (0.050 g, 1.3 mmol) was added under Ar, and the mixture was stirred at 0° C. for 4 h. The reaction was then quenched with water and NaHCO 3 Dilute with saturated aqueous solution (20 mL). 2 After extraction with 2×30 mL of HO (3×30 mL), the combined extracts were washed with anhydrous Na 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography (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 as a colorless oil (0.075 g, 30%). ESI MS m / z 670.377 [M + H] + .

[0200] The above material (0.075 g, 0.11 mmol), Pd(OH) 2 A mixture of 1M NH 3 (20% by weight Pd, 0.050 g, 0.094 mmol) and 2 drops of concentrated HCl in MeOH (20 mL) was stirred under hydrogen and 1 atm overnight. The mixture was filtered through a cake of Celite, and the filtrate was collected and concentrated to dryness. The residue was diluted with 1M NH 3 Neutralized with a solution of MeOH (0.5M NH 3Purification on silica gel with MeOH / DCM (1:5) gave (2S,3R,4R,5S)-1-(((1r,4S)-4-(difluoromethyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol as a white solid (0.021 g, 60%). 1 H NMR (400 MHz, CD 3 OD) δ 5.71 (td, J = 57.1, 4.5 Hz, 1H), 3.89-3.77 (m, 2H), 3.70 (dd, J = 9.2, 5.4 Hz, 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, 5.4 Hz, 1H), 2.65-2.46 (m, 3H), 2.00-1.81 (m, 4H), 1.80-1.62 (m, 1H), 1.55-1.41 (m, 1H), 1.26-1.10 (m, 2H), 1.00-0.82 (m, 2H); ESI MS m / z 310.183 [M + H] + . Example 313 (2S,3R,4R,5S)-1-(((1s,4R)-4-(1,1-difluoroethyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol JPEG0007674389000119.jpg3965

[0201] A solution of cis / trans-4-(hydroxymethyl)cyclohexanecarboxylic acid (3.20 g, 20.2 mmol) in anhydrous MeOH (50 mL) was dissolved in SOCl 2 (4.8 g, 40 mmol) was added dropwise and the mixture was stirred at RT for 4 h. The solvent was removed in vacuo and the residue was concentrated with NaHCO 3 The mixture was diluted with saturated aqueous solution (40 mL). After extraction with DCM (3×40 mL), the combined extracts were washed with anhydrous Na 2 SO 4After filtration, the solvent was evaporated under vacuum to give a clear liquid. The liquid was dissolved in anhydrous DMF (30 mL) and cooled to 0° C., followed by addition of imidazole (2.72 g, 40.0 mmol) and TBDMSCl (4.52 g, 30.0 mmol). After stirring at RT 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 washed with anhydrous Na 2 SO 4 After filtration, the solvent was evaporated under vacuum and the residue was purified on silica gel by flash chromatography (EtOAc / Hexane, 1:9) to give a colorless oil. The oil was dissolved in anhydrous THF (50 mL) under Ar and the solution was cooled to 0° C. LAH (1.00 g, 26.3 mmol) was added in portions and the mixture was stirred at 0° C. for 1 h. Wet sodium sulfate heptahydrate (50 g) was added to quench the reaction and the suspension was stirred for 30 min. After filtration, the solvent was evaporated under vacuum and the residue was purified on silica gel by flash chromatography (EtOAc / Hexane, 1:4 to 1:2) to give a mixture of cis- and trans-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)methanol as a colorless oil (4.6 g, 88%, 3 steps).

[0202] To a solution of DMSO (1.95 g, 25.0 mmol) in anhydrous DCM (80 mL) cooled to -78°C, a solution of oxalyl chloride (1.93 g, 15.0 mmol) in anhydrous DCM (20 mL) was added under Ar. After the addition, the mixture was stirred at -78°C for 1 h, and then a solution of the above material (2.58 g, 10.0 mmol) in anhydrous DCM (20 mL) was added. The mixture was stirred at -78°C for 1 h, and then Et 3 N (5.4 mL, 40 mmol) was added and the mixture was stirred at -78 °C for 30 min, then at RT for 30 min. The mixture was then diluted with NaHCO 3 The organic layer was collected after dilution with saturated aqueous solution (50 mL). The aqueous layer was extracted with DCM (50 mL) and the combined organic extracts were washed with anhydrous Na 2 SO 4After filtration, the solvent was evaporated in vacuo and the residue was purified on silica gel by flash chromatography (EtOAc / hexanes, 1:9) to give 4-(((tert-butyldimethylsilyl)oxy)methyl)-cyclohexanecarbaldehyde as a colorless oil (2.30 g, 90%).

[0203] To a solution of the above material (2.30 g, 9.00 mmol) in anhydrous THF (40 mL) cooled to 0° C. under Ar was added MeMgCl (3.0 M in THF, 4.0 mL, 12 mmol) and the mixture was stirred at RT for 16 h. The mixture was quenched with ice water and NH 4 The mixture was diluted with saturated aqueous Cl (30 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with anhydrous Na 2 SO 4 After filtration, the solvent was evaporated in vacuo and the residue was purified on silica gel by flash chromatography (EtOAc / hexanes, 1:4) to give 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)ethanol as a colorless oil (2.40 g, 98%).

[0204] A mixture 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 RT for 3 h to form a white suspension. Hexanes (50 mL) were added and the suspension was filtered through a cake of Celite. The filtrate was collected and concentrated under vacuum, and the residue was purified on silica gel by flash chromatography (EtOAc / Hexanes, 1:15 to 1:6) to give 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)ethanone as a colorless oil (2.11 g, 89%).

[0205] To a solution of the above material (2.11 g, 7.8 mmol) in anhydrous THF (30 mL) cooled to 0° C., TBAF (1.0 M in THF, 10.0 mL, 10.0 mmol) was added under Ar, and the mixture was stirred at RT for 3 h. 3After dilution with aqueous solution (40 mL), the mixture was extracted with EtOAc (2×30 mL) and the combined extracts were washed with anhydrous Na 2 SO 4 After filtration, the solvent was evaporated in vacuo and the residue was purified on silica gel by flash chromatography (EtOAc / Hexanes, 2:3 to 1:1) to give 1-(4-(hydroxymethyl)cyclohexyl)ethanone as a clear liquid (1.10 g, 92%).

[0206] To a solution of the above material (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 under Ar. The mixture was stirred at RT for 16 h and then cooled with NaHCO 3 The mixture was diluted with saturated aqueous solution (30 mL). After extraction with DCM (3×30 mL), the combined extracts were washed with anhydrous Na 2 SO 4 After filtration, the solvent was evaporated in vacuo and the residue was purified on silica gel by flash chromatography (EtOAc / hexanes, 1:6 to 1:3) to give methyl (4-acetylcyclohexyl)benzoate as a pale yellow oil (1.85 g, 99%).

[0207] To a solution of the above material (1.70 g, 6.53 mmol) in anhydrous DCM (15 mL) was added DAST (5.74 g, 35.9 mmol) under Ar and the mixture was stirred at RT for 1 h and then heated at reflux for 4 days. The mixture was cooled to -78 °C and NaHCO 3 The mixture was quenched with saturated aqueous solution (50 mL). After extraction with DCM (2×50 mL), the combined extracts were washed with anhydrous Na 2 SO 4 After filtration, the solvent was evaporated in vacuo and the residue was purified on silica gel by flash chromatography (EtOAc / Hexanes, 1:11 to 1:9) to give methyl (4-(1,1-difluoroethyl)cyclohexyl)benzoate as a pale yellow oil (1.45 g, 79%).

