Azetidinyl O-glycoprotein-2-acetamido-2-deoxy-3-D-glucopyranosidase inhibitors

Abstract

Described herein are compounds represented by formula (I): TIFF2022524077000095.tif4093 or a pharmaceutically acceptable salt thereof, pharmaceutical compositions containing same, and methods for preparing and using same. 1 , R 3 , R 4 , Y 1 , Y 2 , and Z are defined herein.

Description

Related Applications

[0001] This application claims priority under 35 U.S.C. §119(e) of the filing date of U.S. Provisional Application No. 62 / 815,553, filed March 8, 2019, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] A wide variety of cellular proteins, both nuclear and cytoplasmic, are post-translationally modified by the addition of the monosaccharide 2-acetamido-2-deoxy-β-D-glucopyranoside (β-N-acetylglucosamine), which is attached via an O-glycosidic bond. This monosaccharide is generally referred to as O-linked N-acetylglucosamine or O-GlcNAc. The enzyme responsible for the post-translational attachment of β-N-acetylglucosamine (GlcNAc) to specific serine and threonine residues of many nucleocytoplasmic proteins is O-GlcNAc transferase (OGTase). A second enzyme, known as O-glycoprotein-2-acetamido-2-deoxy-3-D-glucopyranosidase or O-GlcNAcase or OGA, removes this post-translational modification to release the protein, making O-GlcNAc modification a dynamic cycle that occurs several times during the life of a protein.

[0003] O-GlcNAc-modified proteins regulate a wide range of cellular functions that govern life, including, for example, transcription, proteasomal degradation, and intracellular signaling. O-GlcNAc is also found in many structural proteins, including the cytoskeletal protein "tau," which is responsible for stabilizing the critical cellular network of microtubules, which are essential for distributing proteins and nutrients within neurons. Importantly, tau has been clearly implicated in the pathogenesis of several diseases, including tauopathies, Alzheimer's disease, Parkinson's disease, dementia, and cancer.

[0004] It is well established that Alzheimer's disease, as well as many related tauopathies including progressive supranuclear palsy (PSP) and amyotrophic lateral sclerosis (ALS), are characterized in part by the development of neurofibrillary tangles (NFTs). These NFTs are aggregates of paired helical filaments (PHFs) and are composed of abnormal forms of tau. In AD patients, hyperphosphorylation of tau inhibits the normal function of tau, leading to the formation of PHFs, which eventually aggregate to form NFTs.

[0005] Six tau isoforms are found in the human brain. In AD patients, all six tau isoforms are found in NFTs and are significantly hyperphosphorylated. Tau in healthy brain tissue has only two or three phosphate groups, but tau in AD brains has an average of eight phosphate groups.

[0006] It has recently been shown that increased phosphorylation levels decrease O-GlcNAc levels, and conversely, increased O-GlcNAc levels correlate with decreased phosphorylation levels. It has been shown that decreased glucose availability in the brain leads to hyperphosphorylation of tau. A gradual decline in glucose transport and metabolism leads to decreased O-GlcNAc and hyperphosphorylation of tau (and other proteins). Thus, inhibition of O-GlcNAcase (preventing the removal of O-GlcNAc from tau, thereby preventing tau hyperphosphorylation) should counteract the age-related decline in glucose metabolism in the brain of healthy individuals and patients suffering from Alzheimer's disease or related neurodegenerative disorders.

[0007] However, a major challenge in developing inhibitors to block the function of mammalian glycosidases, including O-GlcNAcase, is the presence of a large number of functionally related enzymes in higher eukaryotic tissues. Thus, the use of non-selective inhibitors in studying the physiological role of one particular enzyme in cells and organisms becomes cumbersome, since simultaneous inhibition of such functionally related enzymes results in complex phenotypes. In the case of β-N-acetylglucosaminidase, existing compounds that act to block the function of O-GlcNAcase are non-specific and act potently to inhibit lysosomal β-hexosaminidase.

[0008] In view of the above technical challenges, and considering the potential of modulating O-GlcNAcase to treat AD, tauopathy and other neurological diseases, there remains a need for the development of potent and selective O-GlcNAcase inhibitors. Summary of the Invention

[0009] Described herein are compounds that are useful for the treatment of a variety of diseases, disorders and conditions, including, but not limited to, those associated with proteins that are modified by O-GlcNAcase.

[0010] A first embodiment of the compound of the present invention is represented by the following structural formula: [ka] or a pharma- ceutical acceptable salt thereof, wherein: Ar is an optionally substituted 6- to 10-membered aryl or an optionally substituted 5- to 10-membered heteroaryl, with the proviso that when X is absent, Ar is not phenyl; X is absent or -CR 2 R 2 -, -(CR 2 R 2 )2-, -O-, -(CR 2 R 2)O-, -O(CR 2 R 2 )-, -NR d -, -NR d (CR 2 R 2 )- or -(CR 2 R 2 )NR d - and Y 1 and Y 2 are respectively CR c or N and Y 1 or Y 2 At least one of is N; Z is -CR 2 R 2 -, -C(=O)-, -(CR 2 R 2 )2-, or -CH2C(=O)-, R c is -H, halo, -C1-C4 alkyl, or -C1-C4 haloalkyl; R d is -H, -C1-C4 alkyl, -C1-C4 haloalkyl, or -C(=O)C1-C4 alkyl; n is 0 or an integer from 1 to 5; When n is nonzero, R 1 is independently at each occurrence halo, -C1-C4 alkyl, -C1-C4 haloalkyl, or -C1-C4 alkoxy; R 2 is independently at each occurrence -H, halo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C 10 Haloalkyl, or -C3-C 10 is an alkoxy; Or alternatively, two R 2 together with the carbon atom to which they are attached form -C3-C 10 Forming a cycloalkyl, R 3 is -H, or -C1-C4 alkyl; R 4is -H, -C1-C4 alkyl, -C1-C4 haloalkyl, or -C3-C6 cycloalkyl; Or alternatively, R 3 and R 4 together with their intervening atoms form an optionally substituted 5- to 7-membered heterocyclyl.

[0011] Pharmaceutical compositions are provided that include at least one compound described herein, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

[0012] Also provided is a method of treating a subject with a disease or condition selected from a neurodegenerative disease, a tauopathy, diabetes, cancer, and stress, comprising administering to the subject an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising at least one compound described herein or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

[0013] Also provided is a method for inhibiting O-GlcNAcase in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein, or a pharma- ceutical salt thereof, or an effective amount of a pharmaceutical composition comprising at least one compound described herein, or a pharma- ceutical salt thereof, and at least one pharma- ceutical acceptable excipient.

[0014] Also provided is a method for treating a disease or condition characterized by hyperphosphorylation of tau in the brain, comprising administering to the subject an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising at least one compound described herein or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient. In one embodiment, the disease or condition characterized by hyperphosphorylation of tau in the brain is Alzheimer's disease. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Described herein are compounds useful for the treatment of a variety of diseases, disorders and conditions, including, but not limited to, those associated with proteins modified by O-GlcNAcase.

