Non-lysosomal glucosylceramidase inhibitors and uses thereof

Abstract

The present invention provides a compound for inhibiting glucosylceramidase, a prodrug of the compound, and a pharmaceutical composition comprising the compound or the prodrug of the compound.

Description

Technical Field

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

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

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

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

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

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

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

[0008]

[0009] Among them, R 1 It can be (CH2) n R 2 , where n can be 1, 2, or 3, and R 2It can be cyclohexyl, phenyl, thiophen-2-yl, thiophen-3-yl, pyridin-2-yl, adamantyl, 2,3-dihydro-1H-inden-2-yl, 1,2,3,4-tetrahydronaphthalen-2-yl, spiro[2.5]oct-6-yl, spiro[3.5]non-7-yl, spiro[4.5]dec-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]dec-8-yl, (benzo[d][1,3]dioxol-5-yl)methyl, (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl, 1-cyclohexylazetidin-3-yl, Each of which is optionally replaced by F, Cl, C 1-6 Alkyl, C 2-6 alkenyl, cyclopropyl, difluoromethyl, 1,1-difluoroethyl-1-yl, 2-fluoropropyl-2-yl, methoxymethyl, OCF3, CF3, phenyl, pyrrolidin-1-yl, piperidin-1-yl, 4-morpholinyl, C 1-6 substituted by one or more substituents from alkoxy, 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, and / or 3,5-dimethyl-1H-pyrazol-4-yl;

[0010] Among them, R 3 Can be C 1-6 alkyl, phenyl, pyridin-2-yl, pyridin-3-yl, benzo[d]thiazol-2-yl, cyclohexylmethylsulfonyl or cyclohexylcarboxamido, each of which is optionally substituted with F, Cl, C 1-6 Alkyl, C 2-6 Alkenyl, cyclopropyl, C 1-6 One or more substituents in alkoxy, OCF3, and / or CF3 are substituted from one to the maximum number; and

[0011] Among them, R 4 Can be C 1-6 Alkyl, C 3-7 cycloalkyl, phenyl, thien-3-yl, phenylmethyl or cyclopentylmethyl, each of which is optionally substituted with F, C 1-6 Alkyl, OCH3, and / or CF3 are substituted with one or more substituents to the maximum number; and

[0012] And, where m can be 1 or 2;

[0013] And, where R 5It can be phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, thien-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, phenylcarbonyl, thiazol-2-yl, benzo[d]oxazol-2-yl or benzo[d]thiazol-2-yl, each of which is optionally replaced by F, Cl, C 1-6 Alkyl, C 1-6 One or more substituents in alkoxy, OCF3 and / or CF3 are substituted from one to the maximum number;

[0014] The condition is R 1 Not benzyl or 3-phenylpropyl.

[0015] In an alternative embodiment, the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0016]

[0017] Among them, R 1 It can be (CH2) n R 2 , where n can be 1 or 2, and R 2 It can be cyclohexyl, cyclohexylmethyl, phenethyl, 4-phenylcyclohexyl, 4-(trifluoromethoxy)cyclohexyl, spiro[2.5]oct-6-yl, spiro[3.5]non-7-yl, spiro[4.5]dec-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]dec-8-yl, 1,2,3,4-tetrahydronaphthalen-2-yl, 2,3-dihydro-1H-inden-2-yl, (adamantyl)methyl, (pyridin-2-yl)methyl, (benzo[d][1,3]dioxol-5-yl)methyl, (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl )methyl, ([1,1'-biphenyl]-4-yl)methyl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, 1-(pyridin-3-yl)piperidin-4-yl, 1-(pyridin-2-yl)piperidin-4-yl, 1-(benzo[d]thiazol-2-yl)piperidin-4-yl, 1-(cyclohexylcarboxamido)piperidin-4-yl, 1-(cyclohexylmethylsulfamido)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazetidin-3-yl, thiophen-2-yl, 2-(thiophen-2-yl)methyl or 2-(thiophen-3-yl)methyl, each of which is optionally substituted with F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, difluoromethyl, 1,1-difluoroethyl-1-yl, 2-fluoroprop-2-yl, methoxymethyl, C 1-6 One or more substituents in the alkoxy group and / or CF3 are substituted by one to the maximum number; or

[0018] R 1It may be a benzyl group, which is replaced by one or more F, Cl, C 1-6 Alkyl, phenyl, pyrrolidin-1-yl, piperidin-1-yl, C 1-6 One or more substituents in alkoxy, cyclopropylmethoxy, phenoxy and / or CF3 are substituted by one to the maximum number; or

[0019] R 1 It can be phenethyl, optionally substituted with one or more of pyrrolidin-1-yl, piperidin-1-yl, 4-morpholinyl, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, F, Cl, C 1-6 Alkyl, cyclopropyl, propen-2-yl, OCH3 and / or CF3 are substituted by one or more substituents to the maximum number; or

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

[0021] R 1 Can be Among them, R 6 The phenyl group may be selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, thien-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, phenylcarbonyl, thiazol-2-yl, benzo[d]oxazol-2-yl and benzo[d]thiazol-2-yl, each of which is optionally replaced by F, Cl, C 1-6 Alkyl, C 1-6 One or more substituents in alkoxy, OCF3 and / or CF3 are substituted from one to the maximum number;

[0022] The condition is R 1 Not benzyl or 3-phenylpropyl.

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

[0024]

[0025] Among them, R7 and R 8 Can be independently selected from the group consisting of: H, F, Cl, C 1-6 alkyl, OCH3, phenyl, cyclopropyl, vinyl, methoxymethyl, difluoromethyl, 1,1-difluoroethyl-1-yl, 2-fluoroprop-2-yl and / or CF3. In some embodiments, R 7 Can be H, and R 8 Can be CF3, difluoromethyl, 1,1-difluoroethyl-1-yl, 2-fluoroprop-2-yl, isopropyl or tert-butyl. In some embodiments, R 7 It can be CF3, difluoromethyl, 1,1-difluoroethyl-1-yl, 2-fluoroprop-2-yl, isopropyl or tert-butyl, R 8 It can be H.

[0026] In an alternative embodiment, the present invention provides a compound represented by formula (Ib) or a pharmaceutically acceptable salt thereof:

[0027]

[0028]

[0029] Among them, R 7 and R 8 Can be independently selected from the group consisting of: H, F, Cl, C 1-6 Alkyl, OCH3, phenyl, cyclopropyl, vinyl, methoxymethyl, difluoromethyl, 1,1-difluoroethyl-1-yl, 2-fluoroprop-2-yl and / or CF3.

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

[0031]

[0032] Among them, R 9 , R 10 and R 11 May be independently selected from the group consisting of pyrrolidin-1-yl, piperidin-1-yl, 4-morpholinyl, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, H, F, Cl, C 1-6 alkyl, cyclopropyl, propen-2-yl, OCH3 and / or CF3. In some embodiments, R 9 , R 10 and R11 and may be independently selected from the group consisting of H, F, Cl, tetrahydro-2H-pyran-4-yl, 4-morpholinyl, pyrrolidin-1-yl, and piperidin-1-yl.

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

[0034]

[0035] Among them, R 9 , R 10 and R 11 Can be independently selected from the group consisting of: H, F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoroprop-2-yl, methoxymethyl, C 1-6 Alkoxy, and / or CF3, provided that R 9 , R 10 and R 11 At least one of them is not H.

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

[0037]

[0038] Among them, R 9 , R 10 and R 11 Can be independently selected from the group consisting of: H, F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoroprop-2-yl, methoxymethyl, C 1-6 Alkoxy, and / or CF3, in some embodiments, R 9 , R 10 and R 11 May be independently selected from the group consisting of: H, F and CF3.

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

[0040]

[0041] Among them, R 12 Can be selected from the group consisting of: C 1-6 Alkyl, C 3-7 cycloalkyl, phenyl, thien-3-yl, benzyl or cyclopentylmethyl, each of which is optionally substituted with F, C 1-6 One or more substituents in the alkyl group, OCH3 and / or CF3 are substituted from one to the maximum number.

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

[0043]

[0044] Among them, R 13 The phenyl group may be selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, thien-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl or phenylcarbonyl, each of which is optionally substituted with F, Cl, C 1-6 Alkyl, C 1-6 One or more substituents in alkoxy, OCF3 and / or CF3 replace one to the maximum number. In some embodiments, R 13 It can be selected from: 2-(trifluoromethyl)phenyl, 2-(trifluoromethyl)pyridin-3-yl, 3-(trifluoromethyl)pyridin-2-yl, 4-(trifluoromethyl)pyridin-2-yl, 5-(trifluoromethyl)pyridin-3-yl, 6-(trifluoromethyl)pyridin-2-yl, 4-(trifluoromethyl)pyrimidin-5-yl and 4-(trifluoromethyl)thiazol-2-yl.

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

[0046]

[0047] Among them, R 13 The phenyl group may be selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, thien-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl or phenylcarbonyl, each of which is optionally substituted with F, Cl, C 1-6 Alkyl, C 1-6 One or more substituents in alkoxy, OCF3 and / or CF3 replace one to the maximum number. In some embodiments, R 13 It can be selected from: 2-(trifluoromethyl)phenyl, 2-(trifluoromethyl)pyridin-3-yl, 3-(trifluoromethyl)pyridin-2-yl, 4-(trifluoromethyl)pyridin-2-yl, 5-(trifluoromethyl)pyridin-3-yl, 6-(trifluoromethyl)pyridin-2-yl, 4-(trifluoromethyl)pyrimidin-5-yl and 4-(trifluoromethyl)thiazol-2-yl.

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

[0049]

[0050] Among them, R 13 The phenyl group may be selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, thien-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl or phenylcarbonyl, each of which is optionally substituted with F, Cl, C 1-6 Alkyl, C 1-6 One or more substituents in alkoxy, OCF3 and / or CF3 replace one to the maximum number. In some embodiments, R 13 It can be selected from: 2-(trifluoromethyl)phenyl, 2-(trifluoromethyl)pyridin-3-yl, 3-(trifluoromethyl)pyridin-2-yl, 4-(trifluoromethyl)pyridin-2-yl, 5-(trifluoromethyl)pyridin-3-yl, 6-(trifluoromethyl)pyridin-2-yl, 4-(trifluoromethyl)pyrimidin-5-yl and 4-(trifluoromethyl)thiazol-2-yl.

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

[0052]

[0053] Among them, R 13 The phenyl group may be selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, thien-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl or phenylcarbonyl, each of which is optionally substituted with F, Cl, C 1-6 Alkyl, C 1-6 One or more substituents in alkoxy, OCF3 and / or CF3 replace one to the maximum number. In some embodiments, R 13 It can be selected from: 2-(trifluoromethyl)phenyl, 2-(trifluoromethyl)pyridin-3-yl, 3-(trifluoromethyl)pyridin-2-yl, 4-(trifluoromethyl)pyridin-2-yl, 5-(trifluoromethyl)pyridin-3-yl, 6-(trifluoromethyl)pyridin-2-yl, 4-(trifluoromethyl)pyrimidin-5-yl and 4-(trifluoromethyl)thiazol-2-yl.

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

[0055]

[0056] Among them, R 14 , R 15 and R 16 Can be independently selected from the group consisting of: H, F, Cl, C 1-6 Alkyl, phenyl, pyrrolidin-1-yl, piperidin-1-yl, C1-6 alkoxy, cyclopropylmethoxy, phenoxy and / or CF3, provided that R 14 , R 15 and R 16 At least one of them is not H.

[0057] In alternative embodiments, the compound may be a prodrug; the compound may inhibit non-lysosomal glucosylceramidase (GBA2); the compound may inhibit GBA2 (eg, mammalian GBA2); the compound may inhibit wild-type GBA2; or the compound may inhibit mutant GBA2.

[0058] In alternative embodiments, compounds of Formula (I)-(Ia)-(Ib)-(Ic)-(Id)-(Ie)-(If)-(Ig)-(Ih)-(Ii)-(Ij) or (Ik)-(Ik) may exhibit enhanced selectivity and / or permeability.

[0059] In alternative embodiments, compounds of Formula (Ia)-(Ib)-(Ic)-(Id)-(Ie)-(If)-(Ig)-(Ih)-(Ii)-(Ij) or (Ik)-(Ik) may exhibit enhanced selectivity and / or permeability.

[0060] In alternative embodiments, compounds of Formula (Ia)-(Ic)-(Ie)-(Ig)-(Ih)-(Ii)-(Ij) or (Ik)-(Ik) may exhibit enhanced selectivity and / or permeability.

[0061] In alternative embodiments, compounds of Formula (Ia), Formula (Ic), Formula (Ie), Formula (Ig), Formula (Ih), Formula (Ii), Formula (Ij) or Formula (Ik) may exhibit enhanced selectivity. In alternative embodiments, compounds according to Formula (Ia) may exhibit enhanced selectivity. In alternative embodiments, compounds according to Formula (Ic) may exhibit enhanced selectivity. In alternative embodiments, compounds according to Formula (Ie) may exhibit enhanced selectivity. In alternative embodiments, compounds according to Formula (Ig) or Formula (Ih) may exhibit enhanced selectivity. In alternative embodiments, compounds according to Formula (Ii) or Formula (Ij) may exhibit enhanced selectivity. In alternative embodiments, compounds according to Formula (Ik) may exhibit enhanced selectivity.

[0062] In alternative embodiments, when administered in vivo, compounds of Formula (Ia), (Ic), (Ie), (Ig), (Ih), (Ii), (Ij), or (Ik) can achieve higher brain concentrations. In alternative embodiments, when administered in vivo, compounds according to Formula (Ia) can achieve higher brain concentrations. In alternative embodiments, when administered in vivo, compounds according to Formula (Ic) can achieve higher brain concentrations. In alternative embodiments, when administered in vivo, compounds according to Formula (Ie) can achieve higher brain concentrations. In alternative embodiments, when administered in vivo, compounds according to Formula (Ig) or (Ih) can achieve higher brain concentrations. In alternative embodiments, when administered in vivo, compounds according to Formula (Ii) or (Ij) can achieve higher brain concentrations. In alternative embodiments, when administered in vivo, compounds according to Formula (Ik) can achieve higher brain concentrations.

[0063] In an alternative aspect, the present invention provides a pharmaceutical composition comprising a compound according to the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0064] In alternative embodiments, the present invention provides a method for inhibiting GBA2 in a subject in need thereof, or a method for treating a neurological disease, a lysosomal storage disease, or a liver disease in a subject in need thereof, by administering to the subject an effective amount of a compound of formula (I) as described herein, including any one or more of formulas (Ia)-(Ik), or a pharmaceutically acceptable salt thereof. The neurological disease may be, but is not limited to, Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), addiction, anxiety, argyrophilic grain dementia, ataxia-telangiectasia (AT), attention-deficit / hyperactivity disorder (ADHD), autism spectrum disorder (ASD), Becker muscular dystrophy (BMD), bipolar disorder (BD), Blunt disease, cerebellar ataxia, Charcot-Marie-Tooth disease (CMT), chronic fatigue syndrome, corticobasal degeneration (CBD), dementia pugilistica, dementia with Lewy bodies (DLB), DeGelis-Sotas disease, diffuse neurofibrillary tangles with calcifications, Down syndrome, Duchenne muscular dystrophy (DMD), epilepsy, essential tremor (ET), familial British dementia, familial Danish dementia dementia), fibromyalgia, frontotemporal dementia linked to chromosome 17 with Parkinsonism (FTDP-17), Friedreich's ataxia, Gerstmann-Straussler-Scheinker disease, glaucoma, Guadeloupean parkinsonism, Guillain-Barré syndrome, Hallervorden-Spatz disease (neurodegeneration with brain iron accumulation type 1), insomnia, Lambert-Eaton myasthenic syndrome (LEMS), major depressive disorder (MDD), migraine, mild cognitive impairment (MCI), multi-infarct dementia, multiple system atrophy (MSA), myasthenia gravis, myotonic dystrophy (including DM1 and DM2), neuronal ceroid lipofuscinosis (including 1, 2, 3, 4, 5, 6, 7, 8 , 9, and 10), neuropathies (including peripheral neuropathy, autonomic neuropathy, neuritis, diabetic neuropathy), oculopharyngeal muscular dystrophy, pain, pallidopontinonigral degeneration, Guam Parkinsonism-dementia complex, Pick's disease (PiD), postencephalitic parkinsonism (PEP), primary lateral sclerosis (PLS), prion diseases (including Creutzfeldt-Jakob disease (CJD), variant Creutzfeldt-Jakob disease (vCJD), fatal familial insomnia, and kuru), progressive subcortical gliosis, progressive supranuclear palsy (PSP), Richardson's syndromesyndrome), schizophrenia, seizures, spinal cord injury, spinal muscular atrophy (SMA), spinocerebellar ataxia (including types 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 28, and 29), stroke, subacute sclerosing panencephalitis, dementia with entanglement, tardive dyskinesia, Tourette syndrome (TS), vascular dementia, or Wilson disease.

[0065] 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.

[0066] The liver disease may be nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), Alagille syndrome, alcohol-related liver disease, alpha-1 antitrypsin deficiency, autoimmune hepatitis, autoimmune cholangitis, benign liver tumor, biliary atresia, cirrhosis, Crigler-Najjar syndrome, drug-induced liver injury (DILI), galactosemia, Gilbert syndrome, hemochromatosis, hepatic encephalopathy, hepatocellular carcinoma (HCC), intrahepatic cholestasis of pregnancy (ICP), lysosomal acid lipase deficiency (LAL-D), liver cyst, liver cancer, neonatal jaundice, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), Reye syndrome, type I glycogen storage disease, or viral hepatitis (including types A, B, C, D, and E).

[0067] In an alternative embodiment, the present invention provides a method for treating a neurological disease in a subject in need thereof, the method being by administering to the subject an effective amount of a compound of any one or more of Formula (Ia), (Ic), (Ie), (Ig), (Ih), (Ii), (Ij), or (Ik) of the present invention, or a pharmaceutically acceptable salt thereof. In an alternative embodiment, the present invention provides a method for treating a neurological disease in a subject by administering to a subject in need thereof an effective amount of a compound as shown in Formula (Ia) of the present invention, or a pharmaceutically acceptable salt thereof. In an alternative embodiment, the present invention provides a method for treating a neurological disease in a subject by administering to a subject in need thereof an effective amount of a compound as shown in Formula (Ic) of the present invention, or a pharmaceutically acceptable salt thereof. In an alternative embodiment, the present invention provides a method for treating a neurological disease in a subject by administering to a subject in need thereof an effective amount of a compound as shown in Formula (Ig) of the present invention, or a pharmaceutically acceptable salt thereof. In an alternative embodiment, the present invention provides a method for treating a neurological disease in a subject by administering to a subject in need thereof an effective amount of a compound as shown in Formula (Ih) of the present invention, or a pharmaceutically acceptable salt thereof. In an alternative embodiment, the present invention provides a method for treating a neurological disease of a subject in need by administering an effective amount of a compound shown in formula (Ii) of the present invention or a pharmaceutically acceptable salt thereof to a subject in need thereof. In an alternative embodiment, the present invention provides a method for treating a neurological disease of a subject in need thereof by administering an effective amount of a compound shown in formula (Ij) of the invention or a pharmaceutically acceptable salt thereof to a subject in need thereof. In an alternative embodiment, the present invention provides a method for treating a neurological disease of a subject in need thereof by administering an effective amount of a compound shown in formula (Ik) of the present invention or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0068] In alternative embodiments, administration can reduce the level of GBA2 enzymatic activity in a subject. In alternative embodiments, administration can modulate the level of glucosylceramide and / or glycosphingolipids in a subject. In alternative embodiments, administration can increase the level of glucosylceramide in a subject. In alternative embodiments, administration can increase the level of ganglioside GM1 in a subject. In alternative embodiments, the administration can modulate the level of ceramide and / or sphingosine and / or sphingosine-1-phosphate (S1P) in a subject. The subject can be human.

[0069] In an alternative aspect, the present invention provides the use of an effective amount of a compound of formula (I), including any one or more of formulas (Ia)-(Ik), or a pharmaceutically acceptable salt thereof, as described herein, in the preparation of a medicament. The medicament can be used to inhibit GBA2, to treat conditions regulated by GBA2, or to treat neurological diseases, lysosomal storage diseases, or liver diseases.

[0070] This summary does not necessarily describe all features of the invention. DETAILED DESCRIPTION

[0071] Detailed description

[0072] The present invention provides, in part, compounds for inhibiting non-lysosomal glucosylceramidase (GBA2) and their uses.

[0073] "Non-lysosomal glucosylceramidase" or "GBA 2" refers to a non-lysosomal membrane-associated enzyme (EC 3.2.1.45) with glucosylceramidase activity located on the cytoplasmic side of the ER and Golgi membranes that catalyzes the hydrolytic cleavage of the β-glucosidic bond of the glycolipid glucosylceramide. Alternative names for GBA2 include: NLGase, glucosylceramidase β2, β-glucocerebrosidase 2, β-glucosidase 2, glucosylceramidase 2, bile acid β-glucosidase, "glucosidase, β-(bile acid) 2", KIAA1605, DKFZp762K054, SPG46, and AD035. In some embodiments, GBA2 can be mammalian GBA2, such as rat, mouse, or human GBA2. GBA2 can be wild-type GBA2 or mutant GBA2. In some embodiments, GBA2 can be wild-type mammalian GBA2, such as rat, mouse, or human wild-type GBA2. In some embodiments, GBA2 can be a mutant mammalian GBA2, such as a rat, mouse, or human mutant GBA2. In some embodiments, GBA2 can have a sequence as set forth in any of the following accession numbers: Q9HCG7, Q69ZF3, D3DRP2, Q5TCV6, Q96A51, Q96LY1, Q96SJ2, Q9H2L8, Q5M868, or O16581. In alternative embodiments, GBA2 can have an alternative splice isoform sequence as set forth in any of the following accession numbers: Q9HCG7-1, Q9HCG7-2, or Q9HCG7-3. In alternative embodiments, GBA2 may be encoded by the sequence set forth in any of the following accession numbers: NP_065995.1, NP_001317589.1, NP_766280.2, NP_001013109.2, NM_020944, NM_172692, NM_001330660, XM_011517973, XP_005251583.1, XP_006716872.1, In an alternative embodiment, human GBA2 may have the sequence listed below:

[0074]

[0075]

[0076] In an alternative embodiment, human GBA2 may have a nucleic acid sequence encoding a nucleic acid molecule having the sequence shown in SEQ ID NO:1.

[0077] In some embodiments, one or more compounds according to the present invention can inhibit the activity of GBA2, such as inhibiting the ability to cleave glucose from glucosylceramide or inhibiting the ability to cleave glucose from a suitable substrate molecule, such as 4-methylumbelliferyl-β-D-glucopyranoside. "Inhibit," "inhibition," or "inhibiting" means that the activity of GBA2 is reduced by any value between about 10% and about 90%, or by any value between about 30% and about 60%, or by more than about 100%, or by about 1-fold, 2-fold, 5-fold, 10-fold, or more, compared to a reference sample or compound, or compared to wild-type GBA2. It should be understood that inhibition does not require complete inhibition. In some embodiments, the inhibition can be temporary, e.g., lasting from 5 minutes to 60 minutes, from 1 hour to 5 hours, from 1 hour to 12 hours, from 1 hour to 24 hours, from 24 hours to 48 hours, from 1 day to 2 days, from 1 day to 5 days, from 1 day to 7 days, from 1 day to 14 days, from 1 day to 28 days, or any specific time within any of these ranges, e.g., 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 60 minutes, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 1.5 days, 2 days, 2.5 days, 3 days, 3.5 days, 4 days, 4.5 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days or 14 days. In some embodiments, the inhibition can be local. For example, one or more compounds according to the present invention can inhibit GBA2 in a specific cellular compartment, such as the endoplasmic reticulum (ER) or the Golgi apparatus; or one or more compounds according to the present invention can inhibit GBA2 in a specific tissue type, such as the brain or liver.

[0078] In some embodiments, one or more compounds according to the present invention may specifically bind to GBA2. In alternative embodiments, one or more compounds according to the present invention may specifically bind to the active site of GBA2. In some embodiments, one or more compounds according to the present invention that specifically bind to the active site of GBA2 may also inhibit the activity of GBA2. In alternative embodiments, one or more compounds according to the present invention may specifically bind to human non-lysosomal glucosylceramidase (GBA2) but not human lysosomal glucosylceramidase (GCase) and / or human cytosolic glucosylceramidase (GBA3). In alternative embodiments, one or more compounds according to the present invention may specifically bind to human non-lysosomal glucosylceramidase (GBA2) but not human glucosylceramide synthase (GCS). In alternative embodiments, one or more compounds according to the present invention may specifically bind to human non-lysosomal glucosylceramidase (GBA2) but not intestinal α-glucosidase, where the intestinal α-glucosidase may be sucrase-isomaltase or maltase-glucoamylase. By "specifically binds" is meant that the compound binds to GBA2 but does not substantially bind to other molecules in a sample, such as lactase, sucrase, maltase, isomaltase, sucrase-isomaltase, glucoamylase, maltase-glucoamylase, glucosylceramide synthase, α-glucosidase II, ER α-glucosidase, intestinal α-glucosidase, glycogen phosphorylase, acid α-glucosidase, β-hexosaminidase, acetylglucosaminase (O-GlcNAcase), GCase, or GBA3. By "substantially no binding" is meant a binding specificity within the range of about 5-fold to about 100,000-fold, or about 10-fold to about 100,000-fold, or within the range of about 100-fold to about 100,000-fold, or within the range of about 1000-fold to about 100,000-fold, or at least about 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 200-fold, 500-fold, 1000-fold, 1500-fold, 2000-fold, 2500-fold, 3000-fold, 3500-fold, 4000-fold, 4500-fold, 5000-fold, 6000-fold, 7000-fold, 10,000-fold, 25,000-fold, 50,000-fold, 75,000-fold, or any value within or around the recited ranges, wherein "binding specificity" refers to the ratio of the respective binding constants, i.e., Ki (其他分子) / Ki (GBA2) , or respective IC 50 The ratio, IC 50(其他分子) / IC 50(GBA2)Examples of compounds that exhibit enhanced binding specificity include, but are not limited to, compounds of Examples 1, 2, 3, 7, 9, 10, 11, 12, 13, 14, 15, 18, 20, 21, 29, 30, 31, 33, 34, 35, 36, or 38. In some embodiments, one or more compounds of the invention may exhibit enhanced binding specificity or enhanced selectivity 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 some embodiments, "enhanced binding 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%, such as about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, or an increase by about 1-fold to about 100,000-fold, or about 5-fold to about 100,000-fold, or about 10-fold to about 100,000-fold, or within the range of about 100-fold to about 100,000-fold, or about 1000-fold to about 100,000-fold. In some embodiments, the present invention provides an improvement in the amount of the active ingredient in the pharmaceutical composition or the pharmaceutical composition to an amount greater than or equal to 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, 300 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 said range, or more, compared to an appropriate reference compound.

[0079] In alternative embodiments, one or more compounds of the present invention may specifically bind to human non-lysosomal glucosylceramidase (GBA 2) rather than rat intestinal α-glucosidase, wherein the rat intestinal α-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 α-glucosidase 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 some embodiments, "does not substantially inhibit" means a percent inhibition of less than about 30% in an assay described below for inhibition of rat intestinal glucosidase. In some embodiments, "does not substantially inhibit" means a percent inhibition of less than about 20% in an assay described below for inhibition of rat intestinal glucosidase. In some embodiments, "does not substantially inhibit" means a percent inhibition of less than about 10% in an assay described below for inhibition of rat intestinal glucosidase.

[0080] In some embodiments, one or more compounds of the present invention can inhibit the cleavage of GBA2 from glucosylceramide to glucose. In some embodiments, one or more compounds of the present invention can inhibit the aggregation of alpha-synuclein and / or inhibit the formation of Lewy bodies. "Inhibit," "inhibition," or "inhibiting" means a reduction of any value between about 10% and about 90%, or any value between about 30% and about 60%, or greater than about 100%, or a reduction of about 1-fold, 2-fold, 5-fold, 10-fold, or more, compared to a reference sample or compound, or to wild-type GBA2. It should be understood that inhibition does not require complete inhibition. In some embodiments, inhibition can be temporary.

[0081] In some embodiments, one or more compounds of the present invention can reduce inflammation in the CNS. In some embodiments, one or more compounds of the present invention can reduce alpha-synuclein aggregation and / or Lewy body formation. "Reduce (decreasing)" or "reduce (decrease)" means compared to a reference sample or compound, reducing any value between about 5% and about 90%, or any value between about 30% and about 60%, or more than about 100%, or reducing about 1 times, 2 times, 5 times, 10 times, 15 times, 25 times, 50 times, 100 times or more.

[0082] In some embodiments, one or more compounds of the present invention may increase glucosylceramide levels. In some embodiments, one or more compounds of the present invention may increase glycosphingolipid levels. In some embodiments, one or more compounds of the present invention may increase GM1 ganglioside levels. "Elevating" or "enhancing" or "increasing" means an increase of any value between about 5% and about 90%, or any value between about 30% and about 60%, or more than about 100%, or an increase of about 1-fold, 2-fold, 5-fold, 10-fold, 15-fold, 25-fold, 50-fold, 100-fold or more, as compared to a reference sample. In some embodiments, one or more compounds according to the present invention may increase glucosylceramide levels and / or glycosphingolipid levels and / or GM1 ganglioside levels in the brain.

[0083] In some embodiments, one or more compounds of the present invention can increase GCase activity levels and / or GCase protein levels in vivo and can be effective in treating conditions requiring or responsive to increased GCase activity. In some embodiments, one or more compounds of the present invention can increase GCase activity levels and / or GCase protein levels in vivo specifically by interacting with GBA2 and can be effective in treating conditions requiring or responsive to increased GCase activity. "Elevating" or "enhancing" or "increasing" refers to an increase of about 5% to about 100%, for example, about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, or an increase of about 1-fold, 2-fold, 5-fold, 10-fold, 15-fold, 25-fold, 50-fold, 100-fold, or more, compared to a reference sample or compound, or compared to wild-type or mutant GCase.

[0084] In some embodiments, one or more compounds according to the present invention may exhibit enhanced permeability. Permeability can be assessed using a variety of standard experimental techniques, including but not limited to in situ perfusion, ex vivo tissue diffusion, in vitro cell monolayers (e.g., Caco-2 cells, MDCK cells, LLC-PK1 cells), and artificial cell membranes (e.g., PAMPA assay); for measuring effective permeability (P eff ) or apparent permeability (P app ) are reviewed, for example, by Volpe in AAPS Journal, 2010, 12(4), 670-678. In some embodiments, when the eff or P appOne or more of the compounds according to the present invention may exhibit enhanced permeability when tested in one or more of these assays. In some embodiments, compounds exhibiting enhanced permeability may exhibit greater oral absorption. In some embodiments, compounds exhibiting enhanced permeability may exhibit greater brain penetrance when administered in vivo. In some embodiments, compounds exhibiting enhanced permeability may achieve higher brain concentrations when administered in vivo. In some embodiments, compounds exhibiting enhanced permeability may exhibit higher brain / plasma concentration ratios when administered in vivo. In some embodiments, "enhanced permeability" means that the measured permeability is compared to a suitable reference compound such as, for example, (2R,3R,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol (NB-DNJ, miglustat) or (2R,3R,4R,5S)-1-(5-((3R,5R,7R)-adamantan-1-ylmethoxy)pentyl)-2-(hydroxymethyl)piperidine-3,4,5-triol (AMP-DNM, Genz-529648). eff or P app Any value between about 10% and about 100%, or any integer value between 10% and 100%, such as about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or more than 100%, or an increase of about 1-fold, 2-fold, 3-fold or more. In some embodiments, "enhanced permeability" means that the permeability of the cell is measured using an in vitro cell monolayer. app Measurable P in a suitable test app In some embodiments, "enhanced permeability" means that the permeability of the cell membrane is measured using an in vitro cell monolayer. app P in the appropriate test app Value greater than 2x10 -6 In alternative embodiments, "enhanced permeability" means the permeability measured using an in vitro cell monolayer. app Suitable assays for P app Value is 2x10 -6 cm / s to 40x10 -6In some embodiments, "higher brain concentration" refers to a higher brain concentration when the compound is administered in vivo compared to a suitable reference compound such as, for example, (2R,3R,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol (NB-DNJ, miglustat) or (2R,3R,4R,5S)-1-(5-((3R,5R,7R)-adamantan-1-ylmethoxy)pentyl)-2-(hydroxymethyl)piperidine-3,4,5-triol. (AMP-DNM, Genz-529648), the measured brain concentration is increased by any value between about 10% and about 100%, or any integer value between about 10% and about 100%, such as about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, or by about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, or 50-fold or more, compared to AMP-DNM, Genz-529648.

[0085] A "reference compound" or "control" can be a carbohydrate mimetic iminosugar described in the literature as a GBA2 inhibitor. Examples of reference compounds or controls that are GBA2 inhibitors include, but are not limited to, (2R,3R,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol (NB-DNJ, miglustat), (2R,3R,4R,5S)-1-(5-((3R,5R,7R)-adamantan-1-ylmethoxy)pentyl)-2-(hydroxymethyl)piperidine-3,4,5-triol (AMP-DNM, Genz-529648). 26

[0086] In some embodiments, the present invention provides compounds generally described by Formula (I), including any one or more of Formulas (Ia)-(Ik), and salts, prodrugs, and enantiomeric forms thereof:

[0087]

[0088] As shown in formula (I): 1 It can be (CH2) n R 2 , where n can be 1, 2, or 3, and R 2It can be cyclohexyl, phenyl, thiophen-2-yl, thiophen-3-yl, pyridin-2-yl, adamantyl, 2,3-dihydro-1H-inden-2-yl, 1,2,3,4-tetrahydronaphthalen-2-yl, spiro[2.5]oct-6-yl, spiro[3.5]non-7-yl, spiro[4.5]dec-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]dec-8-yl, (benzo[d][1,3]dioxol-5-yl)methyl, (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl, 1-cyclohexylazetidin-3-yl, Each of which is optionally replaced by F, Cl, C 1-6 Alkyl, C 2-6 alkenyl, cyclopropyl, difluoromethyl, 1,1-difluoroethyl-1-yl, 2-fluoropropyl-2-yl, methoxymethyl, OCF3, CF3, phenyl, pyrrolidin-1-yl, piperidin-1-yl, 4-morpholinyl, C 1-6 Alkoxy, 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, and / or 3,5-dimethyl-1H-pyrazol-4-yl, substituted by one or more substituents up to the maximum number;

[0089] Among them, R 3 Can be C 1-6 alkyl, phenyl, pyridin-2-yl, pyridin-3-yl, benzo[d]thiazol-2-yl, cyclohexylmethylsulfonyl or cyclohexylcarboxamido, each of which is optionally substituted with F, Cl, C 1-6 Alkyl, C 2-6 Alkenyl, cyclopropyl, C 1-6 One or more substituents in alkoxy, OCF3, and / or CF3 are substituted from one to the maximum number; and

[0090] Among them, R 4 Can be C 1-6 Alkyl, C 3-7 cycloalkyl, phenyl, thien-3-yl, benzyl or cyclopentylmethyl, each of which is optionally substituted with F, C 1-6 Alkyl, OCH3, and / or CF3 are substituted with one or more substituents to the maximum number; and

[0091] And, where m can be 1 or 2;

[0092] And, where R 5It can be phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, thien-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, phenylcarbonyl, thiazol-2-yl, benzo[d]oxazol-2-yl or benzo[d]thiazol-2-yl, each of which is optionally replaced by F, Cl, C 1-6 Alkyl, C 1-6 One or more substituents in alkoxy, OCF3 and / or CF3 are substituted from one to the maximum number;

[0093] The condition is R 1 Not benzyl or 3-phenylpropyl.

[0094] In some embodiments, as shown in formula (I): R 1 It can be (CH2) n R 2 , where n can be 1, 2, or 3, and R 2 It can be cyclohexyl, phenyl, thiophen-2-yl, thiophen-3-yl, pyridin-2-yl, adamantyl, 2,3-dihydro-1H-inden-2-yl, 1,2,3,4-tetrahydronaphthalen-2-yl, spiro[2.5]oct-6-yl, spiro[3.5]non-7-yl, spiro[4.5]dec-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]dec-8-yl, (benzo[d][1,3]dioxol-5-yl)methyl, (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl, 1-cyclohexylazetidin-3-yl, Each of which is optionally replaced by F, Cl, C 1-6 Alkyl, C 2-6 alkenyl, cyclopropyl, difluoromethyl, 1,1-difluoroethyl-1-yl, 2-fluoropropyl-2-yl, methoxymethyl, OCF3, CF3, phenyl, pyrrolidin-1-yl, piperidin-1-yl, 4-morpholinyl, C 1-6 Alkoxy, 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, and / or 3,5-dimethyl-1H-pyrazol-4-yl, substituted by one or more substituents to the maximum number; wherein R 3 Can be C 1-6 alkyl, phenyl, pyridin-2-yl, pyridin-3-yl, benzo[d]thiazol-2-yl, cyclohexylmethylsulfonyl or cyclohexylcarboxamido, each of which is optionally substituted with F, Cl, C 1-6 Alkyl, C 2-6 Alkenyl, cyclopropyl, C 1-6One or more substituents in alkoxy, OCF3, and / or CF3 are substituted from one to the maximum number; and wherein, R 4 Can be C 1-6 Alkyl, C 3-7 cycloalkyl, phenyl, thien-3-yl, benzyl or cyclopentylmethyl, each of which is optionally substituted with F, C 1-6 One or more substituents in alkyl, OCH3, and / or CF3 are substituted from one to the maximum number; and wherein m can be 1 or 2; and wherein R 5 It can be phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, thien-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, phenylcarbonyl, thiazol-2-yl, benzo[d]oxazol-2-yl or benzo[d]thiazol-2-yl, each of which is optionally replaced by F, Cl, C 1-6 Alkyl, C 1-6 One or more substituents in alkoxy, OCF3 and / or CF3 replace one to the maximum number; provided that R 1 Not benzyl or 3-phenylpropyl.