[0208] The above material (1.45 g, 5.13 mmol) and K 2 CO 3 (1.5 g, 11 mmol) in MeOH (40 mL) was stirred for 16 h. The solvent was removed in vacuo and the residue was purified on silica gel by flash chromatography (EtOAc / Hexanes, 1:4 to 1:2) to give (4-(1,1-difluoroethyl)cyclohexyl)methanol as a clear liquid (0.85 g, 93%).

[0209] The above material (0.85 g, 4.8 mmol) was cooled to 0°C and dissolved in acetone (40 mL) of CrO 3 (1.5 g, 15 mmol) of 2.0MH 2 SO 4 Aqueous solution (10 mL) was added. The mixture was stirred at 0° C. for 1 h and then at RT for 16 h. Isopropanol (5 mL) was then added and the mixture was stirred for another 1 h. After concentration in vacuo, the mixture was diluted with water (50 mL) and extracted with DCM (3×30 mL). The combined extracts were washed with anhydrous Na 2 SO 4 After filtration, the solvent was evaporated in vacuum to give 4-(1,1-difluoroethyl)cyclohexanecarboxylic acid as a white solid (0.90 g, 98%). 1 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.

[0210] 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 RT for 16 h. The mixture was diluted with NaHCO 3The mixture was diluted with saturated aqueous solution (20 mL) and extracted with EtOAc (3×20 mL). The combined extracts were washed with brine (2×20 mL) and anhydrous Na 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified and separated on silica gel by flash chromatography (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.

[0211] 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 Et 2 To the O solution (15 mL) 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 NaHCO 3 Dilute with saturated aqueous solution (20 mL). 2 After extraction with 2×20 mL of HO (3×20 mL), the combined extracts were washed with anhydrous Na 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography (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] +.

[0212] The above material (0.099 g, 0.14 mmol), Pd(OH) 2 A mixture of 1M NH 3 / C (20% by weight Pd, 0.050 g, 0.094 mmol) and 2 drops of concentrated HCl in MeOH (20 mL) was stirred under hydrogen and 1 atm overnight. The mixture was filtered through a cake of Celite, and the filtrate was collected and concentrated to dryness. The residue was diluted with 1M NH 3 Neutralized with a solution of MeOH (0.5M NH 3 Purification on silica gel with MeOH / DCM (1:5) gave (2S,3R,4R,5S)-1-(((1s,4R)-4-(1,1-difluoroethyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol as a white solid (0.034 g, 72%). 1 H NMR (400 MHz, DMSO-d 6 ) 4.74 (d, J = 4.6 Hz, 1H), 4.65 (d, J = 4.2 Hz, 1H), 4.61 (d, J = 5.1 Hz, 1H), 4.10 (t, J = 5.3 Hz, 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, 8.3 Hz, 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] + . Example 314 (2S,3R,4R,5S)-1-(((1r,4S)-4-(1,1-difluoroethyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol JPEG0007674389000120.jpg4264

[0213] 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 Et 2 To the O solution (20 mL) 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 quenched with water and NaHCO 3 Dilute with saturated aqueous solution (20 mL). 2 After extraction with 2×30 mL of HO (3×30 mL), the combined extracts were washed with anhydrous Na 2 SO 4 After filtration, the solvent was evaporated under reduced pressure and the residue was purified on silica gel by flash chromatography (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] + .

[0214] The above material (0.23 g, 0.34 mmol), Pd(OH) 2 A mixture of 1M NH 2 O (20% by weight Pd, 0.080 g, 0.15 mmol) and 3 drops of concentrated HCl in MeOH (25 mL) was stirred under hydrogen and 1 atm overnight. The mixture was filtered through Celite, and the filtrate was collected and concentrated to dryness. The residue was diluted with 1M NH 3 Neutralized with a solution of MeOH (0.5M NH 3 Purification on silica gel with MeOH / DCM (1:5) gave (2S,3R,4R,5S)-1-(((1r,4S)-4-(1,1-difluoroethyl)cyclohexyl)methyl)-2-(hydroxymethyl)-piperidine-3,4,5-triol as a white solid (0.092 g, 85%). 1 H NMR (400 MHz, DMSO-d 6) δ 4.74 (d, J = 4.6 Hz, 1H), 4.64 (d, J = 4.2 Hz, 1H), 4.60 (d, J = 5.0 Hz, 1H), 4.09 (t, J = 5.1 Hz, 1H), 3.67-3.58 (m, 2H). 3.42 (dt, J = 9.6, 5.1 Hz, 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 = 19.4 Hz, 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] + .

[0215] As shown in Table 1, Examples 33-310 were synthesized following procedures similar to the schemes and examples outlined herein. biological activity IC for inhibition of GBA2 in cell lysates 50 Assays to measure values

[0216] Stable GBA2 expressing HEK293T cells were generated as follows. PCR amplified human GBA2 (GBA2 nucleotide accession number BC011363) was cloned into pLenti-GIII-CMV by ABM Inc. using the following primers: sense 5'---CGC AAA TGG GCG GTA GGC GTG---3' and antisense 5'---TAG TCA GCC ATG GGG CGG AGA---3'. The accuracy of the construct was verified by sequencing. GBA2-containing lentiviral particles in pLenti-GIII-CMV plasmid were prepared using the third generation Virus Packaging Mix (ABM catalog number LV053-G074) in HEK293T cells and delivered as a viral particle suspension. The viral suspension was used to infect HEK293T cells. A cell population stably expressing human GBA2 was selected using puromycin for several weeks as measured by activity assay and Western blot.

[0217] Various concentrations of test compounds were prepared in DMSO and then diluted in a buffer consisting of 100 mM citric acid, 200 mM disodium phosphate (pH 5.5) containing 1% v / v C10E6. Cell homogenates (0.25 mg / mL) of a stable HEK293T overexpressing GBA2 cell line were preincubated with an inhibitor of GCase (20 μM (6R,7R,8S)-8-ethyl-4-azaspiro[2.5]octane-6,7-diol) on ice for 10 min. The reaction solution consisted of 20 μL of 5% DMSO solution of 750 μM 4-methylumbelliferone-β-D glucopyranoside in the same buffer, 20 μL of GBA2 cell homogenate pretreated with (6R,7R,8S)-8-ethyl-4-azaspiro[2.5]octane-6,7-diol, and 20 μL of 10% DMSO solution of various concentrations of test compound in the same buffer. The final concentrations in the reaction were 0.083 mg / mL GBA2 cell homogenate, 250 μM 4-methylumbelliferone-β-D glucopyranoside, and various concentrations of inhibitor. The inhibitor and GBA2 cell homogenate were both preincubated at 37° C. for 5 min. The reaction was initiated by the addition of substrate and allowed to proceed for 20 min at 37° C. to assess GBA2 activity. The reaction was stopped by adding an equal volume (60 μL) of 0.5 M NaOH and 0.3 M glycine (pH 10.5). Fluorescence was measured using a Biotek Synergy H4 plate reader at an excitation wavelength of 365 nm and an emission wavelength of 450 nm. Incubations without enzyme or with inhibitor were used to define no enzyme activity and maximum enzyme activity, respectively. IC 50 IC values ​​were determined by fitting the data to a log [inhibitor concentration] versus response curve using GraphPad Prism. 50 Values ​​were calculated as the concentration of inhibitor required to inhibit GBA2 activity by 50%.