[0016] In a first embodiment, the compound of the present invention is represented by the following structural formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined in the Summary of the Invention above for the compounds represented by Formula (I) or a pharma- ceutically acceptable salt thereof.

[0017] In a second embodiment, the compound of the present invention is represented by the following structural formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein the remaining variables are as defined in the first embodiment.

[0018] In a third embodiment, the compound of the present invention is represented by the following structural formula (III): [ka] or a pharma- ceutically acceptable salt thereof, wherein the remaining variables are as defined in the first or second embodiment.

[0019] In a fourth embodiment, the compound of the present invention is represented by one of the following structural formulas (IV-A) and (IV-B): [ka] or a pharma- ceutically acceptable salt thereof, wherein the remaining variables are as defined in the first, second, or third embodiment.

[0020] In a fifth embodiment, the compound of the present invention is represented by the following structural formula (V): [ka] or a pharma- ceutical acceptable salt thereof, wherein R 1 is -C1-C4 alkyl, R 2 teeth -H, -CH3, or -CH2CH3, and the remaining variables are as defined in the first, second, or third embodiment.

[0021] In a sixth embodiment, in a compound of the invention according to the first, second, or third embodiment, or a pharma- ceutically acceptable salt thereof, X is -CR 2 R 2 -, -(CR 2 R 2 )O-, -NR d -, or -NR d (CR 2 R 2 )-, wherein R d is -H or -C1-C4 alkyl.

[0022] In a seventh embodiment, in a compound of the invention according to the first or second embodiment, or a pharma- ceutically acceptable salt thereof, R c is -H or halo, R 4 is -H and -C1-C4 alkyl.

[0023] In an eighth embodiment, in a compound of the invention according to the first, second, third, fourth, fifth, sixth, or seventh embodiment, or a pharma- ceutically acceptable salt thereof, Ar is an optionally substituted 5-10 membered heteroaryl.

[0024] In a ninth embodiment, in a compound of the invention according to the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment, or a pharma- ceutically acceptable salt thereof, Ar is an optionally substituted 5- or 6-membered monocyclic heteroaryl.

[0025] In a tenth embodiment, in a compound of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment, or a pharma- ceutically acceptable salt thereof, Ar is an optionally substituted 6-membered monocyclic heteroaryl.

[0026] In an eleventh embodiment, in a compound of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment, or a pharma- ceutically acceptable salt thereof, Ar is an optionally substituted pyridinyl, an optionally substituted pyrimidinyl, or an optionally substituted pyrazinyl.

[0027] In a twelfth embodiment, in the compound of the invention according to the first, second, third, fourth, fifth, sixth, seventh embodiment, or a pharma- ceutically acceptable salt thereof, Ar is optionally substituted [ka] Arbitrarily substituted [ka] Arbitrarily substituted [ka] Arbitrarily substituted [ka] Arbitrarily substituted [ka] Arbitrarily substituted [ka] or optionally substituted [ka] It is.

[0028] In a thirteenth embodiment, in a compound of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment, or a pharma- ceutically acceptable salt thereof, Ar is optionally substituted [ka] or optionally substituted [ka] It is.

[0029] In a fourteenth embodiment, in the compounds of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth embodiments, or pharma- ceutically acceptable salts thereof, Ar is C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, halo, -CN, -NO2, -OR z , -NR x R y , -S(O) i R x , -NR x S(O) i R y , -S(O) i NR x R y , -C(=O)OR x , -OC(=O)OR x , -C(=S)OR y , -O(C=S)R x , -C(=O)NR x R y , -NR x C(=O)R y , -C(=S)NR x R y , -NR x C(=S)R y , -NR x (C=O)OR y , -O(C=O)NR x R y , -NR x (C=S)OR y , -O(C=S)NR x R y, -NR x (C=O)NR x R y , -NR x (C=S)NR x R y , -C(=S)R x , -C(=O)R x , phenyl, and monocyclic heteroaryl; During the ceremony, The C1-C4 alkyl substituents of Ar are -CN, -NO2, -OR z , -NR x R y , -S(O) i R x , -NR x S(O) i R y , -S(O) i NR x R y , -C(=O)OR x , -OC(=O)OR x , -C(=S)OR x , -O(C=S)R x , -C(=O)NR x R y , -NR x C(=O)R y , -C(=S)NR x R y , -NR x C(=S)Ry, -NR x (C=O)OR y , -O(C=O)NR x R y , -NR x (C=S)OR y , -O(C=S)NR x R y , -NR x (C=O)NR x R y , -NR x (C=S)NR x R y , -C(=S)R x , and -C(=O)R y, optionally substituted with C3-C6 cycloalkyl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy, and halomethoxy), monocyclic heteroaryl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy, or halomethoxy), and phenyl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy, and halomethoxy); The C3-C6 cycloalkyl, C3-C6 heterocyclyl, phenyl, and monocyclic heteroaryl substituents of Ar are C1-C4 alkyl, C1-C4 haloalkyl, halo, -CN, -NO2, -OR. z , -NR x R y , -S(O) i R x , -NR x S(O) i R y , -S(O) i NR x R y , -C(=O)OR x , -OC(=O)OR x , -C(=S)OR x , -O(C=S)R y , -C(=O)NR x R y , -NR x C(=O)R y , -C(=S)NR x R y , -NR x C(=S)R y , -NR x (C=O)OR y , -O(C=O)NR x R y , -NR x (C=S)OR y , -O(C=S)NR x R y , -NR x (C=O)NR x R y , -NR x (C=S)NR x R y , -C(=S)R x, and -C(=O)R x is optionally and independently substituted with Each R x and each R y are independently -H, C1-C4 alkyl or C3-C8 cycloalkyl; R x or R y wherein the C1-C4 alkyl or C3-C8 cycloalkyl represented by the formula: is optionally substituted with one or more substituents selected from halo, hydroxyl, C3-C6 cycloalkyl, and phenyl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy, or halomethoxy); R z is -H, C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, or C3-C8 heterocyclyl; R z C1-C4 alkyl or C3-C8 cycloalkyl represented by the formula: is optionally substituted with one or more substituents selected from -CN, halo, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, and phenyl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy, and halomethoxy); i is 0, 2, or 2.

[0030] In a fifteenth embodiment, in a compound of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment, or a pharma- ceutically acceptable salt thereof, Ar is C1-C4 alkyl, C1-C4 haloalkyl, halo, -CN, -NO2, -OR z , -SR z , -NR x S(O) i R y , -C(=O)OR x , -OC(=O)OR x , -C(=S)OR y , -O(C=S)R x , -C(=O)NR x R y , -C(=S)NR x Ry , -NR x C(=S)R y , -NR x (C=O)OR y , -O(C=O)NR x R y , -NR x (C=S)OR y , -O(C=S)NR x R y , -NR x (C=O)NR x R y , -NR x (C=S)NR x R y , -C(=S)R x , and -C(=O)R x wherein each R x , each R y , and R z are each independently -H or C1-C4 alkyl.