[0095] In some embodiments, as shown in formula (I): R 1 It can be (CH2) n R 2 , where n can be 1 or 2, and R 2 It can be cyclohexyl, cyclohexylmethyl, phenethyl, 4-phenylcyclohexyl, 4-(trifluoromethoxy)cyclohexyl, spiro[2.5]oct-6-yl, spiro[3.5]non-7-yl, spiro[4.5]dec-8-yl, (5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]dec-8-yl, 1,2,3,4-tetrahydronaphthalen-2-yl, 2,3-dihydro-1H-inden-2-yl, (adamantyl)methyl, (pyridin-2-yl)methyl, (benzo[d][1,3]dioxol-5-yl)methyl, (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl )methyl, ([1,1'-biphenyl]-4-yl)methyl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, 1-(pyridin-3-yl)piperidin-4-yl, 1-(pyridin-2-yl)piperidin-4-yl, 1-(benzo[d]thiazol-2-yl)piperidin-4-yl, 1-(cyclohexylcarboxamido)piperidin-4-yl, 1-(cyclohexylmethylsulfamido)piperidin-4-yl, 1-phenylpiperidin-4-yl, 1-cyclohexylazetidin-3-yl, thiophen-2-yl, 2-(thiophen-2-yl)methyl or 2-(thiophen-3-yl)methyl, each of which is optionally substituted with F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, difluoromethyl, 1,1-difluoroethyl-1-yl, 2-fluoroprop-2-yl, methoxymethyl, C1-6 Alkoxy, and / or one or more substituents in CF3 are substituted from one to the maximum number, provided that R 1 Not 3-phenylpropyl.

[0096] In some embodiments, R 1 It may be a benzyl group, which is replaced by one or more F, Cl, C 1-6 Alkyl, phenyl, pyrrolidin-1-yl, piperidin-1-yl, C 1-6 Alkoxy, cyclopropylmethoxy, phenoxy, and / or one or more substituents in CF3 are substituted by one to the maximum number, provided that R 1 Not benzyl.

[0097] In some embodiments, R 1 It can be phenethyl, optionally substituted with one or more of pyrrolidin-1-yl, piperidin-1-yl, 4-morpholinyl, cyclopropylmethoxy, (tetrahydrofuran-3-yl)oxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, phenoxy, (tetrahydrofuran-3-yl)methoxy, tetrahydro-2H-pyran-4-yl, 3,5-dimethylisoxazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, F, Cl, C 1-6 One or more substituents among alkyl, cyclopropyl, propen-2-yl, OCH3, and / or CF3 are substituted from one to the maximum number.

[0098] In some embodiments, R 1 It may be (1-formylpiperidin-4-yl)methyl, substituted on the formyl group by one of the following: C 1-6 Alkyl, C 3-7 cycloalkyl, phenyl, thien-3-yl, benzyl or cyclopentylmethyl, each of which is optionally substituted with F, C 1-6 One or more substituents in the alkyl group, OCH3 and / or CF3 are substituted from one to the maximum number.

[0099] In some embodiments, R 1 Can be Among them, R 6 The phenyl group may be selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, thien-3-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-2-yl, phenylcarbonyl, thiazol-2-yl, benzo[d]oxazol-2-yl and benzo[d]thiazol-2-yl, each of which is optionally replaced by F, Cl, C 1-6 Alkyl, C 1-6 One or more substituents in the alkoxy group, OCF3 and / or CF3 are substituted from one to the maximum number.

[0100] In some embodiments, R 1 It can be (CH2) n R 2 , where n can be 1, and R 2 It may be cyclohexyl or 1-phenylpiperidin-4-yl, each of which is optionally substituted with one or more of F, Cl, C 1-6 Alkyl, cyclopropyl, vinyl, 2-fluoroprop-2-yl, methoxymethyl, C 1-6 One or more substituents in the alkoxy group and / or CF3 are substituted from one to the maximum number.

[0101] In some embodiments, R 1It may be cyclohexylmethyl, (4,4-dimethylcyclohexyl)methyl, (4,4-difluorocyclohexyl)methyl, (4,4-dichlorocyclohexyl)methyl, (4-ethylcyclohexyl)methyl, ((1s,4S)-4-vinylcyclohexyl)methyl, ((1s,4S)-4-isopropylcyclohexyl)methyl, ((1r,4R)-4-isopropylcyclohexyl)methyl, 4-(tert-butyl)cyclohexyl)methyl, ((1s,4S)-4-(tert-butyl)cyclohexyl)methyl, ((1r,4R)-4-(tert-butyl)cyclohexyl)methyl, ((1s,4S)-4-(trifluoromethyl)cyclohexyl)methyl, ((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl, ((1s,4S)-4-( 2-(2-fluoropropyl)cyclohexyl)methyl, ((1r,4R)-4-(2-fluoropropyl)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]dec-8-yl)methyl, 2-cyclohexylethyl, 2-(4,4-difluorocyclohexyl)ethyl, 2-((1s,4S)-4-(trifluoromethyl)cyclohexyl)methyl cyclohexyl)ethyl, 2-((1r,4R)-4-(trifluoromethyl)cyclohexyl)ethyl, 2-(adamantan-1-yl)ethyl, 3-cyclohexylpropyl, phenethyl, 2-methylphenethyl, 2-methoxyphenethyl, 2-fluorophenethyl, 2-chlorophenethyl, 2,3-difluorophenethyl, 2,4-difluorophenethyl, 2,5-difluorophenethyl, 3,4-difluorophenethyl, 2-fluoro-4-methoxyphenethyl, 3-chloro-2-fluorophenethyl, 4-chloro-2-fluorophenethyl, 5-chloro-2-fluorophenethyl, 2,6-difluorophenethyl, 3-chloro-2,6-difluorophenethyl, 2,6-difluoro-4-(prop-1-en-2-yl)phenethyl, 2,6-difluoro-4-isopropylphenethyl, 2,6-difluoro-3 -isopropylphenethyl, 4-cyclopropyl-2,6-difluorophenethyl, 2,6-difluoro-4-(trifluoromethyl)phenethyl, 2,6-difluoro-4-(pyrrolidin-1-yl)phenethyl, 2,6-difluoro-4-(piperidin-1-yl)phenethyl, 2,6-difluoro-4-morpholinylphenethyl, 4-butoxy-2,6-difluorophenethyl, 4-(cyclopropylmethoxy)-2,6-difluorophenethyl, 4-((tetrahydrofuran-3-yl)oxy)phenethyl, 4-((tetrahydro-2H-pyran-3-yl)oxy)phenethyl, 4-((tetrahydro-2H-pyran-4-yl)oxy)phenethyl, 4-phenoxyphenethyl, 4-((tetrahydrofuran-3-yl)methoxy)phenethyl, (R)-2-phenylpropyl,(S)-2-phenylpropyl, 2-([1,1'-biphenyl]-4-yl)ethyl, 2-(3,5-difluoro-[1,1'-biphenyl]-4-yl)ethyl, 2-(benzo[d][1,3]dioxol-5-yl)ethyl, 2-(6-fluorobenzo[d][1,3]dioxol-5-yl)ethyl, 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl, 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl, 2-(thiophen-2-yl)ethyl, 2-(thiophen-3-yl)ethyl, 2-(pyridin-2-yl)ethyl, 3-(2-fluorophenyl)propyl, 3-(4-fluorophenyl)propyl, 3-(6-fluorophenyl)propyl 1-(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-(1-(4-methyl-2-piperidin-4-yl)methyl, (1-(1-(4-methyl-2-piperidin-4-yl)methyl), (1-(1-(4-methyl-2-piperidin-4-yl)methyl), (1-(1-(4-methyl-2-piperidin-4-yl)methyl), (1-(1-(4-methyl-2-piperidin-4-yl)methyl), (1-(1-(4-methyl-2-piperidin-4-yl)methyl), (1-(1-(1-methyl-2-piperidin-4-yl)methyl), (1-(1-(4-methyl-2-piperidin-4-yl)methyl), (1-(1-(1-methyl-2-piperidin-4-yl)methyl), (1-(1-(1-methyl-2-piperidin-4-yl)methyl), (1-(1-(1-methyl-2-piperidin-4-yl)methyl), (1-(1-(1-methyl-2-piperidin-4-yl)methyl), (1-(1-(1-methyl-2-piperidin-4-yl)methyl)), (1-(1-(1-methyl-2-piperidin-4-yl)methyl), (1-(1-(1-methyl-2-piperidin-4-yl)methyl)), (1-(1-(1-methyl-2-piperidin-4-yl)methyl) 4-yl)methyl, (1-(4-(trifluoromethyl)cyclohexylcarbonyl)piperidin-4-yl)methyl, (1-benzoylpiperidin-4-yl)methyl, (1-(3-(trifluoromethyl)benzoyl)piperidin-4-yl)methyl, (1-(2-phenylacetyl)piperidin-4-yl)methyl, (1-(thiophene-3-carbonyl)piperidin-4-yl)methyl, ((5S,8s)-3,3-dimethyl-2-oxaspiro[4.5]dec-8-yl)methyl, (1,2,3,4-tetrahydronaphthalen-2-yl)methyl, (2,3-dihydro-1H-inden-2-yl)methyl, 2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenethyl, (1-(pyridin-3-yl)piperidin-4-yl)methyl,(1-(cyclohexylcarboxamido)piperidin-4-yl)methyl, (1-(cyclohexylmethylsulfamido)piperidin-4-yl)methyl, (1-((1S,2R)-2-(trifluoromethyl)cyclohexyl)azetidin-3-yl)methyl, ((R)-1-phenylpyrrolidin-3-yl)methyl, ((R)-1-(o-tolyl)pyrrolidin-3-yl)methyl, ((R)-1-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl, ((S)-1-(2-(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) methyl, ((R)-1-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl, (R)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl, ((R)-1-(4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl, ((R)-1-(pyridin-3-yl)pyrrolidin-3-yl)methyl, ((R)-1-(4-methylpyridin-3-yl)pyrrolidin-3-yl)methyl, ((R)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl, ((R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl, ((R)-1-(2- 1-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl, ((R)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl, ((R)-1-(thiophen-3-yl)pyrrolidin-3-yl)methyl, ((R)-1-(benzo[d]thiazol-4-yl)pyrrolidin-3-yl)methyl, (S)-(1-(4-(trifluoromethyl)benzoyl)pyrrolidin-3-yl)methyl, ((R)-1-(o-tolyl)piperidin-3-yl)methyl, ((R)-1-(2-fluorophenyl)piperidin-3-yl)methyl, ((R)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl, ((R)-1-(6-(trifluoromethyl)pyridin-2-yl) 4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl, ((R)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl, 3-fluorophenethyl, 4-fluorophenethyl, 3,4-dichlorophenethyl, 3-(trifluoromethyl)phenethyl, 4-(trifluoromethyl)phenethyl, ((R)-1-(benzo[d]thiazol-2-yl)pyrrolidin-3-yl)methyl, ((R)-1-(2-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl, 4-(3,5-dimethylisoxazol-4-yl)-2,6-difluorophenethyl, 4-(3,5-dimethyl-1H-pyrazol-4-yl)-2,6-difluorophenethyl, ((R)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl,((R)-1-(Benzo[d]oxazol-2-yl)pyrrolidin-3-yl)methyl, ((R)-1-(5-isopropylthiazol-2-yl)piperidin-3-yl)methyl, ((R)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl, ((R)-1-(Benzo[d]thiazol-2-yl)piperidin-3-yl)methyl, ((R)-1-(Benzo[d]thiazol-4-yl)piperidin-3-yl)methyl, ((S)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl alkyl)methyl, ((S)-1-(benzo[d]thiazol-4-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-(Benzo[d]thiazol-4-yl)piperidin-3-yl)methyl, ((R)-1-(5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl, ((R)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl, ((R)-1-(3- ((S)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl, ((S)-1-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl, ((S)-1-(5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl, ((S)-1-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl, ((S)-1-(5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl, ((S)-1-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl 3-(trifluoromethyl)pyridin-3-yl)methyl, ((S)-1-(3-(trifluoromethyl)pyridin-4-yl)pyrrolidin-3-yl)methyl, ((S)-1-(2-(trifluoromethyl)pyridin-4-yl)pyrrolidin-3-yl)methyl, ((R)-1-(5-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl, ((R)-1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl, ((R)-1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl, ((R)-1-(6-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl, ((R)-1-(3-(trifluoromethyl)pyridin-4-yl)piperidin-3-yl)methyl,((R)-1-(2-(trifluoromethyl)pyridin-4-yl)piperidin-3-yl)methyl, ((S)-1-(2-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl, ((S)-1-(5-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl, ((S)-1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl, ((S)-1-(5-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl ((S)-1-(6-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl, ((S)-1-(3-(trifluoromethyl)pyridin-4-yl)piperidin-3-yl)methyl, ((S)-1-(2-(trifluoromethyl)pyridin-4-yl)piperidin-3-yl)methyl, 1-(3-chloro-2-fluorophenyl)propan-2-yl, 4-(3- chloro-2-fluorophenyl)butan-2-yl, ((1r,4R)-4-(difluoromethyl)cyclohexyl)methyl, ((1s,4S)-4-(difluoromethyl)cyclohexyl)methyl, ((1s,4S)-4-(1,1-difluoroethyl)cyclohexyl)methyl, ((1r,4R)-4-(1,1-difluoroethyl)cyclohexyl)methyl, ((1r,4R)-4-(trifluoromethoxy)cyclohexyl)methyl, ( 4,7-difluoro-2,3-dihydro-1H-inden-2-yl)methyl, (4-fluoro-1-(2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl, (4-fluoro-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl, 4-butoxybenzyl, 4-(pentyloxy)benzyl, 4-(cyclopropylmethoxy)benzyl, 4-phenoxybenzyl or [1,1'-biphenyl]-4-ylmethyl.

[0102] In some embodiments, R 1It can be (4-ethylcyclohexyl)methyl, ((1s,4S)-4-isopropylcyclohexyl)methyl, ((1r,4R)-4-isopropylcyclohexyl)methyl, ((1s,4S)-4-(tert-butyl)cyclohexyl)methyl, ((1r,4R)-4-(tert-butyl)cyclohexyl)methyl, ((1s,4S)-4-(trifluoromethyl)cyclohexyl)methyl, ((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl, ((1s,4S)-4-(2-fluoropropyl-2-yl)cyclohexyl)methyl, ((1r,4R)-4-(2-fluoropropyl-2-yl)cyclohexyl 1-cyclopropyl) methyl, ((1s,4S)-4-cyclopropylcyclohexyl) methyl, ((1r,4R)-4-cyclopropylcyclohexyl) methyl, 2-((1s,4S)-4-(trifluoromethyl)cyclohexyl)ethyl, 2-((1r,4R)-4-(trifluoromethyl)cyclohexyl)ethyl, 2,5-difluorophenethyl, 3-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-(pyrrolidin-1-yl)phenethyl, 2,6-difluoro-4-(piperidin-1-yl)phenethyl, 2,6-difluoro-4-morpholinylphenethyl, 4-butoxy-2,6-difluorophenethyl, 4-(cyclopropylmethoxy)-2,6-difluorophenethyl, 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 1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)methyl, (2,3-dihydro-1H-inden-2-yl)methyl, (1-(2-fluorophenyl)piperidin-4-yl)methyl, (1-(3-fluorophenyl)piperidin-4-yl)methyl, (1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)methyl, (2,3-dihydro-1H-inden-2-yl)methyl, (1,2,3,4-tetrahydronaphthyl-2-yl)methyl, ((R)-1-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl, ((S)-1-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl, ((R)-1-phenylpyrrolidin-3-yl)methyl, ((R)-1-(thiophen-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-(2-fluorophenyl)piperidin-3-yl)methyl, ((R)-1-(2-fluorophenyl)pyrrolidin-3-yl)methyl, ((R)-1-(3- methyl, ((R)-1-(4-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl, ((R)-1-(4-(trifluoromethyl)pyridin-5-yl)pyrrolidin-3-yl)methyl, ((R)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl, ((R)-1-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl, ((R)-1-( methyl, ((R)-1-(benzo[d]thiazol-4-yl)pyrrolidin-3-yl)methyl, ((R)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl, ((R)-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl, ((R)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl, 2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenethyl, ((S)-1-(3-(trifluoromethyl)pyridin-2-yl)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-(Benzo[d]thiazol-4-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-(Benzo[d]thiazol-4-yl)piperidin-3-yl)methyl, ((1s,4S)-4-(1,1-difluoroethyl)cyclohexyl)methyl, ((1r,4R)-4-(1,1-difluoroethyl)cyclohexyl)methyl, ((1r,4R)-4-(trifluoromethoxy)cyclohexyl)methyl or (4,7-difluoro-2,3-dihydro-1H-inden-2-yl)methyl, (4-fluoro-1-(2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl, 4-butoxybenzyl, 4-(pentyloxy)benzyl, 4-phenoxybenzyl or [1,1'-biphenyl]-4-ylmethyl.

[0103] In particular embodiments of the present invention, the compounds according to formula (I) include the compounds described in Table 1.

[0104] Table 1

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130] As will be appreciated by those skilled in the art, the above formula (I) may alternatively be expressed as follows:

[0131]

[0132] In an alternative embodiment of the present invention, compounds A and B in Table 2 are specifically excluded from the compounds described in formula (I) or formula (Id).

[0133] Table 2

[0134]

[0135] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, "a compound" refers to one or more such compounds, and "an enzyme" includes the specific enzyme as well as other equivalents of the family members known to those skilled in the art.

[0136] Throughout this application, the term "compound" is intended to refer to the compounds discussed herein, and includes precursors and derivatives of the compounds, including acyl-protected derivatives, and pharmaceutically acceptable salts of the compounds, precursors, and derivatives. The present invention also includes prodrugs of the compounds, pharmaceutical compositions comprising the compounds and a pharmaceutically acceptable carrier, and pharmaceutical compositions comprising a prodrug of the compounds and a pharmaceutically acceptable carrier.

[0137] 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 formulas (Ia)-(Ik), and therefore may exist as single enantiomers, diastereomeric mixtures, and individual diastereomers. Depending on the nature of the various substituents on the molecule, such additional asymmetric centers may exist. Each such additional asymmetric center will independently produce two optical isomers, and it is intended that all such possible asymmetric centers will independently produce two optical isomers. Optical isomers and diastereomers in the mixture and as pure or partially purified compounds are included within the scope of the present invention. Any formula, structure, or name of the compound described in this specification (not specifying the specific stereochemistry of the additional asymmetric center) is intended to encompass any and all existing isomers and mixtures thereof in any ratio as described above. When specifying the stereochemistry of the additional asymmetric center, the present invention is intended to encompass the specific isomer in pure form or as part of a mixture with other isomers in any ratio.

[0138] "Alkyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, free of unsaturated bonds, comprising, for example, 1-10 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, and connected to the rest of the molecule by a single bond. In alternative embodiments, the alkyl group can contain 1 to 8 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. In alternative embodiments, the alkyl group can contain 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5 or 6 carbon atoms. Unless otherwise specifically stated in the specification, the alkyl group can optionally be substituted with one or more substituents as described herein. Unless otherwise specifically stated herein, it should be understood that substitution can occur on any carbon of the alkyl group.

[0139] "Cycloalkyl" refers to a stable monovalent monocyclic, bicyclic, or tricyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having, for example, 3-15 carbon atoms, which is saturated and attached to the remainder of the molecule by a single bond. In alternative embodiments, the cycloalkyl radical may contain 3 to 6 carbon atoms, for example, 3, 4, 5, or 6 carbon atoms. Unless otherwise specifically stated herein, the term "cycloalkyl" is intended to include cycloalkyl radicals that are optionally substituted as described herein.

[0140] "Alkoxy" refers to a group of the formula -OR a A group in which each R a are independently C as described herein 1-10 Alkyl or C 1-6 Alkyl or C 1-5 Alkyl and alkoxy groups may be optionally substituted as described herein.

[0141] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs one or more times and instances where it does not occur. For example, "optionally substituted alkyl" means that the alkyl group may or may not be substituted, and that the description includes substituted and unsubstituted alkyl groups, 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 optionally substituted groups include, but are not limited to, H, F, Cl, CH3, OH, OCH3, CF3, CHF2, CH2F, and CN.

[0142] Treatment indications

[0143] The present invention provides, in part, methods for treating conditions that are directly or indirectly regulated by the GBA2 enzyme or the level of GBA2 activity, e.g., conditions that benefit from inhibiting the GBA2 enzyme or by reducing the level of GBA2 enzyme activity. Such conditions may include, but are not limited to, neurological diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis (ALS), as well as lysosomal storage diseases such as Gaucher disease, Niemann-Pick disease type C, mucolipidosis type IV, and Sandhoff disease, and liver diseases such as non-alcoholic steatohepatitis (NASH). Thus, one or more compounds of the present invention can be used to treat subjects who are at risk of developing or have been diagnosed with various neurological or other diseases. As used herein, the term "treating" can include treatment, prevention, and / or amelioration.

[0144] In alternative embodiments, one or more compounds of the present invention may also be used to treat diseases or conditions associated with a deficiency or overexpression of GBA2 or an accumulation or depletion of glucosylceramide, or any disease or condition responsive to glycosidase inhibitor therapy or glycosidase inhibition therapy. Such diseases and conditions may include, but are not limited to, neurological diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis (ALS), and lysosomal storage diseases such as Gaucher disease, Niemann-Pick type C, type IV mucolipidosis, and Sandhoff disease, and liver diseases such as non-alcoholic steatohepatitis (NASH). Such diseases and conditions may also include diseases or conditions associated with an accumulation or deficiency of glucosylceramide synthase or an imbalance in glycosphingolipid metabolism and / or homeostasis. Also included are methods of protecting or treating target cells expressing GBA2, the imbalance of which may lead to disease or pathology.

[0145] In alternative embodiments, the present invention provides methods for reducing the level of GBA2 enzyme activity in animal subjects, such as veterinary and human subjects. This reduction in GBA2 activity levels can be used to prevent or treat neurological or neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis (ALS)); provide neuroprotection; prevent damage to dopaminergic neurons; and prevent or treat lysosomal storage diseases (e.g., Gaucher disease, Niemann-Pick disease type C, mucolipidosis type IV, and Sandhoff disease); and prevent or treat liver diseases (e.g., non-alcoholic steatohepatitis (NASH)).

[0146] In alternative embodiments, the present invention provides methods of inhibiting the GBA2 enzyme in animal subjects, such as veterinary and human subjects.

[0147] In alternative embodiments, the present invention provides methods for reducing CNS inflammation in animal subjects, such as veterinary and human subjects. Disease states of interest may include neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis (ALS), in which neuroinflammation is implicated in disease pathogenesis. In some embodiments, compounds according to the present invention can be used to prevent, treat, or ameliorate neuroinflammation by reducing the level of GBA2 enzyme activity, thereby providing therapeutic benefit.

[0148] In alternative embodiments, the present invention provides methods for inhibiting α-synuclein aggregation or inhibiting Lewy body formation in animal subjects, such as veterinary and human subjects. Disease states of interest may include Parkinson's disease (PD) and related neurodegenerative synucleinopathies, in which abnormal aggregation of α-synuclein is implicated in disease pathogenesis. In certain embodiments, compounds according to the present invention can be used to block the aggregation of α-synuclein by reducing the level of GBA2 enzyme activity, thereby providing therapeutic benefit.

[0149] Neurological diseases that can be treated with the compounds of the present invention may be, 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), Blunt disease, cerebellar ataxia, Charcot-Marie-Tooth disease (CMT), chronic fatigue syndrome, corticobasal degeneration (CBD), boxer's dementia, Lewy body dementia (DLB), DeGelina-Sotas 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-Straussner disease, glaucoma, Guadiaro-Parkinson disease, Guillain-Barré syndrome, Hallervorden-Spatz disease (neurodegeneration with brain iron accumulation type 1), insomnia, Lambert-Eaton myasthenic syndrome (LEMS), major depressive disorder (MDD), migraine, mild 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), neuropathies (including peripheral neuropathy, autonomic neuropathy, neuritis, diabetic neuropathy), oculopharyngeal muscular dystrophy, pain, globus pallidus ponto-nigral degeneration, Guam Parkinsonism-dementia complex, Pick's disease (PiD), postencephalitis parkinsonism (PEP), primary lateral sclerosis (PLS), prion diseases (including Creutzfeldt-Jakob disease (CJD), Variant Creutzfeldt-Jakob disease (vCJD), fatal familial insomnia and kuru), progressive subcortical gliosis, progressive supranuclear palsy (PSP), Richardson syndrome, schizophrenia, seizures, spinal cord injury, 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, entanglement dementia, tardive dyskinesia, Tourette syndrome (TS), vascular dementia, and Wilson disease.

[0150] Lysosomal storage diseases that may be treated with the compounds of the present invention may include, but are not limited to, Gaucher disease (including types I, II, and III), Niemann-Pick disease (including types A, B, and C), mucolipidosis (including types I, II, III, IV, VI, and VII), cerebrotendinous xanthomatosis, Fabry disease, Farber disease, GM1 gangliosidosis, Krabbe disease, metachromatic leukodystrophy (MLD), multiple sulfatase deficiency, Pompe disease, Sandhoff disease, or Tay-Sachs disease.

[0151] Liver diseases that can be treated with the compounds of the present invention can include, but are not limited to, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), Alagille syndrome, alcohol-related liver disease, alpha-1 antitrypsin deficiency, autoimmune hepatitis, autoimmune cholangitis, benign liver tumors, biliary atresia, cirrhosis, Crigler-Najjar syndrome, drug-induced liver injury (DILI), galactosemia, Gilbert's syndrome, hemochromatosis, hepatic encephalopathy, hepatocellular carcinoma (HCC), intrahepatic cholestasis of pregnancy (ICP), lysosomal acid lipase deficiency (LAL-D), liver cysts, liver cancer, neonatal jaundice, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), Reye's syndrome, type I glycogen storage disease, or viral hepatitis (including types A, B, C, D, and E).

[0152] In some embodiments, the compounds according to the present invention are useful in treating diseases in which modulation of GBA2 enzyme activity levels is implicated, or any of the conditions described herein.

[0153] Other conditions that may be treated using one or more compounds according to the present invention are those conditions that are triggered, influenced, or in any other way related to the level of GBA2 enzyme activity. It is expected that one or more compounds of the present invention may be used to treat such conditions, in particular, but not limited to, Parkinson's disease, neuronal ceroid lipofuscinosis (Patton disease), Gaucher disease, Niemann-Pick disease type C, mucolipidosis type IV, and Sandhoff disease.

[0154] Pharmaceutical and veterinary compositions, dosages and administration

[0155] Pharmaceutical compositions comprising compounds according to the present invention or for use according to the present invention are considered to be within the scope of the present invention. In some embodiments, pharmaceutical compositions are provided comprising an effective amount of a compound of formula (I), including any one or more of formulas (Ia)-(Ik).

[0156] The compound shown in formula (I), including any one or more of formula (Ia)-(Ik), and pharmaceutically acceptable salts, enantiomers, solvates or derivatives thereof may be useful because they may have pharmacological activity in animals (including humans). In some embodiments, when administered to a subject (e.g., a human), one or more compounds according to the present invention may be stable in blood plasma.

[0157] Generally, the compounds according to the present invention can be administered to a subject in need thereof, or by contacting a cell or sample with, for example, a pharmaceutical composition comprising a therapeutically effective amount of a compound according to formula (I) (including any one or more of formulas (Ia)-(Ik)).

[0158] In some embodiments, the compounds according to the present invention or the compounds for use according to the present invention may be provided in combination with any other active agent or pharmaceutical composition. Pharmaceutical compositions, wherein such combination therapy can be used to inhibit GBA2 activity levels, for example, to treat neurological diseases or lysosomal storage diseases or liver diseases or any of the conditions described herein. In some embodiments, the compounds according to the present invention or the compounds for use according to the present invention may be provided in combination with one or more agents useful for preventing or treating Parkinson's disease. Examples of such agents may include, but are not limited to:

[0159] Levodopa (L-DOPA);

[0160] Peripheral dopa decarboxylase inhibitors (DDCIs), such as carbidopa

[0161] Carbidopa / levodopa combination

[0162] Carbidopa / levodopa / entacapone combination

[0163] Amantadine

[0164] Dopamine antagonists, such as bromocriptine Pergolide Pramipexole Ropinirole Piribedil (Trivastal ), Cabergoline Apomorphine Rotigotine (AY-27,110), (DAR-0100), Epicryptine (β-dihydroergocryptine), N-propylnorapomorphine (NPA), quinagolide (EMD-49,980), (PNU-95,666), Padruno, Aplindo, etc.;

[0165] Monoamine oxidase-B (MAO-B) inhibitors, such as selegiline Rasagiline ( AGN 1135), safinamide, etc.;

[0166] Anticholinergics, such as benztropine ), diphenhydramine Orphenadrine Benhexyphenidyl ( benzhexol, trihex), etc.

[0167] Catechol-O-methyltransferase (COMT) inhibitors, such as entacapone Tolcapone Niticapine, nebicapone, etc.

[0168] Adenosine A 2A Receptor antagonists, such as istradefylline (KW-6002), preladenant, fipamezole (JP-1730), SCH-420814, BIIA-014, LuAA4707, etc.;

[0169] Metabotropic glutamate receptor 5 (mgluR5) modulators, such as dipraglurant;

[0170] AMPA receptor antagonists, such as perampanel wait;

[0171] Anticonvulsants, such as zonisamide wait;

[0172] Nicotinic acetylcholine receptor (nAChR) agonists, such as nicotine, ABT-418, WAY-317, 538 (SEN-12333), EVP-6124, MEM 3454, nefiracetam, etc.

[0173] Acetylcholinesterase inhibitors (AChEIs), such as (donepezil), (rivastigmine), (Razadyne Galantamine), (tacrine), huperzine A, phenylserine, Debio-9902SR (ZT-1SR), zanapezil (TAK0147), ganstigmine, NP7557, etc.;

[0174] Atypical antipsychotics, such as clozapine; or

[0175] Modafinil

[0176] It should be understood that the combination of the compound according to the present invention or the compound used according to the present invention with a medicament useful for treating Parkinson's disease is not limited to the embodiments described herein, but may include a combination with any medicament useful for treating Parkinson's disease. The combination of the compound according to the present invention or the compound used according to the present invention with other medicaments useful for treating Parkinson's disease may be administered alone or in combination. Administration of one medicament may be before, simultaneously with, or after administration of the other medicament.

[0177] In some embodiments, the compounds according to the present invention or the compounds used according to the present invention may be provided in combination with one or more agents for preventing or treating Gaucher disease. Examples of these agents may include, but are not limited to:

[0178] Recombinant human GCase enzyme replacement therapy, such as imigranase velaglucerase alfa Taliglucerase alfa wait;

[0179] Glucosylceramide synthase inhibitors, such as EXEL-0346, Genz-123346, (Genz-112638), etc.

[0180] Bisphosphonates, such as zoledronate Alendronate sodium Etidronate Clodronate Tiludronate Pamidronate Neridronate Olapadronate, ibandronate Risedronate wait;

[0181] Antiepileptic drugs, such as ( carbamazepine), (ethosuximide), (Felbamate), (Tiagabine), (levetiracetam), (lamotrigine), (pregabalin), (gabapentin), (phenytoin), (topiramate), (oxcarbazepine), ( Valproate, valproic acid), (Zonisamide), (diazepam), (lorazepam) (clonazepam), (perampanel), Oxtellar (oxcarbazepine), etc.; or

[0182] Gene therapy

[0183] It should be understood that the combination of the compound according to the present invention or the compound used according to the present invention with a pharmaceutical agent useful for treating Gaucher disease is not limited to the embodiments described herein, but may include a combination with any pharmaceutical agent useful for treating Gaucher disease. The combination of the compound according to the present invention or the compound used according to the present invention with other pharmaceutical agents useful for treating Gaucher disease may be administered alone or in combination. Administration of one pharmaceutical agent may be before, simultaneously with, or after administration of the other pharmaceutical agent.

[0184] In alternative embodiments, the compounds of the present invention can be provided as "prodrugs" or as protected forms that release the compound after being administered to a subject. For example, the compound can carry a blocking group that is split by hydrolysis in body fluids (e.g., in the bloodstream) to release the active compound, or is oxidized or reduced to release the compound in body fluids. Accordingly, "prodrugs" mean compounds that can be converted into the bioactive compounds of the present invention under physiological conditions or by solvolysis. Therefore, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of the compounds of the present invention. When administered to a subject in need, the prodrug can be inactive, but can be converted into the active compound of the present invention in vivo. Prodrugs are typically rapidly converted in vivo to produce the parent compound of the present invention, such as by hydrolysis in the blood. Prodrug compounds typically provide advantages of solubility, tissue compatibility, or delayed release in a subject.

[0185] The term "prodrug" also includes any covalently bound carrier that releases the active compound of the invention in vivo when such prodrug is administered to a subject. Prodrugs of the compounds of the invention can be prepared by modifying functional groups present in the compounds of the invention in such a way that the modifications are cleaved into the parent compound of the invention during routine manipulation or in vivo. Prodrugs include compounds of the invention in which a hydroxyl, amino, or sulfhydryl group is attached to any group that, when the prodrug of the compounds of the invention is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol functional groups and acetamide, formamide, and benzamide derivatives of amine functional groups in one or more compounds of the invention.

[0186] Discussion of prodrugs can be found in "Introduction to the Principles of Drug Design by Smith and Williams", HJ Smith, Wright, 2nd ed., London (1988); Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam), The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31, (Academic Press, 1996); A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pgs 113191 (Harwood Academic Press, 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.

[0187] Suitable prodrug forms of one or more compounds of the present invention may include embodiments wherein one or more OH groups of formula (I), including any one or more of formulas (Ia)-(Ik), may be protected as OC(O)R, wherein R may optionally be replaced by C1-6 In these cases, the ester group can be hydrolyzed in vivo (e.g., in body fluids), releasing the OH group and releasing the active compound. Preferred prodrug embodiments of the present invention may include compounds of formula (I), including any one or more of formulas (Ia)-(Ik), wherein one or more OH groups may be protected with acetate, such as OC(O)CH3

[0188] The compound according to the present invention or used according to the present invention can be provided separately, or provided in combination with other compounds in the presence of liposomes, nanoparticles, adjuvants or any pharmaceutically acceptable carriers, diluents or excipients, to be suitable for being applied to a form of a subject (e.g., mammal, such as people, cattle, sheep, etc.). If desired, the treatment with the compound according to the present invention can be combined with more traditional and existing therapies for the treatment indications described in the present invention. The compound according to the present invention can be provided for a long time or intermittently. " Chronic " administration refers to the administration of compounds in a continuous mode opposite to the acute mode, so that the initial therapeutic effect (activity) is maintained over an extended period of time. " Intermittent " administration is not the treatment that is continuously performed uninterruptedly, but is essentially cyclical. These terms, such as " administration (administration) ", " administerable (administrable) " or " administering (administering) " used in the present invention should be understood as meaning that the subject in need of treatment provides the compound of the present invention.

[0189] A "pharmaceutically acceptable carrier, diluent or excipient" may include, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved, for example, by the U.S. Food and Drug Administration or other governmental agency for use in humans or veterinary medicine.

[0190] The compounds of the present invention can be administered in the form of a pharmaceutically acceptable salt. In this case, the pharmaceutical composition according to the present invention may include a salt of this compound, preferably a physiologically acceptable salt, which is known in the art. In some embodiments, the term "pharmaceutically acceptable salt" as used herein refers to an active ingredient comprising a compound shown in the formula I (including any one or more of formulas (Ia)-(Ik)) used in its salt form, particularly wherein the salt form imparts improved pharmacokinetic properties to the active ingredient compared to the free form or other previously disclosed salt forms of the active ingredient.

[0191] "Pharmaceutically acceptable salts" may include acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" refer to those salts that retain the biological effectiveness and properties of the free bases, which may not be biologically or otherwise undesirable, and can 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.).

[0192] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acids, which may not be biologically or otherwise undesirable. These salts can be prepared by adding inorganic or organic bases to the free acids. 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, halamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Particularly preferred organic bases may be salts of isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0193] Thus, the term "pharmaceutically acceptable salt" includes all acceptable salts, including but not limited to acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, methanesulfonate, borate, methyl bromide, bromide, methylnitrite, calcium edetate, methylsulfate, camphorsulfonate, mucate, carbonate, naphthylsulfonate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisulphonate,

[0014] Examples of the present invention include benzoate, benzoate, bis(ophthalate), benzoic acid, ...

[0194] The pharmaceutically acceptable salts of the compounds of this invention can be used as dosages that change solubility or hydrolysis characteristics, or can be used in sustained-release or prodrug formulations. In addition, the pharmaceutically acceptable salts of the compounds of this invention can include salts formed by cations (e.g., sodium, potassium, aluminum, calcium, lithium, magnesium, zinc) and bases (e.g., ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)methylamine, and tetramethylammonium hydroxide).

[0195] Pharmaceutical preparations can generally include one or more acceptable carriers for the administration of the preparation, which can be injection, inhalation, topical administration, irrigation, or other modes suitable for the selected treatment. Suitable carriers can be those known in the art for such administration.