[0218] The compounds of the invention tested had IC values ​​ranging from 0.1 nM to 50 μM for inhibition of GBA2. 50 Indicates the value.

[0219] Representative data from the GBA2 inhibition assay described above are shown in Table 3, where the symbols "***" indicate IC 50 <100 nM, and the symbol "**" indicates 100 nM <IC 50 <1 μM, and the symbol "*" indicates IC<1 μM 50 <25 μM. Table 3 JPEG0007674389000121.jpg199146JPEG0007674389000122.jpg210147JPEG0007674389000123.jpg168146

[0220] The present invention has been described in terms of one or more embodiments, however, it will be apparent to those skilled in the art that a number of variations and modifications can be made without departing from the scope of the invention as defined in the claims.

[0221] Thus, although various embodiments of the present invention are disclosed herein, many adaptations and modifications can be made within the scope of the present invention according to the common general knowledge of those skilled in the art. Such modifications include the replacement of any aspect of the present invention with a known equivalent to achieve the same result in substantially the same way. It should be understood that the specific embodiments can be combined in any manner and in any number to create additional embodiments, and any permutation and combination of the embodiments should be considered to be disclosed by the specification of this application unless the context indicates otherwise. Numeric ranges include the numerical values ​​that define the range. The recitation of numerical ranges of values ​​herein is only intended to serve as a shorthand method of individually referring to each individual value falling within the range. Unless otherwise indicated herein, each individual value is incorporated herein as if set forth individually herein. The terms "a", "an" and "the" and similar references used in the context of describing the present invention should be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. As used herein, the word "comprising" is used as an open-ended term substantially equivalent to the phrase "including, but not limited to," and the word "comprises" has a corresponding meaning. However, it should be understood that when the word "comprising" or "comprises," or variations of the same root are used herein, variations or modifications to "consisting of" or "consisting of" that exclude unspecified elements, steps, or ingredients, or variations or modifications to "consisting essentially of" or "consisting essentially of" that limit the particular materials or recited steps, as well as those that do not materially affect the basic and novel characteristics of the claimed invention, are also contemplated. The citation of a reference herein should not be construed as an admission that such reference is 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 by reference and was fully set forth herein.The present invention includes substantially all of the embodiments and variations described above with reference to the examples. Reference materials 1. Grabowski, GA Lancet 2008, 372, 1263-1271. 2. Massimo, A. et al. Neurochem Res 2016, 41, 210-20. 3. Woeste, MA et al. Front Mol Neurosci 2017, 10, 386. 4. Hayashi, Y. et al. J Biol Chem 2007, 282, 30889-30900. 5. Lahiri, S. et al. Cell Mol Life Sci 2007, 64, 2270-2284. 6. Mutoh, T. et al. CNS Neurol Disord Drug Targets 2006, 5, 375-380. 7. Kim, S. et al. Proc Natl Acad Sci USA 2018, 115, 798-803. 8. Halmer, R. et al. Cell Physiol Biochem 2014, 34, 111-118. 9. Di Pardo, A. et al. Front Neurosci 2017, 11, 698. 10. Dodge, JC et al. Proc Natl Acad Sci USA 2015, 112, 8100-5. 11. Somogyi, A. et al. Int J Mol Sci 2018, 19, 625. 12. Zervas, M. et al. Curr Biol 2001, 11, 1283-7. 13. Boudewyn, LC et al. Neurobiol Dis 2017, 105, 257-270. 14. Ashe, K.M. et al. PLoS One 2011, 6, e21758. 15. Ilan, Y. Am J Physiol-Gast Liver Physiol 2016, 310, G1102-G1117. 16. Marques, A.R. et al. PLoS One 2015, 10, e0135889. 17. Nietupski, J.B. et al. Mol Genet Metab 2012, 105, 621-8. 18. PCT Int. Appl. WO 2017 / 185010. 19. Mistry, P.K. et al. Proc Natl Acad Sci U S A 2014, 111, 4934-9. 20. Loberto, N. et al. PLoS One 2014, 9, e104763. 21. Margalit, M. et al. J Pharm Exp Ther 2006, 319, 105-110. 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. 24. Zhang, W. et al. Clin & Exp Immunol 2009, 157, 359-364. 25. Mizrahi, M. et al. J Clin Trans Hepatol 2018, 6, 127-134. 26. Ghisaidoobe, A.T. et al. J Med Chem 2014, 57, 9096-104. 27. Farfel-Becker, T. et al. Dis Model Mech 2011, 4, 746-752.

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt thereof: R 1 But, CH 2 OH, R 2 is H, and R 3 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, ((1s,4S)-4-(2-fluoropropan-2-yl)cyclohexyl)methyl, ((1r,4R)-4-(2-fluoropropan-2-yl)cyclohexyl)methyl, ((trans)-3-(trifluoromethyl)cyclohexyl)methyl, ((cis)-3-(trifluoromethyl)cyclohexyl)methyl, ((1s,4S)-4-methoxy cyclohexyl)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]octan-6-yl)methyl, (spiro[3.5]nonan-7-yl)methyl, (spiro[4.5]decan-8-yl)methyl, 2-cyclohexylethyl, 2-(4,4-difluorocyclohexyl)ethyl, 2-((1s,4S)-4-(trifluoromethyl)cyclohexyl)ethyl, 2-((1r,4R)-4-(trifluoromethyl)cyclohexyl)ethyl, 2-(adamantan-1-yl)ethyl, 3-cyclohexylpropyl, 2-methylphenethyl, 2-methoxyphenethyl, 2-fluorophenethyl, 2-chlorophenethyl, 2,3-difluorophenethyl, 2,4-difluorophenethyl, 2,5-difluorophenethyl, 3,4-difluorophenethyl, 2-fluoro-4-methoxyphenethyl, 3-chloro-2-fluorophenethyl,4-chloro-2-fluorophenethyl, 5-chloro-2-fluorophenethyl, 2,6-difluorophenethyl, 3-chloro-2,6-difluorophenethyl, 2,6-difluoro-4-(prop-1-en-2-yl)phenethyl, 2,6-difluoro-4-isopropylphenethyl, 2,6-difluoro-3-isopropylphenethyl, 4-cyclopropyl-2,6-difluorophenethyl, 2,6-difluoro-4-(trifluoromethyl)phenethyl, 2,6-difluoro-4-(pyrrolidin-1-yl)phenethyl, 2,6-difluoro- 4-(piperidin-1-yl)phenethyl, 2,6-difluoro-4-morpholinophenethyl, 4-butoxy-2,6-difluorophenethyl, 4-(cyclopropylmethoxy)-2,6-difluorophenethyl, 4-((tetrahydrofuran-3-yl)oxy)phenethyl, 4-((tetrahydro-2H-pyran-3-yl)oxy)phenethyl, 4-((tetrahydro-2H-pyran-4-yl)oxy)phenethyl, 4-phenoxyphenethyl, 4-((tetrahydrofuran-3-yl)methoxy)phenethyl, 2-([1,1'-biphenyl 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-methylbutanoyl)piperidin-4-yl)methyl, (1-(3,3-dimethylbutanoyl)piperidin-4-yl)methyl, (1-(2-cyclopentylacetyl)piperidin-4-yl)methyl, (1-(cyclopropanecarbonyl)piperidin-4-yl)methyl, (1-(cyclobutanecarbonyl)piperidin-4-yl)methyl aryl, (1-(cyclopentanecarbonyl)piperidin-4-yl)methyl, (1-(cyclohexanecarbonyl)piperidin-4-yl)methyl, (1-((1s,4s)-4-(tert-butyl)cyclohexanecarbonyl)piperidin-4-yl)methyl, (1-((1r,4r)-4-(tert-butyl)cyclohexanecarbonyl)piperidin-4-yl)methyl, (1-(4-methoxycyclohexanecarbonyl)piperidin-4-yl)methyl, (1-(4-(trifluoromethyl)cyclohexanecarbonyl)piperidin-4-yl)methyl, (1-benzoylpiperidin-4-yl)methyl, (1-(3-(trifluoromethyl)benzoyl)piperidin-4-yl)methyl, ( 1-(2-phenylacetyl)piperidin-4-yl)methyl, (1-(thiophene-3-carbonyl)piperidin-4-yl)methyl, ((5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-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)piperidine- 4-yl)methyl, (1-(cyclohexylcarbamoyl)piperidin-4-yl)methyl, (1-(cyclohexylcarbamoyl)piperidin-4-yl)methyl, (1-(cyclohexylcarbamothioyl)piperidin-4-yl)methyl, (1-((1S,2R)-2-(trifluoromethyl)cyclohexyl))azetidin-3-yl)methyl,((R)-1-phenylpyrrolidin-3-yl)methyl, ((R)-1-(o-tolyl)pyrrolidin-3-yl)methyl, ((R)-1-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl, ((S)-1-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl, (R)-1-(2-fluorophenyl)pyrrolidin-3-yl)methyl, (R)-1-(3-fluorophenyl)pyrrolidin-3-yl)methyl, ((R)-1-(2-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)methyl, ((R)-1-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl, ((R)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl, ((R)-1-(4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl 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)pyrrolidine -3-yl)methyl, ((R)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl, ((R)-1-(thiophen-3-yl)pyrrolidin-3-yl)methyl, ((R)-1-(benzo[d]thiazol-4-yl)pyrrolidin-3-yl)methyl, (S)-(1-(4-(trifluoromethyl)benzoyl)pyrrolidin-3-yl)methyl, ((R)-1-(o-tolyl)piperidin-3-yl)methyl, ((R) -1-(2-fluorophenyl)piperidin-3-yl)methyl, ((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 (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)piperidin-3-yl)methyl pyrrolidin-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl, ((S)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl, (( S)-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl, 4-butoxyphenethyl, ((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.