[0031] In a sixteenth embodiment, in a compound of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment, or a pharma- ceutically acceptable salt thereof, Ar is C1-C4 alkyl, C1-C4 haloalkyl, halo, -CN, -OR z , and -C(=O)NR x R y and optionally substituted with one or more groups selected from:

[0032] In a seventeenth embodiment, in a compound of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment, or a pharma- ceutically acceptable salt thereof, Ar is optionally substituted with one or more groups selected from -CH3, -F, -CN, and -OCH3.

[0033] In another embodiment, the compound of the present invention is selected from the compounds set forth in the Examples herein, including pharma- ceutically acceptable salts thereof, as well as natural forms.

[0034] As used herein, the term "alkyl" refers to a fully saturated branched or straight chain hydrocarbon moiety. Unless otherwise specified, alkyl contains 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, or most preferably 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0035] As used herein, the term "alkoxy" refers to the group -OR, where R is alkyl or cycloalkyl, as those terms are defined above. Non-limiting examples of alkoxy groups include -OCH, -OCHCH, -OCHCHCH, -OCH(CH), -OCH(CH), -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, and -O-cyclohexyl.

[0036] As used herein, the terms "aryl", "aryl group", "aryl ring", "aromatic group" and "aromatic ring" are used interchangeably and refer to a 6-12 membered aromatic monocyclic or bicyclic carbocyclic ring system. Examples of monocyclic aromatic ring systems include, but are not limited to, phenyl, and the like. Examples of bicyclic aromatic ring systems include, but are not limited to, naphthyl, and the like. As used herein, a bicyclic aryl or bicyclic aromatic ring system includes a bicyclic system in which a monocyclic aryl is fused to another monocyclic aryl, and a bicyclic system in which a monocyclic aryl is fused to a monocyclic alicyclic ring.

[0037] The number of carbon atoms in a group is referred to herein as "C x-xx " where x and xx are integers. For example, "C1-4 "Alkyl" is an alkyl group having 1 to 4 carbon atoms.

[0038] As used herein, the term "halogen" or "halo" may refer to fluoro, chloro, bromo, or iodo.

[0039] As used herein, the term "haloalkyl" refers to an alkyl, as defined herein, substituted with one or more halo groups, as defined herein.

[0040] As used herein, the terms "alicyclic", "alicyclic group", or "alicyclic ring" are used interchangeably and refer to a saturated (i.e., cycloalkyl, also defined below), unsaturated non-aromatic, monocyclic or bicyclic carbocyclic ring system having 3 to 12 ring members. Examples of monocyclic alicyclic ring systems include, but are not limited to, cyclopropyl, cyclopentenyl, and the like. Examples of bicyclic alicyclic ring systems include, but are not limited to, octahydronaphthalenyl, decalinyl, and the like.

[0041] As used herein, the terms “heterocyclyl,” “heterocyclyl group,” “heterocyclic,” and “heterocyclic ring” are used interchangeably and refer to a saturated, unsaturated, non-aromatic, monocyclic, or bicyclic ring system having 3 to 12 ring members, or particularly 3 to 6 ring members or 5 to 7 ring members, of which at least one is a heteroatom and up to four (e.g., 1, 2, 3, or 4) heteroatoms are independently selected from O, S, and N, where C may be oxidized (e.g., C(═O)) or quaternized (e.g., N(O)) or quaternized (e.g., N +) and S may be optionally oxidized to sulfoxide and sulfone. Examples of monocyclic heterocyclic ring systems include aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, isoxazolidinyl, isothiazolidinyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl, thiepanyl, dihydrofuranyl, imidazolinyl, dihydropyranyl, hydantoinyl, pyrrolidinonyl, tetrahydrothiopyranyl, tetrahydropyridinyl, and thiopyranyl. Examples of bicyclic heterocyclic ring systems include benzo[1,3]dioxolyl, tetrahydroindolyl, and 2-azaspiro[3.3]heptanyl. As used herein, a bicyclic heterocyclyl or bicyclic heterocyclic ring system includes bicyclic systems in which a monocyclic heterocyclyl is fused to another monocyclic heterocyclyl, a monocyclic heterocyclyl is fused to an alicyclic ring, and a monocyclic heterocyclyl is fused to a phenyl ring.

[0042] As used herein, the terms "heteroaryl", "heteroaryl group", "heteroaromatic" and "heteroaromatic ring" are used interchangeably to refer to a 5-12 membered monocyclic or bicyclic aromatic ring system having 1-4 heteroatoms independently selected from O, S and N, where N can be oxidized (e.g., N(O)) or quaternized, and S can be optionally oxidized to sulfoxide and sulfone. "Heteroaryl" includes a heteroaromatic ring fused to another heteroaromatic ring, a heteroaromatic ring fused to a phenyl ring, a heteroaromatic ring fused to an alicyclic ring, or a heteroaromatic ring fused to a non-aromatic heterocycle such as tetrahydrofuran, pyran, pyrrolidine, piperidine, etc. As used herein, the heteroaryl group Ar can be attached to the remainder of the compound of the invention at any ring having an open valence. Non-limiting examples of monocyclic heteroaromatic ring systems include pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl, tetrazinyl, 1-oxo-pyridyl, thienyl, etc. Non-limiting examples of bicyclic heteroaromatic ring systems include azaindonyl, benzimidazolyl, benzofuryl, benzoisoxazolyl, benzoisothiazolyl, benzothiadiazolyl, benzothienyl, benzotriazolyl, benzoxadiazolyl, benzoxazolyl, cyclopentaimidazolyl, cyclopentatriazolyl, furopyridinyl, imidazopyridyl, imidazopyrimidinyl, indazolyl, indolizinyl, Examples of such aryl groups include indolyl, isoquinolinyl, oxazolopyridinyl, purinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyridopyrazinyl, pyridopyrimidinyl, pyrrolo[2,3]pyrimidinyl, pyrrolopyrazolyl, pyrroloimidazolyl, pyrrolotriazolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, thiazolopyridinyl, thienopyridinyl, thienopyrimidinyl, thienopyrazinyl, and naphthyridyl.As used herein, the term "cycloalkyl" refers to a fully saturated monocyclic or bicyclic (e.g., fused) hydrocarbon group of 3 to 12 carbon atoms, 3 to 6 carbon atoms, or 5 to 7 carbon atoms.

[0043] As used herein, the term "halocycloalkyl" refers to a cycloalkyl, as defined herein, that is substituted with one or more halo groups, as defined herein.