[0196] Suitable pharmaceutical compositions can be prepared by methods known in the art, and their mode of administration and dosage are determined by technicians. For parenteral administration, the compound can be dissolved in sterile water or saline or a pharmaceutically acceptable carrier, which is used for the administration of water-insoluble compounds, such as those for vitamin K. For enteral administration, the compound can be administered in tablets, capsules, or dissolved in liquid form. Tablets or capsules can be enteric-coated, or in sustained-release formulations. Many suitable preparations are known, including polymers or protein microparticles, ointments, gels, hydrogels, or solutions encapsulating the compound to be released, which can be used topically or locally to administer the compound. Sustained-release patches or implants can be used to provide release over an extended period of time. Many technical descriptions known to those skilled in the art are in Remington: The Science & Practice of Pharmacy by Alfonso Gennaro, 20 th Ed., Williams & Wilkins, (2000). Preparations for parenteral administration can, for example, contain excipients, polyalkylene glycols such as polyethylene glycol, oils of plant origin, or hydrogenated naphthalene. Biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers can be used to control the release of the compound. Other potentially useful parenteral delivery systems for regulating the compound can include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Preparations for inhalation can contain excipients, such as lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate, and deoxycholate, or can be oily solutions for use in the form of nasal drops or as a gel.

[0197] The compounds or pharmaceutical compositions according to the present invention can be administered orally or non-orally, such as intramuscularly, intraperitoneally, intravenously, intracisternal injection or infusion, subcutaneously, transdermally or transmucosally. In some embodiments, the compounds or pharmaceutical compositions according to the present invention or the compounds or pharmaceutical compositions used in the present invention can be administered by medical devices or appliances such as implants, grafts, prostheses, stents, etc. Implants can be designed to contain and release these compounds or compositions. An example is an implant made of a polymer material suitable for releasing the compound over a period of time. The compound can be administered alone or in a mixture with a pharmaceutically acceptable carrier, such as a solid preparation such as a tablet, capsule, granule, powder, etc.; a liquid preparation such as a syrup, an injection, etc.; an injection, drops, a suppository, a vaginal suppository. In some embodiments, the compounds or pharmaceutical compositions according to the present invention or used in the present invention can be administered by inhalation spray, nasal, vaginal, rectal, sublingual or topical routes, and can be formulated alone or together into suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles suitable for each route of administration.

[0198] The compounds of the present invention can be used to treat animals, including mice, rats, horses, cattle, sheep, dogs, cats and monkeys. However, the compounds of the present invention can also be used in other organisms, such as avian species (e.g., chickens). One or more compounds of the present invention can also be effectively used in humans. The term "subject" or, as used herein, "patient" is intended to refer to an animal, preferably a mammal, most preferably a human, that has been the subject of treatment, observation or experiment. However, one or more compounds, methods and pharmaceutical compositions of the present invention can be used to treat animals. Accordingly, as used herein, a "subject" can be a human, non-human primate, rat, mouse, cattle, horse, pig, sheep, goat, dog, cat, etc. The subject may be suspected of having a condition that may require inhibition of GBA2 activity or be at risk of having a condition that may require inhibition of GBA2 activity.

[0199] An "effective amount" of a compound according to the present invention may include a therapeutically effective amount or a prophylactically effective amount. A "therapeutically effective amount" refers to an amount effective at the dosage and time period necessary to achieve the desired therapeutic outcome (e.g., inhibition of GBA2, reduction in GBA2 enzyme activity levels, inhibition of α-synuclein aggregation, or any of the conditions described herein). The therapeutically effective amount of a compound may vary depending on factors such as the individual's disease state, age, sex, and weight, as well as the compound's ability to elicit a desired response in the individual. The dosage regimen may be adjusted to provide the optimal therapeutic response. A therapeutically effective amount may also be an amount in which any toxic or deleterious effects of the compound are outweighed by the therapeutic benefits. A "prophylactically effective amount" may refer to an amount effective at the dosage and time period necessary to achieve the desired prophylactic outcome, such as inhibition of GBA2, reduction in GBA2 enzyme activity levels, inhibition of α-synuclein aggregation, or any of the conditions described herein. Generally, a prophylactic dose may be administered to a subject prior to or at an early stage of disease, such that the prophylactically effective amount may be less than the therapeutically effective amount. Suitable ranges for a therapeutically or prophylactically effective amount of a compound may be any integer from 0.1 nM to 0.1 M, 0.1 nM to 0.05 M, 0.05 nM to 15 μM, or 0.01 nM to 10 μM.

[0200] In alternative embodiments, in the treatment or prevention of conditions that may require inhibition of GBA2 activity, suitable dosage levels may generally be about 0.01-500 mg / kg of subject body weight / day, and may be administered in single or multiple doses. In some embodiments, dosage levels may be from about 0.1 to about 250 mg / kg / day per day. It should be understood that the specific dosage level and frequency of administration for any particular patient may vary and may depend on a variety of factors, including the activity of the particular compound used, the metabolic stability and duration of action of the compound, age, body weight, general health, sex, diet, route and timing of administration, rate of excretion, drug combination, severity of the particular condition, and the patient being treated.

[0201] It should be noted that dosage values ​​may vary with the severity of the condition to be alleviated. For any particular subject, the specific dosage regimen may be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition. The dosage ranges described herein are exemplary only and do not limit the dosage range that may be selected by a medical practitioner. The amount of active compound in the composition may vary according to factors such as the subject's disease state, age, sex, and weight. The dosage regimen may be adjusted to provide the optimal therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased depending on the urgency of the therapeutic situation. It may be advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Generally, the compounds of the present invention should be used without causing substantial toxicity, and as described herein, one or more compounds may exhibit a suitable safety profile for therapeutic use. The toxicity of the compounds of the present invention can be determined using standard techniques, for example, by testing in cell cultures or experimental animals and determining the therapeutic index, i.e., the ratio between the LD50 (the dose lethal to 50% of the population) and the LD100 (the dose lethal to 100% of the population). However, in some circumstances, such as in severe disease conditions, it may be necessary to administer a substantial excess of the composition.

[0202] In the compounds of formula (I), including any one or more of formulas (Ia)-(Ik), the atoms may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched with a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is intended to include all suitable isotopic variants of the compounds of formula (I), including any one or more of formulas (Ia)-(Ik). For example, different isotopic forms of hydrogen (H) include protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H). Protium is the predominant hydrogen isotope found in nature. Deuterium enrichment can provide certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements, or can provide compounds useful as standards for characterizing biological samples. Isotopically enriched compounds within Formula (I), including any one or more of Formulas (Ia)-(Ik), can be prepared by conventional techniques familiar to those skilled in the art or by processes analogous to those described in the technical solutions and examples of the present invention, using appropriate isotopically enriched reagents and / or intermediates.

[0203] Other uses

[0204] In alternative embodiments, one or more compounds of the present invention can be used to study the physiological effects of GBA2 at the cellular and organismal levels. In some embodiments, one or more compounds can be used to develop animal models for studying diseases or conditions that may be associated with GBA2 deficiency, GBA2 overexpression, glucosylceramide accumulation, glucosylceramide depletion, glycosphingolipid accumulation, or glycosphingolipid depletion, as well as for studying the treatment of diseases and conditions that may be associated with GBA2 deficiency or overexpression, or glucosylceramide accumulation or depletion, or glycosphingolipid accumulation or depletion. Such diseases and conditions may include, but are not limited to, neurological diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, amyotrophic lateral sclerosis (ALS), and neuronal ceroid lipofuscinosis (Patton disease); lysosomal storage diseases, including Gaucher disease, Niemann-Pick disease type C, mucolipidosis type IV, and Sandhoff disease; or liver diseases, including non-alcoholic steatohepatitis (NASH).

[0205] The effectiveness of a compound in treating pathologies associated with a lysosomal storage disease (e.g., Gaucher disease, Niemann-Pick disease type C, mucolipidosis type IV, or Sandhoff disease) can be demonstrated using standard techniques, for example, by testing the compound's ability to prevent, treat, or ameliorate disease symptoms in established cellular and / or transgenic animal disease models. 13,14,16,17,27

[0206] The present invention has been described in detail with reference to various alternative embodiments and examples of the present invention. These embodiments and examples are illustrative and should not be construed as limiting the scope of the present invention.

[0207] Example

[0208] The following examples are intended to illustrate embodiments of the present invention and are not intended to be construed in a limiting sense.

[0209] abbreviation

[0210] ABCN = 1,1′-azobis(cyclohexanecarbonitrile)

[0211] DAST = diethylaminosulfur trifluoride

[0212] DCM = dichloromethane

[0213] DIPEA = diisopropylethylamine

[0214] DMF=N,N-dimethylformamide

[0215] DMA = dimethylacetamide

[0216] DMP = Dess-Martin Periodinane

[0217] Et2O = ether

[0218] LAH = lithium aluminum hydride

[0219] MeOH = methanol

[0220] MsCl = methanesulfonyl chloride

[0221] RT = Room temperature

[0222] RuPhos=2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl

[0223] TBDMSCl = tert-butyldimethylsilyl chloride

[0224] TFA=2,2,2-trifluoroacetic acid

[0225] THF = Tetrahydrofuran

[0226] Example 1

[0227] (3S,4R,5R)-1-(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol

[0228]

[0229] To a stirred solution of (3S,4r,5R)-3,4,5-tris(benzyloxy)piperidine (30 mg, 0.074 mmol) and (1r,4r)-4-(trifluoromethyl)cyclohexanecarboxaldehyde (20 mg, 0.11 mmol) in anhydrous DCM (2 mL) was added HOAc (2 drops) and the mixture was stirred for 30 minutes. NaBH(OAc)3 (31 mg, 0.15 mmol) was added and the resulting mixture was stirred at room temperature for 18 h. The reaction was quenched with saturated NaHCO3 aqueous solution at 0 ° C. The mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with water (2 × 20 mL), separated and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel to give (3S,4R,5R)-3,4,5-tris(benzyloxy)-1-(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine as an oil (40 mg, 95%). ESI MS m / z 568.31 [M+H] + .

[0230] At -78 ° C and N2, BCl3 (concentration in DCM is 1M, 0.35mL, 0.35mmol) was added to a stirred solution of the above substance (40mg, 0.070mmol) in anhydrous DCM (5mL). The mixture was stirred at 0 ° C for 2h and then quenched with anhydrous MeOH (1mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum, and the residue was dissolved in a 1M NH3 solution of MeOH (10mL) and stirred for another 10 minutes, and then the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel to obtain (3S, 4R, 5R) -1- (((1r, 4R) -4- (trifluoromethyl) cyclohexyl) methyl) piperidine -3,4,5- triol as a white solid (15mg, 72%). 1 H NMR (400MHz, CD3OD) δ3.54-3.45(m,2H),3.09(t,J=8.9Hz,1H),2.97-2.88(m,2H),2.22(d,J=7.1Hz,2 H),2.17-2.01(m,1H),2.01-1.83(m,6H),1.60-1.44(m,1H),1.44-1.26(m,2H),1.05-0.89(m,2H); ESI MS m / z 298.16[M+H] + .

[0231] Example 2

[0232] (3S,4R,5R)-1-(((1s,4S)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol

[0233]

[0234] DIPEA (0.52 mL, 3.0 mmol) was added to a stirred solution of (3S, 4r, 5R)-3,4,5-tris(benzyloxy)piperidine (400 mg, 0.99 mmol) and 4-(trifluoromethyl)cyclohexanecarboxylic acid (292 mg, 1.49 mmol) in DMF (10 mL) at 0 ° C, followed by the addition of HATU (566 mg, 1.49 mmol). The mixture was stirred at room temperature for 2 h. Water was added to quench the reaction. The mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×30 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel to give ((1s,4S)-4-(trifluoromethyl)cyclohexyl)((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methanone as an oil (274 mg, 48%). ESI MS m / z 582.67 [M+H]+ .

[0235] To a solution of the above substance (94 mg, 0.16 mmol) in anhydrous THF (3 mL) was added LAH (25 mg, 0.65 mmol) at 0°C, and the mixture was stirred at 0°C for 2 hours. The mixture was slowly quenched with saturated Na2SO4 and filtered. The solid was washed with EtOAc. The combined organic layers were washed with water (2×20 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel to give (3S,4R,5R)-3,4,5-tris(benzyloxy)-1-(((1s,4S)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine as an oil (45 mg, 50%). ESI MS m / z 568.69 [M+H] + .

[0236] At -78 ° C and N2, BCl3 (1M concentration in DCM, 0.35 mL, 0.35 mmol) was added to a stirred solution of the above-mentioned substance (40 mg, 0.07 mmol) in anhydrous DCM (5 mL). The mixture was stirred at 0 ° C for 2 h and then quenched with anhydrous MeOH (1 mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum, and the residue was dissolved in 1M NH3 in MeOH (10 mL) and stirred for another 10 min, then the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel to obtain (3S, 4R, 5R)-1-(((1s, 4S)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol as a white solid (16 mg, 77%). 1 H NMR(400MHz,CD3OD)δ3.54-3.45(m,2H),3.10(t,J=8.8Hz,1H),2.99-2.91(m,2H), 2.35(d,J=7.6Hz,2H),2.25-2.11(m,1H),1.97-1.83(m,3H),1.74-1.48(m,8H); ESI MS m / z 298.16[M+H] + .

[0237] Example 3

[0238] (3S,4R,5R)-1-(((1s,4S)-4-(2-fluoropropan-2-yl)cyclohexyl)methyl)piperidine-3,4,5-triol

[0239]

[0240] To a solution of (3S,4r,5R)-3,4,5-tris(benzyloxy)piperidine (0.70 g, 1.7 mmol) in anhydrous DCM (20 mL) was added BCl3 (1.0 M in DCM, 10.0 mL, 10.0 mmol) at -78 ° C and Ar, and the mixture was stirred at 0 ° C for 3 h. The reaction mixture was cooled at -78 ° C, quenched with MeOH, and then concentrated to dryness. The residue was washed with mixed EtOAc / hexane (1: 1) (3 × 20 mL) and dried under high vacuum overnight to give the HCl salt as a light yellow solid. A mixture of the above solid (0.16 g, 0.94 mmol), cis-4-(2-fluoropropan-2-yl)cyclohexanecarbaldehyde (0.18 g, 1.0 mmol), NaOAc (0.082 g, 1.0 mmol) and NaBH3CN (0.15 g, 2.4 mmol) in MeOH (10 mL) was stirred at room temperature for 16 h under Ar. The reaction mixture was diluted with water (3 mL) and concentrated to dryness at 40°C, and the residue was purified by flash chromatography on silica gel (0.5 M NH3MeOH / DCM, 1:6) to give (3S,4R,5R)-1-(((1s,4S)-4-(2-fluoropropan-2-yl)cyclohexyl)methyl)piperidine-3,4,5-triol (0.058 g, 21% over two steps) as a white solid. 1 H NMR (400MHz, CD3OD) δ3.49(ddd,J=10.2,8.8,4.7Hz,2H),3.09(t,J=8.9Hz,1H),2.94(ddd,J=10.7,4.8,1.6Hz,2 H),2.37(d,J=7.5Hz,2H),1.96-1.82(m,3H),1.80-1.71(m,2H),1.62-1.42(m,5H),1.33-1.10(m,8H,including 1.27(d,J=21.8Hz,6H)); ESI MS m / z290.216[M+H] + .

[0241] Example 4

[0242] (3S,4r,5R)-1-(2-cyclohexylethyl)piperidine-3,4,5-triol

[0243]

[0244] A mixture of (3S,4r,5R)-3,4,5-tris(benzyloxy)piperidine (0.20 g, 0.50 mmol), (2-bromoethyl)cyclohexane (0.30 g, 1.5 mmol), and DIPEA (0.22 g, 1.7 mmol) in anhydrous DMF (5 mL) was stirred at 90°C for 16 hours in a sealed tube. The reaction mixture was cooled to room temperature and diluted with saturated aqueous NaHCO₃ (10 mL). After extraction with EtOAc (3 x 10 mL), the combined extracts were washed with brine (2 x 15 mL) and dried over anhydrous Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:9 to 1:5) to give (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-(2-cyclohexylethyl)piperidine as a light yellow solid (0.23 g, 90%). ESI MS m / z 514.338 [M+H] + .

[0245] To a solution of the above material (0.23 g, 0.45 mmol) in anhydrous DCM (6 mL) was added BCl 3 (1.0 M in DCM, 4.0 mL, 4.0 mmol) at -78 ° C under Ar, and the mixture was stirred at 0 ° C for 3 h. The reaction mixture was cooled at -78 ° C, quenched with MeOH, and concentrated to dryness. The residue was neutralized with 1M NH 3 in MeOH and then flash chromatographed on silica gel (0.5M NH 3 in 1:5 MeOH / DCM) to give (3S,4r,5R)-1-(2-cyclohexylethyl)piperidine-3,4,5-triol as a white solid (0.075 g, 69%). 1 H NMR (400MHz, DMSO-d6) δ4.67(d,J=4.3Hz,1H),4.64(d,J=4.8Hz,2H),3.29-3.16(m,2H),2.85(td,J=8.7,4.3Hz,1H) ,2.76(ddd,J=10.2,4.6,1.5Hz,2H),2.35-2.19(m,2H),1.75-1.53(m,7H),1.35-1.04(m,6H),0.97-0.76(m,2H); ESI MS m / z 244.194[M+H] + .

[0246] Example 5

[0247] (3S,4r,5R)-1-(3-cyclohexylpropyl)piperidine-3,4,5-triol

[0248]

[0249] A mixture of (3S,4r,5R)-3,4,5-tris(benzyloxy)piperidine (0.15 g, 0.37 mmol), (3-bromopropyl)cyclohexane (0.30 g, 1.5 mmol) and DIPEA (0.22 g, 1.7 mmol) in anhydrous DMF (4 mL) was stirred at 90°C for 16 hours in a sealed tube. The reaction mixture was cooled at room temperature and diluted with saturated aqueous NaHCO3 (10 mL). After extraction with EtOAc (3 x 10 mL), the combined extracts were washed with brine (2 x 15 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:9 to 1:6) to give (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-(3-cyclohexylpropyl)piperidine as a light yellow oil (0.16 g, 83%). ESIMS m / z 528.351 [M+H] + .

[0250] To a solution of the above material (0.15 g, 0.28 mmol) in anhydrous DCM (5 mL) was added BCl 3 (1.0 M in DCM, 2.5 mL, 2.5 mmol) at -78 ° C under Ar, and the mixture was stirred at 0 ° C for 3 hours. The reaction mixture was cooled at -78 ° C, quenched with MeOH, and concentrated to dryness. The residue was neutralized with 1 M NH 3 in MeOH and then purified by flash chromatography on silica gel (0.5 M NH 3 in 1:6 MeOH / DCM) to give (3S,4r,5R)-1-(3-cyclohexylpropyl)piperidine-3,4,5-triol as a white solid (0.062 g, 86%). 1 H NMR (400MHz, DMSO-d6) δ4.67(d,J=4.3Hz,1H),4.65(d,J=4.8Hz,2H),3.22(dq,J=13.5,4.8Hz,2H),2.85(td,J=8.6,4.3Hz,1H) ,2.82-2.70(m,2H),2.22(t,J=7.4Hz,2H),1.79-1.53(m,7H),1.37(p,J=7.5Hz,2H),1.25-1.06(m,6H),0.91-0.73(m,2H); ESI MS m / z 258.210[M+H] + .

[0251] Example 6

[0252] (3S,4r,5R)-1-(3-chloro-2-fluorophenethyl)piperidine-3,4,5-triol

[0253]

[0254] Using the method described in Example 7, (3S,4r,5R)-1-(3-chloro-2-fluorophenethyl)piperidine-3,4,5-triol was synthesized from (3S,4r,5R)-3,4,5-tris(benzyloxy)piperidine and 2-(3-chloro-2-fluorophenyl)acetaldehyde. 1 H NMR (400MHz, CD3OD) δ7.32(ddd,J=8.5,7.1,1.7Hz,1H),7.24(td,J=7.2,6.7,1.7Hz,1H),7.10(td,J=7.9,1.1Hz,1H),3.54-3.45(m,2H ),3.12(t,J=8.9Hz,1H),3.06-3.01(m,2H),2.89(dd,J=9.0,6.5Hz,2H),2.67(dd,J=9.2,6.3Hz,2H),2.04(dd,J=11.2,10.3Hz,2H); ESI MS m / z290.06[M+H] + .

[0255] Example 7

[0256] (3S,4r,5R)-1-(3-chloro-2,6-difluorophenethyl)piperidine-3,4,5-triol

[0257]

[0258] To a solution of xylitol (25.0 g, 164 mmol) and imidazole (34.0 g, 500 mmol) in anhydrous DMF (300 mL) at 0°C under Ar was added TBDMSCl (54.5 g, 362 mmol). The mixture was stirred at room temperature for 5 h and then diluted with brine (1 L). The mixture was extracted with EtOAc (4×150 mL), and the combined extracts were washed with brine (1 L) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:1) to give (6R,7r,8S)-2,2,3,3,11,11,12,12-octamethyl-4,10-dioxa-3,11-disilatridecane-6,7,8-triol as a white solid (58.5 g, 94%). ESI MS m / z 403.224[M+Na] + .

[0259] At 0 ° C and Ar, a solution of the above substance (57.7 g, 152 mmol) in anhydrous DMF (200 mL) was slowly added to a suspension of NaH (60% mineral oil, 24.3 g, 605 mmol). After addition, the mixture was stirred at 0 ° C for 1 hour, and a solution of BnBr (103 g, 602 mmol) in anhydrous DMF (150 mL) was slowly added. The mixture was allowed to reach room temperature and stirred at room temperature overnight. Cooled at 0 ° C, the reaction was carefully quenched with water (1 L). After extraction with EtOAc (4 × 150 mL), the combined extracts were washed with brine (2 × 500 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was treated with a MeOH solution of HCl (0.5N, 600 mL) at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous NaHCO3 solution (500 mL) and extracted with DCM (4×200 mL). The combined extracts were washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:2 to 1:1) to give (2R,3r,4S)-2,3,4-tris(benzyloxy)pentane-1,5-diol as a white solid (44.0 g, 69%). ESI MS m / z 445.206 [M+Na] + .

[0260] To a solution of the above substance (27.0 g, 63.9 mmol) and DIPEA (20.7 g, 160 mmol) in anhydrous DCM (300 mL) at -10 ° C and Ar was added MsCl (16.0 g, 140 mmol) dropwise, and the mixture was stirred at 0 ° C for 2 hours. The reaction mixture was diluted with water (500 mL), the DCM layer was collected, and the aqueous layer was extracted with DCM (2 × 50 mL). The combined extracts were washed with saturated NaHCO3 aqueous solution (300 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure at room temperature, and the residue was further dried under high vacuum to obtain a viscous oil. The viscous oil was dissolved in allylamine (50 mL), and the mixture was stirred at 50 ° C for 3 days. After concentration under reduced pressure, the residue was diluted with saturated NaHCO3 aqueous solution (200 mL) and extracted with EtOAc (3 × 100 mL). The combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:3) to give (3S,4r,5R)-1-allyl-3,4,5-tris(benzyloxy)piperidine as a light yellow oil (16.2 g, 69%). ESI MS m / z 444.260 [M+H] + .

[0261] To a solution of the above material (10.5 g, 23.7 mmol) in anhydrous DMSO (50 mL) was added KO at 75 °C under Ar. t To the mixture of 4-nitro-1-oxo-2-nitro-4-oxo-6-nitro-1 ... 1 H NMR (400MHz, CD3OD) δ7.36-7.21(m,15H),4.83(s,2H),4.65(s,4H),3.47-3.41(m,3H),3.21-3.12(m,2H),2.44-2.33(m,2H); ESI MS m / z 404.227[M+H] + .

[0262] Under Ar, a mixture of (3S,4r,5R)-3,4,5-tris(benzyloxy)piperidine (0.18 g, 0.45 mmol), 2-(3-chloro-2,6-difluorophenyl)acetaldehyde (0.10 g, 0.52 mmol) and NaBH(OAc) (0.15 g, 0.72 mmol) in DCM (10 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous NaHCO (10 mL) and extracted with DCM (3 × 15 mL). The combined extracts were dried over anhydrous NaSO. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:12 to 1:6) to give (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-(3-chloro-2,6-difluorophenethyl)piperidine as a colorless oil (0.24 g, 92%). ESI MS m / z 578.232 [M+H] + .

[0263] To a solution of the above substance (0.24 g, 0.42 mmol) in anhydrous DCM (10 mL) was added BCl (1.0 M solution in DCM, 3.0 mL, 3.0 mmol) at -78 ° C and Ar, and the mixture was stirred at 0 ° C for 3 h. The reaction mixture was cooled at -78 ° C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with a 1 M NH solution in MeOH and then purified by flash chromatography (0.5 M NH in 1:6 MeOH / DCM) on silica gel to give (3S, 4r, 5R) -1- (3-chloro-2,6-difluorophenethyl) piperidine-3,4,5-triol as a white solid (0.10 g, 81%). 1 H NMR(400MHz, DMSO-d6)δ7.50(td,J=8.8,5.8Hz,1H),7.13(td,J=9.0,1.8Hz,1H),),4.72-4.6 7(m,3H),3.26-3.11(m,2H),2.93-2.70(m,5H),2.52-2.45(m,2H),1.83(t,J=10.5Hz,2H); ESI MS m / z 308.089[M+H] + .

[0264] Example 8

[0265] (3S,4r,5R)-1-(3,4-dichlorophenethyl)piperidine-3,4,5-triol

[0266]

[0267] To a solution of 2-(3,4-dichlorophenyl)acetic acid (2.05 g, 10.0 mmol) in anhydrous THF (20 mL) was added LAH (0.48 g, 12.7 mmol) at 0°C under Ar, and the mixture was stirred at 0°C for 1 h. Wet sodium sulfate heptahydrate (100 g) was added to quench the reaction, and the suspension was stirred at room temperature for 1 hour. After filtration, the solvent was evaporated, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:3 to 1:2) to give 2-(3,4-dichlorophenyl)ethanol as a clear liquid (1.50 g, 79%). 1 H NMR (500MHz, CDCl3) δ7.37 (d, J = 8.2 Hz, 1H), 7.34 (d, J = 2.1 Hz, 1H), 7.07 (dd, J = 8.2, 2.1 Hz, 1H), 3.86 (t, J = 6.5 Hz, 2H), 2.82 (t, J = 6.5 Hz, 2H).

[0268] A mixture of the above substance (1.50 g, 7.85 mmol) and DMP (4.0 g, 9.4 mmol) in DCM (40 mL) was stirred at room temperature for 1.5 hours to form a white suspension. Hexane (100 mL) was added and the suspension was filtered through a diatomaceous earth filter cake. The filtrate was collected and concentrated to dryness under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:6 to 1:4) to give 2-(3,4-dichlorophenyl)acetaldehyde (1.15 g, 77%) as a light green liquid. 1 H NMR (400MHz, CDCl3) δ9.75 (t, J = 1.9 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.05 (dd, J = 8.2, 2.1 Hz, 1H), 3.68 (d, J = 1.9 Hz, 2H).

[0269] A solution of (3S,4r,5R)-3,4,5-tris(benzyloxy)piperidine (0.10 g, 0.25 mmol), 2-(3,4-dichlorophenyl)acetaldehyde (0.070 g, 0.37 mmol), and NaBH(OAc)3 (0.11 g, 0.52 mmol) in DCM (5 mL) was stirred at room temperature under Ar for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO3 (5 mL) and extracted with DCM (2 x 5 mL). The combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:6 to 1:4) to afford (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-(3,4-dichlorophenethyl)piperidine as a colorless oil (0.15 g, 100%). ESI MS m / z 576.209[M+H] + .

[0270] To a solution of the above substance (0.14 g, 0.25 mmol) in anhydrous DCM (5 mL) was added BCl (1.0 M in DCM, 2.5 mL, 2.5 mmol) at -78 ° C and Ar, and the mixture was stirred at 0 ° C for 3 h. The reaction mixture was cooled at -78 ° C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with a 1 M NH solution in MeOH, and then purified by flash chromatography (0.5 M NH in 1:6 MeOH / DCM) on silica gel to give (3S, 4r, 5R) -1- (3,4- dichlorophenethyl) piperidine -3,4,5- triol as a white solid (0.053 g, 69%). 1H NMR(400MHz, DMSO-d6)δ7.57-7.47(m,2H),7.23(dd,J=8.3,2.0Hz,1H),4.73-4.67(m,3H),3.26-3.10 (m,2H),2.93-2.79(m,3H),2.70(dd,J=8.6,6.8Hz,2H),2.55-2.50(m,2H),1.81(t,J=10.5Hz,2H); ESI MS m / z306.065[M+H] + .

[0271] Example 9

[0272] (3S,4r,5R)-1-(4-(cyclopropylmethoxy)-2,6-difluorophenethyl)piperidine-3,4,5-triol

[0273]

[0274] A mixture of (3S,4r,5R)-3,4,5-tris(benzyloxy)piperidine (0.10 g, 0.25 mmol), 2-(4-(cyclopropylmethoxy)-2,6-difluorophenyl)acetaldehyde (0.066 g, 0.29 mmol) and NaBH(OAc) (0.10 g, 0.47 mmol) in DCM (5 mL) was stirred at room temperature under Ar for 16 hours. The reaction mixture was diluted with saturated aqueous NaHCO (10 mL) and extracted with DCM (3 x 10 mL). The combined extracts were dried over anhydrous NaSO. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:10 to 1:6) to give (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-(4-(cyclopropylmethoxy)-2,6-difluorophenethyl)piperidine as a white solid (0.14 g, 92%). ESI MS m / z 614.311 [M+H] + .

[0275] A mixture of the above material (0.14 g, 0.23 mmol) and Pd(OH)2 / C (20% weight Pd, 0.050 g, 0.094 mmol) and three drops of concentrated HCl in MeOH (20 mL) was stirred overnight under hydrogen at one atmosphere. The mixture was filtered through a celite filter cake, and the filtrate was collected and concentrated to dryness. The residue was neutralized with 1 M NH3 in MeOH and then purified by flash chromatography on silica gel (0.5 M NH3MeOH / DCM, 1:6) to give (3S,4r,5R)-1-(4-(cyclopropylmethoxy)-2,6-difluorophenethyl)piperidine-3,4,5-triol (0.057 g, 73%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ6.70-6.59(m,2H),4.72-4.65(m,3H),3.80(d,J=7.1Hz,2H),3.28-3.15(m,2H),2.92-2.73(m,3H),2.6 3(t,J=7.5Hz,2H),2.42(t,J=7.4Hz,2H),1.81(t,J=10.4Hz,2H),1.26-1.10(m,1H),0.63-0.50(m,2H),0.38-0.25(m,2H); ESI MS m / z 344.169[M+H] + .

[0276] Example 10

[0277] (3S,4r,5R)-1-(2,6-difluoro-4-(pyrrolidin-1-yl)phenethyl)piperidine-3,4,5-triol

[0278]

[0279] A solution of (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-(4-bromo-2,6-difluorophenethyl)piperidine (0.18 g, 0.29 mmol), pyrrolidine (0.10 g, 1.4 mmol), CsCO (0.26 g, 0.80 mmol), RuPhos (0.026 g, 0.056 mmol) and Pd(dba) (0.025 g, 0.028 mmol) in anhydrous toluene (15 mL) was sparged with Ar for 10 min and then stirred in a sealed tube at 100° C. for 16 h. After cooling, the reaction mixture was filtered through a celite cake. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:9 to 1:6) to give (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-(2,6-difluoro-4-(pyrrolidin-1-yl)phenethyl)piperidine (0.17 g, 96%) as a light yellow oil.

[0280] To a solution of the above material (0.14 g, 0.23 mmol) in anhydrous DCM (5 mL) was added BCl (1.0 M in DCM, 3.0 mL, 3.0 mmol) at -78 ° C under Ar, and the mixture was stirred at 0 ° C for 3 hours. The reaction mixture was cooled at -78 ° C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with 1M NH in MeOH and then purified by flash chromatography on silica gel (0.5M NH in 1:6 MeOH / DCM) to give (3S,4r,5R)-1-(2,6-difluoro-4-(pyrrolidin-1-yl)phenethyl)piperidine-3,4,5-triol as a white solid (0.043 g, 55%). 1 H NMR(400MHz,DMSO-d6)δ6.22-6.08(m,2H),4.72-4.66(m,3H),3.27-3.10(m,6H),2.93-2.74(m,3H), 2.58(t,J=7.6Hz,2H),2.39(dd,J=8.7,6.4Hz,2H),2.04-1.86(m,4H),1.80(t,J=10.5Hz,2H); ESIMS m / z 343.187[M+H] + .

[0281] Example 11

[0282] (3S,4r,5R)-1-(2,6-difluoro-4-(piperidin-1-yl)phenethyl)piperidine-3,4,5-triol

[0283]

[0284] To a solution of (methoxymethyl)triphenylphosphonium chloride (22.0 g, 64.2 mmol) in anhydrous THF (150 mL) was added KO at -10°C under Ar. t Bu (7.20 g, 64.2 mmol) was added, and the reaction mixture was stirred at -10°C for 1 hour. 4-Bromo-2,6-difluorobenzaldehyde (7.10 g, 32.1 mmol) was added to the above solution, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with saturated aqueous NaHCO₃ (100 mL) and extracted with EtOAc (2 × 50 mL). The combined extracts were dried over anhydrous Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:19 to 1:9) to yield a light yellow solid (8.20 g, 100%, a mixture of trans and cis isomers). Aqueous HCl (2.5 N, 40 mL) was added to a solution of the light yellow solid (2.0 g, 8.0 mmol) in THF (40 mL), and the mixture was stirred at reflux for 5 hours. The reaction mixture was diluted with ice water (50 mL) and extracted with EtOAc (2×40 mL). The combined extracts were washed with saturated aqueous NaHCO₃ (50 mL) and dried over anhydrous Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:15 to 1:6) to give 2-(4-bromo-2,6-difluorophenyl)acetaldehyde as a light yellow oil (1.29 g, 70%). 1 H NMR (400MHz, CDCl3) δ9.74 (s, 1H), 7.18-7.08 (m, 2H), 3.76 (s, 2H).

[0285] A solution of the above material (0.90 g, 3.8 mmol) and NaBH(OAc)3 (1.2 g, 5.7 mmol) in DCM (30 mL) was stirred at room temperature for 16 h under Ar. The reaction mixture was diluted with saturated aqueous NaHCO3 (30 mL) and extracted with DCM (2×20 mL). The combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:12 to 1:6) to give (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-(4-bromo-2,6-difluorophenethyl)piperidine as a light yellow oil (2.03 g, 86%). ESI MS m / z 626.315 [M+H] + .

[0286] A solution of the above substance (0.18 g, 0.29 mmol), piperidine (0.10 g, 1.2 mmol), Cs2CO3 (0.26 g, 0.80 mmol), RuPhos (0.026 g, 0.056 mmol) and Pd2(dba)3 (0.025 g, 0.028 mmol) in anhydrous toluene (15 mL) was bubbled with Ar for 10 min, then stirred at 100 ° C in a sealed tube for 16 h. After cooling, the reaction mixture was filtered through a diatomaceous earth filter cake. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (EtOAc / hexane, 1: 9 to 1: 6) on silica gel to provide (3S, 4r, 5R) -3,4,5- tris (benzyloxy) -1- (2,6- difluoro -4- (piperidin-1-yl) phenethyl) piperidine (0.18 g, 99%) as a light yellow oil. ESI MS m / z 627.372[M+H] + .

[0287] To a solution of the above material (0.18 g, 0.29 mmol) in anhydrous DCM (10 mL) was added BCl (1.0 M in DCM, 3.0 mL, 3.0 mmol) at -78 ° C under Ar, and the mixture was stirred at 0 ° C for 3 hours. The reaction mixture was cooled at -78 ° C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with 1M NH in MeOH and then purified by flash chromatography on silica gel (0.5M NH in 1:6 MeOH / DCM) to give (3S,4r,5R)-1-(2,6-difluoro-4-(piperidin-1-yl)phenethyl)piperidine-3,4,5-triol as a white solid (0.079 g, 76%). 1 H NMR(400MHz,DMSO-d6)δ6.60-6.47(m,2H),4.72-4.66(m,3H),3.28-3.06(m,6H),2.90-2.78 (m,3H),2.62-2.52(m,2H),2.44-2.36(m,2H),1.80(t,J=10.5Hz,2H),1.63-1.43(m,6H); ESI MS m / z 357.206[M+H] + .

[0288] Example 12

[0289] (3S,4r,5R)-1-(2,6-difluoro-4-morpholinylphenethyl)piperidine-3,4,5-triol

[0290]

[0291] A solution of (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-(4-bromo-2,6-difluorophenethyl)piperidine (0.18 g, 0.29 mmol), morpholine (0.10 g, 1.2 mmol), CsCO (0.26 g, 0.80 mmol), RuPhos (0.026 g, 0.056 mmol) and Pd(dba) (0.025 g, 0.028 mmol) in anhydrous toluene (15 mL) was sparged with Ar for 10 min and then stirred in a sealed tube at 100° C. for 16 h. After cooling, the reaction mixture was filtered through a celite cake. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:4 to 1:3) to give 4-(3,5-difluoro-4-(2-((3S,4r,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)ethyl)phenyl)morpholine (0.15 g, 83%) as a light yellow oil. ESI MS m / z 629.326 [M+H] + .