2. The compound is (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-((4,4-dimethylcyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-((4,4-difluorocyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-((4,4-dichlorocyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-((4-ethylcyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((1s,4S)-4-vinylcyclohexyl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((1s,4S)-4-isopropylcyclohexyl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((1r,4R)-4-isopropylcyclohexyl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((1s,4S)-4-(tert-butyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((1r,4R)-4-(tert-butyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((1s,4S)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((1r,4R)-4-(2-fluoropropan-2-yl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((1s,4S)-4-methoxycyclohexyl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((1r,4R)-4-methoxycyclohexyl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-((4-(methoxymethyl)cyclohexyl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((1s,4S)-4-cyclopropylcyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((1r,4R)-4-cyclopropylcyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-((4-phenylcyclohexyl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(spiro[2.5]octan-6-ylmethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(spiro[3.5]nonan-7-ylmethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(spiro[4.5]decan-8-ylmethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-8-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-((1,2,3,4-tetrahydronaphthalen-2-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2-(4,4-difluorocyclohexyl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(2-((1s,4S)-4-(trifluoromethyl)cyclohexyl)ethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(2-((1r,4R)-4-(trifluoromethyl)cyclohexyl)ethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2-((3R,5R,7R)-adamantan-1-yl)ethyl)-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-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(4-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(2-methylphenethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(3-(trifluoromethyl)phenethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(4-(trifluoromethyl)phenethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(2-methoxyphenethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2-chlorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2,3-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2,4-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2,5-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(3,4-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2-fluoro-4-methoxyphenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(4-chloro-2-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(5-chloro-2-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(3,4-dichlorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(3-chloro-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2,6-difluoro-4-(prop-1-en-2-yl)phenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2,6-difluoro-4-isopropylphenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2,6-difluoro-3-isopropylphenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(4-cyclopropyl-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2,6-difluoro-4-(trifluoromethyl)phenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2,6-difluoro-4-(pyrrolidin-1-yl)phenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2,6-difluoro-4-(piperidin-1-yl)phenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2,6-difluoro-4-morpholinophenethyl)-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-(4-(cyclopropylmethoxy)-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(4-((tetrahydrofuran-3-yl)oxy)phenethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(4-((tetrahydro-2H-pyran-3-yl)oxy)phenethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(4-phenoxyphenethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(4-((tetrahydrofuran-3-yl)methoxy)phenethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2-(3,5-difluoro-[1,1'-biphenyl]-4-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(4-(3,5-dimethylisoxazol-4-yl)-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2-(6-fluorobenzo[d][1,3]dioxol-5-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-((R)-2-phenylpropyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-((S)-2-phenylpropyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(2-(pyridin-2-yl)ethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(2-(thiophen-2-yl)ethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(2-(thiophen-3-yl)ethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(3-(2-fluorophenyl)propyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(3-(4-fluorophenyl)propyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(3-(thiophen-2-yl)propyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(3-(thiophen-3-yl)propyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-((1-phenylpiperidin-4-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-((1-(2-fluorophenyl)piperidin-4-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-((1-(3-fluorophenyl)piperidin-4-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-((1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-((4-methyl-1-phenylpiperidin-4-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-((4-fluoro-1-phenylpiperidin-4-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(2-(1-phenylpiperidin-4-yl)ethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-((1-(pyridin-3-yl)piperidin-4-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)piperidine-3,4,5-triol, 2-methyl-1-(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)propan-1-one, 2,2-dimethyl-1-(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)propan-1-one, 1-(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)butan-1-one, 3-methyl-1-(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)butan-1-one, 3,3-dimethyl-1-(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)butan-1-one, 2-cyclopentyl-1-(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)ethanone, cyclopropyl(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, Cyclobutyl(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, cyclopentyl(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, cyclohexyl(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, ((1s,4S)-4-(tert-butyl)cyclohexyl)(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, ((1r,4R)-4-(tert-butyl)cyclohexyl)(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, (4-methoxycyclohexyl)(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, (4-(trifluoromethyl)cyclohexyl)(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, Phenyl(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, (3-(trifluoromethyl)phenyl)(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, 2-phenyl-1-(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)ethanone, Thiophen-3-yl(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, N-cyclohexyl-4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidine-1-carboxamide, N-cyclohexyl-4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidine-1-carbothioamide, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-((1-((1S,2R)-2-(trifluoromethyl)cyclohexyl)azetidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-phenylpyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(o-tolyl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((R)-1-(2-fluorophenyl)pyrrolidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((R)-1-(3-fluorophenyl)pyrrolidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(2-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-methylpyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(2-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(thiophen-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((R)-1-(benzo[d]thiazol-4-yl)pyrrolidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((R)-1-(benzo[d]oxazol-2-yl)pyrrolidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((R)-1-(benzo[d]thiazol-2-yl)pyrrolidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (4-(trifluoromethyl)phenyl)((R)-3-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)pyrrolidin-1-yl)methanone, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(o-tolyl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((R)-1-(2-fluorophenyl)piperidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(2-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(5-isopropylthiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((R)-1-(benzo[d]thiazol-2-yl)piperidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((R)-1-(benzo[d]thiazol-4-yl)piperidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(6-(trifluoromethyl)pyridin-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, 2. The compound of claim 1, which is (2S,3R,4R,5S)-1-(((1r,4S)-4-(1,1-difluoroethyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, or a pharma- ceutically acceptable salt of any of said compounds.