[0044] A substituted alkyl, phenyl, heteroaryl, non-aromatic heterocyclyl or heterocyclyl group is an alkyl, phenyl, heteroaryl, non-aromatic heterocyclyl or heterocyclyl group having one or more substituents. Suitable substituents are those that do not significantly reduce the O-GlcNAcase inhibitory activity of the compound of formula (I), (II), (III), (IV) or (V) (hereinafter collectively referred to as any one of the compounds of formula (I) to (V)) or a pharma- ceutically acceptable salt thereof. Suitable examples of the substituents of the alkyl, phenyl, heteroaryl, non-aromatic heterocyclyl or heterocyclyl group include C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, halo, -CN, -NO2, -OR, -C1-C4 haloalkyl, -C1-C4 haloalkyl, -C1-C4 cyclo ... z , -NR x R y , -S(O) i R x , -NR x S(O) i R y , -S(O) i NR x R y , -C(=O)OR x , -OC(=O)OR x , -C(=S)OR y , -O(C=S)R y , -C(=O)NR x R y , -NR x C(=O)R y , -C(=S)NR x R y , -NR x C(=S)R y , -NR x(C=O)OR y , -O(C=O)NR x R y , -NR x (C=S)OR y , -O(C=S)NR x R y , -NR x (C=O)NR x R y , -NR x (C=S)NR x R y , -C(=S)R x , -C(=O)R x C1-C4 alkyl substituents include, but are not limited to, -CN, -NO2, -OR, -C1-C4 alkyl, -C1-C4 alkyl aryl ... z , -NR x R y , -S(O) i R x , -NR x S(O) i R y , -S(O) i NR x R y , -C(=O)OR x , -OC(=O)OR x , -C(=S)OR x , -O(C=S)R x , - C(=O)NR x R y , -NR x C(=O)R y , - C(=S)NR x R y , -NR x C(=S)R y , -NR x (C=O)OR y , -O(C=O)NR x R y , -NR x (C=S)OR y , -O(C=S)NR x R y , -NR x (C=O)NR x R y , -NR x (C=S)NR x R y, -C(=S)R x , and C(=O)R y , C3-C6 cycloalkyl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy, and halomethoxy), monocyclic heteroaryl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy, or halomethoxy), and phenyl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy, and halomethoxy). The C3-C6 cycloalkyl, phenyl, and monocyclic heteroaryl substituents are C1-C4 alkyl, C1-C4 haloalkyl, halo, -CN, -NO2, -OR z , -NR x R y , -S(O) i R x , -NR x S(O) i R y , -S(O) i NR x R y , -C(=O)OR x , -OC(=O)OR x , -C(=S)OR x , -O(C=S)R y , -C(=O)NR x R y , -NR x C(=O)R y , -C(=S)NR x R y , -NR x C(=S)R y , -NR x (C=O)OR y , -O(C=O)NR x R y , -NR x (C=S)OR y , -O(C=S)NR x R y , -NR x (C=O)NR x R y , -NR x (C=S)NR x R y , -C(=S)Rx , and -C(=O)R x In these substituents, each R x and each R y are independently -H, C1-C4 alkyl, or C3-C8 cycloalkyl, where R x or R y The C1-C4 alkyl or C3-C8 cycloalkyl represented by the formula (I) is optionally substituted with one or more substituents selected from halo, hydroxyl, C3-C6 cycloalkyl, and phenyl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy, or halomethoxy). In these substituents, R z is -H, C1-C4 alkyl, or C3-C8 cycloalkyl, where R z The C1-C4 alkyl or C3-C8 cycloalkyl group represented by is optionally substituted with one or more substituents selected from halo, hydroxyl, C3-C6 cycloalkyl, and phenyl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy, and halomethoxy). In these substituents, i is 0, 1, or 2.

[0045] Pharmaceutically acceptable salts of the compounds disclosed herein are also included in the present invention.When the compounds provided herein are sufficiently basic or acidic to form stable non-toxic acid salts or base salts, it may be appropriate to prepare and administer the compounds as pharma-ceutically acceptable salts.Examples of pharma-ceutically acceptable salts are organic acid addition salts formed with acids that form physiologically acceptable anions, such as tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate or α-glycerophosphate.Inorganic salts, including hydrochloride, sulfate, nitrate, bicarbonate and carbonate, may also be formed.

[0046] Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound, such as an amine, with an appropriate acid which provides a physiologically acceptable anion. Alkali metal (e.g., sodium, potassium or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be made.

[0047] Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Suitable bases include, but are not limited to, alkali metal hydroxides, alkaline earth metal hydroxides, carbonates, bicarbonates, and the like.

[0048] Some of the compounds of the present disclosure, or their pharma- ceutically acceptable salts, contain one or more asymmetric centers in the molecule. According to the present disclosure, any structure in which stereochemistry is not specified is to be understood as including all of the various stereoisomers (e.g., diastereomers and enantiomers) in pure or substantially pure form, as well as mixtures thereof (such as racemic mixtures or enantiomerically enriched mixtures). Methods for preparing such optically active forms (e.g., resolution of racemates by recrystallization techniques, synthesis by chiral synthesis from optically active starting materials, or chromatographic separation using chiral stationary phases) are well known in the art. Compounds of the present disclosure may also exist in tautomeric forms, and mixtures and isolated individual tautomers are contemplated. Additionally, some compounds may exhibit polymorphism.

[0049] When a particular stereoisomer (e.g., enantiomer, diastereomer, etc.) of a compound used in the disclosed methods is designated by name or structure, the stereochemical purity of the compound is at least 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5% or 99.9%. "Stereochemical purity" means the percent by weight of the desired stereoisomer based on the total weight of all stereoisomers.

[0050] When the stereochemistry of a disclosed compound is depicted by a name or structure, and the named or depicted structure includes more than one stereoisomer (e.g., in a pair of diastereomers), it is understood to include one of the stereoisomers or any mixture of the stereoisomers. It is further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. Stereoisomeric purity in this case is determined by dividing the total weight of the mixture of stereoisomers encompassed by the name or structure by the total weight of the mixture of all stereoisomers.

[0051] It is also contemplated that in one embodiment any position occupied by hydrogen is enriched with deuterium beyond the natural abundance of deuterium. For example, one or more hydrogen atoms are replaced with deuterium at a greater abundance (0.015% (i.e., a deuteration ratio of at least 50.1%)), at least 3500 times (a deuteration ratio of 52.5% at each given deuterium atom), at least 4000 times (a deuteration ratio of 60%), at least 4500 times (a deuteration ratio of 67.5%), at least 5000 times (a deuteration ratio of 75%), at least 5500 times (a deuteration ratio of 82.5%), at least 6000 times (a deuteration ratio of 90%), at least 6333.3 times (a deuteration ratio of 95%), at least 6466.7 times (a deuteration ratio of 97%), at least 6600 times (a deuteration ratio of 99%) or at least 6633.3 times (a deuteration ratio of 99.5%), than the natural abundance of deuterium. In one embodiment, hydrogen is present at its natural abundance at all positions. The compounds described herein, or pharma- ceutically acceptable salts thereof, may also exist in tautomeric forms, and mixtures and separated individual tautomers are contemplated.