[0292] To a solution of the above material (0.15 g, 0.24 mmol) in anhydrous DCM (5 mL) was added BCl (1.0 M in DCM, 3.0 mL, 3.0 mmol) at -78 ° C under Ar, and the mixture was stirred at 0 ° C for 3 hours. The reaction mixture was cooled at -78 ° C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with 1M NH in MeOH and then purified by flash chromatography on silica gel (0.5M NH in 1:6 MeOH / DCM) to give (3S,4r,5R)-1-(2,6-difluoro-4-morpholinylphenethyl)piperidine-3,4,5-triol as a white solid (0.054 g, 63%). 1 H NMR(400MHz,DMSO-d6)δ6.72-6.50(m,2H),4.72-4.66(m,3H),3.79-3.61(m,4H),3.28-3.15(m,2H),3.16 -3.03(m,4H),2.94-2.74(m,3H),2.61(t,J=7.5Hz,2H),2.44-2.37(m,2H),1.81(t,J=10.5Hz,2H); ESIMS m / z 359.187[M+H] + .

[0293] Example 13

[0294] (3S,4r,5R)-1-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenethyl)piperidine-3,4,5-triol

[0295]

[0296] A solution of (3S,4r,5R)-3,4,5-tris(benzyloxy)piperidine (0.25 g, 0.62 mmol), 2-(4-(3,6-dihydro-2H-pyran-4-yl)-2,6-difluorophenyl)acetaldehyde (0.19 g, 0.80 mmol) and NaBH(OAc) (0.21 g, 1.0 mmol) in DCM (15 mL) was stirred at room temperature for 16 h under N2. The reaction mixture was diluted with saturated aqueous NaHCO3 (15 mL) and extracted with DCM (2×20 mL). The combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:6 to 1:3) to give (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-(4-(3,6-dihydro-2H-pyran-4-yl)-2,6-difluorophenethyl)piperidine as a light yellow solid (0.34 g, 88%). ESI MS m / z 626.315 [M+H] + .

[0297] The above material (0.14 g, 0.22 mmol) was mixed with Pd(OH)2 / C (20% Pd by weight, 0.075 g, 0.14 mmol) and 5 drops of concentrated HCl in MeOH / THF (15 / 5 mL) and stirred overnight under an atmosphere of hydrogen. The mixture was filtered through a celite pad, and the filtrate was collected and concentrated to dryness. The residue was neutralized with 1M NH3 in MeOH and then purified by flash chromatography on silica gel (0.5M NH3 in MeOH / DCM, 1:6) to afford (3S,4r,5R)-1-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenethyl)piperidine-3,4,5-triol (0.058 g, 73%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.01-6.89(m,2H),4.75-4.63(m,3H),3.97-3.87(m,2H),3.39(td,J=11.4,2.7Hz,2H ),3.28-3.16(m,2H),2.96-2.62(m,6H),2.45(t,J=7.6Hz,2H),1.82(t,J=10.5Hz,2H),1.75-1.47(m,4H); ESI MS m / z 358.183[M+H] + .

[0298] Example 14

[0299] (3S,4r,5R)-1-(4-(3,5-dimethylisoxazol-4-yl)-2,6-difluorophenethyl)piperidine-3,4,5-triol

[0300]

[0301] A mixture of (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-(4-bromo-2,6-difluorophenethyl)piperidine (0.15 g, 0.24 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (0.042 g, 0.30 mmol), K2CO3 (0.69 g, 0.50 mmol, in 1 mL of water) and Pd(PPh3)4 (0.028 g, 0.024 mmol) in 1,4-dioxane (6 mL) was bubbled with Ar for 10 minutes and then stirred at 90 ° C in a sealed tube for 16 hours. After cooling, the reaction mixture was diluted with saturated aqueous NaHCO3 (20 mL). After extraction with EtOAc (2×20 mL), the combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:4 to 1:3) to give 4-(3,5-difluoro-4-(2-((3S,4r,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)ethyl)phenyl)-3,5-dimethylisoxazole as a clear oil (0.13 g, 85%). ESI MS m / z 639.403 [M+H] + .

[0302] To a solution of the above substance (0.13 g, 0.20 mmol) in anhydrous DCM (5 mL) was added BCl3 (1.0 M in DCM, 2.0 mL, 2.0 mmol) at -78 ° C and under Ar, and the mixture was stirred at 0 ° C for 3 hours. The reaction mixture was cooled at -78 ° C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with 1M NH3 in MeOH. It was then purified by flash chromatography on silica gel (0.5M NH3 in 1:6 MeOH / DCM) to provide (3S,4r,5R)-1-(4-(3,5-dimethylisoxazol-4-yl)-2,6-difluorophenethyl)piperidine-3,4,5-triol as a white solid (0.063 g, 85%). 1H NMR (400MHz, DMSO-d6) δ7.19-7.10(m,2H),4.76-4.65(m,3H),3.24(tt,J=9.6,4.8Hz,2H),2.92-2.83( m,3H),2.78(t,J=7.6Hz,2H),2.55-2.48(m,2H),2.42(s,3H),2.24(s,3H),1.85(t,J=10.5Hz,2H); ESI MS m / z 369.163[M+H] + .

[0303] Example 15

[0304] (3S,4r,5R)-1-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-2,6-difluorophenethyl)piperidine-3,4,5-triol

[0305]

[0306] A solution of (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-(4-bromo-2,6-difluorophenethyl)piperidine (0.15 g, 0.24 mmol), (3,5-dimethyl-1H-pyrazol-4-yl)boronic acid (0.042 g, 0.30 mmol), KCO (0.69 g, 0.50 mmol, in 1 mL of water), and Pd(PPh) (0.028 g, 0.024 mmol) in 1,4-dioxane (6 mL) was bubbled with Ar for 10 min and then stirred in a sealed tube at 90° C. for 16 h. After cooling, the reaction mixture was diluted with saturated aqueous NaHCO (20 ml). After extraction with EtOAc (2×20 mL), the combined extracts were dried over anhydrous NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 2:1 to 5:1) to give (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-2,6-difluorophenethyl)piperidine as a clear oil (0.048 g, 31%). ESI MS m / z 638.420 [M+H] + .

[0307] To a solution of the above material (0.048 g, 0.075 mmol) in anhydrous DCM (5 mL) was added BCl (1.0 M in DCM, 1.5 mL, 1.5 mmol) at -78 ° C under Ar, and the mixture was stirred at 0 ° C for 3 hours. The reaction mixture was cooled at -78 ° C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with 1M NH in MeOH and then purified by flash chromatography on silica gel (0.5M NH in 1:4 MeOH / DCM) to give (3S,4r,5R)-1-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-2,6-difluorophenethyl)piperidine-3,4,5-triol as a white solid (0.016 g, 58%). 1 HNMR(400MHz,CD3OD)δ6.91-6.83(m,2H),3.51(ddd,J=10.0,8.7,4.6Hz,2H),3.18-3.01(m,3H ), 2.91 (t, J = 7.7Hz, 2H), 2.68 (dd, J = 9.1, 6.3Hz, 2H), 2.26 (s, 6H), 2.08 (t, J = 10.6Hz, 2H); ESI MS m / z 368.178[M+H] + .

[0308] Example 16

[0309] (3S,4r,5R)-1-(1-(3-chloro-2-fluorophenyl)propan-2-yl)piperidine-3,4,5-triol

[0310]

[0311] To a stirred solution of 3-chloro-2-fluorophenylacetic acid (1.0 g, 5.30 mmol) in pyridine (5 mL), acetic anhydride (5 mL) was added and heated at 125 ° C for 5 hours. The reaction was quenched with water (50 mL) at 0 ° C. The mixture was extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with water (2 × 20 mL), separated, and dried with Na SO. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel to obtain 1-(3-chloro-2-fluorophenyl) propan-2-one as an oily substance (347 mg, 35%). 1 H NMR (400MHz, CDCl3) δ7.35 (td, J = 7.1, 2.7Hz, 1H), 7.14-7.03 (m, 2H), 3.79 (d, J = 1.5Hz, 2H), 2.26 (s, 3H).

[0312] To a stirred solution of (3S,4r,5R)-3,4,5-tris(benzyloxy)piperidine (150 mg, 0.37 mmol) and 1-(3-chloro-2-fluorophenyl)propan-2-one (138 mg, 0.74 mmol) in anhydrous DCM (5 mL) was added HOAc (5 drops) and stirred for 30 minutes. NaBH(OAc)3 (157 mg, 0.74 mmol) was added and the resulting mixture was stirred at room temperature for 18 h. The reaction was quenched with saturated NaHCO3 aqueous solution at 0°C. The mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (2×20 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-(1-(3-chloro-2-fluorophenyl)propan-2-yl)piperidine as an oil (43 mg, 20%). ESI MS m / z [M+H] + 574.26.

[0313] At -78 ° C, under nitrogen, BCl3 (1M concentration in DCM, 0.35 mL, 0.35 mmol) was added to a stirred solution of the above substance (40 mg, 0.07 mmol) in anhydrous DCM (5 mL). The mixture was stirred at 0 ° C for 2 h and then quenched with anhydrous MeOH (1 mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum, and the residue was dissolved in a 1M NH3 solution in MeOH (10 mL) and stirred for another 10 minutes, and then the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel to obtain (3S, 4r, 5R) -1- (1- (3-chloro-2-fluorophenyl) propan-2-yl) piperidine-3,4,5-triol as a white solid (16 mg, 75%). 1 H NMR (400MHz, CD3OD) δ7.31(ddd,J=8.4,7.1,1.7Hz,1H),7.20(ddd,J=8.1,6.6,1.7Hz,1H),7.08(td,J=7.8,1.1Hz,1H),3.46-3.34(m,2H),3.07(t ,J=8.8Hz,1H),3.03-2.92(m,3H),2.90-2.83(m,1H),2.66-2.56(m,1H), 2.27(t,J=10.4Hz,1H),2.20(t,J=10.4Hz,1H),1.02(d,J=6.3Hz,3H); ESI MS m / z[M+H] + 304.15.

[0314] Example 17

[0315] (3S,4r,5R)-1-(4-(3-chloro-2-fluorophenyl)butan-2-yl)piperidine-3,4,5-triol

[0316]

[0317] To a stirred solution of 3-chloro-2-fluorobenzyl bromide (1.0 g, 4.47 mmol) and acetylacetone (0.50 mL, 4.92 mmol) in anhydrous EtOH (20 mL) was added KCO (618 mg, 4.47 mmol) and the mixture was refluxed for 18 h. The reaction was quenched with water (50 mL) at 0°C. The mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (2 x 20 mL), separated and dried over NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give 4-(3-chloro-2-fluorophenyl)butan-2-one as an oil (595 mg, 66%). 1 H NMR (400MHz, CDCl3) δ7.28-7.23(m,1H),7.16-7.09(m,1H),7.01(td,J=7.8,1.1Hz,1H),2.96(t,J=7.5Hz,2H),2.79(t,J=7.5Hz,2H),2.17(s,3H).

[0318] To a stirred solution of (3S,4r,5R)-3,4,5-tris(benzyloxy)piperidine (150 mg, 0.37 mmol) and 4-(3-chloro-2-fluorophenyl)butan-2-one (138 mg, 0.74 mmol) in anhydrous DCM (5 mL) was added HOAc (5 drops), the mixture was stirred for 30 minutes, NaBH(OAc)3 (157 mg, 0.74 mmol) was added, and the resulting mixture was stirred at room temperature for 18 hours. The reaction was quenched with saturated aqueous NaHCO3 at 0°C. The mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (2×20 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-(4-(3-chloro-2-fluorophenyl)butan-2-yl)piperidine as an oil (107 mg, 49%). ESI MS m / z 588.27 [M+H] + .

[0319] To a stirred solution of the above material (107 mg, 0.18 mmol) in anhydrous DCM (5 mL) at -78°C under N₂ was added BCl₃ (1 M in DCM, 0.97 mL, 0.97 mmol). The mixture was stirred at 0°C for 2 h and then quenched with anhydrous MeOH (1 mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum, and the residue was dissolved in 1 M NH₃ in MeOH (10 mL) and stirred for an additional 10 minutes, then the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel to yield (3S,4r,5R)-1-(4-(3-chloro-2-fluorophenyl)butan-2-yl)piperidine-3,4,5-triol as a white solid (34 mg, 59%). 1 H NMR (400MHz, CD3OD) δ7.29 (ddd, J=8.4, 7.1, 1.7Hz, 1H), 7.21 (td, J=7.2, 6.6, 1.7Hz,1H),7.08(td,J=7.8,1.1Hz,1H),3.55-3.38(m,2H),3.07(t,J=8.8Hz, 1H),2.90-2.86(m,1H),2.82-2.60(m,4H),2.28(t,J=10.4Hz,1H),2.03(t,J= 10.5Hz,1H),1.88-1.74(m,1H),1.66-1.53(m,1H),1.02(d,J=6.6Hz,3H); ESI m / z 318.13[M+H] + .

[0320] Example 18

[0321] (3S,4R,5R)-1-(((R)-1-(o-Tolyl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol

[0322]

[0323] To a stirred solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-((S)-pyrrolidin-3-ylmethyl)piperidine (150 mg, 0.31 mmol) and 2-bromotoluene (106 mg, 0.62 mmol) in toluene (5 mL) under Ar was added Pd(dba) (28 mg, 0.031 mmol) and RuPhos (29 mg, 0.062 mmol), followed by CsCO (304 mg, 1.24 mmol). The mixture was stirred at 90°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 10 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give (3S,4R,5R)-3,4,5-tris(benzyloxy)-1-(((R)-1-(o-tolyl)pyrrolidin-3-yl)methyl)piperidine as an oil (122 mg, 68%). ESI MS m / z [M+H] + 577.35.

[0324] At -78 ° C and N2, BCl3 (1M in DCM, 1.06 mL, 1.06 mmol) was added to a stirred solution of the above-mentioned substance (122 mg, 0.21 mmol) in anhydrous DCM (5 mL). The mixture was stirred at 0 ° C for 2 h and then quenched with anhydrous MeOH (1 mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum, and the residue was dissolved in a 1M NH3 solution of MeOH (10 mL) and stirred for another 10 minutes, then the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel to obtain (3S, 4R, 5R) -1- (((R) -1- (o-tolyl) pyrrolidin-3-yl) methyl) piperidine -3,4,5- triol as a white solid (49 mg, 76%). 1 H NMR (400MHz, DMSO-d6) δ7.09-7.02(m,2H),6.84(d,J=7.7Hz,1H),6.77(td,J=7.3,1.1Hz,1H),4.72-4.67(m,3H),3.30-3.22(m,2H) ,3.18-3.03(m,3H),2.96-2.74(m,4H),2.46-2.29(m,3H),2.23(s,3H),2.04-1.93(m,1H),1.84-1.70(m,2H),1.61-1.49(m,1H); ESI MS m / z[M+H] + 307.21.

[0325] Example 19

[0326] (3S,4R,5R)-1-(((R)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol

[0327]

[0328] To a stirred solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-((S)-pyrrolidin-3-ylmethyl)piperidine (150 mg, 0.31 mmol) and 2-chloro-3-(trifluoromethyl)pyridine (113 mg, 0.62 mmol) in toluene (5 mL) under Ar was added Pd(dba) (28 mg, 0.031 mmol) and RuPhos (29 mg, 0.062 mmol), followed by CsCO (304 mg, 1.24 mmol). The mixture was stirred at 90°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 10 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give 3-(trifluoromethyl)-2-((R)-3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)pyrrolidin-1-yl)pyridine as an oil (100 mg, 51%). ESI MS m / z [M+H] + 632.31.

[0329] To a stirred solution of the above material (100 mg, 0.16 mmol) in anhydrous DCM (5 mL) at -78°C under N₂ was added BCl₃ (1 M in DCM, 0.80 mL, 0.80 mmol). The mixture was stirred at 0°C for 2 h and then quenched with anhydrous MeOH (1 mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum, and the residue was dissolved in 1 M NH₃ in MeOH (10 mL) and stirred for an additional 10 minutes before the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel to yield (3S,4R,5R)-1-(((R)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol as a white solid (29 mg, 50%). 1H NMR (400MHz, CD3OD) δ8.26(dd,J=4.7,1.8Hz,1H),7.88(dd,J=7.8,1.9Hz,1H),6.75(dd,J=7.8,4.7Hz,1H),3.74-3.60(m,3H),3.57-3.47(m,2H ),3.41-3.34(m,1H),3.11(t,J=8.8Hz,1H),3.07-2.94(m,2H),2.59-2. 31(m,3H),2.18-2.07(m,1H),2.04-1.91(m,2H),1.78-1.65(m,1H);ESI MS m / z[M+H] + 362.17.

[0330] Example 20

[0331] (3S,4R,5R)-1-(((R)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol

[0332]

[0333] To a stirred solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-((S)-pyrrolidin-3-ylmethyl)piperidine (150 mg, 0.31 mmol) and 3-bromo-4-(trifluoromethyl)pyridine (139 mg, 0.62 mmol) in toluene (5 mL) under Ar was added Pd(dba) (28 mg, 0.031 mmol) and RuPhos (29 mg, 0.062 mmol), followed by CsCO (304 mg, 1.24 mmol). The mixture was stirred at 90°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 10 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give 4-(trifluoromethyl)-3-((R)-3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)pyrrolidin-1-yl)pyridine as an oil (115 mg, 59%). ESI MS m / z [M+H] + 632.31.

[0334] To a stirred solution of the above substance (115 mg, 0.18 mmol) in anhydrous DCM (5 mL) was added BCl (1 M in DCM, 0.91 mL, 0.91 mmol) at -78 ° C and N2. The mixture was stirred at 0 ° C for 2 h and then quenched with anhydrous MeOH (1 mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum, and the residue was dissolved in a 1M NH3 solution in MeOH (10 mL) and stirred for another 10 minutes, then the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel to obtain (3S, 4R, 5R)-1-(((R)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol as a white solid (38 mg, 58%). 1 H NMR (400MHz, CD3OD) δ8.33(s,1H),8.01(d,J=5.2Hz,1H),7.50(d,J=5.2Hz,1H),3.60-3.43(m,5H),3.32-3.25(m,1H),3.12(t,J= 8.8Hz,1H),3.08-2.94(m,2H),2.64-2.53(m,1H),2.52-2.46(m,2H),2.23-2.11(m,1H),2.06-1.92(m,2H),1.82-1.70(m,1H); ESI MS m / z[M+H] + 362.17.

[0335] Example 21

[0336] (3S,4R,5R)-1-(((R)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol

[0337]

[0338] To a stirred solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-((S)-pyrrolidin-3-ylmethyl)piperidine (100 mg, 0.21 mmol) and 2-bromo-5-(trifluoromethyl)thiazole (72 mg, 0.31 mmol) in DMA (3 mL) was added CsCO (276 mg, 0.84 mmol). The mixture was stirred at 70°C for 24 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 10 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give 5-(trifluoromethyl)-2-((R)-3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)pyrrolidin-1-yl)thiazole as an oil (68 mg, 51%). ESI MS m / z [M+H] + 638.27.

[0339] To a stirred solution of the above material (68 mg, 0.11 mmol) in anhydrous DCM (5 mL) at -78°C under N₂ was added BCl₃ (1 M in DCM, 0.55 mL, 0.55 mmol). The mixture was stirred at 0°C for 2 h and then quenched with anhydrous MeOH (1 mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum, and the residue was dissolved in 1 M NH₃ in MeOH (10 mL) and stirred for an additional 10 minutes before the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel to yield (3S,4R,5R)-1-(((R)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol as a white solid (19 mg, 47%). 1 H NMR (400MHz, CD3OD) δ7.15(q,J=1.1Hz,1H),3.69-3.60(m,1H),3.60-3.43(m,4H),3.23(dd,J=10.1,7.1Hz,1H),3.12(t,J=8.8Hz,1H),3.09- 2.95(m,2H),2.76-2.63(m,1H),2.56-2.44(m,2H),2.29-2.18(m,1H),2.01(t,J=10.5Hz,1H),1.95(t,J=10.5Hz,1H),1.90-1.78(m,1H); MS m / z[M+H] + 368.13.

[0340] Example 22

[0341] (3S,4R,5R)-1-(((R)-1-(Benzo[d]oxazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol

[0342]

[0343] To a stirred solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-((S)-pyrrolidin-3-ylmethyl)piperidine (108 mg, 0.22 mmol) and 2-chlorobenzo[d]oxazole (68 mg, 0.44 mmol) in DMA (3 mL) was added CsCO (289 mg, 0.88 mmol). The mixture was stirred at 80°C for 24 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 10 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give 2-((R)-3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)pyrrolidin-1-yl)benzo[d]oxazole as an oil (128 mg, 96%). ESI MS m / z [M+H] + 604.31.

[0344] To a stirred solution of the above material (128 mg, 0.21 mmol) in anhydrous DCM (5 mL) at -78°C under N₂ was added BCl₃ (1 M in DCM, 1.06 mL, 1.06 mmol). The mixture was stirred at 0°C for 2 h and then quenched with anhydrous MeOH (1 mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum, and the residue was dissolved in a 1M NH₃ solution in MeOH (10 mL) and stirred for an additional 10 minutes, then the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel to give (3S,4R,5R)-1-(((R)-1-(benzo[d]oxazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol as a white solid (27 mg, 39%). 1H NMR(400MHz,DMSO-d6)δ7.38(dd,J=7.9,1.0Hz,1H),7.27-7.22(m,1H),7.12(td ,J=7.6,1.1Hz,1H),6.97(td,J=7.7,1.2Hz,1H),4.76-4.70(m,3H),3.71-3.60(m ,2H),3.57-3.49(m,1H),3.32-3.22(m,3H),2.93-2.85(m,2H),2.84-2.75(m,1H) ,2.60-2.52(m,1H),2.39-2.30(m,2H),2.11-2.02(m,1H),1.87-1.65(m,3H);ESI MS m / z[M+H] + 334.18.

[0345] Example 23

[0346] (3S,4R,5R)-1-(((R)-1-(Benzo[d]thiazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol

[0347]

[0348] To a stirred solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-methyl-1-((S)-pyrrolidin-3-ylmethyl)piperidine (100 mg, 0.21 mmol) and 2-bromobenzo[d]thiazole (66 mg, 0.31 mmol) in DMA (3 mL) was added CsCO (276 mg, 0.84 mmol). The mixture was stirred at 70°C for 24 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 10 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give 2-((R)-3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)pyrrolidin-1-yl)benzo[d]thiazole as an oil (68 mg, 51%). ESI MS m / z [M+H] + 620.30.

[0349] At -78 ° C, N2, to the stirred anhydrous DCM (5 mL) solution of the above substance (68 mg, 0.11 mmol) was added BCl3 (concentration in DCM was 1M, 0.55 mL, 0.55 mmol). The mixture was stirred at 0 ° C for 2 h and then quenched with anhydrous MeOH (1 mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum, and the residue was dissolved in 1M NH3 in MeOH (10 mL) and stirred for another 10 min, and then the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel to give (3S, 4R, 5R) -1- (((R) -1- (benzo [d] thiazol-2-yl) pyrrolidin-3-yl) methyl) piperidine -3,4,5- triol as a white solid (19 mg, 49%). 1 H NMR (400MHz, CD3OD) δ7.68-7.62(m,1H),7.49(dd,J=8.4,1.0Hz,1H),7.30(ddd,J=8.3, 7.3,1.3Hz,1H),7.12-7.04(m,1H),3.77-3.63(m,2H),3.62-3.48(m,3H),3.36-3.29(m ,1H),3.13(t,J=8.8Hz,1H),3.09-2.95(m,2H),2.76-2.63(m,1H),2.56-2.44(m,2H),2 .29-2.18(m,1H),2.02(t,J=10.5Hz,1H),1.96(t,J=10.5Hz,1H),1.92-1.80(m,1H); ESI MS m / z[M+H] + 350.15.

[0350] Example 24

[0351] (3S,4S,5R)-1-(((S)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol

[0352]

[0353] Under Ar, a mixture of (3S, 4R, 5R) -3, 4, 5- tris (benzyloxy) piperidine (2.02 g, 5.00 mmol), (R) -3- formyl pyrrolidine -1- carboxylic acid tert-butyl ester (1.60 g, 8.03 mmol) and NaBH (OAc) 3 (2.12 g, 10.0 mmol) in DCM (40 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous NaHCO 3 (40 mL) and extracted with DCM (2 × 30 mL). The combined extracts were dried over anhydrous Na 2 SO 4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:6 to 1:3) to give (S)-tert-butyl 3-(((3S,4S,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate as a light yellow oil (2.7 g, 92%). ESI MS m / z 587.352 [M+H] + .

[0354] To a solution of the above substance (2.7 g, 4.6 mmol) in DCM (30 mL) was added TFA (8 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous NaHCO3 solution (50 mL). After extraction with DCM (3×50 mL), the combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was flash chromatographed on silica gel (1M NH3 in 1:10 MeOH / DCM) to give (3S,4R,5R)-3,4,5-tris(benzyloxy)-1-((R)-pyrrolidin-3-ylmethyl)piperidine as a light yellow oil (2.2 g, 98%). ESI MS m / z 487.298 [M+H] + .

[0355] A mixture of (3S, 4R, 5R) -3, 4, 5- tris (benzyloxy) -1- ((R) -pyrrolidin-3-ylmethyl) piperidine (0.25 g, 0.51 mmol), 2-chloro-3- (trifluoromethyl) pyridine (0.18 g, 1.0 mmol) and DIPEA (0.26 g, 2.0 mmol) in anhydrous DMF (6 mL) was stirred in a sealed tube at 100 ° C for 3 days. After cooling, the mixture was diluted with saturated NaHCO aqueous solution (30 mL). It was extracted with EtOAc (2 × 30 mL). The combined extracts were washed with brine (20 mL) and then dried over anhydrous Na SO. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:5 to 1:3) to give (3S,4S,5R)-1-(((S)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol as a light yellow oil (0.26 g, 80%). ESI MS m / z 632.301 [M+H] + .

[0356] To a solution of the above material (0.23 g, 0.36 mmol) in anhydrous DCM (8 mL) was added BCl (1.0 M in DCM, 3.0 mL, 3.0 mmol) at -78 ° C under Ar, and the mixture was stirred at 0 ° C for 3 hours. The reaction mixture was cooled at -78 ° C, quenched with MeOH, and concentrated to dryness. The residue was neutralized with 1M NH in MeOH. It was then purified by flash column chromatography on silica gel (0.5M NH in 1:7 MeOH / DCM) to give (3S,4S,5R)-1-(((S)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol as a white solid (0.102 g, 78%). 1H NMR(500MHz,DMSO-d6)δ8.32(dd,J=4.6,1.8Hz,1H),7.90(dd,J=7.8,1.8Hz,1H),6.77(d d,J=7.8,4.6Hz,1H),4.73(d,J=4.4Hz,1H),4.70(dd,J=4.9,1.3Hz,2H),3.60-3.47(m,3H ),3.30-3.19(m,3H),2.96-2.81(m,2H),2.81-2.72(m,1H),2.47-2.38(m,1H),2.38-2.20 (m,2H),2.00(dq,J=11.8,5.9Hz,1H),1.77(dt,J=26.1,10.4Hz,2H),1.64-1.54,1H); ESI MSm / z 362.167[M+H] + .

[0357] Example 25

[0358] (3S,4S,5R)-1-(((S)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol

[0359]

[0360] A solution of (3S,4R,5R)-3,4,5-tris(benzyloxy)-1-((R)-pyrrolidin-3-ylmethyl)piperidine (0.14 g, 0.28 mmol), 3-bromo-4-(trifluoromethyl)pyridine (0.11 g, 0.50 mmol), CsCO (0.26 g, 0.80 mmol), RuPhos (0.026 g, 0.056 mmol) and Pd(dba) (0.026 g, 0.028 mmol) in anhydrous toluene (6 mL) was sparged with Ar for 10 min and then stirred in a sealed tube at 100° C. for 16 h. After cooling, the reaction mixture was filtered through a celite cake. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:2 to 1:1) to give 4-(trifluoromethyl)-3-((S)-3-(((3S,4S,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)pyrrolidin-1-yl)pyridine as a light yellow oil (0.15 g, 85%). ESI MS m / z 632.315 [M+H] + .

[0361] To a solution of the above material (0.14 g, 0.22 mmol) in anhydrous DCM (6 mL) was added BCl3 (1.0 M in DCM, 2.0 mL, 2.0 mmol) at -78°C under Ar, and the mixture was stirred at 0°C for 3 hours. The reaction mixture was cooled at -78°C, quenched with MeOH, and concentrated to dryness. The residue was neutralized with 1 M NH3 in MeOH. It was then purified by flash column chromatography on silica gel (0.5 M NH3 in 1:6 MeOH / DCM) to give (3S,4S,5R)-1-(((S)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol as a white solid (0.033 g, 41%). 1 H NMR (400MHz, DMSO-d6) δ8.37(s,1H),8.05(d,J=5.1Hz,1H),7.46(d,J=5.1Hz,1H),4.75-4.65(m,3H),3.52-3.38(m,3H),3.35-3.20(m,2H) ,3.20-3.14(m,1H),2.95-2.85(m,3H),2.50-2.40(m,1H),2.40-2.28(m,2H),2.09-1.98(m,1H),1.85-1.70(m,2H),1.70-1.60(m,1H); ESI MS m / z 362.166[M+H] + .

[0362] Example 26

[0363] (3S,4S,5R)-1-(((S)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol

[0364]

[0365] A mixture of (3S,4R,5R)-3,4,5-tris(benzyloxy)-1-((R)-pyrrolidin-3-ylmethyl)piperidine (0.20 g, 0.41 mmol), 5-bromo-4-(trifluoromethyl)pyrimidine (0.12 g, 0.53 mmol), CsCO (0.30 g, 0.92 mmol), RuPhos (0.035 g, 0.075 mmol) and Pd(dba) (0.035 g, 0.038 mmol) in anhydrous toluene (8 mL) was sparged with Ar for 10 minutes and then stirred in a sealed tube at 100° C. for 16 hours. After cooling, the reaction mixture was filtered through a celite cake. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:4 to 1:2) to give 4-(trifluoromethyl)-5-((S)-3-(((3S,4S,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)pyrrolidin-1-yl)pyrimidine (0.16 g, 62%) as a light yellow oil. ESI MS m / z 633.298 [M+H] + .

[0366] To a solution of the above material (0.16 g, 0.25 mmol) in anhydrous DCM (8 mL) was added BCl (1.0 M in DCM, 2.0 mL, 2.0 mmol) at -78 ° C under Ar, and the mixture was stirred at 0 ° C for 3 hours. The reaction mixture was cooled at -78 ° C, quenched with MeOH, and concentrated to dryness. The residue was neutralized with 1M NH in MeOH. It was then purified by flash column chromatography on silica gel (0.5M NH in 1:5 MeOH / DCM) to give (3S,4S,5R)-1-(((S)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol as a white solid (0.030 g, 33%). 1 H NMR(400MHz,DMSO-d6)δ8.59(s,1H),8.58(s,1H),4.82-4.62(m,3H),3.51-3.41(m,3H),3.35-3.15(m, 3H),2.98-2.70(m,3H),2.50-2.40(m,1H),2.40-2.24(m,2H),2.10-1.98(m,1H),1.90-1.58(m,3H); ESI MS m / z 363.159[M+H] + .

[0367] Example 27

[0368] (3S,4S,5R)-1-(((S)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol

[0369]

[0370] A mixture of (3S,4R,5R)-3,4,5-tris(benzyloxy)-1-((R)-pyrrolidin-3-ylmethyl)piperidine (0.19 g, 0.39 mmol), 2-bromo-4-(trifluoromethyl)thiazole (0.12 g, 0.52 mmol), CsCO (0.30 g, 0.92 mmol), RuPhos (0.035 g, 0.075 mmol) and Pd(dba) (0.035 g, 0.038 mmol) in anhydrous toluene (8 mL) was sparged with Ar for 10 minutes and then stirred in a sealed tube at 100° C. for 16 hours. After cooling, the reaction mixture was filtered through a celite cake. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:4 to 1:3) to give 4-(trifluoromethyl)-2-((S)-3-(((3S,4S,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)pyrrolidin-1-yl)thiazole (0.20 g, 80%) as a light yellow oil. ESI MS m / z 638.262 [M+H] + .

[0371] To a solution of the above material (0.20 g, 0.31 mmol) in anhydrous DCM (8 mL) was added BCl (1.0 M in DCM, 2.0 mL, 2.0 mmol) at -78 ° C under Ar, and the mixture was stirred at 0 ° C for 3 h. The reaction mixture was cooled at -78 ° C, quenched with MeOH, and concentrated to dryness. The residue was neutralized with 1M NH in MeOH. Flash column chromatography on silica gel (0.5M NH in MeOH / DCM, 1:6) gave (3S,4S,5R)-1-(((S)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol as a white solid (0.078 g, 68%). 1H NMR (400MHz, DMSO-d6) δ7.41(t,J=1.2Hz,1H),4.78-4.67(m,3H),3.57-3.41(m,2H),3.41-3.19(m,3H),3.09(dd,J=10.0,6 .9Hz,1H),2.92-2.75(m,3H),2.63-2.51(m,1H),2.33(d,J=7.5Hz,2H),2.07(td,J=12.0,6.8Hz,1H),1.87-1.52(m,3H); ESI MS m / z 368.123[M+H] + .

[0372] Example 28

[0373] (3S,4S,5R)-1-(((S)-1-(Benzo[d]thiazol-4-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol

[0374]

[0375] A solution of (3S,4R,5R)-3,4,5-tris(benzyloxy)-1-((R)-pyrrolidin-3-ylmethyl)piperidine (0.14 g, 0.28 mmol), 4-bromobenzo[d]thiazole (0.12 g, 0.56 mmol), CsCO (0.26 g, 0.80 mmol), RuPhos (0.026 g, 0.056 mmol) and Pd(dba) (0.026 g, 0.028 mmol) in anhydrous toluene (6 mL) was sparged with Ar for 10 min and then stirred in a sealed tube at 100° C. for 16 h. After cooling, the reaction mixture was filtered through a celite cake. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:5 to 1:3) to give 4-((S)-3-(((3S,4S,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)pyrrolidin-1-yl)benzo[d]thiazole (0.17 g, 98%) as a yellow oil. ESI MS m / z 620.295 [M+H] + .

[0376] To a solution of the above material (0.16 g, 0.26 mmol) in anhydrous DCM (8 mL) was added BCl (1.0 M in DCM, 2.0 mL, 2.0 mmol) at -78°C under Ar, and the mixture was stirred at 0°C for 3 hours. The reaction mixture was cooled at -78°C, quenched with MeOH, and concentrated to dryness. The residue was neutralized with 1 M NH in MeOH. The product was then purified by flash column chromatography on silica gel (0.5 M NH in MeOH / DCM, 1:7) to give (3S,4S,5R)-1-(((S)-1-(benzo[d]thiazol-4-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol as a light blue solid (0.048 g, 53%). 1 H NMR(500MHz,DMSO-d6)δ9.07(s,1H),7.29(dd,J=7.8,1.0Hz,1H),7.23(t,J=7.8Hz,1H),6.52(dd,J=8 .0,1.1Hz,1H),4.73(d,J=4.3Hz,1H),4.71(d,J=4.9Hz,2H),3.81(dd,J=10.3,7.2Hz,1H),3.75-3.71( m,1H),3.67-3.62(m,1H),3.40(dd,J=10.3,6.8Hz,1H),3.32-3.25(m,2H),2.94-2.77(m,3H),2.53-2. 44(m,1H),2.42-2.31(m,2H),2.14-1.99(m,1H),1.78(dt,J=13.5,10.5Hz,2H),1.72-1.64(m,1H); ESI MS m / z 350.151[M+H] + .

[0377] Example 29

[0378] (3S,4R,5R)-1-(((R)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0379]

[0380] A solution of (3S,4S,5R)-3,4,5-tris(benzyloxy)-1-((S)-piperidin-3-ylmethyl)piperidine (0.3 g, 0.6 mmol) and 2-chloro-3-(trifluoromethyl)pyridine (0.3 g, 1.8 mmol) in 1,4-dioxane (3 mL) was added to a microwave vial. DIPEA (0.5 mL, 3.0 mmol) was added and the reaction mixture was microwaved at 150° C. for 90 minutes. The reaction mixture was partitioned between EtOAc (50 mL) and water, and the organics were separated and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give 3-(trifluoromethyl)-2-((R)-3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)pyridine as an oil (0.22 g, 56.7%). 1 H NMR (400MHz, CDCl3) δ8.42 (dd, J=4.8, 1.8Hz, 1H), 7.85 (dd, J=7.8, 1.9Hz, 1H), 7.40-7.24 (m, 15H), 6.95(dd,J=7.8,4.8Hz,1H),4.91(s,2H),4.76-4.61(m,4H),3.74-3.66(m,1H),3.63-3.53(m,3H), 3.42(t,J=8.9Hz,1H),3.21(ddd,J=10.9,5.1,2.1Hz,1H),2.97-2.87(m,2H),2.52(dd,J=12.4,9.9 Hz,1H),2.28-2.21(m,2H),2.02-1.91(m,2H),1.89-1.62(m,4H),1.08(qd,J=13.1,7.3Hz,1H); ESI MS m / z 376.189[M+H] + .