3. (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-(thiophen-2-yl)ethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(2-(thiophen-3-yl)ethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-((4,4-dimethylcyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-((4,4-difluorocyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-((4,4-dichlorocyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-((4-ethylcyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((1s,4S)-4-vinylcyclohexyl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((1s,4S)-4-isopropylcyclohexyl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((1r,4R)-4-isopropylcyclohexyl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((1s,4S)-4-(tert-butyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((1r,4R)-4-(tert-butyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((1s,4S)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((1s,4S)-4-(2-fluoropropan-2-yl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((1r,4R)-4-(2-fluoropropan-2-yl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((1s,4S)-4-methoxycyclohexyl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((1r,4R)-4-methoxycyclohexyl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-((4-(methoxymethyl)cyclohexyl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((1s,4S)-4-cyclopropylcyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((1r,4R)-4-cyclopropylcyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-((4-phenylcyclohexyl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(spiro[2.5]octan-6-ylmethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(spiro[3.5]nonan-7-ylmethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(spiro[4.5]decan-8-ylmethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-8-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-((1,2,3,4-tetrahydronaphthalen-2-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-((2,3-dihydro-1H-inden-2-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2-(4,4-difluorocyclohexyl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(2-((1s,4S)-4-(trifluoromethyl)cyclohexyl)ethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(2-((1r,4R)-4-(trifluoromethyl)cyclohexyl)ethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2-((3R,5R,7R)-adamantan-1-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(2-methylphenethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(2-methoxyphenethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2-chlorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2,3-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2,4-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2,5-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(3,4-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2-fluoro-4-methoxyphenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(3-chloro-2-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(4-chloro-2-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(5-chloro-2-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(3,4-dichlorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(3-chloro-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2,6-difluoro-4-(prop-1-en-2-yl)phenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2,6-difluoro-4-isopropylphenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2,6-difluoro-3-isopropylphenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(4-cyclopropyl-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2,6-difluoro-4-(trifluoromethyl)phenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2,6-difluoro-4-(pyrrolidin-1-yl)phenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2,6-difluoro-4-(piperidin-1-yl)phenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2,6-difluoro-4-morpholinophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(4-butoxy-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(4-(cyclopropylmethoxy)-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(4-((tetrahydrofuran-3-yl)oxy)phenethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(4-((tetrahydro-2H-pyran-3-yl)oxy)phenethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(4-phenoxyphenethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(4-((tetrahydrofuran-3-yl)methoxy)phenethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2-([1,1'-biphenyl]-4-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2-(3,5-difluoro-[1,1'-biphenyl]-4-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(4-(3,5-dimethylisoxazol-4-yl)-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2-(6-fluorobenzo[d][1,3]dioxol-5-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(3-(2-fluorophenyl)propyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(3-(4-fluorophenyl)propyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(3-(thiophen-2-yl)propyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(3-(thiophen-3-yl)propyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-((1-phenylpiperidin-4-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-((1-(2-fluorophenyl)piperidin-4-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-((1-(3-fluorophenyl)piperidin-4-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-((1-(4-fluorophenyl)piperidin-4-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-((1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-((4-methyl-1-phenylpiperidin-4-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-((4-fluoro-1-phenylpiperidin-4-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(2-(1-phenylpiperidin-4-yl)ethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-((1-(pyridin-3-yl)piperidin-4-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)piperidine-3,4,5-triol, 2-methyl-1-(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)propan-1-one, 2,2-dimethyl-1-(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)propan-1-one, 1-(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)butan-1-one, 3-methyl-1-(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)butan-1-one, 3,3-dimethyl-1-(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)butan-1-one, 2-cyclopentyl-1-(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)ethanone, cyclopropyl(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, Cyclobutyl(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, cyclopentyl(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, cyclohexyl(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, ((1s,4S)-4-(tert-butyl)cyclohexyl)(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, ((1r,4R)-4-(tert-butyl)cyclohexyl)(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, (4-methoxycyclohexyl)(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, (4-(trifluoromethyl)cyclohexyl)(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, phenyl(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, (3-(trifluoromethyl)phenyl)(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, 2-phenyl-1-(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)ethanone, Thiophen-3-yl(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, N-cyclohexyl-4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidine-1-carboxamide, N-cyclohexyl-4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidine-1-carbothioamide, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-((1-((1S,2R)-2-(trifluoromethyl)cyclohexyl)azetidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-phenylpyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(o-tolyl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((R)-1-(2-fluorophenyl)pyrrolidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((R)-1-(3-fluorophenyl)pyrrolidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(2-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-methylpyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(2-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(thiophen-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((R)-1-(benzo[d]thiazol-4-yl)pyrrolidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((R)-1-(benzo[d]oxazol-2-yl)pyrrolidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((R)-1-(benzo[d]thiazol-2-yl)pyrrolidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (4-(trifluoromethyl)phenyl)((R)-3-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)pyrrolidin-1-yl)methanone, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(o-tolyl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((R)-1-(2-fluorophenyl)piperidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(2-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(5-isopropylthiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((R)-1-(benzo[d]thiazol-2-yl)piperidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((R)-1-(benzo[d]thiazol-4-yl)piperidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, or The compound is (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol.

4. The compound according to any one of claims 1 to 3, wherein the compound inhibits non-lysosomal glucosylceramidase (GBA2).

5. The compound according to any one of claims 1 to 4, wherein the compound specifically binds to GBA2.

6. The compound according to any one of claims 1 to 5, wherein the compound reduces the enzymatic activity level of GBA2.

7. The compound according to any one of claims 4 to 6, wherein the GBA2 is a mammalian GBA2.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, in combination with a pharma- ceutically acceptable carrier.

9. A pharmaceutical composition for inhibiting GBA2 in a subject in need thereof, the pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt thereof: In the formula, R 1 is H and R 2 But, CH 2 OH or R 1 But, CH 2 OH and R 2 is H, and R 3 But (CH 2 ) n R 4 wherein n is 1 or 2, and R 4 cyclohexyl, cyclohexylmethyl, phenylethyl, 4-phenylcyclohexyl, spiro[2.5]octan-6-yl, spiro[3.5]nonan-7-yl, spiro[4.5]decan-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-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-(cyclohexylcarbamoyl)piperidin-4-yl, 1-(cyclohexylcarbamothioyl)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazetidin-3-yl, 2-(thiophen-2-yl)methyl, or 2-(thiophen-3-yl)methyl, with one or more of F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropan-2-yl, methoxymethyl, C 1-5 Alkoxy, CHF 2 , C.F. 2 CH 3 , and / or CF 3 or R 3 pyrrolidin-1-yl, piperidin-1-yl, 4-morpholino, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, F, Cl, C 1-6 Alkyl, cyclopropyl, propen-2-yl, OCH 3 , and / or CF 3 or phenylethyl optionally substituted with one to a maximum of the following substituents: R 3 On the formyl group, C 1-6 Alkyl, C 3-7 (1-formylpiperidin-4-yl)methyl substituted with one of cycloalkyl, phenyl, thiophen-3-yl, phenylmethyl, or cyclopentylmethyl; 1-6 Alkyl, OCH 3 , and / or CF 3 or R 3 but, Wherein R 5 is selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophen-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, and one or more of F, Cl, C 1-6 Alkyl, C 1-6 Alkoxy, OCF 3 , and / or CF 3 each optionally substituted with one to a maximum of However, R 1 H and R 2 CH 2 In the case of OH, 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 R 1 CH 2 OH and R 2 If H, then R 3 but is not phenylethyl, 3-phenylpropyl, (R)-2-phenylpropyl, or (S)-2-phenylpropyl.