[0052] One aspect of the present invention includes a method for inhibiting glycosidases and / or glycosidase signaling pathways in a cell, comprising contacting the cell with an effective amount of a compound of any one of formulas (I)-(V), or a pharma- ceutically acceptable salt thereof. The glycosidase is preferably a glycoside hydrolase, more preferably a glycoside hydrolase family 84, even more preferably an O-glycoprotein-2-acetamido-2-deoxy-3-D-glucopyranosidase (O-GlcNAcase or OGA), and most preferably a mammalian O-GlcNAcase. In one embodiment, the cell is contacted in vitro or in vivo. In one embodiment, contacting the cell comprises administering a compound to a subject.

[0053] One aspect of the present invention includes a method of inhibiting glycosidases and / or glycosidase signaling pathways in a subject in need of inhibition of glycosidases and / or glycosidase signaling pathways, comprising administering to the subject a therapeutically effective amount of a compound of any one of formulas (I)-(V), or a pharma- ceutically acceptable salt thereof, thereby activating glycosidases in the subject. The glycosidase is preferably a glycoside hydrolase, more preferably glycoside hydrolase family 84, even more preferably O-glycoprotein-2-acetamido-2-deoxy-3-D-glucopyranosidase (O-GlcNAcase or OGA), and most preferably a mammalian O-GlcNAcase.

[0054] One aspect of the invention includes a method of promoting survival or extending the lifespan of a eukaryotic cell (e.g., a mammalian cell), comprising administering to a subject a therapeutically effective amount of a compound of any one of Formulas (I)-(V), or a pharma- ceutical acceptable salt thereof, thereby promoting survival or extending the lifespan of the eukaryotic cell.

[0055] One aspect of the present invention includes a method for treating a disease or condition caused, mediated and / or propagated by activity of O-GlcNAcase in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any one of formulas (I)-(V), or a pharma- ceutically acceptable salt thereof. Preferably, the disease or condition is neuropathy, diabetes, cancer or stress. More preferably, the disease or condition is neuropathy. In one embodiment, the neurological disorder is acute ischemic stroke (AIS), Alzheimer's disease, dementia, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), argyrophilic grain dementia, Bluit's disease, corticobasal degeneration (CBP), kogakuin dementia, diffuse neurofibrillary tangle disease with calcifications, Down's syndrome, epilepsy, familial british dementia, familial danish dementia, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Gerstmann-Sträussler-Scheinker disease, Guadeloupe syndrome, and one or more tauopathies selected from Parkinsonism type 1, Hallervorden-Spatz disease (neurodegenerative disease with cerebral iron deposition type 1), ischemic stroke, mild cognitive impairment (MCI), multiple system atrophy, myotonic dystrophy, Niemann-Pick disease (type C), pallidopontonigral degeneration, Parkinsonism-Dementia Complex of Guam, Pick's disease (PiD), postencephalitic Parkinsonism (PEP), prion diseases (including Creutzfeldt-Jakob disease (GJD) and variant Creutzfeldt-Jakob disease (vCJD)), fatal familial insomnia, kuru, progressive supercortical gliosis, progressive supranuclear palsy (PSP), Steele-Richardson-Olszewski syndrome, subacute sclerosing panencephalitis, neurofibrillary senile dementia, Huntington's disease, and Parkinson's disease. In another embodiment, the neurological disorder is one or more tauopathies selected from acute ischemic stroke (AIS), Alzheimer's disease, dementia, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), argyrophilic grain dementia, epilepsy, mild cognitive impairment (MCI), Huntington's disease, and Parkinson's disease. In yet another embodiment, the neurological disorder is Alzheimer's disease.

[0056] One aspect of the invention includes a method of treating a disease or condition characterized by tau hyperphosphorylation (e.g., hyperphosphorylation of tau in the brain) in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any one of Formulae (I)-(V), or a pharma- ceutically acceptable salt thereof. In one embodiment, the disease or condition is selected from the group consisting of acute ischemic stroke (AIS), Alzheimer's disease, dementia, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), argyrophilic grain dementia, Bluit's disease, corticobasal degeneration (CBP), dementia pugilistica, diffuse neurofibrillary tangle disease with calcifications, Down's syndrome, epilepsy, familial British dementia, familial Danish dementia, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Gerstmann-Sträussler-Scheinker disease, Guadalcanalicular leukemia, and glaucoma. The present invention relates to a method for treating cerebral infarction and / or cerebrovascular accidents, comprising administering to the patient a therapeutically effective amount of medication such as cerebrovascular accident, chronic encephalopathy ... In another embodiment, the disease or condition is selected from acute ischemic stroke (AIS), Alzheimer's disease, dementia, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), argyrophilic grain dementia, epilepsy, ischemic stroke, mild cognitive impairment (MCI), Huntington's disease, and Parkinson's disease. In yet another embodiment, the disease or condition is Alzheimer's disease.

[0057] As used herein, the terms "subject" and "patient" may be used interchangeably and refer to a mammal in need of treatment, such as companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human in need of treatment.

[0058] As used herein, the term "treating" or "treatment" refers to obtaining a desired pharmacological and / or physiological effect, which may be a therapeutic effect, including partially or substantially achieving one or more of the following results: reducing the severity of a disease, disorder or syndrome, improving or reversing clinical symptoms or indicators associated with the disorder, and slowing, inhibiting or reducing the likelihood of progression of the disease, disorder or syndrome.

[0059] The term "effective amount" refers to an amount of a compound of any one of formulas (I)-(V) or a pharma- ceutically acceptable salt thereof, which, when administered to a subject, produces a beneficial or desired result, including a clinical result, i.e., reverses, alleviates, inhibits, reduces or delays the progression of a disease or condition treatable by a compound of any one of formulas (I)-(V) or a pharma- ceutically acceptable salt thereof, and reduces the likelihood of recurrence of a disease or condition treatable by a compound of any one of formulas (I)-(V) or a pharma- ceutically acceptable salt thereof, or one or more symptoms thereof, as judged by clinical symptoms, for example, as compared to a control, e.g., 0.1 mg to 1000 mg per kg of body weight. The term "effective amount" also includes an amount that is effective for improving normal physiological function, e.g., 0.01 mg / kg / day to 500 mg / kg / day.

[0060] Another embodiment of the present invention is a pharmaceutical composition comprising at least one compound described herein, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier.