[0381] To a solution of the above material (0.31 g, 0.46 mmol) in DCM (8 mL) was added BCl₃ (1.0 M in DCM, 2.3 mL, 2.3 mmol) at -78°C under Ar, and the mixture was stirred for 3 hours while the bath temperature reached room temperature. The mixture was then cooled to -78°C, and MeOH (2 mL) was carefully added. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. The resulting residue was neutralized with a 1M NH₃ solution in MeOH (2 × 5 mL) and concentrated again under reduced pressure. The residue was purified by flash chromatography on silica gel (MeOH / DCM, 1:9) to give (3S,4R,5R)-1-(((R)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol (0.11 g, 63%) as a white solid. 1 H NMR (400MHz, CD3OD) δ8.44(dd,J=4.9,1.8Hz,1H),7.98(dd,J=7.8,1.9Hz,1H),7.14-7.08(m,1 H),3.66(dt,J=12.4,2.4Hz,1H),3.52-3.43(m,3H),3.13-3.01(m,2H),2.94(ddd,J=13.3,11.2 ,2.8Hz,1H),2.86(ddd,J=10.9,5.0,2.2Hz,1H),2.60(dd,J=12.4,9.7Hz,1H),2.36-2.23(m,2H ),2.03-1.92(m,2H),1.89-1.76(m,3H),1.75-1.64(m,1H),1.17(qd,J=12.8,4.6Hz,1H); ESIMS m / z 376.179[M+H] + .

[0382] Example 30

[0383] (3S,4R,5R)-1-(((R)-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0384]

[0385] To a solution of (S)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (1.07 g, 5 mmol) in anhydrous DCM (15 mL) was added DMP (2.7 g, 6.5 mmol) at 0°C. After stirring at 0°C for 30 minutes, the reaction mixture was warmed to room temperature for 1.5 hours. The reaction mixture was diluted with a 1:1 mixture of 1M Na2S2O3 and saturated NaHCO3 (50 mL) aqueous solution and stirred for 30 minutes. DCM (30 mL) was added and the organic matter was separated, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:1) to give (S)-tert-butyl 3-formylpiperidine-1-carboxylate (0.79 g, 74%) as a gummy solid. 1 H NMR (400MHz, CDCl3) δ9.63(s,1H),3.86(d,J=13.3Hz,1H),3.57(dt,J=13.4,4.8Hz,1H),3.27(dd,J=13.6,8.3Hz,1H),3.03(ddd, J=13.1,9.3,3.4Hz,1H),2.36(qd,J=9.8,9.2,4.7Hz,1H),1.95-1.82(m,1H),1.69-1.53(m,2H),1.49-1.41(m,1H),1.39(s,9H).

[0386] To (3S, 4r, 5R) -3,4,5- three (benzyloxy) piperidine (0.98g, 2.42mmol) DCM (20mL) solution, add (S) -3- formyl piperidine -1- carboxylic acid tert-butyl ester (0.7g, 3.6mmol) and HOAc (0.3mL). After stirring at room temperature for 10 minutes, NaBH (OAc) was added (0.8g, 4.1mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and then diluted with DCM (25mL). By organic matter saturated NaHCO aqueous solution, salt water washing, through anhydrous Na SO dried and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 3:7) to give (R)-tert-butyl 3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidine-1-carboxylate (1.37 g, 94%) as an oil. 1H NMR (400MHz, CDCl3) δ7.43-7.24(m,15H),4.92(s,2H),4.80-4.62(m,4H),4.05-3.83 (m,2H),3.66-3.54(m,2H),3.44(t,J=8.9Hz,1H),3.15-3.02(m,1H),3.02-2.92(m,1 H),2.88-2.74(m,1H),2.49(m,1H),2.25-2.21(m,2H),2.0-1.88(m,2H),1.75(d,J=1 3.3Hz,1H),1.68-1.56(m,2H),1.52-1.59(m,1H),1.48(s,9H),1.12-1.00(m,1H); ESI MS m / z 601.369[M+1] + .

[0387] The above material (1.37 g, 2.28 mmol) was dissolved in 1:1 TFA:DCM (10 mL) at 0°C and stirred for 30 minutes. The reaction mixture was allowed to warm to room temperature over 2 hours and then concentrated to dryness. The residue was diluted with EtOAc (30 mL) and washed with saturated aqueous NaHCO₃ (2 x 50 mL), dried over anhydrous Na₂SO₄, and then concentrated to afford (3S,4S,5R)-3,4,5-tris(benzyloxy)-1-((S)-piperidin-3-ylmethyl)piperidine as an oil (1.01 g, 88%). 1 H NMR (400MHz, CDCl3) δ7.45-7.23(m,15H),6.77(bs,1H),4.91(s,2H),4.77-4.59(m,4H),3.63-3.49(m,2H),3.4 3(t,J=8.8Hz,1H),3.27(dd,J=12.4,3.6Hz,1H),3.19(dd,J=12.5,3.4Hz,1H),3.10(ddd,J=11.0,5.1,2.0Hz,1 H),2.96(ddd,J=11.0,5.1,2.0Hz,1H),2.67(tt,J=12.3,3.9Hz,1H),2.35(dd,J=12.4,10.7Hz,1H),2.25-2.19 (m,2H),2.00(t,J=10.6Hz,1H),1.94-1.85(m,2H),1.82-1.74(m,2H),1.72-1.59(m,1H),1.10-0.95(m,1H); ESI MS m / z 501.318[M+1] + .

[0388] To a stirred solution of the above material (0.15 g, 0.3 mmol) and 2-chloro-6-(trifluoromethyl)pyridine (0.1 g, 0.6 mmol) in toluene (5 mL) under Ar was added Pd2(dba)3 (28 mg, 0.03 mmol) and RuPhos (28 mg, 0.06 mmol), followed by Cs2CO3 (0.3 g, 0.9 mmol). The mixture was stirred at 100°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give 2-(trifluoromethyl)-6-((R)-3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)pyridine as an oil (0.14 g, 72%). 1 H NMR (400MHz, CDCl3) δ7.50(t,J=8.0Hz,1H),7.42-7.24(m,15H),6.88(d,J=7.1Hz,1H),6.75(d,J=8.8H z,1H),4.93(s,2H),4.75(dd,J=11.5,5.8Hz,2H),4.67(dd,J=11.5,3.2Hz,2H),4.23-4.10(m,2H),3.6 5(bs,2H),3.47(t,J=8.8Hz,1H),3.17-3.06(m,2H),2.98(s,1H),2.73(t,J=11.2Hz,1H),2.40-2.20(m ,2H),2.07-2.01(m,1H),1.91(d,J=11.2Hz,1H),1.87-1.69(m,3H),1.62-1.47(m,1H),1.21(m,1H); ESI MS m / z 646.318[M+H] + .

[0389] To a solution of the above material (0.14 g, 0.21 mmol) in DCM (5 mL) was added BCl₃ (1.0 M in DCM, 1.08 mL, 1.08 mmol) at -78°C under Ar, and the mixture was stirred for 3 hours while the bath temperature reached room temperature. The mixture was then cooled to -78°C, and MeOH (2 mL) was carefully added. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. The resulting residue was neutralized with 1M NH₃ in MeOH (2×5 mL) and concentrated again under reduced pressure. The residue was purified by flash chromatography on silica gel (MeOH / DCM, 1:9) to give (3S,4R,5R)-1-(((R)-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol (0.05 g, 63%) as a white solid. 1 H NMR (400MHz, CD3OD) δ7.64(t,J=8.0Hz,1H),6.96(d,J=8.8Hz,1H),6.89(d,J=7.2Hz,1H),4.35-4.27(m,1H ),4.17(dt,J=13.5,4.2Hz,1H),3.59-3.51(m,2H),3.15-3.01(m,3H),2.90(ddd,J=11.0,5.0,2.1Hz,1H), 2.77(dd,J=13.2,9.5Hz,1H),2.36(dd,J=12.4,8.5Hz,1H),2.26(dd,J=12.4,5.8Hz,1H),2.03-1.94(m,1H ),1.92-1.85(m,1H),1.85-1.71(m,3H),1.56(dddd,J=15.0,13.2,7.9,4.0Hz,1H),1.34-1.23(m,1H); ESI MS m / z 376.189[M+H] + .

[0390] Example 31

[0391] (3S,4R,5R)-1-(((R)-1-(2-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0392]

[0393] To a stirred solution of (3S,4S,5R)-3,4,5-tris(benzyloxy)-1-((S)-piperidin-3-ylmethyl)piperidine (0.14 g, 0.28 mmol) and 3-bromo-2-(trifluoromethyl)pyridine (0.12 g, 0.56 mmol) in toluene (5 mL) under Ar was added Pd(dba) (26 mg, 0.028 mmol) and RuPhos (26 mg, 0.056 mmol), followed by CsCO (0.27 g, 0.84 mmol). The mixture was stirred at 100°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give 2-(trifluoromethyl)-3-((R)-3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)pyridine as an oil (0.098 g, 54%). 1 H NMR (500MHz, CDCl3) δ8.42(dd,J=4.6,1.3Hz,1H),7.63(d,J=8.2Hz,1H),7.43(dd,J=8.3,4.5Hz,1H),7.40-7.24(m ,15H),4.94-4.87(m,2H),4.74-4.62(m,4H),3.59-3.52(m,2H),3.42(t,J=8.9Hz,1H),3.28-3.22(m,1H),3.21-3. 14(m,1H),3.06(d,J=11.2Hz,1H),2.97-2.90(m,1H),2.75(td,J=10.4,3.0Hz,1H),2.33(t,J=10.6Hz,1H),2.28-2 .23(m,2H),2.03-1.94(m,2H),1.84(t,J=10.6Hz,1H),1.81-1.70(m,3H),1.05(dq,J=14.2,8.1,6.5Hz,1H); ESIMS m / z 646.318[M+H] + .

[0394] To a solution of the above material (0.098 g, 0.15 mmol) in DCM (5 mL) was added BCl₃ (1.0 M in DCM, 0.75 mL, 0.75 mmol) at -78°C under Ar, and the mixture was stirred for 3 hours while the bath temperature reached room temperature. The mixture was then cooled to -78°C, and MeOH (2 mL) was carefully added. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. The resulting residue was neutralized with 1M NH₃ in MeOH (2 × 5 mL) and concentrated again under reduced pressure. The residue was purified by flash chromatography on silica gel (MeOH / DCM, 1:9) to give (3S,4R,5R)-1-(((R)-1-(2-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol (0.05 g, 88%) as a white solid. 1 H NMR (400MHz, CD3OD) δ8.36 (dd, J=4.6, 1.3Hz, 1H), 7.91 (dd, J=8.3, 1.3Hz, 1H), 7.60 (dd, J=8.3, 4 .5Hz,1H),3.50-3.40(m,2H),3.28-3.21(m,1H),3.08(t,J=8.9Hz,1H),3.05-3.01(m,2H),2.87( ddd,J=10.9,4.9,2.2Hz,1H),2.80(td,J=10.8,2.7Hz,1H),2.46(dd,J=11.3,9.3Hz,1H),2.37-2 .25(m,2H),2.05-1.96(m,1H),1.94(t,J=10.6Hz,1H),1.86-1.65(m,4H),1.21-1.09(m,1H); ESI MS m / z 376.193[M+H] + .

[0395] Example 32

[0396] (3S,4R,5R)-1-(((R)-1-(5-isopropylthiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0397]

[0398] To a stirred solution of (3S,4S,5R)-3,4,5-tris(benzyloxy)-1-((S)-piperidin-3-ylmethyl)piperidine (0.14 g, 0.28 mmol) and 2-bromo-5-isopropylthiazole (0.11 g, 0.56 mmol) in toluene (5 mL) under Ar was added Pd(dba) (26 mg, 0.028 mmol) and RuPhos (26 mg, 0.056 mmol), followed by CsCO (0.27 g, 0.84 mmol). The mixture was stirred at 100°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give 5-isopropyl-2-((R)-3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)thiazole as an oil (0.1 g, 57%). 1 H NMR (400MHz, CDCl3) δ7.41-7.23(m,15H),6.82(d,J=1.1Hz,1H),4.90(s,2H),4.76-4.61(m,4H),3. 94-3.79(m,2H),3.67-3.59(m,2H),3.43(t,J=8.9Hz,1H),3.12(ddd,J=10.9,5.1,2.1Hz,1H),3.06 -2.92(m,3H),2.69(dd,J=12.8,9.8Hz,1H),2.33-2.20(m,2H),2.02(t,J=10.6Hz,1H),1.89(t,J=1 0.7Hz,1H),1.83-1.69(m,3H),1.69-1.51(m,1H),1.27(s,3H),1.25(s,3H),1.21-1.06(m,2H); ESI MS m / z 626.746[M+H] + .

[0399] To a solution of the above material (0.1 g, 0.15 mmol) in DCM (5 mL) was added BCl₃ (1.0 M in DCM, 0.7 mL, 0.7 mmol) at -78°C under Ar, and the mixture was stirred for 3 h while the bath temperature reached room temperature. The mixture was then cooled to -78°C, and MeOH (2 mL) was carefully added. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. The resulting residue was neutralized with 1M NH₃ in MeOH (2×5 mL) and concentrated again under reduced pressure. The residue was purified by flash chromatography on silica gel (MeOH / DCM, 1:9) to give (3S,4R,5R)-1-(((R)-1-(5-isopropylthiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol (0.026 g, 48.7%) as a white solid. 1 H NMR (400MHz, CD3OD) δ6.77(s,1H),3.86(dd,J=13.0,3.8Hz,1H),3.79(dt,J=12.9,4.1Hz,1H),3. 60-3.51(m,2H),3.13(t,J=8.8Hz,1H),3.09-2.97(m,3H),2.91(ddd,J=10.9,5.0,2.0Hz,1H),2.7 7(dd,J=12.8,9.7Hz,1H),2.38-2.25(m,2H),2.00(t,J=10.6Hz,1H),1.92-1.82(m,3H),1.78(dt, J=13.4,3.8Hz,1H),1.69-1.57(m,1H),1.29(s,J=6.8Hz,3H),1.27(s,3H),1.26-1.19(m,2H); ESI MS m / z 356.502[M+H] + .

[0400] Example 33

[0401] (3S,4R,5R)-1-(((R)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0402]

[0403] To a stirred solution of (3S,4S,5R)-3,4,5-tris(benzyloxy)-1-((S)-piperidin-3-ylmethyl)piperidine (0.14 g, 0.28 mmol) and 2-bromo-4-(trifluoromethyl)thiazole (0.13 g, 0.56 mmol) in DMA (5 mL) was added CsCO (0.27 g, 0.84 mmol) under Ar. The mixture was stirred at 100°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give 4-(trifluoromethyl)-2-((R)-3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)thiazole as an oil (0.09 g, 49.3%). 1 H NMR (400MHz, CDCl3) δ7.41-7.24(m,15H),6.91(s,1H),4.91(s,2H),4.76-4.63(m,4H),3.96-3.8 0(m,2H),3.61(bs,2H),3.44(t,J=8.8Hz,1H),3.15(ddd,J=12.8,10.8,3.1Hz,1H),3.10-3.03(m ,1H),2.94(d,J=8.9Hz,1H),2.78(t,J=11.4Hz,1H),2.34-2.17(m,2H),2.03(t,J=10.7Hz,1H),1 .93-1.84(m,1H),1.83-1.71(m,3H),1.60(ddt,J=14.4,10.6,7.8Hz,1H),1.23-1.08(m,1H);ESI MS m / z652.295[M+H] + .

[0404] To a solution of the above substance (0.09 g, 0.14 mmol) in DCM (5 mL) was added BCl₃ (1.0 M in DCM, 0.7 mL, 0.7 mmol) at -78°C under Ar, and the mixture was stirred for 3 hours while the bath temperature reached room temperature. The mixture was then cooled at -78°C and MeOH (2 mL) was carefully added. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. The resulting residue was neutralized with a 1M NH₃ solution in MeOH (2 × 5 mL) and concentrated again under reduced pressure. The residue was purified by flash chromatography on silica gel (MeOH / DCM, 1:9) to give (3S,4R,5R)-1-(((R)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol (0.041 g, 76%) as a white solid. 1 H NMR(400MHz,CD3OD)δ7.18(s,1H),3.98-3.87(m,2H),3.57-3.50(m,2H),3.21-3.15( m,1H),3.14-3.08(m,1H),3.04(ddd,J=11.0,4.9,2.1Hz,1H),2.94-2.83(m,2H),2.3 7(dd,J=12.5,8.7Hz,1H),2.28(dd,J=12.5,5.5Hz,1H),2.00(t,J=10.5Hz,1H),1.94 -1.84(m,3H),1.80(dt,J=13.4,3.8Hz,1H),1.71-1.58(m,1H),1.34-1.20(m,1H);ESI MS m / z382.140[M+H] + .

[0405] Example 34

[0406] (3S,4R,5R)-1-(((R)-1-(Benzo[d]thiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0407]

[0408] To a stirred solution of (3S,4S,5R)-3,4,5-tris(benzyloxy)-1-((S)-piperidin-3-ylmethyl)piperidine (0.14 g, 0.28 mmol) and 2-bromobenzo[d]thiazole (0.12 g, 0.56 mmol) in toluene (5 mL) under Ar was added Pd(dba) (26 mg, 0.028 mmol) and RuPhos (26 mg, 0.056 mmol), followed by CsCO (0.27 g, 0.84 mmol). The mixture was stirred at 100°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give 2-((R)-3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)benzo[d]thiazole as an oil (0.1 g, 57%). 1 H NMR (400MHz, CDCl3) δ7.59-7.52(m,2H),7.42-7.23(m,16H),7.06(td,J=7.6,1.2Hz,1H),4. 93(s,2H),4.81-4.63(m,4H),4.11-3.94(m,2H),3.75-3.61(m,2H),3.46(t,J=8.8Hz,1H),3. 26(ddd,J=13.6,10.8,3.1Hz,1H),3.14(bs,1H),3.03-2.84(m,2H),2.33-2.21(m,2H),2.11- 2.01(m,1H),1.98-1.88(m,1H),1.88-1.73(m,3H),1.72-1.61(m,1H),1.30-1.14(m,1H); ESI MS m / z 634.716[M+H] + .

[0409] At -78 ° C, under Ar, to a solution of the above substance (0.14 g, 0.22 mmol) in DCM (5 mL) was added BCl3 (1.0 M in DCM, 0.75 mL, 0.75 mmol), and the mixture was stirred for 3 h while the bath temperature reached room temperature. The mixture was then cooled at -78 ° C and MeOH (2 mL) was carefully added. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. The resulting residue was neutralized with 1M NH3 in MeOH (2 × 5 mL) and concentrated under reduced pressure again. The residue was purified by flash chromatography on silica gel (MeOH / DCM, 1: 9) to give (3S, 4R, 5R) -1- (((R) -1- (benzo [d] thiazol-2-yl) piperidin-3-yl) methyl) piperidine -3,4,5- triol (0.06 g, 75%) as a white solid. 1 H NMR (400MHz, CD3OD) δ7.63 (dd, J=7.9, 1.2Hz, 1H), 7.49-7.44 (m, 1H), 7.28 (td, J=8.2, 7.7, 1.3Hz, 1H), 7.0 8(td,J=7.6,1.2Hz,1H),4.09-3.99(m,2H),3.63-3.52(m,2H),3.26(ddd,J=13.0,11.1,3.3Hz,1H),3.13(t ,J=8.8Hz,1H),3.07(ddd,J=11.0,5.0,2.1Hz,1H),3.01-2.87(m,2H),2.37(dd,J=12.4,8.9Hz,1H),2.28(d d,J=12.4,5.4Hz,1H),2.01(t,J=10.5Hz,1H),1.94-1.77(m,4H),1.74-1.60(m,1H),1.35-1.25(m,1H); ESI MS m / z 364.169[M+H] + .

[0410] Example 35

[0411] (3S,4R,5R)-1-(((R)-1-(Benzo[d]thiazol-4-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0412]

[0413] To a stirred solution of (3S,4S,5R)-3,4,5-tris(benzyloxy)-1-((S)-piperidin-3-ylmethyl)piperidine (0.14 g, 0.28 mmol) and 3-bromo-2-(trifluoromethyl)pyridine (0.12 g, 0.56 mmol) in toluene (5 mL) under Ar was added Pd(dba) (26 mg, 0.028 mmol) and RuPhos (26 mg, 0.056 mmol), followed by CsCO (0.27 g, 0.84 mmol). The mixture was stirred at 100°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×20 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel to give 4-((R)-3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)benzo[d]thiazole as an oil (0.11 g, 62%). 1 H NMR(500MHz, CDCl3)δ8.81(s,1H),7.52(d,J=7.9Hz,1H),7.40-7.24(m,15H),6.94(d,J=7.8Hz,1H),4.91 (s,2H),4.77-4.61(m,4H),4.11-4.05(m,1H),3.99(d,J=11.5Hz,1H),3.64-3.55(m,2H),3.44(t,J=8.9H z,1H),3.31-3.24(m,1H),3.07-3.00(m,1H),2.79(t,J=11.2Hz,1H),2.46(t,J=10.9Hz,1H),2.37-2.29( m,2H),2.19-2.10(m,1H),2.02(t,J=10.7Hz,1H),1.96-1.81(m,4H),1.64(bs,1H),1.16-1.01(m,1H); ESI MS m / z 634.316[M+H] + .

[0414] At -78 ℃, under Ar, to DCM (5mL) solution of the above-mentioned substance (0.11g, 0.17mmol), add BCl (concentration in DCM is 1.0M, 0.85mL, 0.85mmol), and the mixture is stirred for 3h, and the bath temperature reaches room temperature simultaneously.Then the mixture is cooled at -78 ℃, and MeOH (2mL) is carefully added. After stirring at room temperature for 30 minutes, the mixture is concentrated under reduced pressure. The gained residue is neutralized with MeOH solution (2×5mL) of 1MNH and, and concentrated under reduced pressure again. The thick residue is redissolved in pyridine (6mL) and treated with Ac O (0.6mL). After stirring at room temperature overnight, the contents were concentrated and purified by flash chromatography on silica gel (EtOAc / hexanes, 3:7) to give the acetate derivative (3S,4R,5R)-1-(((R)-1-(benzo[d]thiazol-4-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triyl triacetate, which was further hydrolyzed by stirring with 1M NH3 in MeOH (10 mL) overnight. After concentration, the residue was purified by flash chromatography on silica gel (MeOH / DCM, 1:9) to give (3S,4R,5R)-1-(((R)-1-(benzo[d]thiazol-4-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol (0.034 g, 55.8%) as a white solid. 1 H NMR (400MHz, CD3OD) δ9.11(s,1H),7.57(dd,J=8.1,0.9Hz,1H),7.34(t,J=7.9Hz,1H),6.98(dd,J=7.9,1.0Hz,1H),4.04(d,J=11.6Hz ,1H),3.74(d,J=11.4Hz,1H),3.55-3.45(m,2H),3.24-3.04(m,2H),2.99-2.88(m,1H),2.88-2.73(m,1H),2.55-2.25(m,3H),2.15(br s,1H),2.04-1.95(m,1H),1.92-1.77(m,4H),1.20-1.09(m,1H); ESI MS m / z 364.169[M+H] + .

[0415] Example 36

[0416] (3S,4S,5R)-1-(((S)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0417]

[0418] Under Ar, a mixture of (3S,4r,5R)-3,4,5-tris(benzyloxy)piperidine (1.50 g, 3.71 mmol), (R)-tert-butyl 3-formylpiperidine-1-carboxylate (1.07 g, 5.00 mmol) and NaBH(OAc) (1.5 g, 7.0 mmol) in DCM (30 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with NaHCO (40 mL) and extracted with DCM (2 × 30 mL). The combined extracts were dried over anhydrous NaSO. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:6 to 1:3) to give (S)-tert-butyl 3-(((3S,4S,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidine-1-carboxylate as a light yellow oil (2.2 g, 99%). ESI MS m / z 601.358 [M+H] + .

[0419] To a solution of the above substance (2.2 g, 3.7 mmol) in DCM (20 mL) was added TFA (8 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous NaHCO3 solution (50 mL). After extraction with DCM (3×30 mL), the combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (1MNH3 in MeOH / DCM, 1:10) to give (3S,4R,5R)-3,4,5-tris(benzyloxy)-1-((R)-piperidin-3-ylmethyl)piperidine as a light yellow oil (1.8 g, 97%). ESI MS m / z 501.306 [M+H] + .

[0420] Example 37

[0421] (3S,4S,5R)-1-(((S)-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0422]

[0423] To a stirred solution of (3S,4R,5R)-3,4,5-tris(benzyloxy)-1-((R)-piperidin-3-ylmethyl)piperidine (0.13 g, 0.27 mmol) and 2-chloro-6-(trifluoromethyl)pyridine (0.1 g, 0.6 mmol) in toluene (5 mL) under Ar was added Pd(dba) (28 mg, 0.03 mmol) and RuPhos (28 mg, 0.06 mmol), followed by CsCO (0.26 g, 0.8 mmol). The mixture was stirred at 100°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 2:8) to give 2-(trifluoromethyl)-6-((S)-3-(((3S,4S,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)pyridine as an oil (0.15 g, 85%). 1 H NMR (400MHz, CDCl3) δ7.49(t,J=8.0Hz,1H),7.41-7.26(m,15H),6.87(d,J=7.2Hz,1H),6.75(d,J=8.7Hz,1H),4.92(s,2H ),4.75(dd,J=11.5,5.7Hz,2H),4.67(dd,J=11.5,3.1Hz,2H),4.19-4.12(m,2H),3.67-3.59(m,2H),3.46(t,J=8.9Hz,1H) ,3.15-3.06(m,2H),3.01-2.93(m,1H),2.72(dd,J=13.2,9.3Hz,1H),2.33(dd,J=12.4,8.8Hz,1H),2.24(dd,J=12.3,5.7H z,1H),2.08-1.98(m,1H),1.91(t,J=10.7Hz,1H),1.84-1.69(m,3H),1.62-1.48(m,1H),1.20(q,J=12.2,11.2Hz,1H); ESI MS m / z 646.312[M+H] + .

[0424] To a solution of the above substance (0.15 g, 0.23 mmol) in DCM (8 mL) was added BCl₃ (1.0 M in DCM, 1.2 mL, 1.2 mmol) at -78°C under Ar, and the mixture was stirred for 3 h while the bath temperature reached 0°C. The mixture was then cooled at -78°C and MeOH (2 mL) was carefully added. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. The resulting residue was neutralized with a 1M NH₃ solution in MeOH (2 × 5 mL) and concentrated again under reduced pressure. The residue was purified by flash chromatography on silica gel (MeOH / DCM, 1:9) to give (3S,4S,5R)-1-(((S)-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol (0.058 g, 67%) as a white solid. 1 H NMR (400MHz, CD3OD) δ7.63(ddt,J=8.8,7.3,0.8Hz,1H),6.96(d,J=8.8Hz,1H),6.89(d,J=7.2Hz,1H),4.31( ddt,J=13.1,3.4,1.5Hz,1H),4.17(dt,J=13.1,4.2Hz,1H),3.59-3.51(m,2H),3.16-2.99(m,3H),2.90(ddd, J=10.9,4.9,2.2Hz,1H),2.77(dd,J=13.2,9.5Hz,1H),2.36(dd,J=12.4,8.5Hz,1H),2.25(dd,J=12.4,5.8Hz ,1H),1.98(t,J=10.6Hz,1H),1.92-1.70(m,4H),1.56(dtt,J=13.3,11.1,4.0Hz,1H),1.34-1.23(m,1H); ESI MS m / z 376.179[M+H] + .

[0425] Example 38

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

[0427]

[0428] A solution of (3S,4R,5R)-3,4,5-tris(benzyloxy)-1-((R)-piperidin-3-ylmethyl)piperidine (0.22 g, 0.44 mmol), 3-bromo-4-(trifluoromethyl)pyridine (0.12 g, 0.53 mmol), CsCO (0.30 g, 0.92 mmol), RuPhos (0.035 g, 0.075 mmol) and Pd(dba) (0.035 g, 0.038 mmol) in anhydrous toluene (8 mL) was bubbled with Ar for 10 minutes and then stirred in a sealed tube at 100° C. for 16 hours. After cooling, the reaction mixture was filtered through a celite cake. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:2 to 1:1) to give 4-(trifluoromethyl)-3-((S)-3-(((3S,4S,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)pyridine as a light yellow oil (0.10 g, 35%).

[0429] At -78 DEG C and Ar, to anhydrous DCM (8mL) solution of the above-mentioned substance (0.10g, 0.16mmol) was added BCl (concentration in DCM is 1.0M, 2.0mL, 2.0mmol), the mixture was stirred at 0 DEG C for 3 hours. The reaction mixture was cooled at -78 DEG C, quenched with MeOH, and concentrated to dryness. The residue was neutralized with 1M NH MeOH. Then flash chromatography (0.5M NH in 1:5 MeOH / DCM) was performed on silica gel to obtain (3S, 4S, 5R) -1- (((S) -1- (4- (trifluoromethyl) pyridin-3-yl) piperidin-3-yl) methyl) piperidine -3,4,5- triol as a white solid (0.032g, 55%). 1 H NMR (400MHz, DMSO-d6) δ8.73(s,1H),8.52(d,J=4.9Hz,1H),7.62(d,J=5.0Hz,1H),4.79-4.59(m,3H),3.26-3.12(m,3H),3.06-3. 00(m,1H),2.96-2.75(m,3H),3.73-2.64(m,1H),2.53-2.41(m,1H),2.20-2.15(m,2H),1.94-1.39(m,6H),1.09-1.01(m,1H); ESI MS m / z 376.180[M+H] + .

[0430] Example 39

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

[0432]

[0433] A solution of (3S,4R,5R)-3,4,5-tris(benzyloxy)-1-((R)-piperidin-3-ylmethyl)piperidine (0.22 g, 0.44 mmol), 2-bromo-4-(trifluoromethyl)thiazole (0.13 g, 0.56 mmol), CsCO (0.30 g, 0.92 mmol), RuPhos (0.035 g, 0.075 mmol) and Pd(dba) (0.035 g, 0.038 mmol) in anhydrous toluene (8 mL) was sparged with Ar for 10 min and then stirred in a sealed tube at 100° C. for 16 h. After cooling, the reaction mixture was filtered through a celite cake. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:4 to 1:3) to give 4-(trifluoromethyl)-2-((S)-3-(((3S,4S,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)thiazole as a light yellow oil (0.19 g, 66%).

[0434] To anhydrous DCM (10 mL) solution of the above-mentioned substance (0.18 g, 0.28 mmol) was added BCl at -78 ° C and Ar (1.0 M in DCM, 2.5 mL, 2.5 mmol), and the mixture was stirred at 0 ° C for 3 h. The reaction mixture was cooled at -78 ° C, quenched with MeOH, and concentrated to dryness. The residue was neutralized with a 1 M NH solution in MeOH, then purified by flash chromatography (0.5 M NH in 1:6 MeOH / DCM) on silica gel to give (3S, 4S, 5R) -1- (((S) -1- (4- (trifluoromethyl) thiazol-2-yl) piperidin-3-yl) methyl) piperidine -3,4,5- triol as a white solid (0.070 g, 94%). 1H NMR(400MHz, DMSO-d6)δ7.48(q,J=1.1Hz,1H),4.78-4.64(m,3H),3.98-3.64(m,2H),3.33-3.27(m,2H),3.15-3.04(m,1H),2.95-2.76(m ,3H),2.76-2.66(m,1H),2.30-2.19(m,1H),2.14(dd,J=12.3,5.6Hz,1H),1.85-1.64(m,5H),1.55-1.45(m,1H),1.24-1.10(m,1H); ESIMS m / z 382.138[M+H] + .

[0435] Example 62

[0436] (3S,4r,5R)-1-((2,3-dihydro-1H-inden-2-yl)methyl)piperidine-3,4,5-triol

[0437]

[0438] To a stirred solution of (3S,4R,5R)-3,4,5-tris(benzyloxy)-1-((R)-piperidin-3-ylmethyl)piperidine (104 mg, 0.26 mmol) and 2,3-dihydro-1H-indene-2-carbaldehyde (38 mg, 0.26 mmol) in anhydrous DCM (5 mL) was added HOAc (0.1 mL) and stirred for 30 minutes. NaBH(OAc)3 (73 mg, 0.35 mmol) was added and the resulting mixture was stirred at room temperature for 18 h. The reaction was quenched with saturated aqueous NaHCO3 at 0°C. The mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×10 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel to give (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-((2,3-dihydro-1H-inden-2-yl)methyl)piperidine as an oil (64 mg, 46%). ESI MS m / z 534.30 [M+H] + .

[0439] To a stirred solution of the above substance (63 mg, 0.12 mmol) in anhydrous DCM (5 mL) was added BCl (1 M in DCM, 0.75 mL, 0.75 mmol) at -78 ° C and N2. The mixture was stirred at 0 ° C for 4 h and then quenched with anhydrous MeOH (1 mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum, and the residue was dissolved in 1M NH3 in MeOH (10 mL) and stirred for another 10 min, then the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel to obtain (3S, 4r, 5R) -1- ((2,3-dihydro-1H-inden-2-yl) methyl) piperidine-3,4,5-triol as a white solid (13 mg, 41%). 1 H NMR (400MHz, CD3OD) δ7.17(dd,J=5.4,3.3Hz,2H),7.12-7.07(m,2H),3.58-3.48(m,2H),3.12(t,J=8.9 Hz,1H),3.08-2.96(m,4H),2.78-2.64(m,3H),2.45(d,J=6.9Hz,2H),1.95(dd,J=11.3,10.2Hz,2H); ESI MS m / z 264.16[M+H] + .

[0440] Example 106

[0441] (3S,4r,5R)-1-((1-phenylpiperidin-4-yl)methyl)piperidine-3,4,5-triol

[0442]

[0443] To a stirred solution of (((3S,4r,5R)-3,4,5-tris(benzyloxy)piperidine (260 mg, 0.64 mmol) and 1-phenylpiperidine-4-carbaldehyde (153 mg, 0.81 mmol) in anhydrous DCM (5 mL) was added NaBH(OAc)3 (206 mg, 0.97 mmol) and the resulting mixture was stirred at room temperature for 18 h. The reaction was quenched with saturated aqueous NaHCO3 at 0°C. The mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (2×20 mL), separated and dried over Na2SO4. After filtration, the solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel to give (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-((1-phenylpiperidin-4-yl)methyl)piperidine as a white foam (340 mg, 92%).

[0444] At -78 ° C and N2, BCl3 (concentration in DCM is 1M, 4mL, 4mmol) was added to a stirred solution of the above-mentioned substance (340mg, 0.6mmol) in anhydrous DCM (5mL). The mixture was stirred at 0 ° C for 2h and then quenched with anhydrous MeOH (1mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum, and the residue was dissolved in 1M NH3 in MeOH (10mL) and stirred for another 10min, and then the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel to obtain (3S, 4r, 5R)-1-((1-phenylpiperidin-4-yl)methyl)piperidine-3,4,5-triol as a white solid (47mg, 22%). 1 H NMR (400MHz, CD3OD) δ7.24(dd,J=8.7,7.3Hz,2H),7.07-6.96(m,2H),6.92-6.73(m,1H),3.66(d,J=12.2Hz,2H),3.60-3.46(m,2H),3.11(t,J=8.8 Hz,1H),2.97(dd,J=10.8,4.8Hz,2H),2.69(t,J=12.0Hz,2H),2.30(d,J= 7.1Hz,2H),2.06-1.75(m,4H),1.70-1.67(m,1H),1.48-1.26(m,2H); ESI MS m / z 307.2[M+H] + .

[0445] Example 142

[0446] (3S,4R,5R)-1-(((R)-1-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol

[0447]

[0448] To a stirred solution of (3S,4S,5R)-3,4,5-tris(benzyloxy)-1-((S)-pyrrolidin-3-ylmethyl)piperidine (0.13 g, 0.28 mmol) and 2-chloro-6-(trifluoromethyl)pyridine (0.10 g, 0.56 mmol) in toluene (6 mL) under Ar was added Pd(dba) (26 mg, 0.03 mmol) and RuPhos (28 mg, 0.06 mmol), followed by CsCO (0.27 g, 0.84 mmol). The mixture was stirred at 100°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 3:7) to give 2-(trifluoromethyl)-5-((R)-3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)pyrrolidin-1-yl)pyridine as an oil (0.12 g, 67%). 1 H NMR (400MHz, CDCl3) δ7.56-7.49(m,1H),7.44-7.27(m,15H),6.89(d,J=7.2Hz,1H),6.48(d,J=8.6Hz,1H),4.94(s,2H),4.78-4.74(m,2H),4.69 -4.66(m,2H),3.66-3.54(m,4H),3.51-3.40(m,2H),3.18-3.01(m,3H), 2.50-2.39(m,3H),2.11-1.94(m,3H),1.71(dq,J=12.6,7.6Hz,1H);ESI MS m / z 632.314[M+H] + .

[0449] To a solution of the above substance (0.12 g, 0.19 mmol) in DCM (8 mL) was added BCl₃ (1.0 M in DCM, 1.0 mL, 1.0 mmol) at -78°C under Ar, and the mixture was stirred for 4 hours while the bath temperature reached 0°C. The mixture was then cooled to -78°C and MeOH (3 mL) was carefully added. After stirring at room temperature for 30 minutes, the mixture was concentrated in vacuo. The resulting residue was neutralized with a 1M NH₃ solution in MeOH (2 × 5 mL) and concentrated in vacuo again. The crude residue was purified and separated by flash chromatography on silica gel (MeOH / DCM, 1:9) to give (3S,4R,5R)-1-(((R)-1-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol (0.040 g, 58%) as a white solid. 1 H NMR (400MHz, CD3OD) δ7.61(t,J=7.9Hz,1H),6.88(d,J=7.2Hz,1H),6.63(d,J=8.6Hz,1H),3.69(dd,J=1 0.5,7.1Hz,1H),3.64-3.49(m,3H),3.44(dt,J=10.4,7.7Hz,1H),3.18(dd,J=10.6,7.2Hz,1H),3.12(t, J=8.9Hz,1H),3.06(ddd,J=11.1,5.0,2.0Hz,1H),3.00(ddd,J=10.9,5.0,2.1Hz,1H),2.61(dq,J=14.7 ,7.2Hz,1H),2.52-2.47(m,2H),2.23-2.13(m,1H),1.02-1.93(m,2H),1.78(dq,J=12.4,8.2Hz,1H); ESI MS m / z 362.168[M+H] + .