10. A pharmaceutical composition for reducing GBA2 enzyme activity in a subject in need thereof, the pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt thereof: In the formula, R 1 is H and R 2 But, CH 2 OH or R 1 But, CH 2 OH and R 2 is H, and R 3 But (CH 2 ) n R 4 wherein n is 1 or 2, and R 4 cyclohexyl, cyclohexylmethyl, phenylethyl, 4-phenylcyclohexyl, spiro[2.5]octan-6-yl, spiro[3.5]nonan-7-yl, spiro[4.5]decan-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-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-(cyclohexylcarbamoyl)piperidin-4-yl, 1-(cyclohexylcarbamothioyl)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazetidin-3-yl, 2-(thiophen-2-yl)methyl, or 2-(thiophen-3-yl)methyl, with one or more of F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropan-2-yl, methoxymethyl, C 1-5 Alkoxy, CHF 2 , C.F. 2 CH 3 , and / or CF 3 or R 3 pyrrolidin-1-yl, piperidin-1-yl, 4-morpholino, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, F, Cl, C 1-6 Alkyl, cyclopropyl, propen-2-yl, OCH 3 , and / or CF 3 or phenylethyl optionally substituted with one to a maximum of the following substituents: R 3 On the formyl group, C 1-6 Alkyl, C 3-7 (1-formylpiperidin-4-yl)methyl substituted with one of cycloalkyl, phenyl, thiophen-3-yl, phenylmethyl, or cyclopentylmethyl; 1-6 Alkyl, OCH 3 , and / or CF 3 or R 3 but, Wherein R 5 is selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophen-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, and one or more of F, Cl, C 1-6 Alkyl, C 1-6 Alkoxy, OCF 3 , and / or CF 3 each optionally substituted with one to a maximum of However, R 1 H and R 2 CH 2 In the case of OH, 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 R 1 CH 2 OH and R 2 If H, then R 3 but is not phenylethyl, 3-phenylpropyl, (R)-2-phenylpropyl, or (S)-2-phenylpropyl.

11. A pharmaceutical composition for treating a condition modulated by GBA2 in a subject in need thereof, the pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt thereof: In the formula, R 1 is H and R 2 But, CH 2 OH or R 1 But, CH 2 OH and R 2 is H, and R 3 But (CH 2 ) n R 4 wherein n is 1 or 2, and R 4 cyclohexyl, cyclohexylmethyl, phenylethyl, 4-phenylcyclohexyl, spiro[2.5]octan-6-yl, spiro[3.5]nonan-7-yl, spiro[4.5]decan-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-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-(cyclohexylcarbamoyl)piperidin-4-yl, 1-(cyclohexylcarbamothioyl)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazetidin-3-yl, 2-(thiophen-2-yl)methyl, or 2-(thiophen-3-yl)methyl, with one or more of F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropan-2-yl, methoxymethyl, C 1-5 Alkoxy, CHF 2 , C.F. 2 CH 3 , and / or CF 3 or R 3 pyrrolidin-1-yl, piperidin-1-yl, 4-morpholino, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, F, Cl, C 1-6 Alkyl, cyclopropyl, propen-2-yl, OCH 3 , and / or CF 3 or phenylethyl optionally substituted with one to a maximum of the following substituents: R 3 On the formyl group, C 1-6 Alkyl, C 3-7 (1-formylpiperidin-4-yl)methyl substituted with one of cycloalkyl, phenyl, thiophen-3-yl, phenylmethyl, or cyclopentylmethyl; 1-6 Alkyl, OCH 3 , and / or CF 3 or R 3 but, Wherein R 5 is selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophen-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, and one or more of F, Cl, C 1-6 Alkyl, C 1-6 Alkoxy, OCF 3 , and / or CF 3 each optionally substituted with one to a maximum of However, R 1 H and R 2 CH 2 In the case of OH, 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 R 1 CH 2 OH and R 2 If H, then R 3 but is not phenylethyl, 3-phenylpropyl, (R)-2-phenylpropyl, or (S)-2-phenylpropyl.

12. 1. A pharmaceutical composition for treating a condition selected from a neurological disorder, a lysosomal storage disorder, and a hepatic disorder in a subject in need thereof, the pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt thereof: In the formula, R 1 is H and R 2 But, CH 2 OH or R 1 But, CH 2 OH and R 2 is H, and R 3 But (CH 2 ) n R 4 wherein n is 1 or 2, and R 4 cyclohexyl, cyclohexylmethyl, phenylethyl, 4-phenylcyclohexyl, spiro[2.5]octan-6-yl, spiro[3.5]nonan-7-yl, spiro[4.5]decan-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-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-(cyclohexylcarbamoyl)piperidin-4-yl, 1-(cyclohexylcarbamothioyl)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazetidin-3-yl, 2-(thiophen-2-yl)methyl, or 2-(thiophen-3-yl)methyl, with one or more of F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropan-2-yl, methoxymethyl, C 1-5 Alkoxy, CHF 2 , C.F. 2 CH 3 , and / or CF 3 or R 3 pyrrolidin-1-yl, piperidin-1-yl, 4-morpholino, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, F, Cl, C 1-6 Alkyl, cyclopropyl, propen-2-yl, OCH 3 , and / or CF 3 or phenylethyl optionally substituted with one to a maximum of the following substituents: R 3 On the formyl group, C 1-6 Alkyl, C 3-7 (1-formylpiperidin-4-yl)methyl substituted with one of cycloalkyl, phenyl, thiophen-3-yl, phenylmethyl, or cyclopentylmethyl; 1-6 Alkyl, OCH 3 , and / or CF 3 or R 3 but, Wherein R 5 is selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophen-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, and one or more of F, Cl, C 1-6 Alkyl, C 1-6 Alkoxy, OCF 3 , and / or CF 3 each optionally substituted with one to a maximum of However, R 1 H and R 2 CH 2 In the case of OH, 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 R 1 CH 2 OH and R 2 If H, then R 3 but is not phenylethyl, 3-phenylpropyl, (R)-2-phenylpropyl, or (S)-2-phenylpropyl.