[0061] Also included herein is the use of any one of the compounds of formula (I)-(V), or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating one or more of the diseases or conditions described herein. Also included herein is a pharmaceutical composition comprising any one of the compounds of formula (I)-(V), or a pharma- ceutically acceptable salt thereof, optionally together with a pharma- ceutically acceptable carrier, in the manufacture of a medicament for treating one or more of the diseases or conditions described herein. Also included herein is a compound of any one of formula (I)-(V), or a pharma- ceutically acceptable salt thereof, for use in treating a subject having one or more of the diseases or conditions described herein. Also included herein is a pharmaceutical composition comprising any one of the compounds of formula (I)-(V), or a pharma- ceutically acceptable salt thereof, optionally together with a pharma- ceutically acceptable carrier, for use in treating one or more of the diseases or conditions described herein.

[0062] The term "pharmaceutical acceptable carrier" refers to a non-toxic carrier, diluent, adjuvant, vehicle or excipient that does not adversely affect the pharmacological activity of the compound with which it is formulated and is also safe for human use. Pharmaceutically acceptable carriers that can be used in the compositions of the present disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, magnesium stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, salts or electrolytes such as zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances (e.g., microcrystalline cellulose, hydroxypropylmethylcellulose, lactose monohydrate, sodium lauryl sulfate, and croscarmellose sodium), polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0063] Other excipients, such as flavoring agents, sweeteners, and preservatives, such as methyl, ethyl, propyl, and butyl paraben, may also be included. A more complete list of suitable excipients can be found in Handbook of Pharmaceutical Excipients (5th Ed., a Pharmaceutical Press (2005)). Those skilled in the art will know how to prepare suitable formulations for various types of administration routes. Conventional procedures and ingredients for selecting and preparing suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003, 20th edition) and The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999.

[0064] A compound of any one of formulas (I)-(V) or a pharma- ceutically acceptable salt thereof, or a composition of the present teachings, may be administered, for example, orally, parenterally, sublingually, topically, rectally, nasally, bucally, vaginally, transdermally, by patch, by pump, or by implanted reservoir, and the pharmaceutical composition will be formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, intrapulmonary, intrathecal, rectal, and topical methods of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0065] Other dosage forms encompassed by the present disclosure are described in WO2013 / 075083, WO2013 / 075084, WO2013 / 078320, WO2013 / 120104, WO2014 / 124418, WO2014 / 151142 and WO2015 / 023915, the contents of which are incorporated herein by reference.

[0066] Useful dosages of the compounds described herein or their pharma- ceutically acceptable salts can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for translating effective dosages in mice, and other animals, to humans are known to the art; see, for example, U.S. Patent No. 4,938,949, incorporated by reference in its entirety. EXAMPLES

[0067] General method Chromatography on silica gel was performed using either a Teledyne ISCO Combiflash RF or a Grace Reveleris X2 equipped with an ELSD purification system using 20-40uM (particle size), 250-400 mesh, or 400-632 mesh silica gel.

[0068] Analytical HPLC Acidic HPLC: Performed on a Shimadzu 20A instrument equipped with an Ultimate C18 3.0×50 mm, 3 um column, eluted with 2.75 mL / 4 L of TFA in water (solvent A) and 2.5 mL / 4 L of TFA in acetonitrile (solvent B) in the following manner. Method A: Use a gradient of 0% to 60% (solvent B) in 6 minutes and hold at 60% for 2 minutes, elution at a flow rate of 1.2 ml / min. Wavelengths: UV 220 nm, 215 nm, and 254 nm. Method B: Use a gradient of 10% to 80% (solvent B) in 6 minutes and hold at 60% for 2 minutes, elution at a flow rate of 1.2 ml / min. Wavelengths: UV 220 nm, 215 nm, and 254 nm. Method C: Use a gradient of 30% to 90% (solvent B) in 6 minutes and hold at 60% for 2 minutes, elution at a flow rate of 1.2 ml / min. Wavelengths: UV 220 nm, 215 nm, and 254 nm. Basic HPLC: Performed on a Shimadzu 20A instrument equipped with an Xbridge Shield RP-18, 5um, 2.1x50mm column, eluted with 2mL / 4L of aqueous NH3H2O ​​(solvent A) and acetonitrile (solvent B) in the following manner. Method D: Use a gradient of 0% to 60% (solvent B) in 4.0 min and a 2 min hold at 60%, with an elution flow rate of 1.2 ml / min. Method E: Use a gradient of 10% to 80% (solvent B) in 4.0 min and a 2 min hold at 60%, with an elution flow rate of 1.2 ml / min. Method F: Use a gradient of 30% to 90% (solvent B) in 4.0 min and a 2 min hold at 60%, with an elution flow rate of 1.2 ml / min.

[0069] Analytical LCMS Acidic LCMS: Performed on a Shimadzu 2010 series, Shimadzu 020 series, or Waters Acquity UPLC BEH (MS ionization: ESI) instrument equipped with a C18 column (2.1mm x 30mm, 3.0mm or 2.1mm x 50mm, C18, 1.7um), eluted with 1.5mL / 4L in water (solvent A) and 0.75mL / 4L in acetonitrile (solvent B) using the following method: 1.5 division method: General method: Use a gradient of 5% to 95% (solvent B) in 0.7 min and hold at 95% for 0.4 min, elution at a flow rate of 1.5 ml / min. Wavelengths: UV 220 nm and 254 nm.

[0070] Dichotomous method: Method A: Use a gradient of 0% to 60% (solvent B) in 0.9 min and hold at 60% for 0.6 min, elution at a flow rate of 1.2 ml / min. Wavelengths: UV 220 nm and 254 nm. Method B: Use a gradient of 10% to 80% (solvent B) in 0.9 min and hold at 60% for 0.6 min, elution at a flow rate of 1.2 ml / min. Wavelengths: UV 220 nm and 254 nm. Method C: Use a gradient of 30% to 90% (solvent B) in 0.9 min and hold at 60% for 0.6 min, elution at a flow rate of 1.2 ml / min. Wavelengths: UV 220 nm and 254 nm.

[0071] 3.5 division method: Initial conditions, solvent A-95%:solvent B-5%, initially held for 0.0–0.1 min, linear ramp to solvent A-5%:solvent B-95% from 0.1–3.25 min, held at solvent A-5%:solvent B-95% from 3.25–3.5 min. Diode array / MS detection.

[0072] Quadrant: Method A: Use a gradient of 0% to 60% (solvent B) in 3 minutes and hold at 60% for 0.5 minutes, elution at a flow rate of 0.8 ml / min. Wavelengths: UV 220 nm and 254 nm. Method B: Use a gradient of 10% to 80% (solvent B) in 3 minutes and hold at 60% for 0.5 minutes, elution at a flow rate of 0.8 ml / min. Wavelengths: UV 220 nm and 254 nm. Method C: Use a gradient of 30% to 90% (solvent B) in 3 minutes and hold at 60% for 0.5 minutes, elution at a flow rate of 0.8 ml / min. Wavelengths: UV 220 nm and 254 nm.