[0450] Example 146

[0451] (3S,4R,5R)-1-(((R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol

[0452]

[0453] To a stirred solution of (3S,4S,5R)-3,4,5-tris(benzyloxy)-1-((S)-pyrrolidin-3-ylmethyl)piperidine (0.13 g, 0.28 mmol) and 3-bromo-5-(trifluoromethyl)pyridine (0.12 g, 0.56 mmol) in toluene (6 mL) under Ar was added Pd(dba) (26 mg, 0.03 mmol) and RuPhos (28 mg, 0.06 mmol), followed by CsCO (0.27 g, 0.84 mmol). The mixture was stirred at 100°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 4:6) to give 3-(trifluoromethyl)-5-((R)-3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)pyrrolidin-1-yl)pyridine as an oil (0.13 g, 73%). 1 H NMR (400MHz, CDCl3) δ8.19(d,J=2.1Hz,1H),8.11(d,J=2.8Hz,1H),7.42-7.25(m,1 5H),6.92(t,J=2.3Hz,1H),4.92(s,2H),4.78-4.74(m,2H),4.67-4.65(m,2H),3.67 -3.56(m,2H),3.45(t,J=8.9Hz,1H),3.42-3.29(m,3H),3.08-2.98(m,3H),2.52-2 .39(m,3H),2.18-2.08(m,1H),2.07-1.95(m,2H),1.75(dq,J=12.6,7.7Hz,1H);ESI MS m / z632.309[M+H] + .

[0454] To a solution of the above substance (0.13 g, 0.2 mmol) in DCM (8 mL) was added BCl₃ (1.0 M in DCM, 1.0 mL, 1.0 mmol) at -78°C under Ar, and the mixture was stirred for 4 hours while the bath temperature reached 0°C. The mixture was then cooled to -78°C and MeOH (3 mL) was carefully added. After stirring at room temperature for 30 minutes, the mixture was concentrated in vacuo. The resulting residue was neutralized with a 1M NH₃ solution in MeOH (2 × 5 mL) and concentrated in vacuo again. The crude residue was purified and separated by flash chromatography on silica gel (MeOH / DCM, 1:9) to give (3S,4R,5R)-1-(((R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol (0.052 g, 68%) as a white solid. 1 H NMR(400MHz,CD3OD)δ8.10(d,J=2.7Hz,1H),8.08-8.03(m,1H),7.12(t,J=2.3Hz,1H),3.5 8-3.48(m,3H),3.48-3.43(m,1H),3.40-3.34(m,1H),3.15-3.10(m,2H),3.06(ddd,J=10.9 ,4.9,2.1Hz,1H),2.99(ddd,J=10.9,5.0,2.1Hz,1H),2.72-2.62(m,1H),2.52-2.49(m,2H ),2.23(dtd,J=11.4,7.0,4.2Hz,1H),2.04-1.93(m,2H),1.84(dq,J=12.4,8.1Hz,1H); ESI MSm / z 362.168[M+H] + .

[0455] Example 149

[0456] (3S,4R,5R)-1-(((R)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol

[0457]

[0458] To (2S, 3R, 4R, 5S) -3,4,5- tris (benzyloxy) -2- ((benzyloxy) methyl) piperidine (1.3g, 3.2mmol) in DCM (25mL) solution, add (S) -3- formyl pyrrolidine -1- carboxylic acid tert-butyl ester (0.96g, 4.8mmol) and HOAc (0.5mL). After stirring at room temperature for 10 minutes, NaBH (OAc) was added (1.1g, 5.4mmol) and content was stirred at room temperature overnight. The reaction mixture was concentrated and then diluted with DCM (25mL). By organic matter saturated NaHCO aqueous solution, salt water washing, use anhydrous Na SO dried and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 3:7) to give (R)-tert-butyl 3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate (1.86 g, 98%) as an oil. 1 H NMR (400MHz, CDCl3) δ7.38-7.32(m,15H),4.89(s,2H),4.74-4.71(m,2H),4.65-4.62(m,2H),3.60-3.48(m,2H),3.46-3.3 3(m,3H),3.32-3.20(m,1H),3.05-2.87(m,3H),2.40-2.18(m,3H),1.98-1.83(m,3H),1.56-1.49(m,1H),1.47(s,9H); ESI MSm / z 587.341[M+H] + .

[0459] The above material (0.89 g, 1.51 mmol) was dissolved in a 3:7 solution of TFA:DCM (16 mL) at 0°C and stirred for 30 minutes. The reaction mixture was allowed to warm to room temperature over 2 hours and then concentrated to dryness. The organics were diluted with EtOAc (30 mL) and washed with saturated aqueous NaHCO₃ (2 x 50 mL), dried over anhydrous Na₂SO₄, and concentrated to afford (3S,4S,5R)-3,4,5-tris(benzyloxy)-1-((S)-pyrrolidin-3-ylmethyl)piperidine as an oil (0.7 g, 95%). 1H NMR(400MHz, CDCl3)δ7.71(bs,1H),7.40-7.27(m,15H),4.87(s,2H),4.73- 4.70(m,2H),4.66-4.62(m,2H),3.58-3.48(m,2H),3.41(t,J=8.6Hz,1H),3 .31-3.19(m,2H),3.18-3.12(m,1H),3.02-2.87(m,3H),2.48-2.32(m,3H), 2.09-2.00(m,2H),1.96(t,J=10.6Hz,1H),1.62(dq,J=13.1,7.7Hz,1H); ESI m / z 487.299[M+H] + .

[0460] To a stirred solution of the above material (0.13 g, 0.28 mmol) and 5-bromo-2-(trifluoromethyl)pyridine (0.12 g, 0.56 mmol) in toluene (6 mL) under Ar was added Pd2(dba)3 (26 mg, 0.03 mmol) and RuPhos (28 mg, 0.06 mmol), followed by Cs2CO3 (0.27 g, 0.84 mmol). The mixture was stirred at 100°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 3:7) to give 2-(trifluoromethyl)-5-((R)-3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)pyrrolidin-1-yl)pyridine as an oil (0.13 g, 73.4%). 1 H NMR(400MHz, CDCl3) δ7.98(d,J=2.8Hz,1H),7.47(d,J=8.7Hz,1H),7.40-7.27 (m,15H),6.79(d,J=8.5Hz,1H),4.95-4.86(m,2H),4.76-4.73(m,2H),4.67-4 .63(m,2H),3.62-3.52(m,2H),3.46-3.30(m,4H),3.08-2.95(m,2H),2.52-2. 36(m,2H),2.11(s,1H),2.07-1.89(m,2H),1.80-1.75(m,1H),1.60(s,1H);ESI MSm / z 632.309[M+H] + .

[0461] To a solution of the above substance (0.12 g, 0.19 mmol) in DCM (8 mL) was added BCl₃ (1.0 M in DCM, 1.0 mL, 1.0 mmol) at -78°C under Ar, and the mixture was stirred for 4 hours while the bath temperature reached 0°C. The mixture was then cooled to -78°C and MeOH (3 mL) was carefully added. After stirring at room temperature for 30 minutes, the mixture was concentrated in vacuo. The resulting residue was neutralized with a 1M NH₃ solution in MeOH (2×5 mL) and concentrated in vacuo again. The crude residue was purified and isolated by flash chromatography on silica gel (MeOH / DCM, 1:9) to give (3S,4R,5R)-1-(((R)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol (0.052 g, 75%) as a white solid. 1 H NMR (400MHz, CD3OD) δ7.95(d,J=2.8Hz,1H),7.56(d,J=8.8Hz,1H),7.03(dd,J=8.8, 2.9Hz,1H),3.58-3.45(m,4H),3.43-3.35(m,1H),3.17-3.10(m,2H),3.06(ddd,J=1 0.9,4.9,2.1Hz,1H),3.00(ddd,J=10.9,5.0,2.1Hz,1H),2.72-2.59(m,1H),2.53-2 .48(m,2H),2.28-2.18(m,1H),2.04-1.92(m,2H),1.83(dq,J=12.4,8.1Hz,1H);ESI MS m / z362.171[M+H] + .

[0462] Example 161

[0463] (3S,4S,5R)-1-(((S)-1-(5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol

[0464]

[0465] To a stirred solution of (3S,4R,5R)-3,4,5-tris(benzyloxy)-1-((R)-pyrrolidin-3-ylmethyl)piperidine (0.13 g, 0.28 mmol) and 2-chloro-5-(trifluoromethyl)pyridine (0.10 g, 0.56 mmol) in toluene (6 mL) under Ar was added Pd(dba) (26 mg, 0.03 mmol) and RuPhos (28 mg, 0.06 mmol), followed by CsCO (0.27 g, 0.84 mmol). The mixture was stirred at 100°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 3:7) to give 5-(trifluoromethyl)-2-((S)-3-(((3S,4S,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)pyrrolidin-1-yl)pyridine as an oil (0.13 g, 78%). 1 H NMR (400MHz, CDCl3) δ8.40 (dt, J=2.2, 1.1Hz, 1H), 7.60 (dd, J=8.9, 2.5Hz, 1H), 7.4 0-7.27(m,15H),6.35(d,J=8.9Hz,1H),4.91(s,2H),4.76-4.73(m,2H),4.67-4.63( m,2H),3.66-3.53(m,4H),3.47-3.42(m,2H),3.16(dd,J=10.5,5.7Hz,1H),3.08-2 .99(m,2H),2.49-2.34(m,3H),2.12-1.93(m,3H),1.72(dq,J=12.2,7.7Hz,1H);ESI MS m / z632.310[M+H] + .

[0466] To a solution of the above substance (0.13 g, 0.20 mmol) in DCM (8 mL) was added BCl 3 (1.0 M in DCM, 1.0 mL, 1.0 mmol) at -78 ° C under Ar, and the mixture was stirred for 4 hours while the bath temperature reached 0 ° C. The mixture was then cooled to -78 ° C and MeOH (3 mL) was carefully added. After stirring at room temperature for 30 minutes, the mixture was concentrated in vacuo. The resulting residue was neutralized with a 1M NH 3 solution in MeOH (2×5 mL) and concentrated in vacuo again. The crude residue was purified and isolated by flash chromatography on silica gel (MeOH / DCM, 1:9) to give (3S,4S,5R)-1-(((S)-1-(5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol (0.031 g, 42.8%) as a white solid. 1 H NMR (400MHz, CD3OD) δ8.30-8.25(m,1H),7.69(dd,J=9.0,2.5Hz,1H),6.58(d,J=9.0Hz,1H),3.70(dd,J=10 .7,7.2Hz,1H),3.62(td,J=9.7,8.7,3.8Hz,1H),3.57-3.43(m,3H),3.23(dd,J=10.7,7.2Hz,1H),3.13(t, J=8.8Hz,1H),3.05(ddd,J=10.9,4.9,2.1Hz,1H),2.99(ddd,J=10.9,5.0,2.1Hz,1H),2.68-2.57(m,1H),2 .55-2.44(m,2H),2.20(dtd,J=11.2,6.9,4.1Hz,1H),2.04-1.94(m,2H),1.80(dq,J=12.5,8.3Hz,1H); ESI MS m / z 362.168[M+H] + .

[0467] Example 162

[0468] (3S,4S,5R)-1-(((S)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol

[0469]

[0470] To a stirred solution of (3S,4R,5R)-3,4,5-tris(benzyloxy)-1-((R)-pyrrolidin-3-ylmethyl)piperidine (0.13 g, 0.28 mmol) and 5-bromo-2-(trifluoromethyl)pyridine (0.12 g, 0.56 mmol) in toluene (6 mL) under Ar was added Pd(dba) (26 mg, 0.03 mmol) and RuPhos (28 mg, 0.06 mmol), followed by CsCO (0.27 g, 0.84 mmol). The mixture was stirred at 100°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 3:7) to give 2-(trifluoromethyl)-5-((S)-3-(((3S,4S,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)pyrrolidin-1-yl)pyridine as an oil (0.14 g, 80%). 1 H NMR (400MHz, CDCl3) δ8.00(d,J=2.8Hz,1H),7.48(d,J=8.7Hz,1H),7.41-7.26(m,15H),6.79(dd,J=8.8,2.8Hz,1H),4.92(s,2H),4.77-4.74(m,2H ),4.67-4.64(m,2H),3.63-3.53(m,2H),3.49-3.28(m,4H),3.08-2.97(m ,3H),2.55-2.36(m,3H),2.12(dq,J=12.9,6.5Hz,1H),2.02(t,J=10.1Hz 1H), 1.97 (t, J=10.8Hz, 1H), 1.75 (dq, J=12.9, 7.8Hz, 1H); ESI MS m / z 632.316[M+H] + .

[0471] To a solution of the above substance (0.14 g, 0.22 mmol) in DCM (8 mL) was added BCl₃ (1.0 M in DCM, 1.3 mL, 1.3 mmol) at -78°C under Ar, and the mixture was stirred for 4 hours while the bath temperature reached 0°C. The mixture was then cooled to -78°C and MeOH (3 mL) was carefully added. After stirring at room temperature for 30 minutes, the mixture was concentrated in vacuo. The resulting residue was neutralized with a 1M NH₃ solution in MeOH (2 × 5 mL) and concentrated in vacuo again. The crude residue was purified and isolated by flash chromatography on silica gel (MeOH / DCM, 1:9) to give (3S,4S,5R)-1-(((S)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol (0.047 g, 59%) as a white solid. 1 H NMR (400MHz, CD3OD) δ7.95(d,J=2.8Hz,1H),7.56(d,J=8.8Hz,1H),7.03(dd,J=8.7,2.8 Hz,1H),3.59-3.45(m,4H),3.44-3.36(m,1H),3.17-3.10(m,2H),3.06(ddd,J=10.9,4.9 ,2.1Hz,1H),2.99(ddd,J=11.0,5.0,2.2Hz,1H),2.72-2.59(m,1H),2.52-2.48(m,2H), 2.23(dtd,J=11.7,7.0,4.2Hz,1H),2.04-1.92(m,2H),1.83(dq,J=12.4,8.1Hz,1H); ESI MS m / z362.169[M+H] + .

[0472] Example 167

[0473] (3S,4R,5R)-1-(((R)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0474]

[0475] Under Ar, a solution of (3S,4r,5R)-3,4,5-tris(benzyloxy)piperidine (2.63 g, 6.52 mmol), (S)-tert-butyl 3-formylpiperidine-1-carboxylate (1.84 g, 8.63 mmol) and NaBH(OAc) (2.12 g, 10.0 mmol) in DCM (25 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO (40 mL) and extracted with DCM (3 × 30 mL). The combined extracts were dried over anhydrous NaSO. After filtration, the solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:4 to 1:3) to give (R)-tert-butyl 3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidine-1-carboxylate as a light yellow oil (2.70 g, 69%).

[0476] To a solution of the above substance (2.70 g, 4.49 mmol) in DCM (20 mL) was added TFA (8 mL) under Ar, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated at room temperature and diluted with saturated NaHCO3 aqueous solution (50 mL). After extraction with DCM (3 × 30 mL), the combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under vacuum, and the residue was purified by flash chromatography on silica gel (MeOH / DCM, containing ammonia, 1:16) to give (3S,4S,5R)-3,4,5-tris(benzyloxy)-1-((S)-piperidin-3-ylmethyl)piperidine as a light yellow oil (2.15 g, 96%).

[0477] A mixture of the above material (0.200 g, 0.400 mmol), 3-bromo-4-(trifluoromethyl)pyridine (0.12 g, 0.53 mmol), RuPhos (0.035 g, 0.075 mmol), CsCO (0.30 g, 0.92 mmol) and Pd(dba) (0.035 g, 0.038 mmol) in anhydrous toluene (8 mL) was sparged with Ar for 10 minutes in a sealed tube and then stirred at 100° C. for 16 hours. The reaction mixture was cooled to room temperature and filtered through a celite filter cake. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:3 to 1:2) to give 4-(trifluoromethyl)-3-((R)-3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)pyridine (0.105 g, 41%) as a light yellow oil. ESIMS m / z 646.325 [M+H] + .

[0478] To a solution of the above material (0.105 g, 0.163 mmol) in anhydrous DCM (8 mL) cooled at -78°C was added BCl3 (1.0 M in DCM, 2.0 mL, 2.0 mmol) under Ar, and the mixture was stirred at 0°C for 3 hours. The reaction mixture was cooled at -78°C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with 1 M NH3 in MeOH and then purified by flash chromatography on silica gel (0.5 M NH3 in MeOH / DCM, 1:6) to give (3S,4R,5R)-1-(((R)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol as a white solid (0.030 g, 49%). 1 H NMR (400MHz, DMSO-d6) δ8.73(s,1H),8.53(d,J=5.0Hz,1H),7.62(d,J=5.0Hz,1H),4.80-4.55(m,3H),3.28-3.14(m,3H),3.08-2. 97(m,1H),2.93-2.74(m,3H),2.74-2.62(m,1H),2.50-2.45(m,1H),2.24-2.10(m,2H),1.96-1.49(m,6H),1.12-0.97(m,1H); ESI MS m / z 376.186[M+H] + .

[0479] Example 168

[0480] (3S,4R,5R)-1-(((R)-1-(5-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0481]

[0482] A mixture of (3S,4S,5R)-3,4,5-tris(benzyloxy)-1-((S)-piperidin-3-ylmethyl)piperidine (0.200 g, 0.400 mmol), 3-bromo-5-(trifluoromethyl)pyridine (0.12 g, 0.53 mmol), RuPhos (0.035 g, 0.075 mmol), CsCO (0.30 g, 0.92 mmol) and Pd(dba) (0.035 g, 0.038 mmol) in anhydrous toluene (8 mL) was bubbled with Ar for 10 minutes in a sealed tube and then stirred at 100° C. for 16 hours. The reaction mixture was cooled to room temperature and filtered through a celite cake. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:4 to 1:2) to give 3-(trifluoromethyl)-5-((R)-3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)pyridine (0.16 g, 62%) as a light yellow oil.

[0483] Under Ar, to a solution of the above-mentioned substance (0.16 g, 0.25 mmol) in anhydrous DCM (6 mL) cooled to -78 ° C, BCl (1.0 M 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 at -78 ° C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with a 1 M NH solution in MeOH, and then purified by flash chromatography (0.5 M NH in 1:6 MeOH / DCM) on silica gel to give (3S, 4R, 5R) -1- (((R) -1- (5- (trifluoromethyl) pyridin-3-yl) piperidin-3-yl) methyl) piperidine -3,4,5- triol as a white solid (0.053 g, 56%). 1H NMR (500MHz, DMSO-d6) δ8.51(dd,J=2.0,1.0Hz,1H),8.21(dd,J=2.0,1.0Hz,1H),7.46(t,J=2.0Hz ,1H),4.75(d,J=4.3Hz,1H),4.70(d,J=4.9Hz,2H),3.76-3.08(m,2H),3.33-3.23(m,2H),2.95-2.8 5(m,2H),2.86-2.78(m,1H),2.75-2.70(m,1H),2.66(dd,J=12.7,9.3Hz,1H),2.26(dd,J=12.2,7.9 Hz,1H),2.13(dd,J=12.2,6.2Hz,1H),1.89-1.65(m,5H),1.58-1.44(m,1H),1.17-1.08(m,1H); ESI MS m / z 376.181[M+H] + .

[0484] Example 169

[0485] (3S,4R,5R)-1-(((R)-1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0486]

[0487] A mixture of (3S,4S,5R)-3,4,5-tris(benzyloxy)-1-((S)-piperidin-3-ylmethyl)piperidine (0.25 g, 0.50 mmol), 2-chloro-4-(trifluoromethyl)pyridine (0.20 g, 1.1 mmol) and DIPEA (0.26 g, 2.0 mmol) in anhydrous DMF (6 mL) was stirred at 100 ° C for 16 hours in a sealed tube. The reaction mixture was cooled to room temperature and diluted with saturated aqueous NaHCO3 (10 mL). After extraction with EtOAc (3×15 mL), the combined extracts were washed with brine (2×15 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:8 to 1:4) to give 4-(trifluoromethyl)-2-((R)-3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)pyridine as a light yellow oil (0.13 g, 50%).

[0488] To a solution of the above material (0.13 g, 0.20 mmol) in anhydrous DCM (8 mL) cooled at -78°C was added BCl3 (1.0 M in DCM, 2.0 mL, 2.0 mmol) under Ar, and the mixture was stirred at 0°C for 3 hours. The reaction mixture was cooled at -78°C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with 1 M NH3 in MeOH and then purified by flash chromatography on silica gel (0.5 M NH3 in 1:6 MeOH / DCM) to give (3S,4R,5R)-1-(((R)-1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol as a white solid (0.061 g, 81%). 1 H NMR (500MHz, DMSO-d6) δ8.29(d,J=5.1Hz,1H),6.98(s,1H),6.79(d,J=5.1Hz,1H),4.74(d,J=4.3 Hz,1H),4.73-4.67(m,2H),4.27-4.19(m,1H),4.16-4.07(m,1H),3.31-3.22(m,2H),3.06-2.97( m,1H),2.88(td,J=8.6,4.3Hz,1H),2.85-2.78(m,1H),2.76-2.60(m,2H),2.23(dd,J=12.2,8.2H z,1H),2.11(dd,J=12.2,6.4Hz,1H),1.83-1.61(m,5H),1.49-1.35(m,1H),1.26-1.10(m,1H); ESI MS m / z 376.182[M+H] + .

[0489] Example 170

[0490] (3S,4R,5R)-1-(((R)-1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0491]

[0492] A mixture of (3S,4S,5R)-3,4,5-tris(benzyloxy)-1-((S)-piperidin-3-ylmethyl)piperidine (0.25 g, 0.50 mmol), 2-chloro-5-(trifluoromethyl)pyridine (0.20 g, 1.1 mmol) and DIPEA (0.26 g, 2.0 mmol) in anhydrous DMF (6 mL) was stirred at 100 ° C for 16 hours in a sealed tube. The reaction mixture was cooled to room temperature and diluted with saturated aqueous NaHCO3 (10 mL). After extraction with EtOAc (3×15 mL), the combined extracts were washed with brine (2×15 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:8 to 1:4) to give 5-(trifluoromethyl)-2-((R)-3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)pyridine as a light yellow oil (0.26 g, 81%).

[0493] To a solution of the above material (0.25 g, 0.39 mmol) in anhydrous DCM (10 mL) cooled at -78°C under Ar was added BCl3 (1.0 M in DCM, 3.0 mL, 3.0 mmol) and the mixture was stirred at 0°C for 3 hours. The reaction mixture was cooled at -78°C and quenched with MeOH before being concentrated to dryness. The residue was neutralized with 1 M NH3 in MeOH and subsequently purified by flash chromatography on silica gel (0.5 M NH3 in 1:6 MeOH / DCM) to give (3S,4R,5R)-1-(((R)-1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol as a white solid (0.14 g, 94%). 1H NMR(500MHz,DMSO-d6)δ8.37(d,J=2.8Hz,1H),7.73(dd,J=9.1,2.8Hz,1H),6.87(d,J=9.1Hz,1H),4 .76-4.68(m,3H),4.31-4.21(m,1H),4.20-4.13(m,1H),3.32-3.24(m,2H),3.11-3.02(m,1H),2.88( td,J=8.6,4.3Hz,1H),2.85-2.79(m,1H),2.77-2.64(m,2H),2.21(dd,J=12.2,8.4Hz,1H),2.11(dd, J=12.2,6.3Hz,1H),1.82-1.73(m,2H),1.73-1.60(m,3H),1.49-1.35(m,1H),1.25-1.13(m,1H); ESI MS m / z 376.182[M+H] + .

[0494] Example 171

[0495] (3S,4R,5R)-1-(((R)-1-(6-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0496]

[0497] A solution of (3S,4S,5R)-3,4,5-tris(benzyloxy)-1-((S)-piperidin-3-ylmethyl)piperidine (0.200 g, 0.400 mmol), 5-bromo-2-(trifluoromethyl)pyridine (0.12 g, 0.53 mmol), RuPhos (0.035 g, 0.075 mmol), Cs2CO3 (0.30 g, 0.92 mmol) and Pd2(dba)3 (0.035 g, 0.038 mmol) in anhydrous toluene (8 mL) was bubbled with Ar for 10 min and then stirred at 100° C. for 16 h. The reaction mixture was cooled to room temperature and filtered through a celite filter cake. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:4 to 1:3) to give 2-(trifluoromethyl)-5-((R)-3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)pyridine (0.25 g, 97%) as a light yellow oil.

[0498] To a solution of the above material (0.24 g, 0.37 mmol) in anhydrous DCM (10 mL) cooled at -78°C under Ar was added BCl3 (1.0 M in DCM, 3.0 mL, 3.0 mmol) and the mixture was stirred at 0°C for 3 hours. The reaction mixture was cooled at -78°C and quenched with MeOH before being concentrated to dryness. The residue was neutralized with 1 M NH3 in MeOH and then purified by flash chromatography on silica gel (0.5 M NH3 in 1:6 MeOH / DCM) to give (3S,4R,5R)-1-(((R)-1-(6-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol as a white solid (0.11 g, 80%). 1 H NMR (400MHz, DMSO-d6) δ8.35(d,J=2.9Hz,1H),7.60(d,J=8.8Hz,1H),7.34(dd,J=8 .8,2.9Hz,1H),4.81-4.64(m,3H),3.86-3.72(m,2H),3.39-3.22(m,2H),3.01-2.85 (m,2H),2.85-2.76(m,1H),2.77-2.66(m,2H),2.25(dd,J=12.2,8.2Hz,1H),2.13(d d,J=12.2,6.0Hz,1H),1.84-1.66(m,5H),1.58-1.45(m,1H),1.25-1.11(m,1H); ESI MS m / z376.189[M+H] + .

[0499] Example 172

[0500] (3S,4R,5R)-1-(((R)-1-(3-(trifluoromethyl)pyridin-4-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0501]

[0502] A mixture of (3S,4S,5R)-3,4,5-tris(benzyloxy)-1-((S)-piperidin-3-ylmethyl)piperidine (0.25 g, 0.50 mmol), 4-chloro-3-(trifluoromethyl)pyridine (0.20 g, 1.1 mmol) and DIPEA (0.26 g, 2.0 mmol) in anhydrous DMF (6 mL) was stirred at 100 ° C for 16 hours in a sealed tube. The reaction mixture was cooled to room temperature and diluted with saturated aqueous NaHCO (10 mL). After extraction with EtOAc (3×15 mL), the combined extracts were washed with brine (2×15 mL) and dried over anhydrous NaSO. After filtration, the solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:3 to 1:2) to give 3-(trifluoromethyl)-4-((R)-3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)pyridine as a light yellow oil (0.22 g, 69%).

[0503] To a solution of the above material (0.22 g, 0.34 mmol) in anhydrous DCM (10 mL) cooled at -78°C under Ar was added BCl3 (1.0 M in DCM, 3.0 mL, 3.0 mmol) and the mixture was stirred at 0°C for 3 hours. The reaction mixture was cooled at -78°C and quenched with MeOH before being concentrated to dryness. The residue was neutralized with 1 M NH3 in MeOH and subsequently purified by flash chromatography on silica gel (0.5 M NH3 in 1:6 MeOH / DCM) to give (3S,4R,5R)-1-(((R)-1-(3-(trifluoromethyl)pyridin-4-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol as a white solid (0.079 g, 62%). 1 H NMR(500MHz,DMSO-d6)δ8.62(s,1H),8.50(d,J=5.7Hz,1H),7.13(d,J=5.7 Hz,1H),4.79-4.63(m,3H),3.55-3.46(m,1H),3.36-3.28(m,1H),3.27-3. 18(m,2H),2.90-2.78(m,3H),2.71-2.60(m,1H),2.54-2.47(m,1H),2.23- 2.07(m,2H),1.90-1.68(m,4H),1.68-1.48(m,2H),1.12-0.99(m,1H);ESI MS m / z 376.183[M+H] + .

[0504] Example 173

[0505] (3S,4R,5R)-1-(((R)-1-(2-(trifluoromethyl)pyridin-4-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0506]

[0507] In a sealed tube, a mixture of (3S,4S,5R)-3,4,5-tris(benzyloxy)-1-((S)-piperidin-3-ylmethyl)piperidine (0.200 g, 0.400 mmol), 4-bromo-2-(trifluoromethyl)pyridine (0.12 g, 0.53 mmol), RuPhos (0.035 g, 0.075 mmol), Cs2CO3 (0.30 g, 0.92 mmol) and Pd2(dba)3 (0.035 g, 0.038 mmol) in anhydrous toluene (8 mL) was bubbled with Ar for 10 min and then stirred at 100° C. for 16 h. The reaction mixture was cooled to room temperature and filtered through a celite filter cake. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:3 to 1:2) to give 2-(trifluoromethyl)-4-((R)-3-(((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)pyridine (0.16 g, 62%) as a light yellow oil.

[0508] To a solution of the above material (0.16 g, 0.25 mmol) in anhydrous DCM (8 mL) cooled at -78°C was added BCl3 (1.0 M in DCM, 2.0 mL, 2.0 mmol) under Ar, and the mixture was stirred at 0°C for 3 hours. The reaction mixture was cooled at -78°C, quenched with MeOH, and then concentrated to dryness. The residue was neutralized with 1 M NH3 in MeOH and then purified by flash chromatography on silica gel (0.5 M NH3 in 1:6 MeOH / DCM) to give (3S,4R,5R)-1-(((R)-1-(2-(trifluoromethyl)pyridin-4-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol as a white solid (0.077 g, 83%). 1H NMR (500MHz, DMSO-d6) δ8.22(d,J=6.0Hz,1H),7.11(d,J=2.6Hz,1H),6.95(dd,J=6.0,2. 6Hz,1H),4.76(d,J=4.2Hz,1H),4.74-4.68(m,2H),3.85-3.75(m,2H),3.35-3.25(m,2H), 3.12-3.02(m,1H),2.94-2.78(m,3H),2.72-2.05(m,1H),2.24(dd,J=12.3,8.5Hz,1H),2 .09(dd,J=12.2,5.9Hz,1H),1.83-1.59(m,5H),1.52-1.39(m,1H),1.26-1.15(m,1H); ESI MS m / z 376.183[M+H] + .

[0509] Example 174

[0510] (3S,4S,5R)-1-(((S)-1-(2-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0511]

[0512] To a stirred solution of (3S,4R,5R)-3,4,5-tris(benzyloxy)-1-((R)-piperidin-3-ylmethyl)piperidine (110 mg, 0.22 mmol) and 3-bromo-2-trifluoromethylpyridine (99 mg, 0.44 mmol) in toluene (5 mL) under Ar was added Pd(dba) (20 mg, 0.022 mmol) and RuPhos (21 mg, 0.044 mmol), followed by CsCO (287 mg, 0.88 mmol). The mixture was stirred at 100°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (2 x 10 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel to give 2-(trifluoromethyl)-3-((S)-3-(((3S,4S,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)pyridine as an oil (60 mg, 42%). ESI MS m / z 646.32 [M+H] + .

[0513] At -78 ° C and N2, BCl3 (concentration in DCM is 1M, 0.75mL, 0.75mmol) was added to a stirred solution of the above-mentioned substance (60mg, 0.09mmol) in anhydrous DCM (5mL). The mixture was stirred at 0 ° C for 4h and then quenched with anhydrous MeOH (1mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum, and the residue was dissolved in 1M NH3 in MeOH solution (10mL) and stirred for another 10 minutes, and then the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel to obtain (3S, 4S, 5R)-1-(((S)-1-(2-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol as a white solid (9mg, 26%). 1 H NMR (400MHz, CD3OD) δ8.37(dd,J=4.5,1.4Hz,1H),7.95-7.87(m,1H),7.62(dd,J=8.3,4.6Hz,1H),3.51-3.41(m,2H),3.25(dd,J=11.5,3.6Hz,1H), 3.15-2.97(m,3H),2.92-2.76(m,2H),2.47(dd,J=11.3,9.3Hz,1H),2.38- 2.24(m,2H),2.09-1.90(m,2H),1.88-1.69(m,4H),1.22-1.10(m,1H);ESI MS m / z 376.19[M+H] + .

[0514] Example 175

[0515] (3S,4S,5R)-1-(((S)-1-(5-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0516]

[0517] To a stirred solution of (3S,4R,5R)-3,4,5-tris(benzyloxy)-1-((R)-piperidin-3-ylmethyl)piperidine (100 mg, 0.20 mmol) and 3-bromo-5-trifluoromethylpyridine (90 mg, 0.40 mmol) in toluene (5 mL) under Ar was added Pd(dba) (18 mg, 0.020 mmol) and RuPhos (19 mg, 0.040 mmol), followed by CsCO (261 mg, 0.81 mmol). The mixture was stirred at 100°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (2 x 10 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel to give 3-(trifluoromethyl)-5-((S)-3-(((3S,4S,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)pyridine as an oil (108 mg, 84%). ESI MS m / z 646.32 [M+H] + .

[0518] At -78 ° C and N2, BCl3 (concentration in DCM is 1M, 0.75mL, 0.75mmol) was added to the stirred anhydrous DCM (5mL) solution of the above-mentioned substance (108mg, 0.17mmol). The mixture was stirred at 0 ° C for 4h and then quenched with anhydrous MeOH (1mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum, and the residue was dissolved in 1M NH3 in MeOH solution (10mL) and stirred for another 10 minutes, then the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel to obtain (3S, 4S, 5R) -1- (((S) -1- (5- (trifluoromethyl) pyridin-3-yl) piperidin-3-yl) methyl) piperidine-3,4,5-triol as a white solid (46mg, 72%). 1H NMR (400MHz, CD3OD) δ8.46(d,J=2.8Hz,1H),8.17(d,J=0.7Hz,1H),7.52(t,J=2.3Hz,1H),3.81(dd,J=12. 5,3.6Hz,1H),3.72(dt,J=12.7,4.2Hz,1H),3.59-3.49(m,2H),3.13(t,J=8.8Hz,1H),3.07-2.94(m,2H), 2.90(ddd,J=11.0,4.9,2.1Hz,1H),2.75(dd,J=12.6,9.3Hz,1H),2.42(dd,J=12.4,8.7Hz,1H),2.27(dd, J=12.4,5.4Hz,1H),2.01(t,J=10.6Hz,1H),1.95-1.79(m,4H),1.75-1.60(m,1H),1.32-1.19(m,1H); ESI MS m / z 376.19[M+H] + .

[0519] Example 176

[0520] (3S,4S,5R)-1-(((S)-1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0521]

[0522] To a stirred solution of (3S,4R,5R)-3,4,5-tris(benzyloxy)-1-((R)-piperidin-3-ylmethyl)piperidine (150 mg, 0.30 mmol) and 2-chloro-4-(trifluoromethyl)pyridine (272 mg, 1.50 mmol) in DMF (5 mL) was added DIPEA (0.42 mL, 2.40 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 x 10 mL), separated, dried over Na2SO4, filtered, and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica gel to afford 4-(trifluoromethyl)-2-((S)-3-(((3S,4S,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)pyridine as an oil (73 mg, 38%). ESI MS m / z 646.33 [M+H] + .

[0523] To a stirred solution of 4-(trifluoromethyl)-2-((S)-3-(((3S,4S,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)pyridine (73 mg, 0.11 mmol) in anhydrous DCM (5 mL) was added BCl (1 M in DCM, 0.75 mL, 0.75 mmol) at -78 °C under N2. The mixture was stirred at 0 °C for 4 h and then quenched with anhydrous MeOH (1 mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum and the residue was dissolved in 1 M NH3 in MeOH (10 mL) and stirred for an additional 10 min before removing the solvent under vacuum. The residue was purified by flash chromatography on silica gel to give (3S,4S,5R)-1-(((S)-1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol as a white solid (37 mg, 89%). 1 H NMR (400MHz, CD3OD) δ8.26(d,J=5.2Hz,1H),6.97(d,J=0.8Hz,1H),6.81-6.73(m,1H),4.29(dd,J =13.0,3.7Hz,1H),4.14(d,J=13.2Hz,1H),3.60-3.48(m,2H),3.17-3.00(m,3H),2.90(ddd,J=10 .9,4.9,2.1Hz,1H),2.79(dd,J=13.1,9.6Hz,1H),2.38(dd,J=12.4,8.5Hz,1H),2.25(dd,J=12.4 ,5.7Hz,1H),1.97(t,J=10.6Hz,1H),1.94-1.74(m,4H),1.66-1.52(m,1H),1.37-1.19(m,1H); ESI MS m / z 376.19[M+H] + .