13. The condition is selected from the group consisting of 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), vascular bruit syndrome (BMSD), and the like. Disease, Cerebellar ataxia, Charcot-Marie-Tooth disease (CMT), Chronic fatigue syndrome, Corticobasal degeneration (CBD), Pugilist dementia, Dementia with Lewy bodies (DLB), Dejerine-Sottas disease, Diffuse neurofibrillary tangles with calcifications, 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, Gerstmann-Sträussler-Scheinker disease, Glaucoma, Guadeloupe parkinsonism, Guillain-Barré syndrome, Hallervorden-Spatz syndrome (neurodegenerative disease 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, autonomic neuropathy, neuritis, and diabetic neuropathy), oculopharyngeal muscular dystrophy, pain, pons pallidus Cerebral substantia nigra degeneration, Parkinson-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 Transcortical Gliosis, Progressive Supranuclear Palsy (PSP), Richardson's Syndrome, Schizophrenia, Seizures, Spinal Cord Disorders, Spinal Muscular Atrophy (SMA), Spinocerebellar Ataxia (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, fibrillary tangle-predominant dementia, tardive dyskinesia, Tourette syndrome (TS), vascular dementia, Wilson's disease, 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 V), Type II), cerebrotendinous xanthomatosis, Fabry disease, Farber disease, GM1 gangliosidosis, Krabbe disease, metachromatic leukodystrophy (MLD), multiple sulfatase deficiency, Pompe disease, Sandhoff disease, Tay-Sachs disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), Alagille syndrome, alcohol-related liver disease, alpha-1 antitrypsin deficiency, autoimmune hepatitis, autoimmune cholangitis, benign liver tumors, biliary atresia, cirrhosis, Klig 13. The pharmaceutical composition according to claim 11 or 12, wherein the condition is Lah-Najjar syndrome, drug-induced liver injury (DILI), galactosemia, Gilbert syndrome, hemochromatosis, hepatic encephalopathy, hepatocellular carcinoma (HCC), intrahepatic cholestasis of pregnancy (ICP), lysosomal acid lipase deficiency (LAL-D), liver cyst, liver cancer, neonatal jaundice, primary sclerosing cholangitis (PBC), primary biliary cholangitis (PSC), Reye's syndrome, glycogen storage disease type I, or viral hepatitis (including types A, B, C, D, and E).

14. 13. The pharmaceutical composition of claim 11 or 12, wherein the condition is Parkinson's disease.

15. 13. The pharmaceutical composition of claim 11 or 12, wherein the condition is Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), or multiple sclerosis.

16. 13. The pharmaceutical composition of claim 11 or 12, wherein the condition is Niemann-Pick disease type C.

17. 13. The pharmaceutical composition of claim 11 or 12, wherein the condition is Gaucher's disease, mucolipidosis type IV, neuronal ceroid lipofuscinosis, or Sandhoff's disease.

18. 13. The pharmaceutical composition of claim 11 or 12, wherein the condition is non-alcoholic steatohepatitis (NASH).

19. 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-(thiophen-2-yl)ethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(2-(thiophen-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, (2R,3R,4R,5S)-1-((4,4-dimethylcyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-((4,4-difluorocyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-((4,4-dichlorocyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-((4-ethylcyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((1s,4S)-4-vinylcyclohexyl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((1s,4S)-4-isopropylcyclohexyl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((1r,4R)-4-isopropylcyclohexyl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((1s,4S)-4-(tert-butyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((1r,4R)-4-(tert-butyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((1s,4S)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((1s,4S)-4-(2-fluoropropan-2-yl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((1r,4R)-4-(2-fluoropropan-2-yl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((1s,4S)-4-methoxycyclohexyl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((1r,4R)-4-methoxycyclohexyl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-((4-(methoxymethyl)cyclohexyl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((1s,4S)-4-cyclopropylcyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((1r,4R)-4-cyclopropylcyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-((4-phenylcyclohexyl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(spiro[2.5]octan-6-ylmethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(spiro[3.5]nonan-7-ylmethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(spiro[4.5]decan-8-ylmethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-8-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-((1,2,3,4-tetrahydronaphthalen-2-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-((2,3-dihydro-1H-inden-2-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2-(4,4-difluorocyclohexyl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(2-((1s,4S)-4-(trifluoromethyl)cyclohexyl)ethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(2-((1r,4R)-4-(trifluoromethyl)cyclohexyl)ethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2-((3R,5R,7R)-adamantan-1-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(2-methylphenethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(2-methoxyphenethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2-chlorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2,3-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2,4-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2,5-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(3,4-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2-fluoro-4-methoxyphenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(3-chloro-2-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(4-chloro-2-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(5-chloro-2-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(3,4-dichlorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(3-chloro-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2,6-difluoro-4-(prop-1-en-2-yl)phenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2,6-difluoro-4-isopropylphenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2,6-difluoro-3-isopropylphenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(4-cyclopropyl-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2,6-difluoro-4-(trifluoromethyl)phenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2,6-difluoro-4-(pyrrolidin-1-yl)phenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2,6-difluoro-4-(piperidin-1-yl)phenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2,6-difluoro-4-morpholinophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(4-butoxy-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(4-(cyclopropylmethoxy)-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(4-((tetrahydrofuran-3-yl)oxy)phenethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(4-((tetrahydro-2H-pyran-3-yl)oxy)phenethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(4-phenoxyphenethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(4-((tetrahydrofuran-3-yl)methoxy)phenethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2-([1,1'-biphenyl]-4-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2-(3,5-difluoro-[1,1'-biphenyl]-4-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(4-(3,5-dimethylisoxazol-4-yl)-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2-(6-fluorobenzo[d][1,3]dioxol-5-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(3-(2-fluorophenyl)propyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(3-(4-fluorophenyl)propyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(3-(thiophen-2-yl)propyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(3-(thiophen-3-yl)propyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-((1-phenylpiperidin-4-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-((1-(2-fluorophenyl)piperidin-4-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-((1-(3-fluorophenyl)piperidin-4-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-((1-(4-fluorophenyl)piperidin-4-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-((1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-((4-methyl-1-phenylpiperidin-4-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-((4-fluoro-1-phenylpiperidin-4-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(2-(1-phenylpiperidin-4-yl)ethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-((1-(pyridin-3-yl)piperidin-4-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)piperidine-3,4,5-triol, 2-methyl-1-(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)propan-1-one, 2,2-dimethyl-1-(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)propan-1-one, 1-(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)butan-1-one, 3-methyl-1-(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)butan-1-one, 3,3-dimethyl-1-(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)butan-1-one, 2-cyclopentyl-1-(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)ethanone, cyclopropyl(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, Cyclobutyl(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, cyclopentyl(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, cyclohexyl(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, ((1s,4S)-4-(tert-butyl)cyclohexyl)(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, ((1r,4R)-4-(tert-butyl)cyclohexyl)(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, (4-methoxycyclohexyl)(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, (4-(trifluoromethyl)cyclohexyl)(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, phenyl(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, (3-(trifluoromethyl)phenyl)(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, 2-phenyl-1-(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)ethanone, Thiophen-3-yl(4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, N-cyclohexyl-4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidine-1-carboxamide, N-cyclohexyl-4-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidine-1-carbothioamide, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-((1-((1S,2R)-2-(trifluoromethyl)cyclohexyl)azetidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-phenylpyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(o-tolyl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((R)-1-(2-fluorophenyl)pyrrolidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((R)-1-(3-fluorophenyl)pyrrolidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(2-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-methylpyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(2-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(thiophen-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((R)-1-(benzo[d]thiazol-4-yl)pyrrolidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((R)-1-(benzo[d]oxazol-2-yl)pyrrolidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((R)-1-(benzo[d]thiazol-2-yl)pyrrolidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (4-(trifluoromethyl)phenyl)((R)-3-(((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)pyrrolidin-1-yl)methanone, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(o-tolyl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((R)-1-(2-fluorophenyl)piperidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(2-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(5-isopropylthiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((R)-1-(benzo[d]thiazol-2-yl)piperidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-1-(((R)-1-(benzo[d]thiazol-4-yl)piperidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2R,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-((4,4-dimethylcyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-((4,4-difluorocyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-((4,4-dichlorocyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-((4-ethylcyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((1s,4S)-4-vinylcyclohexyl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((1s,4S)-4-isopropylcyclohexyl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((1r,4R)-4-isopropylcyclohexyl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((1s,4S)-4-(tert-butyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((1r,4R)-4-(tert-butyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((1s,4S)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((1r,4R)-4-(2-fluoropropan-2-yl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((1s,4S)-4-methoxycyclohexyl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((1r,4R)-4-methoxycyclohexyl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-((4-(methoxymethyl)cyclohexyl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((1s,4S)-4-cyclopropylcyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((1r,4R)-4-cyclopropylcyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-((4-phenylcyclohexyl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(spiro[2.5]octan-6-ylmethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(spiro[3.5]nonan-7-ylmethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(spiro[4.5]decan-8-ylmethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-8-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-((1,2,3,4-tetrahydronaphthalen-2-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2-(4,4-difluorocyclohexyl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(2-((1s,4S)-4-(trifluoromethyl)cyclohexyl)ethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(2-((1r,4R)-4-(trifluoromethyl)cyclohexyl)ethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2-((3R,5R,7R)-adamantan-1-yl)ethyl)-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-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(4-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(2-methylphenethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(3-(trifluoromethyl)phenethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(4-(trifluoromethyl)phenethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(2-methoxyphenethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2-chlorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2,3-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2,4-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2,5-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(3,4-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2-fluoro-4-methoxyphenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(4-chloro-2-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(5-chloro-2-fluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(3,4-dichlorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(3-chloro-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2,6-difluoro-4-(prop-1-en-2-yl)phenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2,6-difluoro-4-isopropylphenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2,6-difluoro-3-isopropylphenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(4-cyclopropyl-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2,6-difluoro-4-(trifluoromethyl)phenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2,6-difluoro-4-(pyrrolidin-1-yl)phenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2,6-difluoro-4-(piperidin-1-yl)phenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2,6-difluoro-4-morpholinophenethyl)-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-(4-(cyclopropylmethoxy)-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(4-((tetrahydrofuran-3-yl)oxy)phenethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(4-((tetrahydro-2H-pyran-3-yl)oxy)phenethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(4-phenoxyphenethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(4-((tetrahydrofuran-3-yl)methoxy)phenethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2-(3,5-difluoro-[1,1'-biphenyl]-4-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(4-(3,5-dimethylisoxazol-4-yl)-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-2,6-difluorophenethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2-(6-fluorobenzo[d][1,3]dioxol-5-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-((R)-2-phenylpropyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-((S)-2-phenylpropyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(2-(pyridin-2-yl)ethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(2-(thiophen-2-yl)ethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(2-(thiophen-3-yl)ethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(3-(2-fluorophenyl)propyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(3-(4-fluorophenyl)propyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(3-(thiophen-2-yl)propyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(3-(thiophen-3-yl)propyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-((1-phenylpiperidin-4-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-((1-(2-fluorophenyl)piperidin-4-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-((1-(3-fluorophenyl)piperidin-4-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-((1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-((4-methyl-1-phenylpiperidin-4-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-((4-fluoro-1-phenylpiperidin-4-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(2-(1-phenylpiperidin-4-yl)ethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-((1-(pyridin-3-yl)piperidin-4-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)piperidine-3,4,5-triol, 2-methyl-1-(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)propan-1-one, 2,2-dimethyl-1-(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)propan-1-one, 1-(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)butan-1-one, 3-methyl-1-(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)butan-1-one, 3,3-dimethyl-1-(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)butan-1-one, 2-cyclopentyl-1-(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)ethanone, cyclopropyl(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, Cyclobutyl(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, cyclopentyl(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, cyclohexyl(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, ((1s,4S)-4-(tert-butyl)cyclohexyl)(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, ((1r,4R)-4-(tert-butyl)cyclohexyl)(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, (4-methoxycyclohexyl)(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, (4-(trifluoromethyl)cyclohexyl)(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, Phenyl(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, (3-(trifluoromethyl)phenyl)(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, 2-phenyl-1-(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)ethanone, Thiophen-3-yl(4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)methanone, N-cyclohexyl-4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidine-1-carboxamide, N-cyclohexyl-4-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)piperidine-1-carbothioamide, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-((1-((1S,2R)-2-(trifluoromethyl)cyclohexyl)azetidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-phenylpyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(o-tolyl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((R)-1-(2-fluorophenyl)pyrrolidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((R)-1-(3-fluorophenyl)pyrrolidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(2-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-methylpyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(2-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(thiophen-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((R)-1-(benzo[d]thiazol-4-yl)pyrrolidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((R)-1-(benzo[d]oxazol-2-yl)pyrrolidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((R)-1-(benzo[d]thiazol-2-yl)pyrrolidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (4-(trifluoromethyl)phenyl)((R)-3-(((2S,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)methyl)pyrrolidin-1-yl)methanone, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(o-tolyl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((R)-1-(2-fluorophenyl)piperidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(2-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((R)-1-(5-isopropylthiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((R)-1-(benzo[d]thiazol-2-yl)piperidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-1-(((R)-1-(benzo[d]thiazol-4-yl)piperidin-3-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol, (2S,3R,4R,5S)-2-(hydroxymethyl)-1-(((S)-1-(6-(trifluoromethyl)pyridin-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, or The pharmaceutical composition according to any one of claims 9 to 18, which is (2S,3R,4R,5S)-1-(((1r,4S)-4-(1,1-difluoroethyl)cyclohexyl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol.