[0073] Seventh rule: Method A: Use a gradient of 0% to 60% (solvent B) in 6 minutes and hold at 60% for 0.5 minutes, elution at a flow rate of 0.8 ml / min. Wavelengths: UV 220 nm and 254 nm. Method B: Use a gradient of 10% to 80% (solvent B) in 6 minutes and hold at 60% for 0.5 minutes, elution at a flow rate of 0.8 ml / min. Wavelengths: UV 220 nm and 254 nm. Method C: Use a gradient of 30% to 900% (solvent B) in 6 minutes and hold at 60% for 0.5 minutes, elution at a flow rate of 0.8 ml / min. Wavelengths: UV 220 nm and 254 nm.

[0074] Basic LCMS: The analysis was performed on a Shimadzu 2020 series or Waters Acquity UPLC BEH (MS ionization: ESI) instrument equipped with an XBridge Shield RP18, 5um column (2.1mm x 30mm, 3.0mm id) or a 2.1mm x 50mm, C18, 1.7um column using the following method eluting with 2mL / 4L aqueous NH3·H2O (solvent A) and acetonitrile (solvent B).

[0075] Trisection rule: Method A: Use a gradient of 0% to 60% (solvent B) in 2 minutes and hold at 60% for 0.48 minutes, elution at a flow rate of 1 ml / min. Wavelengths: UV 220 nm and 254 nm. Method B: Use a gradient of 10% to 80% (solvent B) in 2 minutes and hold at 60% for 0.48 minutes, elution at a flow rate of 1 ml / min. Wavelengths: UV 220 nm and 254 nm. Method C: Use a gradient of 30% to 90% (solvent B) in 2 minutes and hold at 60% for 0.48 minutes, elution at a flow rate of 1 ml / min. Wavelengths: UV 220 nm and 254 nm.

[0076] 3.5 division method: Initial conditions, solvent A-95%:solvent B-5%, initially held for 0.0–0.1 min, linear ramp to solvent A-5%:solvent B-95% from 0.1–3.25 min, held at solvent A-5%:solvent B-95% from 3.25–3.5 min. Diode array / MS detection.

[0077] Seventh rule: Method A: Use a gradient of 0% to 60% (solvent B) in 6 minutes and hold at 60% for 0.5 minutes, elution at a flow rate of 0.8 ml / min. Wavelengths: UV 220 nm and 254 nm. Method B: Use a gradient of 10% to 80% (solvent B) in 6 minutes and hold at 60% for 0.5 minutes, elution at a flow rate of 0.8 ml / min. Wavelengths: UV 220 nm and 254 nm. Method C: Use a gradient of 30% to 90% (solvent B) in 6 minutes and hold at 60% for 0.5 minutes, elution at a flow rate of 0.8 ml / min. Wavelengths: UV 220 nm and 254 nm.

[0078] SFC analysis separation Instrument: Waters UPC2 analytical SFC (SFC-H). Column: ChiralCel OJ, 150 x 4.6 mm ID, 3 μm. Mobile phase: A is CO2, B is ethanol (0.05% DEA). Gradient: B 40%. Flow rate: 2.5 mL / min. Back pressure: 100 bar. Column temperature: 35 °C, wavelength: 220 nm.

[0079] Preparative HPLC purification General methods: Preparative HPLC was performed on a Gilson UV / VIS-156 with UV detection at 220 / 254 nm with a Gilson 281 autocollection. Acidic conditions: Use the two-acid scoring system of hydrochloric acid and formic acid. Method A: Hydrochloric acid: YMC-Actus Triart C18 150 x 30 mm x 5 um, gradient 0-100% acetonitrile and water with the corresponding acid (0.05% HCl). Method B: Formic acid: Phenomenex Synergi C18 150 x 30 mm x 4 um, gradient was 0-100% acetonitrile and water with the corresponding acid (0.225% formic acid), gradient shape was optimized for each individual separation. Neutral conditions: Xtimate C18 150 x 25 mm x 5 um, gradient: 0-100% (water (10 mM NH4HCO3)-ACN), gradient shape was optimized for each individual separation. Basic conditions: Waters Xbridge Prep OBD C18 150x30 10um, gradient 0-100% water (0.04% NH3H2O ​​+ 10mM NH4HCO3)-acetonitrile, gradient shape optimized for individual separation.

[0080] Preparative HPLC-MS purification Columns used: Acid: Waters SunFire Prep, C18 5um, OBD 19×100mm Base: Waters XSelect CSH Prep C18 5um OBD 19×100mm Gradient profile: 12 min run: initial conditions: A-95%:B-5%, initial hold 0.0-0.5 min, linear ramp from A-5% to variable B-% (typical range is B-40% to B-75%) from 0.5-7.5 min, linear ramp from B-% to B-95% from 7.5-8.0 min, hold at A-5%:B-95% from 8.0-10.0 min, final DAD / MS detection, linear ramp down to initial conditions from 10.0-10.5 min, hold at initial conditions for 1.5 min. Mobile phase: Acid: A: Water containing 0.1% trifluoroacetic acid (v / v), Mobile phase B: Acetonitrile containing 0.1% trifluoroacetic acid (v / v). Mobile phase: A is CO2, B is ethanol (0.05% DEA).

[0081] Preparative SFC purification Instrument: MG III preparative SFC (SFC-1). Column: ChiralCel OJ, 250 x 30 mm ID, 5 μm. Mobile phase: A is CO2, B is ethanol (0.1% NH3H2O). Gradient: B 50%. Flow rate: 40 mL / min. Back pressure: 100 bar. Column temperature: 38 °C, wavelength: 220 nm. Cycle time: approximately 8 min.

[0082] 1 H-NMR NMR spectra were recorded on a Bruker Avance III HD 500 MHz, a Bruker Avance III 500 MHz, a Bruker Avance III 400 MHz, a Varian-400 VNMRS, or a Varian-400 MR. Chemical shifts are expressed in parts per million (ppm). Coupling constants (J) are in Hertz (Hz). Splitting patterns indicate apparent multiplicity and are designated as s (singlet), d (doublet), t (triplet), dd (double doublet), dt (double triplet), dq (double quartet), m (multiplet), br (broad).

[0083] The following general reaction schemes 1-6 provide details useful for preparing the compounds of the invention. The requisite intermediates may be commercially available or can be prepared according to literature procedures. The illustrative reaction schemes are not limited by the compounds listed or any particular substituents used for illustrative purposes, and the labeling of the substituents (i.e., R groups) as shown in the reaction schemes does not necessarily correlate to those used in the claims; when multiple substituents are permitted under the definition of any one of formulas (I)-(IV) above, for clarity, a single substituent is often shown as attached to the compound.