[0524] Example 177

[0525] (3S,4S,5R)-1-(((S)-1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0526]

[0527] To a stirred solution of (3S,4R,5R)-3,4,5-tris(benzyloxy)-1-((R)-piperidin-3-ylmethyl)piperidine (120 mg, 0.24 mmol) and 2-chloro-5-(trifluoromethyl)pyridine (218 mg, 1.20 mmol) in DMF (5 mL) was added DIPEA (0.33 mL, 1.92 mmol). The mixture was stirred at 100°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (2 x 10 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under vacuum and the residue was purified by flash chromatography on silica gel to give 5-(trifluoromethyl)-2-((S)-3-(((3S,4S,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)pyridine as an oil (98 mg, 63%). ESI MS m / z 646.33 [M+H] + .

[0528] To a stirred solution of 5-(trifluoromethyl)-2-((S)-3-(((3S,4S,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)pyridine (98 mg, 0.15 mmol) in anhydrous DCM (5 mL) was added BCl (1 M in DCM, 0.75 mL, 0.75 mmol) at -78 ° C under N . The mixture was stirred at 0 ° C for 4 h and then quenched with anhydrous MeOH (1 mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum and the residue was dissolved in 1M NH in MeOH (10 mL) and stirred for an additional 10 minutes, then the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel to give (3S,4S,5R)-1-(((S)-1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol as a white solid (54 mg, 94%). 1H NMR(400MHz,CD3OD)δ8.32(dd,J=1.7,0.9Hz,1H),7.75-7.63(m,1H),6.86(d,J=9.1Hz,1H),4.34 (dd,J=13.3,3.8Hz,1H),4.19(dt,J=13.2,4.2Hz,1H),3.60-3.49(m,2H),3.24-3.09(m,2H),3.04 (ddd,J=10.9,4.9,2.2Hz,1H),2.96-2.77(m,2H),2.36(dd,J=12.4,8.6Hz,1H),2.25(dd,J=12.4 ,5.8Hz,1H),1.98(t,J=10.6Hz,1H),1.93-1.73(m,4H),1.63-1.47(m,1H),1.38-1.24(m,1H); ESI MS m / z 376.18[M+H] + .

[0529] Example 178

[0530] (3S,4S,5R)-1-(((S)-1-(6-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0531]

[0532] To a stirred solution of (3S,4R,5R)-3,4,5-tris(benzyloxy)-1-((R)-piperidin-3-ylmethyl)piperidine (135 mg, 0.27 mmol) and 5-bromo-2-trifluoromethylpyridine (122 mg, 0.54 mmol) in toluene (5 mL) was added Pd(dba) (25 mg, 0.027 mmol) and RuPhos (25 mg, 0.054 mmol), followed by CsCO (264 mg, 0.81 mmol). The mixture was stirred at 100°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (2 x 10 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated under vacuum and the residue was purified by flash chromatography on silica gel to give 2-(trifluoromethyl)-5-((S)-3-(((3S,4S,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)pyridine as an oil (84 mg, 48%). ESI MS m / z 646.33 [M+H] + .

[0533] -78 ℃ and N2, to the anhydrous DCM (5mL) solution of the above-mentioned substance (84mg, 0.13mmol) stirred, BCl3 (concentration in DCM is 1M, 0.75mL, 0.75mmol) was added. The mixture was stirred at 0 ℃ for 4h, then quenched with anhydrous MeOH (1mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum, and the residue was dissolved in 1M NH3 in MeOH (10mL), and stirred for another 10min, and then the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel to obtain (3S, 4S, 5R) -1- (((S) -1- (6- (trifluoromethyl) pyridin-3-yl) piperidin-3-yl) methyl) piperidine -3,4,5- triol as a white solid (33mg, 68%). 1 H NMR (400MHz, CD3OD) δ8.30(d,J=2.9Hz,1H),7.59(d,J=8.9Hz,1H),7.42-7.38(m,1H),3.94-3.85 (m,1H),3.82-3.75(m,1H),3.58-3.49(m,2H),3.13(t,J=8.8Hz,1H),3.10-2.99(m,2H),2.89(ddd ,J=11.0,5.0,2.2Hz,1H),2.80(dd,J=12.9,9.4Hz,1H),2.40(dd,J=12.5,8.7Hz,1H),2.27(dd,J= 12.5,5.4Hz,1H),2.07-1.97(m,1H),1.96-1.77(m,4H),1.74-1.61(m,1H),1.34-1.20(m,1H); ESI MS m / z 376.19[M+H] + .

[0534] Example 179

[0535] (3S,4S,5R)-1-(((S)-1-(3-(trifluoromethyl)pyridin-4-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol

[0536]

[0537] To a stirred solution of (3S,4R,5R)-3,4,5-tris(benzyloxy)-1-((R)-piperidin-3-ylmethyl)piperidine (200 mg, 0.40 mmol) and 4-chloro-3-(trifluoromethyl)pyridine (218 mg, 1.20 mmol) in DMF (5 mL) was added DIPEA (0.56 mL, 3.20 mmol). The mixture was stirred at 100°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (2 x 10 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel to give 3-(trifluoromethyl)-4-((S)-3-(((3S,4S,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)pyridine as an oil (150 mg, 58%). ESIMS m / z 646.32 [M+H] + .

[0538] At -78 ° C and N2, BCl3 (1M, 1.16 mL, 1.16 mmol) was added to a stirred solution of the above-mentioned substance (150 mg, 0.23 mmol) in anhydrous DCM (5 mL). The mixture was stirred at 0 ° C for 4 h and then quenched with anhydrous MeOH (1 mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum, and the residue was dissolved in a 1M NH3 solution of MeOH (10 mL) and stirred for another 10 minutes, then the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel to obtain (3S, 4S, 5R) -1- (((S) -1- (3- (trifluoromethyl) pyridin-4-yl) piperidin-3-yl) methyl) piperidine-3,4,5-triol as an oil (54 mg, 63%). 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),8.43(d,J=5.9Hz,1H),7.16(d,J=6.0Hz,1H),3. 73-3.60(m,1H),3.54-3.41(m,3H),3.10(t,J=8.8Hz,1H),3.06-2.93(m,2H),2.84 (ddd,J=11.0,5.0,2.2Hz,1H),2.64(dd,J=12.5,9.7Hz,1H),2.39-2.20(m,2H),1. 98(t,J=10.6Hz,2H),1.91-1.78(m,3H),1.77-1.64(m,1H),1.26-1.12(m,1H); ESI MS m / z 376.18[M+H] + .

[0539] Examples 185 and 186

[0540] (3S,4R,5R)-1-(((1r,4R)-4-(difluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol and (3S,4R,5R)-1-(((1s,4S)-4-(difluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol

[0541]

[0542] To a solution of cyclohexane-1,4-diyldimethanol (2.00 g, 13.9 mmol) in anhydrous DCM (60 mL) cooled to 0°C under Ar was added DIPEA (2.06 g, 16.0 mmol) and benzoyl chloride (1.97 g, 14.0 mmol). The mixture was stirred at room temperature for 16 hours and then diluted with saturated aqueous NaHCO3 (50 mL). After extraction with DCM (3×30 mL), the combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under vacuum, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:3 to 1:2) to give (4-(hydroxymethyl)cyclohexyl)methyl benzoate (1.51 g, 43%) as a light yellow oil.

[0543] The mixture of the above-mentioned substance (0.950g, 3.83mmol) and DMP (2.12g, 5.0mmol) in DCM (30mL) was stirred at room temperature for 1 hour to form a white suspension. Hexane (40mL) was added, and the suspension was filtered through a diatomaceous earth filter cake. The filtrate was collected and concentrated under vacuum, and the residue was purified by flash chromatography (EtOAc / hexane, 1: 4) on silica gel to obtain (4-formylcyclohexyl) methyl benzoate, which was a colorless oil (0.50g, 53%).

[0544] Under Ar, DAST (0.80 g, 5.0 mmol) was added to anhydrous DCM (10 mL) solution of the above-mentioned substance (0.50 g, 2.0 mmol) cooled at -78 ° C. The mixture was stirred at -78 ° C for 30 minutes, then stirred at room temperature for 5 hours. The reaction mixture was cooled at -78 ° C and quenched with saturated NaHCO aqueous solution (20 mL). The organic layer was collected and the aqueous layer was extracted with DCM (3 × 20 mL). The combined extracts were dried over anhydrous Na SO. After filtration, the solvent was evaporated under vacuum, and the residue was purified by flash chromatography (EtOAc / hexane, 1:10) on silica gel to obtain (4-(difluoromethyl)cyclohexyl)benzoic acid methyl ester, which was a colorless oil (0.40 g, 75%).

[0545] A mixture of the above material (0.40 g, 1.5 mmol) and KCO (0.45 g, 0.33 mmol) in MeOH (25 mL) was stirred at room temperature for 16 h. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:2) to give (4-(difluoromethyl)cyclohexyl)methanol as a clear liquid (0.21 g, 86%).

[0546] To a solution of the above substance (0.21 g, 1.3 mmol) in acetone (25 mL) cooled at 0°C was added a solution of CrO3 (0.60 g, 6.0 mmol) in 2.0 M H2SO4 aqueous solution (6 mL) pre-cooled at 0°C. The mixture was stirred at 0°C for 1 hour and at room temperature for 16 hours. Isopropanol (5 mL) was then added, and the mixture was stirred for another 1 hour. After concentration in vacuo, the mixture was diluted with water (50 mL) and extracted with DCM (3×20 mL). The combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under vacuum, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:1 to 3:1) to give 4-(difluoromethyl)cyclohexanecarboxylic acid (0.22 g, 96%) as a white solid. 1 1H NMR showed that the solid contained a mixture of cis and trans isomers, with cis:trans = 0.32:0.68).

[0547] A mixture of the above cis and trans isomers (0.050 g, 0.28 mmol), (3S,4r,5R)-3,4,5-tris(benzyloxy)piperidine (0.112 g, 0.28 mmol), HATU (0.20 g, 0.53 mmol) and DIPEA (0.11 g, 0.85 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with NaHCO (20 mL) and extracted with EtOAc (3 x 15 mL). The combined extracts were washed with brine (2 x 20 mL) and dried over anhydrous NaSO. After filtration, the solvent was evaporated under vacuum, and the residue was purified and separated by flash chromatography on silica gel (EtOAc / hexane, 1:3 to 1:2) to give ((1s,4S)-4-(difluoromethyl)cyclohexyl)((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methanone (0.048 g, 32%) and ((1r,4R)-4-(difluoromethyl)cyclohexyl)((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methanone (0.105 g, 62%), both as white solids. ESI MS m / z 564.291 [M+H] + .

[0548] Under Ar, to ((1s,4S)-4-(difluoromethyl)cyclohexyl)

[0549] To a solution of ((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methanone (0.10 g, 0.18 mmol) in anhydrous Et2O (10 mL) was added LAH (0.050 g, 1.3 mmol), and the mixture was stirred at 0°C for 4 h. The reaction was then quenched with water and diluted with saturated aqueous NaHCO3 (20 ml). After extraction with Et2O (3 x 30 mL), the combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo, and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:9 to 1:7) to give (3S,4R,5R)-3,4,5-tris(benzyloxy)-1-(((1S,4S)-4-(difluoromethyl)cyclohexyl)methyl)piperidine as a colorless oil (0.085 g, 87%). ESI MS m / z 550.316[M+H] + .

[0550] Under a hydrogen atmosphere at 1 atmosphere, the above material (0.085 g, 0.16 mmol), Pd(OH)2 / C (20% Pd by weight, 0.050 g, 0.094 mmol), and 2 drops of concentrated HCl in MeOH (20 mL) were stirred overnight. The mixture was filtered through a celite pad, and the filtrate was collected and concentrated to dryness. The residue was neutralized with 1M NH3 in MeOH and then purified by flash chromatography on silica gel (0.5M NH3 in 1:6 MeOH / DCM) to provide (3S,4R,5R)-1-(((1S,4S)-4-(difluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol (0.030 g, 68%) as a white solid. 1 H NMR (400MHz, CD3OD) δ5.74(td,J=57.1,5.3Hz,1H),3.48(ddd,J=10.3,8.8,4.7Hz,2H),3.08(t,J =8.9Hz,1H),2.99-2.88(m,2H),2.31(d,J=7.4Hz,2H),1.97-1.73(m,4H),1.62-1.45(m,8H); ESI MS m / z 280.174[M+H] + .

[0551] (3S,4R,5R)-1-(((1r,4R)-4-(difluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol was prepared from ((1r,4R)-4-(difluoromethyl)cyclohexyl)((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methanone as described for (3S,4R,5R)-1-(((1s,4S)-4-(difluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol as a white solid. 1 H NMR (400MHz, CD3OD) δ5.60(td,J=57.1,4.5Hz,1H),3.48(ddd,J=10.2,8.7,4.7Hz,2H),3.08(t,J=8.8Hz,1H),2.92(ddd,J= 10.6, 4.7, 1.6Hz, 2H), 2.20 (d, J = 7.0Hz, 2H), 1.92-162 (m, 7H), 1.55-1.44 (m, 1H), 1.25-1.12 (m, 2H), 1.01-0.84 (m, 2H); ESI MS m / z 280.168[M+H] + .

[0552] Examples 187 and 188

[0553] (3S,4R,5R)-1-(((1s,4S)-4-(1,1-difluoroethyl)cyclohexyl)methyl)piperidine-3,4,5-triol and (3S,4R,5R)-1-(((1r,4R)-4-(1,1-difluoroethyl)cyclohexyl)methyl)piperidine-3,4,5-triol

[0554]

[0555] To a solution of cis / trans-4-(hydroxymethyl)cyclohexanecarboxylic acid (3.20 g, 20.2 mmol) in anhydrous MeOH (50 mL) was added SOCl2 (4.8 g, 40 mmol) dropwise, and the mixture was stirred at room temperature for 4 hours. The solvent was then removed under vacuum, and the residue was diluted with saturated aqueous NaHCO3 (40 ml). After extraction with DCM (3 × 40 mL), the combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under vacuum to obtain a clear liquid. The liquid was dissolved in anhydrous DMF (30 mL) and cooled at 0°C, followed by the addition of imidazole (2.72 g, 40.0 mmol) and TBDMSCl (4.52 g, 30.0 mmol). After stirring at room temperature for 16 h, the reaction mixture was diluted with brine (100 mL) and extracted with EtOAc (3 × 40 mL). The combined extracts were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under vacuum, and the residue was purified by flash chromatography (EtOAc / hexane, 1:9) on silica gel to give a colorless oil. Under Ar, the oil was dissolved in anhydrous THF (50 mL), and the solution was cooled at 0 ° C. LAH (1.00 g, 26.3 mmol) was added in batches, and the mixture was stirred at 0 ° C for 1 hour. Wet sodium sulfate heptahydrate (50 g) was added to quench the reaction, and the suspension was stirred for 30 minutes. After filtration, the solvent was evaporated under vacuum, and the residue was purified by flash chromatography (EtOAc / hexane, 1:4 to 1:2) on silica gel to give a mixture of cis and trans-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)methanol as a colorless oil (4.6 g, 88%, 3 steps).

[0556] Under Ar, to anhydrous DCM (80mL) solution of DMSO (1.95g, 25.0mmol) cooling at -78 ℃, add anhydrous DCM (20mL) solution of oxalyl chloride (1.93g, 15.0mmol).After adding, the mixture was stirred at -78 ℃ for 1 hour, and anhydrous DCM (20mL) solution of the above-mentioned substance (2.58g, 10.0mmol) was added. After the mixture was stirred at -78 ℃ for 1 hour, Et3N (5.4mL, 40mmol) was added, and the mixture was stirred at -78 ℃ for 30 minutes, then stirred at room temperature for 30 minutes. Then the mixture was diluted with saturated NaHCO3 aqueous solution (50mL), and the collected organic layer was extracted with DCM (50mL), and the organic extracts combined were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under vacuum and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:9) to give 4-(((tert-butyldimethylsilyl)oxy)methyl)-cyclohexanecarbaldehyde as a colorless oil (2.30 g, 90%).

[0557] Under Ar, to a solution of the above substance (2.30 g, 9.00 mmol) in anhydrous THF (40 mL) cooled to 0° C., MeMgCl (3.0 M in THF, 4.0 mL, 12 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with ice water, diluted with saturated NH4Cl aqueous solution (30 mL), and extracted with EtOAc (2×50 mL). The combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under vacuum, and the residue was purified by flash chromatography (EtOAc / hexane, 1:4) on silica gel to give 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)ethanol as a colorless oil (2.40 g, 98%).

[0558] The mixture of the above-mentioned substance (2.40g, 8.80mmol) and DMP (5.60g, 13.2mmol) in DCM (50mL) was stirred at room temperature for 3 hours to form a white suspension. Hexane (50mL) was added, and the suspension was filtered through a diatomaceous earth filter cake. The filtrate was collected and concentrated under vacuum, and the residue was purified by flash chromatography (EtOAc / hexane, 1:15 to 1:6) on silica gel to obtain 1- (4- (((tert-butyldimethylsilyl) oxygen base) methyl) cyclohexyl) ethyl ketone, which is a colorless oil (2.11g, 89%).

[0559] To a solution of the above material (2.11 g, 7.8 mmol) in anhydrous THF (30 mL) cooled to 0°C under Ar was added TBAF (1.0 M in THF, 10.0 mL, 10.0 mmol), and the mixture was stirred at room temperature for 3 hours. After dilution with saturated aqueous NaHCO3 (40 mL), the mixture was extracted with EtOAc (2 x 30 mL), and the combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under vacuum, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 2:3 to 1:1) to give 1-(4-(hydroxymethyl)cyclohexyl)ethanone as a clear liquid (1.10 g, 92%).

[0560] To a solution of the above material (1.10 g, 7.20 mmol) in anhydrous DCM (25 mL) cooled to 0° C. under Ar was added DMAP (0.25 g, 2.0 mmol), DIPEA (1.93 g, 15.0 mmol) and benzoyl chloride (1.40 g, 10.0 mmol). The mixture was stirred at room temperature for 16 hours and diluted with saturated aqueous NaHCO₃ (30 ml). After extraction with DCM (3×30 mL), the combined extracts were dried over anhydrous Na₂SO₄. After filtration, the solvent was evaporated under vacuum and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:6 to 1:3) to give methyl (4-acetylcyclohexyl)benzoate as a light yellow oil (1.85 g, 99%).

[0561] To a solution of the above material (1.70 g, 6.53 mmol) in anhydrous DCM (15 mL) under Ar was added DAST (5.74 g, 35.9 mmol), and the mixture was stirred at room temperature for 1 hour and then heated at reflux for 4 days. The reaction mixture was cooled at -78 ° C and quenched with saturated aqueous NaHCO 3 solution (50 mL). After extraction with DCM (2×50 mL), the combined extracts were dried over anhydrous Na 2 SO 4. After filtration, the solvent was evaporated under vacuum, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:11 to 1:9) to give methyl (4-(1,1-difluoroethyl)cyclohexyl)benzoate as a light yellow oil (1.45 g, 79%).

[0562] A mixture of the above substance (1.45 g, 5.13 mmol) and KCO (1.5 g, 11 mmol) in MeOH (40 mL) was stirred for 16 hours. The solvent was removed under vacuum, and the residue was purified by flash chromatography (EtOAc / hexane, 1:4 to 1:2) on silica gel to give (4-(1,1-difluoroethyl)cyclohexyl)methanol (0.85 g, 93%) as a clear liquid.

[0563] To a solution of the above substance (0.85 g, 4.8 mmol) in acetone (40 mL) cooled to 0 ° C was added a 2.0 M H2SO4 (10 mL) solution of CrO3 (1.5 g, 15 mmol) pre-cooled to 0 ° C. The reaction mixture was stirred at 0 ° C for 1 hour and at room temperature for 16 hours. Isopropanol (5 mL) was then added, and the mixture was stirred for another 1 h. After vacuum concentration, the mixture was diluted with water (50 mL) and extracted with DCM (3 × 30 mL). The combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under vacuum to give 4- (1,1-difluoroethyl) cyclohexanecarboxylic acid (0.90 g, 98%) as a white solid. 1 1H NMR showed that the solid contained a mixture of cis and trans isomers, with cis:trans = 0.35:0.65).

[0564] A mixture of the above cis- and trans-isomers (0.190 g, 1.00 mmol), (3S,4S,5R)-3,4,5-tris(benzyloxy)-1-((S)-piperidin-3-ylmethyl)piperidine (0.300 g, 0.743 mmol), HATU (0.46 g, 1.2 mmol), and DIPEA (0.19 g, 1.5 mmol) in DMF (10 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with NaHCO (30 mL) and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (2 x 20 mL) and dried over anhydrous NaSO. After filtration, the solvent was evaporated under vacuum and the residue was purified and separated by flash chromatography on silica gel (EtOAc / hexane, 1:5 to 1:3) to give ((1s,4S)-4-(1,1-difluoroethyl)cyclohexyl)((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methanone (0.127 g, 31%) and ((1r,4R)-4-(1,1-difluoroethyl)cyclohexyl)((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methanone (0.228 g, 55%), both as white solids.

[0565] To a solution of ((1s,4S)-4-(1,1-difluoroethyl)cyclohexyl)((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methanone (0.127 g, 0.220 mmol) in anhydrous Et2O (15 mL) cooled at 0°C was added LAH (0.050 g, 1.3 mmol) under Ar, and the mixture was stirred at 0°C for 4 hours. The reaction was then quenched with water and diluted with saturated aqueous NaHCO3 (20 ml). After extraction with Et2O (3×30 mL), the combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:9 to 1:7) to give (3S,4R,5R)-3,4,5-tris(benzyloxy)-1-(((1s,4S)-4-(1,1-difluoroethyl)cyclohexyl)methyl)piperidine as a colorless oil (0.11 g, 89%). ESI MS m / z 564.326 [M+H] + .

[0566] A mixture of the above material (0.11 g, 0.20 mmol), Pd(OH)2 / C (20% Pd by weight, 0.050 g, 0.094 mmol), and 2 drops of concentrated HCl in MeOH (15 mL) was stirred overnight under hydrogen and 1 atmosphere. The mixture was filtered through a celite pad, and the filtrate was collected and concentrated to dryness. The residue was neutralized with 1 M NH3 in MeOH and then purified by flash chromatography on silica gel (0.5 M NH3 in 1:6 MeOH / DCM) to give (3S,4R,5R)-1-(((1s,4S)-4-(1,1-difluoroethyl)cyclohexyl)methyl)piperidine-3,4,5-triol (0.050 g, 88%) as a white solid. 1 H NMR (400MHz, CD3OD) δ3.48(ddd,J=10.3,8.8,4.7Hz,2H),3.09(t,J=8.8Hz,1H),3.00-2.85(m,2H),2.36(d,J=7.5Hz ,2H),2.01-1.84(m,2H),1.78-1.67(m,2H),1.73(dq,J=13.4,3.7Hz,2H),1.68-1.43(m,7H),1.44-1.28(m,2H); ESI MS m / z 294.188[M+H] + .

[0567] ((3S,4R,5R)-1-(((1r,4R)-4-(1,1-difluoroethyl)cyclohexyl)methyl)piperidine-3,4,5-triol was prepared from ((1r,4R)-4-(1,1-difluoroethyl)cyclohexyl)((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methanone as described for (3S,4R,5R)-1-(((1s,4S)-4-(1,1-difluoroethyl)cyclohexyl)methyl)piperidine-3,4,5-triol and obtained as a white solid. 1 H NMR (400MHz, DMSO-d6) δ4.70(d,J=4.3Hz,1H),4.66(d,J=4.8Hz,2H),3.33-3.18(m,2H),2.87(td,J=8.6,4.4Hz,1H),2.78-2.71(m,2H),2.07 (d,J=7.1Hz,2H),1.83-1.74(m,4H),1.74-1.64(m,3H),1.53(t,J=19.4Hz,3H),1.44-1.33(m,1H),1.21-1.06(m,2H),0.88-0.78(m,2H); ESI MS m / z 294.189[M+H] + .

[0568] Example 189

[0569] (3S,4R,5R)-1-(((1r,4R)-4-(trifluoromethoxy)cyclohexyl)methyl)piperidine-3,4,5-triol

[0570]

[0571] HATU (285 mg, 0.75 mmol) was added to a mixed solution of (3S, 4r, 5R)-3,4,5-tris(benzyloxy)piperidine (200 mg, 0.50 mmol) and 4-(trifluoromethoxy)cyclohexanecarboxylic acid (105 mg, 0.50 mmol) in DMF (10 mL) at 0 ° C, followed by the addition of DIPEA (0.26 mL, 1.5 mmol). The mixture was stirred at room temperature for 18 h. Water was added to quench the reaction. The mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×30 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel to give ((1r,4R)-4-(trifluoromethoxy)cyclohexyl)((3S,4R,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methanone as a white solid (90 mg, 30%). ESI MS m / z 598.27 [M+H] +.

[0572] To a solution of the above substance (90 mg, 0.15 mmol) in anhydrous Et2O (5 mL) was added LAH (30 mg, 0.75 mmol) at 0°C, and the mixture was stirred at 0°C for 4 hours. The mixture was slowly quenched with saturated aqueous Na2SO4 and filtered. The solid was washed with EtOAc. The combined organic layers were washed with water (2×20 mL), separated and dried over Na2SO4. After filtration, the solvent was evaporated in vacuo, and the residue was purified by flash chromatography on silica gel to give (3S,4R,5R)-3,4,5-tris(benzyloxy)-1-(((1r,4R)-4-(trifluoromethoxy)cyclohexyl)methyl)piperidine as an oil (64 mg, 73%). ESI MS m / z 584.29 [M+H] + .

[0573] At -78 ° C and N2, BCl3 (concentration in DCM is 1M, 0.50mL, 0.50mmol) was added to a stirred solution of the above-mentioned substance (60mg, 0.10mmol) in anhydrous DCM (5mL). The mixture was stirred at 0 ° C for 2h and then quenched with anhydrous MeOH (1mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum, and the residue was dissolved in 1M NH3 in MeOH solution (10mL) and stirred for another 10 minutes, and then the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel to obtain (3S, 4R, 5R)-1-(((1r, 4R)-4-(trifluoromethoxy)cyclohexyl)methyl)piperidine-3,4,5-triol as a white solid (18mg, 57%). 1 H NMR (400MHz, CD3OD) δ4.28-4.14(m,1H),3.55-3.42(m,2H),3.09(t,J=8.8Hz b,1H),2.92(ddd,J=10.4,4.3,1.5Hz,2H),2.92(ddd,J=10.4,4.3,1.5Hz,2H), 2.15-2.06(m,2H),1.99-1.83(m,5H),1.59-1.42(m,3H),1.12-0.95(m,2H); ESI MS m / z 314.15[M+H] + .

[0574] Example 190

[0575] (3S,4r,5R)-1-((4,7-difluoro-2,3-dihydro-1H-inden-2-yl)methyl)piperidine-3,4,5-triol

[0576]

[0577] At room temperature, NBS (1.55 g, 8.68 mmol) was added to a solution of 1,4-difluoro-2,3-dimethylbenzene (560 mg, 3.94 mmol) in CHCl3 (20 mL), followed by the addition of ABCN (77 mg, 0.32 mmol). The mixture was stirred at reflux for 3 h and cooled to room temperature. Water was added to quench the reaction. The mixture was extracted with DCM (3 × 20 mL). The combined organic layers were washed with water (2 × 30 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated in vacuo, and the residue was purified by flash chromatography on silica gel to give 2,3-bis(bromomethyl)-1,4-difluorobenzene as an oil (600 mg, 51%).

[0578] Dimethyl malonate (0.28 mL, 2.42 mmol) was added to a solution of NaH (480 mg, 60%, 12 mmol) in THF (150 mL), stirred at room temperature for 30 minutes, and then the above substance (600 mg, 2.01 mmol) was added. The mixture was stirred at room temperature for 18 hours and then slowly quenched with water. The mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×30 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under vacuum, and the residue was purified by flash chromatography on silica gel to give dimethyl 4,7-difluoro-1H-indene-2,2(3H)-dicarboxylate as an oil (136 mg, 25%).

[0579] The above substance (130 mg, 0.44 mmol) was dissolved in dioxane (4 mL) and 6N HCl (8 mL), and the mixture was refluxed for 20 hours and cooled to room temperature. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 30 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under vacuum, and the residue containing 4,7-difluoro-2,3-dihydro-1H-indene-2-carboxylic acid was used in the next step without purification (44 mg, 49%).

[0580] HATU (205 mg, 0.54 mmol) was added to a stirred solution of (3S,4r,5R)-3,4,5-tris(benzyloxy)piperidine (147 mg, 0.36 mmol) and the above-mentioned substance (87 mg, 0.44 mmol) in DMF (8 mL) at 0°C, followed by the addition of DIPEA (0.25 mL, 1.44 mmol). The mixture was stirred at room temperature for 18 h. Water was added to quench the reaction. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 30 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel to give (4,7-difluoro-2,3-dihydro-1H-inden-2-yl)((3S,4r,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methanone as an oil (208 mg, 99%). ESI MS m / z 584.26 [M+H] + .

[0581] To a solution of the above material (140 mg, 0.18 mmol) in anhydrous Et2O (5 mL) was added LAH (30 mg, 0.75 mmol) at 0°C, and the mixture was stirred at 0°C for 4 hours. The mixture was slowly quenched with saturated aqueous Na2SO4 and filtered. The solid was washed with EtOAc. The combined organic layers were washed with water (2×20 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated in vacuo, and the residue was purified by flash chromatography on silica gel to give (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-((4,7-difluoro-2,3-dihydro-1H-inden-2-yl)methyl)piperidine as an oil (102 mg, 99%). ESI MS m / z 570.27 [M+H] + .

[0582] To a stirred solution of the above substance (102 mg, 0.18 mmol) in anhydrous DCM (5 mL) was added BCl (1 M in DCM, 0.88 mL, 0.88 mmol) at -78 ° C and N2. The mixture was stirred at 0 ° C for 2 h and then quenched with anhydrous MeOH (1 mL). The mixture was stirred at room temperature for 10 minutes. The solvent was removed under vacuum, and the residue was dissolved in 1M NH3 in MeOH (10 mL) and stirred for another 10 min, then the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel to obtain (3S, 4r, 5R) -1- ((4,7-difluoro-2,3-dihydro-1H-inden-2-yl) methyl) piperidine-3,4,5-triol as a white solid (42 mg, 78%). 1H NMR (400MHz, CD3OD) δ6.88-6.82(m,2H),3.59-3.49(m,2H),3.19-3.06(m,3H),3.05-2.96( m,2H),2.88-2.79(m,1H),2.78-2.70(m,2H),2.46(d,J=7.6Hz,2H),2.03-1.92(m,2H); ESI MS m / z 300.14[M+H] + .

[0583] Example 191

[0584] Cyclohexyl(4-fluoro-4-(((3S,4r,5R)-3,4,5-trihydroxypiperidin-1-yl)methyl)piperidin-1-yl)methanone

[0585]

[0586] To a mixture of (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-((4-fluoropiperidin-4-yl)methyl)piperidine) (167 mg, 0.32 mmol), cyclohexanecarboxylic acid (41 mg, 0.32 mmol) and DIPEA (0.2 mL, 1.0 mmol) in anhydrous DMF (5 mL) was added HATU (43.5 mg, 0.32 mmol) under Ar. The mixture was stirred at room temperature for 18 h, then saturated aqueous NaHCO3 solution (30 mL) was added and the mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel using 30% EtOAc in hexanes to give cyclohexyl(4-fluoro-4-(((3S,4r,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)methanone as a white foam (80 mg, 40%).

[0587] At -78 ℃ and Ar, to anhydrous DCM (2mL) solution of the above-mentioned substance (80mg, 0.13mmol), BCl solution (0.63mL, concentration in DCM is 1M, 1.50mmol) is added. The mixture is stirred at -78 ℃ for 1 hour and at 0 ℃ for 4 hours, then MeOH (20mL) is added. The mixture is stirred for 2h at 0 ℃ and evaporated to dryness under reduced pressure. Residue is used 10%MeOH and 2%NH in DCM on silica gel by flash chromatography (dry load) solution purification, obtain cyclohexyl (4-fluoro-4-(((3S, 4r, 5R)-3,4,5-trihydroxypiperidin-1-yl) methyl) piperidin-1-yl) ketone (25mg, 55%). 1H NMR (400MHz, CD3OD) δ4.32(d,J=13.0Hz,1H),3.89(d,J=13.8Hz,1H),3.49(ddd,J=10.2,8.7,4.8Hz,2H),3.45-3.35(m,1H),3.15-2.92(m, 4H),-2.72-2.65(m,1H),2.59(d,J=22.8Hz,2H),2.12(dd,J=11.5,9.7Hz,2H),2.05-1.97(m,2H),1.84-1.69(m,5H),1.65-1.20(m,7H); ESI MS m / z 359.2[M+H] + .

[0588] Example 192

[0589] (3S,4r,5R)-1-((4-Fluoro-1-(4-fluorophenyl)piperidin-4-yl)methyl)piperidine-3,4,5-triol

[0590]

[0591] At -78 ℃, DMSO (3.8mL, 53.5mmol) is added to the DCM (100mL) solution of oxalyl chloride (1.80mL, 21.4mmol) that stirs. The mixture is stirred at -78 ℃ for 30 minutes, then the DCM (10mL) solution of 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (2.5g, 10.7mmol) is added. The mixture is stirred at -78 ℃ for 1h and Et3N (14.9mL, 107mmol) is added. The mixture is stirred at -78 ℃ for 15 minutes, then stirred at 0 ℃ for another 15 minutes, then quenched with water. The mixture is extracted with EtOAc (3 × 100mL). The combined organic layer is washed with saturated NaHCO3 aqueous solution (30mL), separated, and dried with Na2SO4. After filtration, the solvent was evaporated under reduced pressure and the crude tert-butyl 4-fluoro-4-formylpiperidine-1-carboxylate was used in the next step without further purification.

[0592] To a stirred solution of ((3S,4r,5R)-3,4,5-tris(benzyloxy)piperidine (2.87 g, 7.13 mmol) and the above material (10.7 mmol crude) in anhydrous DCM (80 mL) was added HOAc (0.5 mL), the mixture was stirred for 30 minutes, NaBH(OAc)3 (2.57 g, 12.1 mmol) was added, and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was washed with saturated NaHC03 at 0°C. The mixture was quenched with aqueous O3. The mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (2×30 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel to give tert-butyl 4-fluoro-4-(((3S,4r,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidine-1-carboxylate as an oil (3.72 g, 84%). ESI MS m / z 619.36 [M+H] + .

[0593] TFA (5 mL) was cooled to 0°C and added to a solution of the above substance (1.80 g, 2.91 mmol) in DCM (30 mL), and the mixture was stirred at 0°C for 10 minutes and then at room temperature for 2 hours. TFA and DCM were removed under reduced pressure. The residue was dissolved in EtOAc (80 mL) and washed with saturated aqueous NaHCO3 (2×20 mL), then washed with water, separated and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel to give (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-((4-fluoropiperidin-4-yl)methyl)piperidine as an oil (1.50 g, 99%). ESI MS m / z 519.31 [M+H] + .

[0594] To a stirred solution of the above material (225 mg, 0.43 mmol) and 4-bromofluorobenzene (152 mg, 0.87 mmol) in toluene (5 mL) under Ar was added Pd2(dba)3 (25 mg, 0.043 mmol) and BINAP (54 mg, 0.086 mmol), followed by sodium tert-butoxide (124 mg, 1.29 mmol). The mixture was stirred at 100°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (2 x 10 mL), separated, and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-((4-fluoro-1-(4-fluorophenyl)piperidin-4-yl)methyl)piperidine as an oil (135 mg, 51%). ESI MS m / z 613.33 [M+H] + .

[0595] To a solution of the above substance (130 mg, 0.21 mmol) in EtOH (10 mL) was added Pd(OH)2 / C (20 wt.%, 8.6 mg, 0.012 mmol) and 6N HCl (0.5 mL). The mixture was treated with hydrogen (1 atm) for 18 h. The catalyst was filtered through diatomaceous earth and the solvent was evaporated under reduced pressure. The residue was dissolved in a 1M NH3 solution in MeOH (10 mL) and stirred for another 10 minutes, then the solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel to obtain (3S, 4r, 5R)-1-((4-fluoro-1-(4-fluorophenyl)piperidin-4-yl)methyl)piperidine-3,4,5-triol as a white solid (45 mg, 63%). 1 H NMR(400MHz,CD3OD)δ7.08-6.90(m,4H),3.57-3.44(m,2H),3.39-3.34(m,1H),3.12-2.93(m,6H) ,2.61(d,J=22.8Hz,2H),2.13(dd,J=11.3,10.2Hz,2H),2.05-1.97(m,2H),1.95-1.70(m,2H);ESI MS m / z 343.19[M+H] + .

[0596] Example 193

[0597] (3S,4r,5R)-1-((4-Fluoro-1-(2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)piperidine-3,4,5-triol

[0598]

[0599] To a stirred solution of (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-((4-fluoropiperidin-4-yl)methyl)piperidine (290 mg, 0.56 mmol) and 1-bromo-2-trifluoromethyl-benzene (256 mg, 1.13 mmol) in toluene (5 mL) was added Pd2(dba)3 (51 mg, 0.056 mmol) and BINAP (70 mg, 0.112 mmol) under Ar, followed by KO t Bu (163 mg, 1.67 mmol). The mixture was stirred at 100 ° C for 18 h, and 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 dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel to give (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-((4-fluoro-1-(2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)piperidine as an oil (136 mg, 37%).