20. The pharmaceutical composition of any one of claims 9 to 19, wherein said compound reduces the level of GBA2 enzyme activity in said subject.

21. The pharmaceutical composition according to any one of claims 9 to 20, wherein the subject is a human.

22. Use of an effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt thereof in the preparation of a medicament, comprising: In the formula, R 1 is H and R 2 But, CH 2 OH or R 1 But, CH 2 OH and R 2 is H, and R 3 But (CH 2 ) n R 4 wherein n is 1 or 2, and R 4 cyclohexyl, cyclohexylmethyl, phenylethyl, 4-phenylcyclohexyl, spiro[2.5]octan-6-yl, spiro[3.5]nonan-7-yl, spiro[4.5]decan-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]decan-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-(cyclohexylcarbamoyl)piperidin-4-yl, 1-(cyclohexylcarbamothioyl)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazetidin-3-yl, 2-(thiophen-2-yl)methyl, or 2-(thiophen-3-yl)methyl, with one or more of F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoropropan-2-yl, methoxymethyl, C 1-5 Alkoxy, CHF 2 , C.F. 2 CH 3 , and / or CF 3 or R 3 pyrrolidin-1-yl, piperidin-1-yl, 4-morpholino, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, F, Cl, C 1-6 Alkyl, cyclopropyl, propen-2-yl, OCH 3 , and / or CF 3 or phenylethyl optionally substituted with one to a maximum of the following substituents: R 3 On the formyl group, C 1-6 Alkyl, C 3-7 (1-formylpiperidin-4-yl)methyl substituted with one of cycloalkyl, phenyl, thiophen-3-yl, phenylmethyl, or cyclopentylmethyl; 1-6 Alkyl, OCH 3 , and / or CF 3 or R 3 but, Wherein R 5 is selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, thiophen-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, and one or more of F, Cl, C 1-6 Alkyl, C 1-6 Alkoxy, OCF 3 , and / or CF 3 each optionally substituted with one to a maximum of However, R 1 H and R 2 CH 2 In the case of OH, 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 R 1 CH 2 OH and R 2 If H, then R 3 is not phenylethyl, 3-phenylpropyl, (R)-2-phenylpropyl, or (S)-2-phenylpropyl; The drug is used for inhibiting GBA2, reducing the level of GBA2 enzyme activity, treating a condition regulated by GBA2, treating a neurological disease, treating a lysosomal storage disease, or treating a liver disease.

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