[0600] To a solution of the above substance (136 mg, 0.13 mmol) in anhydrous MeOH (10 mL) was added two drops of HCl (6 N) and Pd(OH) (cat.). H (1 atm.) was added to the mixture and stirred for 18 hours. The mixture was filtered through a short column filled with celite, then evaporated and flash chromatography (dry loaded) using a 10% MeOH and 2% NH solution in DCM to give (3S, 4r, 5R)-1-((4-fluoro-1-(2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)piperidine-3,4,5-triol (54 mg, 76%). 1 H NMR (400MHz, CD3OD) δ7.73-7.41(m,3H),7.29(t,J=7.3Hz,1H),3.53(td,J=9.3,4.4Hz,2H),3.23-2.96( m,5H),2.93-2.77(m,2H),2.63(d,J=23.1Hz,2H),2.14(dd,J=11.4,10.0Hz,2H),2.04-1.70(m,4H); ESI MS m / z 393.2[M+H] + .

[0601] Example 194

[0602] (3S,4r,5R)-1-((4-Fluoro-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-3,4,5-triol

[0603]

[0604] To a stirred solution of (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-((4-fluoropiperidin-4-yl)methyl)piperidine (152 mg, 0.29 mmol) and 2-chloro-3-trifluoromethyl-pyridine (106 mg, 0.58 mmol) in DMF (5 mL) was added KCO (121 mg, 0.87 mmol) under Ar. The mixture was stirred at 100°C for 18 hours, then water was added. The mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (2 x 10 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give 2-(4-fluoro-4-(((3S,4r,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)-3-(trifluoromethyl)pyridine as an oil (78 mg, 40%).

[0605] At -78 ° C and Ar, to anhydrous DCM (2mL) solution of the above-mentioned substance (74mg, 0.11mmol) was added BCl solution (0.6mL, the concentration in DCM is 1M, 0.6mmol). The mixture was stirred at -78 ° C for 1 hour and at 0 ° C for 4 hours, then MeOH (20mL) was added. The mixture was stirred for 2h at 0 ° C and evaporated to dryness under reduced pressure. The residue was purified by DCM flash chromatography (dry load) using 10% MeOH and 2% NH on silica gel. Obtain (3S, 4r, 5R) -1- ((4- fluoro-1- (3- (trifluoromethyl) pyridin-2-yl) piperidin-4-yl) methyl) piperidine -3,4,5- triol (14mg, 33%). 1 HNMR(400MHz,CD3OD)δ8.66-8.30(m,1H),8.01(dd,J=7.8,1.8Hz,1H),7.15(dd d,J=7.8,4.8,0.9Hz,1H),3.52(ddd,J=10.2,8.8,4.8Hz,2H),3.37(dt,J=13.1, 4.1Hz,2H),3.29-3.18(m,2H),3.15-3.04(m,3H),2.63(d,J=22.9Hz,2H),2.13 (dd,J=11.3,10.1Hz,2H),2.00(dd,J=13.6,10.2Hz,2H),1.95-1.80(m,2H); ESI m / z 394.2[M+H] + .

[0606] Example 195

[0607] (3S,4r,5R)-1-((4-Fluoro-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-3,4,5-triol

[0608]

[0609] To a stirred solution of (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-((4-fluoropiperidin-4-yl)methyl)piperidine (200 mg, 0.39 mmol) and 2-chloro-6-trifluoromethyl-pyridine (200 mg, 0.77 mmol) in DMF (5 mL) was added KCO (161 mg, 1.17 mmol) under Ar. The mixture was stirred at 100°C for 18 hours, then water was added. The mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (2 x 10 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give 2-(4-fluoro-4-(((3S,4r,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)-6-(trifluoromethyl)pyridine as an oil (88 mg, 34%).

[0610] At -78 ° C and Ar, to anhydrous DCM (2mL) solution of the above-mentioned substance (88mg, 0.11mmol) was added BCl solution (0.8mL, 1M concentration in DCM, 0.8mmol). The mixture was stirred at -78 ° C for 1 hour and at 0 ° C for 4 hours, then MeOH (20mL) was added. The mixture was stirred for another 2h at 0 ° C and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography (dry load) on silica gel using 10% MeOH and 2% NH solution in DCM to obtain (3S, 4r, 5R) -1- ((4- fluoro-1- (6- (trifluoromethyl) pyridin-2-yl) piperidin-4-yl) methyl) piperidine -3,4,5- triol (3.9mg, 7.5%). 1H NMR (400MHz, CD3OD) δ8.01-7.44(m,1H),7.04(d,J=8.7Hz,1H),7.04(d,J=8.7Hz,1H),4.19(d,J=13.0Hz,2H),3.50(ddd,J=10.1,8.7,4 .8Hz,2H),3.3-3.1(m,2H),3.14-2.97(m,3H),2.60(d,J=23.0Hz,2H),2.12(t,J=10.7Hz,2H),2.03-1.90(m,2H),1.83-1.58(m,2H); ESI MS m / z 394.2[M+H] + .

[0611] Example 196

[0612] (3S,4r,5R)-1-((1-(Benzo[d]thiazol-2-yl)-4-fluoropiperidin-4-yl)methyl)piperidine-3,4,5-triol

[0613]

[0614] To a stirred solution of (3S,4r,5R)-3,4,5-tris(benzyloxy)-1-((4-fluoropiperidin-4-yl)methyl)piperidine (210 mg, 0.41 mmol) and 2-bromobenzo[d]thiazole (174 mg, 0.81 mmol) in toluene (5 mL) under Ar was added Pd(dba) (38 mg, 0.04 mmol) and RuPhos (37 mg, 0.08 mmol), followed by CsCO (401 mg, 1.23 mmol). The mixture was stirred at 100°C for 18 h, then water was added at 0°C. The mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (2 x 10 mL), separated, and dried over NaSO. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel to give 2-(4-fluoro-4-(((3S,4r,5R)-3,4,5-tris(benzyloxy)piperidin-1-yl)methyl)piperidin-1-yl)benzo[d]thiazole as an oil (200 mg, 75%).

[0615] At -78 ° C and Ar, to anhydrous DCM (2mL) solution of the above-mentioned substance (42mg, 0.064mmol) was added BCl solution (0.35mL, the concentration in DCM is 1M, 0.35mmol). The mixture was stirred at -78 ° C for 1 hour and at 0 ° C for 4 hours, then MeOH (20mL) was added. The mixture was stirred for 2h at 0 ° C and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography (dry load) on silica gel using 10% MeOH and 2% NH solution in DCM to obtain (3S, 4r, 5R) -1- ((1- (benzo [d] thiazol-2-yl) -4-fluoropiperidin-4-yl) methyl) piperidine -3,4,5- triol (13mg, 50%). 1 HNMR(400MHz,CD3OD)δ7.74-7.61(m,1H),7.57-7.42(m,1H),7.30(ddd,J=8.3,7.3,1.3Hz,1H),7.17-7.04(m,1H),4.0 7-3.85(m,2H),3.61-3.44(m,4H),3.21-2.91(m,3H),2.64(d,J=23.0Hz,2H),2.2-2.00(m,4H),1.95-1.74(m,2H); ESI MS m / z 382.2[M+H] + .

[0616] Example 197

[0617] (3S,4r,5R)-1-(4-Butoxybenzyl)piperidine-3,4,5-triol

[0618]

[0619] To a solution of (3S,4r,5R)-3,4,5-tris(benzyloxy)piperidine (4.03 g, 10.0 mmol) in MeOH (150 mL) was added Pd(OH)2 / C (20 wt.%, 0.50 g, 0.94 mmol) and concentrated aqueous HCl (2.0 mL). The mixture was stirred under hydrogen (1 atm) for 18 h. Solid K2CO3 (2.0 g) and anhydrous Na2SO4 (10 g) were added, and the mixture was stirred for an additional 1 h. The solid was filtered off through celite, and the solvent was evaporated under reduced pressure. The residue was dissolved in DMF (50 mL), and then DIPEA (3.5 mL, 20 mmol) and Boc2O (4.5 g, 20 mmol) were added. After stirring for 16 h, the mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (MeOH / EtOAc, 1:9) to give tert-butyl (3S,4r,5R)-3,4,5-trihydroxypiperidine-1-carboxylate as a white solid (2.3 g, 99%).

[0620] At 0 ° C, acetic anhydride (6.0 mL) was added to a stirred solution of the above substance (2.3 g, 9.9 mmol) in pyridine (40 mL). After stirring at room temperature for 18 hours, the mixture was concentrated under reduced pressure at 40 ° C, and the residue was diluted with a saturated NaHCO3 aqueous solution (80 mL). The mixture was extracted with EtOAc (3 × 50 mL), and the combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was co-evaporated with hexane (2 × 100 mL) and further vacuum-dried to obtain a light yellow crystalline solid. The solid was dissolved in DCM (50 mL) and TFA (8 mL) was subsequently added. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure, and the residue was diluted with a saturated NaHCO3 aqueous solution (100 mL). After extraction with DCM (3 × 50 mL), the combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure to give (3S,4r,5R)-piperidine-3,4,5-triyl triacetate as a pale yellow solid (2.5 g, 98%). 1 H NMR (400MHz, CD3OD) δ5.09(t,J=9.3Hz,1H),4.92-4.76(m,2H),3.21-3.15(m,2H),2.53(dd,J=12.9,10.3Hz,2H),2.01(s,3H),2.00(s,6H); ESI MS m / z 260.12[M+H] + .

[0621] To a stirred solution of (3S,4r,5R)-piperidine-3,4,5-triyl triacetate (0.075 g, 0.29 mmol) and 4-butoxybenzaldehyde (0.071 g, 0.40 mmol) in DCM (5 mL) was added NaBH(OAc)3 (0.11 mg, 0.52 mmol), and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with saturated aqueous NaHCO3 (10 mL) and then extracted with DCM (2×10 mL). The combined extracts were dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:6 to 1:4) to give (3S,4r,5R)-1-(4-butoxybenzyl)piperidine-3,4,5-triyl triacetate as a white solid (0.107 g, 88%). ESI MS m / z 422.22[M+H] + .

[0622] The above material (0.107 g, 0.254 mmol) was dissolved in 1 M NH3 in MeOH (10 mL) and stirred, and the mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure, and the residue was dried under high vacuum at 60°C. The acetamide was removed by sublimation to provide (3S,4r,5R)-1-(4-butoxybenzyl)piperidine-3,4,5-triol as a white solid (0.0675 g, 90%). 1 H NMR (400MHz, CD3OD) δ7.30-7.18(m,2H),6.92-6.83(m,2H),3.98(t,J=6.4Hz,2H),3.55-3.44(m,4H),3.09(t,J=8.8 Hz,1H),2.98-2.92(m,2H),1.92(t,J=10.8Hz,2H),1.82-1.70(m,2H),1.59-1.45(m,2H),1.00(t,J=7.4Hz,3H); ESI MS m / z 296.19[M+H] + .

[0623] Example 198

[0624] (3S,4r,5R)-1-(4-(Pentyloxy)benzyl)piperidine-3,4,5-triol

[0625]

[0626] To a stirred solution of (3S,4r,5R)-piperidine-3,4,5-triyl triacetate (0.090 g, 0.35 mmol) and 4-(pentyloxy)benzaldehyde (0.077 g, 0.40 mmol) in DCM (5 mL) was added NaBH(OAc) (0.11 g, 0.52 mmol), and the reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with saturated aqueous NaHCO (10 mL) and extracted with DCM (2 × 10 mL). The combined extracts were dried over anhydrous NaSO. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:6 to 1:4) to give (3S,4r,5R)-1-(4-(pentyloxy)benzyl)piperidine-3,4,5-triyl triacetate as a white solid (0.13 g, 86%). ESI MS m / z 436.24[M+H] + .

[0627] The above material (0.130 g, 0.299 mmol) was dissolved in 1 M NH3 in MeOH (10 mL) and stirred, and the mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure, and the residue was dried under high vacuum at 60 ° C to remove acetamide by sublimation, and then recrystallized from MeOH to give (3S,4r,5R)-1-(4-(pentyloxy)benzyl)piperidine-3,4,5-triol as a white solid (0.063 g, 68%). 1 HNMR (400MHz, CD3OD) δ7.27-7.18(m,2H),6.92-6.84(m,2H),3.97(t,J=6.5Hz,2H),3.55-3.44(m,4H),3.09(t,J=8. 9Hz,1H)2.99-2.90(m,2H),1.92(t,J=10.8Hz,2H),1.85-1.73(m,2H),1.52-1.38(m,4H),0.97(t,J=7.1Hz,3H); ESI MS m / z310.21[M+H] + .

[0628] Example 199

[0629] (3S,4r,5R)-1-(4-Butoxy-2,6-difluorobenzyl)piperidine-3,4,5-triol

[0630]

[0631] To a stirred solution of (3S,4r,5R)-piperidine-3,4,5-triyl triacetate (0.090 g, 0.35 mmol) and 4-butoxy-2,6-difluorobenzaldehyde (0.086 g, 0.40 mmol) in DCM (5 mL) was added NaBH(OAc) (0.11 mg, 0.52 mmol), and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with saturated aqueous NaHCO (10 mL) and extracted with DCM (2 × 10 mL). The combined extracts were dried over anhydrous NaSO. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:6 to 1:4) to give (3S,4r,5R)-1-(4-butoxy-2,6-difluorobenzyl)piperidin-3,4,5-triyl triacetate as a white solid (0.146 g, 92%). ESI MS m / z 458.21 [M+H] + .

[0632] The above material (0.146 g, 0.319 mmol) was dissolved in 1 M NH3 in MeOH (10 mL), and the mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure, and the residue was dried under high vacuum at 60 ° C to remove acetamide by sublimation to give (3S,4r,5R)-1-(4-butoxy-2,6-difluorobenzyl)piperidine-3,4,5-triol as a white solid (0.089 g, 84%). 1 H NMR (400MHz, CD3OD) δ6.64-6.53(m,2H),3.99(t,J=6.4Hz,2H),3.68(d,J=1.5Hz,2H),3.54-3.44(m,2H),3.07 -2.93(m,3H),1.99(dd,J=11.4,10.0Hz,2H),1.83-1.71(m,2H),1.59-1.44(m,2H),1.00(t,J=7.4Hz,3H); ESI MS m / z 332.18[M+H] + .

[0633] Example 200

[0634] (3S,4r,5R)-1-(4-(cyclopropylmethoxy)benzyl)piperidine-3,4,5-triol

[0635]

[0636] To a stirred solution of (3S,4r,5R)-piperidine-3,4,5-triyl triacetate (0.075 g, 0.29 mmol) and 4-(cyclopropylmethoxy)benzaldehyde (0.070 g, 0.40 mmol) in DCM (5 mL) was added NaBH(OAc) (106 mg, 0.50 mmol), and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with saturated aqueous NaHCO (10 mL) and extracted with DCM (2 × 10 mL), and the combined extracts were dried over anhydrous NaSO. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:6 to 1:4) to give (3S,4r,5R)-1-(4-(cyclopropylmethoxy)benzyl)piperidine-3,4,5-triyl triacetate as a white crystalline solid (0.10 g, 82%). ESI MS m / z 420.21[M+H] + .

[0637] The above material (0.100 g, 0.238 mmol) was dissolved in 1 M NH in MeOH (10 mL), and the mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure, and the residue was dried under high vacuum at 60 ° C. to remove acetamide by sublimation, followed by flash chromatography on silica gel (0.5 M NH in 1:7 MeOH / DCM) to give (3S, 4r, 5R) -1- (4- (cyclopropylmethoxy) benzyl) piperidine -3,4,5- triol as a white solid (0.0493 g, 71%). 1 H NMR (400MHz, CD3OD) δ7.31-7.22(m,2H),6.95-6.87(m,2H),3.83(d,J=6.8Hz,2H),3.69-3.64(m,2H),3.62-3.50(m,2H), 3.18(t,J=8.6Hz,1H),3.07-2.98(m,2H),2.14(s,br.,2H),1.33-1.20(m,1H),0.69-0.56(m,2H),0.43-0.31(m,2H); ESI MS m / z 294.18[M+H] + .

[0638] Example 201

[0639] (3S,4r,5R)-1-(4-phenoxybenzyl)piperidine-3,4,5-triol

[0640]

[0641] To a stirred solution of (3S,4r,5R)-piperidine-3,4,5-triyl triacetate (0.100 g, 0.386 mmol) and 4-phenoxybenzaldehyde (0.110 g, 0.557 mmol) in DCM (10 mL) was added NaBH(OAc) (0.15 mg, 0.71 mmol), and the reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with saturated aqueous NaHCO (10 mL) and extracted with DCM (2 x 10 mL). The combined extracts were dried over anhydrous NaSO. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexanes, 1:6 to 1:4) to afford (3S,4r,5R)-1-(4-phenoxybenzyl)piperidine-3,4,5-triyl triacetate as a white solid (0.14 g, 82%). ESI MS m / z 442.19[M+H] + .

[0642] The above material (0.140 g, 0.317 mmol) was dissolved in 1 M NH3 in MeOH (10 mL), and the mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure, and the residue was dried under high vacuum at 60°C. The acetamide was removed by sublimation and then recrystallized from MeOH to give (3S,4r,5R)-1-(4-phenoxybenzyl)piperidine-3,4,5-triol as a white solid (0.095 g, 95%). 1 HNMR (400MHz, CD3OD)δ

[0643] 7.41-7.28(m,4H),7.17-7.07(m,1H),7.03-6.92(m,4H),3.59-3.46(m,4H) ,3.11(t,J=8.9Hz,1H),2.963.00-2.92(m,2H),1.95(t,J=10.7Hz,2H);ESI MS m / z 316.16[M+H] + .

[0644] Example 202

[0645] (3S,4r,5R)-1-([1,1'-biphenyl]-4-ylmethyl)piperidine-3,4,5-triol

[0646]

[0647] To a stirred solution of (3S,4r,5R)-piperidine-3,4,5-triyl triacetate (0.100 g, 0.386 mmol) and [1,1′-biphenyl]-4-carbaldehyde (0.100 g, 0.549 mmol) in DCM (10 mL) was added NaBH(OAc) (0.15 mg, 0.71 mmol) and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with saturated aqueous NaHCO (10 mL) and extracted with DCM (2×10 mL). The combined extracts were dried over anhydrous NaSO. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (EtOAc / hexane, 1:6 to 1:4) to give (3S,4r,5R)-1-([1,1'-biphenyl]-4-ylmethyl)piperidin-3,4,5-triyl triacetate as a white solid (0.14 g, 85%). ESI MS m / z 426.20 [M+H] + .

[0648] The above material (0.146 g, 0.329 mmol) was dissolved in 1 M NH3 in MeOH (10 mL), and the mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure, and the residue was dried under high vacuum at 60°C. The acetamide was removed by sublimation and then recrystallized from MeOH to give (3S,4r,5R)-1-([1,1'-biphenyl]-4-ylmethyl)piperidine-3,4,5-triol as a white solid (0.080 g, 81%). 1 HNMR(500MHz,CD3OD)δ7.65-7.57(m,4H),7.48-7.39(m,4H),7.38-7.31(m,1H),3.63(s,2H ),3.58-3.48(m,2H),3.12(t,J=8.9Hz,1H),3.03-2.95(m,2H),1.98(t,J=10.7Hz,2H); ESI MS m / z 300.16[M+H] + .

[0649] Example 203

[0650] (3S,4r,5R)-1-(4-(Pyrrolidin-1-yl)benzyl)piperidine-3,4,5-triol

[0651]

[0652] To a stirred solution of (3S, 4r, 5R)-piperidine-3,4,5-triyl triacetate (130 mg, 0.50 mmol) and 4-(pyrrolidin-1-yl)benzaldehyde (130 mg, 0.75 mmol) in anhydrous DCM (8 mL) was added HOAc (0.1 mL) followed by NaBH(OAc) (180 mg, 0.55 mmol) and the resulting mixture was stirred at room temperature for 24 hours. The mixture was diluted with DCM, then washed with saturated NaHCO aqueous solution, separated, and dried over NaSO. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel to give (3S, 4r, 5R)-1-(4-(pyrrolidin-1-yl)benzyl)piperidine-3,4,5-triyl triacetate (180 mg, 87%). 1 HNMR(400MHz,CD3OD)δ7.13-7.04(m,2H),6.57-6.48(m,2H),5.02-4.86(m,3H),3.49(s,2H),3.28-3.21 (m,4H),3.08(dd,J=5.1,1.5Hz,1H),3.06-3.04(m,1H),2.08-1.99(m,6H),1.98(s,3H),1.96(s,6H);ESI MS m / z 419.228[M+H] + .

[0653] The above material (180 mg, 0.43 mmol) was dissolved in 2M NH3 in MeOH (30 mL) and stirred at room temperature for 24 hours. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel to give (3S,4r,5R)-1-(4-(pyrrolidin-1-yl)benzyl)piperidine-3,4,5-triol (46.6 mg, 37%). 1 H NMR (400MHz, DMSO-d6) δ7.04-7.02(m,2H),6.48-6.46(m,2H),4.68(d,J=4.3Hz,1H),4.64-4.63(m,2H),3.33-3.31(m,3H),3.26- 3.16(m,5H),2.85(td,J=8.7,4.3Hz,1H),2.76(d,J=5.1Hz,1H),2.73(d,J=5.0Hz,1H),1.95-1.92(m,4H),1.70-1.65(m,2H); ESI MS m / z 293.187[M+H] + .

[0654] Example 204

[0655] (3S,4r,5R)-1-(4-(Piperidin-1-yl)benzyl)piperidine-3,4,5-triol

[0656]

[0657] To a stirred solution of (3S, 4r, 5R)-piperidine-3,4,5-triyl triacetate (130 mg, 0.50 mmol) and 4-(piperidin-1-yl)benzaldehyde (142 mg, 0.75 mmol) in anhydrous DCM (8 mL) was added HOAc (0.1 mL) followed by NaBH(OAc) (180 mg, 0.55 mmol) and the resulting mixture was stirred at room temperature for 24 hours. The mixture was diluted with DCM, then washed with saturated NaHCO aqueous solution, separated, and dried over NaSO. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel to give (3S, 4r, 5R)-1-(4-(piperidin-1-yl)benzyl)piperidine-3,4,5-triyl triacetate (190 mg, 88%). 1 H NMR (400MHz, CD3OD) δ7.23-7.15(m,2H),7.01-6.91(m,2H),5.04-4.90(m,3H),3.56(s,2H),3.17-3.12(m,4H),3.11(dd,J=5 .1,1.4Hz,1H),3.09-3.07(m,1H),2.14-2.05(m,2H),2.01(s,3H),1.99(s,6H),1.75-1.70(m,4H),1.64-1.57(m,2H).ESIMS m / z 433.245[M+H] + .

[0658] The above material (190 mg, 0.44 mmol) was dissolved in 2M NH3 in MeOH (30 mL) and stirred at room temperature for 24 hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel to give (3S,4r,5R)-1-(4-(piperidin-1-yl)benzyl)piperidine-3,4,5-triol (105 mg, 78%). 1HNMR (400MHz, CD3OD) δ7.25-7.14(m,2H),7.00-6.92(m,2H),3.55-3.46(m,4H),3.17-3.12(m,4H),3.09(td,J=9.1,1. 4Hz,1H),2.98-2.95(m,1H),2.94(dd,J=5.2,1.6Hz,1H),1.95-1.89(m,2H),1.76-1.70(m,4H),1.64-1.57(m,2H); ESI MS m / z307.207[M+H] + .

[0659] Example 205

[0660] (3S,4r,5R)-1-(Thien-2-ylmethyl)piperidine-3,4,5-triol

[0661]

[0662] To a stirred solution of (3S,4r,5R)-piperidine-3,4,5-triyl triacetate (130 mg, 0.50 mmol) and thiophene-2-carboxaldehyde (85 mg, 0.75 mmol) in anhydrous DCM (5 mL) was added NaBH(OAc)3 (180 mg, 0.85 mmol), and the resulting mixture was stirred at room temperature for 18 hours. The mixture was diluted with saturated aqueous NaHCO3 (10 mL) and extracted with DCM (2×10 mL). The organic layer was separated and dried over Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel to give (3S,4r,5R)-1-(thiophen-2-ylmethyl)piperidine-3,4,5-triyl triacetate as a white solid (150 mg, 84%). ESI MS m / z 356.12 [M+H] + .

[0663] The above material (150 mg, 0.42 mmol) was dissolved in 2M NH3 in MeOH (10 mL) and stirred at room temperature for 18 hours. The solvent was removed under reduced pressure, dried under high vacuum at 60°C for 4 hours, and the residue was purified by flash chromatography on silica gel to give (3S,4r,5R)-1-(thiophen-2-ylmethyl)piperidine-3,4,5-triol as a white solid (75 mg, 78%). 1H NMR (400MHz, CD3OD) δ7.35-7.32(m,1H),7.00-6.96(m,2H),3.81(s,2H),3.56-3.46( m,2H),3.09(t,J=8.9Hz,1H),3.02-2.94(m,2H),1.98(dd,J=11.2,10.2Hz,2H); ESIMS m / z 230.08[M+H] + .

[0664] Examples 40-61, 63-105, 107-141, 143-145, 147-148, 150-160, 160-166, and 180-184 shown in Table 1 were synthesized according to methods similar to those described in the schemes and examples outlined herein.

[0665] Biological activity

[0666] IC of GBA2 inhibition in cell lysates 50 Method for determining the value

[0667] HEK 293T cells stably expressing GBA2 were generated as follows. Human GBA2 (GBA2 nucleotide accession number BC011363) was PCR amplified using the following primers: sense 5'--CGC AAA TGG GCG GTA GGC GTG---3' and antisense 5'--TAGTCA GCC ATG GGG CGG AGA---3') and cloned into pLenti-GIII-CMV from ABM Inc. The construct was verified by sequencing. Lentiviral particles containing the pLenti-GIII-CMV plasmid (with GBA2 sequences) were prepared using a third-generation viral packaging mix for HEK293T cells (ABM cat#LV053-G074) and provided as a viral particle suspension. The viral suspension was used to infect HEK293T cells. The cell population stably expressing human GBA2 was selected by continuous treatment with puromycin for several weeks and confirmed by activity assays and Western blotting.

[0668] Various concentrations of test compounds were prepared in DMSO and then diluted in a pH 5.5 buffer consisting of 100 mM citric acid, 200 mM sodium phosphate dibasic, and 1% v / v C10E6. Homogenates (0.25 mg / mL) of a stable HEK293T cell line overexpressing GBA2 were preincubated with a GCase inhibitor (20 μM (6R,7R,8S)-8-ethyl-4-azaspiro[2.5]octane-6,7-diol) on ice for 10 minutes. The reactions consisted of 20 μL of 750 μM 4-methylumbelliferyl-β-D-glucopyranoside, pretreated with (6R,7R,8S)-8-ethyl-4-azaspiro[2.5]octane-6,7-diol, in 5% DMSO in the same buffer, followed by 20 μL of various concentrations of test compounds in 10% DMSO in the same buffer. The final concentrations in the reaction were 0.083 mg / mL GBA2-cell homogenate, 250 μM 4-methylumbelliferyl-β-D-glucopyranoside, and various concentrations of inhibitor. The inhibitor and GBA2-cell homogenate were preincubated together at 37°C for 5 minutes. The reaction was initiated by the addition of substrate and allowed to react at 37°C for 20 minutes to assess GBA2 activity. The reaction was terminated by the addition of an equal volume (60 μL) of 0.5 M NaOH, 0.3 M glycine, pH 10.5. Fluorescence was measured using a Biotek Synergy H4 microplate reader at an excitation wavelength of 365 nm and an emission wavelength of 450 nm. Incubations without enzyme or inhibitor were used to determine no enzyme activity and maximal enzyme activity, respectively. The IC was determined by fitting the data to a log[inhibitor concentration] versus response curve using GraphPad Prism. 50 IC 50 The values ​​were calculated as the inhibitor concentration required to inhibit GBA2 activity by 50%.

[0669] The compounds of the present invention tested showed an IC of GBA2 inhibition 50 The values ​​ranged from 0.1 nM to 50 μM.

[0670] Test for determining the inhibitory effect of rat intestinal α-glucosidase

[0671] Test compounds were prepared at varying concentrations in DMSO and then diluted in a buffer solution consisting of 100 mM citric acid and 200 mM sodium phosphate dibasic, pH 6.0. Rat intestinal acetone powder (Sigma) was dissolved in 12.5 mg / mL assay buffer and sonicated in an ice bath. The supernatant was collected, aliquoted, and stored at -20°C until use. On the day of the assay, rat intestinal lysate was diluted to 6.25 mg / mL (sucrose reaction) and 2.1 mg / mL (maltose reaction) in assay buffer. The final sucrose reaction solution contained 2.1 mg / mL rat intestinal lysate, 40 mM sucrose, 50 or 25 μM test compound, and 3.3% DMSO. The final maltose reaction solution contained 0.69 mg / mL rat intestinal lysate, 10 mM maltose, 50 or 25 μM test compound, and 3.3% DMSO. The reaction was initiated by adding substrate (sucrose or maltose) and allowed to proceed at 37°C for 20 minutes to assess rat intestinal α-glucosidase activity. The reaction was terminated by adding 20 μL of 2M Tris-HCl, pH 7.0. The glucose produced during the reaction was detected using a commercial Amplex Red glucose assay kit from Thermo Fisher. For the entire plate, the Amplex Red assay mixture was prepared by mixing 35 μL of glucose oxidase, 35 μL of horseradish peroxidase, and 35 μL of Amplex Red into 3395 μL of 1X Amplex Red assay buffer. A total of 30 μL of the assay mixture was added to each well. Fluorescence was measured in kinetic mode on a Biotek Synergy H4 microplate reader with an excitation wavelength of 573 nm and an emission wavelength of 610 nm for 15 minutes and quantified from the data at 10 minutes. Incubations without the addition of rat intestinal lysate were used to correct for the background amount of glucose present in the samples. Maximum enzyme activity was defined using incubations without the addition of test compounds. The percent inhibition of rat intestinal α-glucosidase was determined by dividing the amount of glucose detected in the presence of the test compound by the amount of glucose detected in the well with maximum enzyme activity. All conditions were analyzed in triplicate. Test compounds were prescreened to ensure that they did not inhibit any of the enzymes included in the Amplex Red assay kit. If inhibition of the Amplex Red kit enzyme was greater than 15%, the test compound was screened using the Hexokinase Glucose Assay Kit from Sigma. The final reaction solution was the same as described above for the Amplex Red assay kit. After 20 minutes of reaction at 37°C, 100 μL of the Hexokinase Glucose Reagent was added to all test wells, except for the control wells where no enzyme was added and the wells where no test compound was added. The plates were incubated for an additional 15 minutes at room temperature, and the absorbance was read at 340 nm on a BioTek Synergy H4 microplate reader.The percent inhibition of rat intestinal α-glucosidase was determined in a similar manner as described above.

[0672] Using sucrose as substrate, compounds of the invention tested at a concentration of 25 μM exhibited a percent inhibition of rat intestinal α-glucosidase of less than 20%.

[0673] Representative data from the above GBA2 inhibition assay are shown in Table 3, where the symbol “***” indicates IC 50 <100nM; the symbol “**” indicates 100nM <IC 50 <1 μM; and the symbol "*" indicates 1 μM <IC 50 <25 μM. Representative data from the above rat intestinal α-glucosidase inhibition assay using a compound concentration of 25 μM and sucrose as a substrate are shown in Table 3. For comparison, the first two table entries show data for the compounds (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).

[0674] Table 3

[0675]

[0676]

[0677]

[0678]

[0679] The present invention has been described with respect to one or more embodiments. However, it will be apparent to those skilled in the art that many variations and modifications may be made without departing from the scope of the invention as defined in the appended claims.

[0680] Therefore, although various embodiments of the present invention are disclosed herein, many adjustments and modifications can be made within the scope of the present invention according to the common knowledge of those skilled in the art. Such modifications include replacing any aspect of the present invention with known equivalents so as to achieve the same results in substantially the same manner. It should be understood that specific embodiments can be combined in any manner and in any quantity to produce another embodiment, and unless the context otherwise indicates, any arrangement and combination of embodiments should be considered to be disclosed by the description of this application. Numerical ranges include the numbers that limit the range. The description of numerical ranges herein is intended only to be used as a shorthand method for individually referring to each individual value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into this specification as if it were individually quoted herein. Unless otherwise indicated herein or clearly contradicted by the context, the terms "one" and "the" and similar references used in the context of describing the present invention should be interpreted as covering both the singular and the plural. In the specification, the word "comprising" is used as an open term, essentially equivalent to the phrase "including but not limited to", and the word "comprising" has a corresponding meaning. However, it should be understood that where the words "comprising" or "comprises" or variations of the same root word are used herein, variations or modifications to "consisting of" or "consisting essentially of" are also contemplated, which exclude any elements, steps or ingredients not specified, or variations or modifications to "consisting essentially of" or "consisting essentially of" which limit the specified materials or steps and those that do not materially affect the basic and novel characteristics of the claimed invention. Citation of references herein should not be construed as an admission that such references are prior art to the present invention. All publications are incorporated herein by reference as if each individual publication was specifically and individually indicated to be incorporated by reference and as if fully set forth herein. The invention includes all embodiments and variations substantially as described above and with reference to the examples.

[0681] References

[0682] 1.Grabowski,GALancet 2008,372,1263-1271.

[0683] 2.Massimo,A.et al.Neurochem Res 2016,41,210-20.

[0684] 3. Woeste, MA et a...

Claims

1. A compound, characterized in that The compound is: (3S,4R,5R)-1-(((1r,4R)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((1s,4S)-4-(trifluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((1s,4S)-4-(2-fluoropropan-2-yl)cyclohexyl)methyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-(2-cyclohexylethyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-(3-cyclohexylpropyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-(3-chloro-2-fluorophenethyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-(3-chloro-2,6-difluorophenethyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-(3,4-dichlorophenethyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-(4-(cyclopropylmethoxy)-2,6-difluorophenethyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-(2,6-difluoro-4-(pyrrolidin-1-yl)phenethyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-(2,6-difluoro-4-(piperidin-1-yl)phenethyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-(2,6-difluoro-4-morpholinylphenethyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenethyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-(4-(3,5-dimethylisoxazol-4-yl)-2,6-difluorophenethyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-2,6-difluorophenethyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-(1-(3-chloro-2-fluorophenyl)propan-2-yl)piperidine-3,4,5-triol; (3S,4r,5R)-1-(4-(3-chloro-2-fluorophenyl)butan-2-yl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((R)-1-(o-Tolyl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((R)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((R)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((R)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((R)-1-(Benzo[d]oxazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((R)-1-(Benzo[d]thiazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4S,5R)-1-(((S)-1-(3-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4S,5R)-1-(((S)-1-(4-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4S,5R)-1-(((S)-1-(4-(trifluoromethyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4S,5R)-1-(((S)-1-(4-(trifluoromethyl)thiazol-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4S,5R)-1-(((S)-1-(Benzo[d]thiazol-4-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((R)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((R)-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((R)-1-(2-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((R)-1-(5-isopropylthiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((R)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((R)-1-(Benzo[d]thiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((R)-1-(Benzo[d]thiazol-4-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4S,5R)-1-(((S)-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4S,5R)-1-(((S)-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4S,5R)-1-(((S)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4S,5R)-1-(((S)-1-(4-(trifluoromethyl)thiazol-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-((2,3-dihydro-1H-inden-2-yl)methyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-((1-phenylpiperidin-4-yl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((R)-1-(6-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((R)-1-(5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((R)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4S,5R)-1-(((S)-1-(5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4S,5R)-1-(((S)-1-(6-(trifluoromethyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((R)-1-(4-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((R)-1-(5-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((R)-1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((R)-1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((R)-1-(6-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((R)-1-(3-(trifluoromethyl)pyridin-4-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((R)-1-(2-(trifluoromethyl)pyridin-4-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4S,5R)-1-(((S)-1-(2-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4S,5R)-1-(((S)-1-(5-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4S,5R)-1-(((S)-1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4S,5R)-1-(((S)-1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4S,5R)-1-(((S)-1-(6-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4S,5R)-1-(((S)-1-(3-(trifluoromethyl)pyridin-4-yl)piperidin-3-yl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((1r,4R)-4-(difluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((1s,4S)-4-(difluoromethyl)cyclohexyl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((1s,4S)-4-(1,1-difluoroethyl)cyclohexyl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((1r,4R)-4-(1,1-difluoroethyl)cyclohexyl)methyl)piperidine-3,4,5-triol; (3S,4R,5R)-1-(((1r,4R)-4-(trifluoromethoxy)cyclohexyl)methyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-((4,7-difluoro-2,3-dihydro-1H-inden-2-yl)methyl)piperidine-3,4,5-triol; Cyclohexyl(4-fluoro-4-(((3S,4r,5R)-3,4,5-trihydroxypiperidin-1-yl)methyl)piperidin-1-yl)methanone; (3S,4r,5R)-1-((4-fluoro-1-(4-fluorophenyl)piperidin-4-yl)methyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-((4-fluoro-1-(2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-((4-fluoro-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-((4-fluoro-1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-((1-(Benzo[d]thiazol-2-yl)-4-fluoropiperidin-4-yl)methyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-(4-Butoxybenzyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-(4-(pentyloxy)benzyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-(4-Butoxy-2,6-difluorobenzyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-(4-(cyclopropylmethoxy)benzyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-(4-phenoxybenzyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-([1,1′-biphenyl]-4-ylmethyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-(4-(Pyrrolidin-1-yl)benzyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-(4-(piperidin-1-yl)benzyl)piperidine-3,4,5-triol; (3S,4r,5R)-1-(Thien-2-ylmethyl)piperidine-3,4,5-triol; or a pharmaceutically acceptable salt of any of the foregoing compounds.

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

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

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

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

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

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

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

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