[0084] Scheme 1 [ka]

[0085] Intermediate 1 [ka] (2-Methoxypyridin-4-yl)methyl methanesulfonate: Mesyl chloride (371.1 mg, 3.24 mmol, 250.77 uL, 1.5 eq) was added dropwise to a mixture of (2-methoxypyridin-4-yl)methanol (300 mg, 2.16 mmol, 1 eq) and triethylamine (437 mg, 4.32 mmol, 598.82 uL, 2 eq) in CHCl (10 mL) at 0° C., then the mixture was stirred at 28° C. for 1 h. TLC (petroleum ether / EtOAc=1 / 1) showed that the starting material was completely consumed. The mixture was concentrated to give the compound (2-methoxypyridin-4-yl)methyl methanesulfonate (470 mg, crude) as a yellow solid, which was used directly in the next step without further purification.

[0086] Intermediate 2 [ka] tert-Butyl 3((2-methoxypyridin-4-yl)methoxy)azetidine-1-carboxylate:Na (173mg, 4.32mmol, 60% purity, 2eq) was added to the mixture of compound tert-butyl 3-hydroxyazetidine-1-carboxylate (411mg, 2.38mmol, 1.1eq) in DMF (10mL) at 0°C, then the mixture was stirred at this temperature for 10 minutes, (2-methoxypyridin-4-yl)methyl methanesulfonate (470mg, 2.16mmol, 1eq) was added to the mixture at 0°C, and the mixture was stirred at 50°C for 1 hour. TLC (petroleum ether / EtOAc=1 / 1) showed that the starting material was completely consumed. The mixture was concentrated with aqueous NH4Cl (1 mL) and the residue was purified by preparative TLC (petroleum ether / EtOAc=1 / 1) to give tert-butyl 3((2-methoxypyridin-4-yl)methoxy)azetidine-1-carboxylate (140 mg, 22% yield) as a yellow oil. LCMS (ESI): [M+H] 295. 1HNMR: (400 MHz, CDCl3) δ 8.13 (d, J = 5.2 Hz, 1H), 6.82 (d, J = 5.6 Hz, 1H), 6.70 (s, 1H), 4.41 (s, 2H), 4.30-4.33 (m, 1H), 4.06-4.11 (m, 2H), 3.94 (s, 3H), 3.87-3.90 (m, 2H), 1.44 (s, 9H).

[0087] Intermediate 3 [ka] 3-((3-Methoxybenzyl)oxy)azetidine: tert-Butyl 3((2-methoxypyridin-4-yl)methoxy)azetidine-1-carboxylate (140 mg, 475.62 μmol, 1 equiv.) in TFA (1.0 mL) and dichloromethane (5.0 mL) was stirred at 28 °C for 1 h. TLC (petroleum ether / EtOAc = 2 / 1) showed that the starting material was consumed. The mixture was concentrated and the residue was adjusted to pH 8-9 with NH3·H2O (5 drops) and then concentrated to give tert-butyl 3((2-methoxypyridin-4-yl)methoxy)azetidine-1-carboxylate (95.0 mg, crude) as a yellow oil, which was used directly in the next step without further purification.

[0088] Example 1-1 [ka] N-(5-((3-((2-Methoxypyridin-4-yl)methoxy)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: A mixture of 3-((3-methoxybenzyl)oxy)azetidine (95 mg, 489.11 μmol, 1 eq) and N-(5-formylthiazol-2-yl)acetamide (125 mg, 733.67 umol, 1.5 eq) in MeOH (10 mL) was stirred at 28° C. for 0.5 h, then sodium cyanoborohydride (92 mg, 1.47 mmol, 3 eq) was added and the mixture was stirred for an additional 2 h. LCMS showed that the starting material was completely consumed and the desired compound was detected. The mixture was concentrated and the residue was purified by preparative HPLC (Column: Xtimate C18 150*25mm*5um; Condition: Water (10mM NH4HCO3)-ACN; Start B: 18; End B: 43; Gradient time (min) 9; 100% B retention time (min): 2; Flow rate (ml / min): 25) to give N-(5-((3-((2-methoxypyridin-4-yl)methoxy)azetidin-1-yl)methyl)thiazol-2-yl)acetamide (120.6mg, 70% yield) as a yellow solid. LCMS: [M+H] 349. 1 HNMR: (500 MHz, CDCl3) δ 11.63 (br s, 1H), 8.11 (d, J = 5.5 Hz, 1H), 7.20 (s, 1H), 6.79-6.81 (m, 1H), 6.69 (s, 1H), 4.36-4.38 (m, 2H), 4.18-4.21 (m, 1H), 3.93 (s, 3H), 3.76 (s, 2H), 3.63-3.66 (m, 2H), 2.99-3.02 (m, 2H), 2.29 (s, 3H).

[0089] Example 1-2 [ka] N-(5-((3-((2,6-dimethylpyridin-4-yl)methoxy)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from (2,6-dimethylpyridin-4-yl)methanol, tert-butyl 3-hydroxyazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 1. LCMS (ESI): [M+H] 347. 1 HNMR: (400 MHz, CDCl3) δ 12.37 (s, 1H), 7.19 (s, 1H), 6.47 (s, 2H), 4.08-4.10 (m, 2H), 3.73 (s, 2H), 3.39-3.43 (m, 2H), 3.10-3.13 (m, 2H), 2.88-2.89 (m, 1H), 2.45 (s, 6H), 2.29 (s, 3H).

[0090] Examples 1-3 [ka] N-(5-((3-((5-Methyl-1,2,4-oxadiazol-3-yl)methoxy)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from (5-methyl-1,2,4-oxadiazol-3-yl)methanol, tert-butyl 3-hydroxyazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 1. LCMS (ESI): [M+H] 348. 1 HNMR: (500 MHz, CD3OD) δ 7.27 (s, 1H), 6.55 (s, 1H), 4.46 (d, J = 6.4 Hz, 2H), 3.81 (s, 2H), 3.47 (t, J=8.0 Hz, 2H), 3.19 (t, J=7.6 Hz, 2H), 2.89-2.96 (m, 1H), 2.51 (s, 3H), 2.38 (s, 3H), 2.19 (s, 3H).

[0091] Scheme 2 [ka]

[0092] Intermediate 4 [ka] tert-Butyl 3-((6-methoxypyrimidin-4-yl)oxy)azetidine-1-carboxylate: To a solution of 4-bromo-6-methoxypyrimidine (1.0 g, 6.92 mmol, 1 eq.) and tert-butyl 3-hydroxyazetidine-1-carboxylate (1.2 g, 6.92 mmol, 1 eq.) in toluene (20 mL) was added Pd2(dba)3 (317 mg, 346 ummol, 0.1 eq.), BINAP (215 mg, 346 ummol, 0.2 eq.) and sodium tert-butoxide (1.3 g, 13.83 mmol, 2 eq.). The reaction was stirred at 110° C. for 1 h. LCMS showed the desired product was detected. The reaction was concentrated to give the crude product, which was purified by column chromatography (petroleum ether:ethyl acetate=3:1) to give compound 3 (450 mg, 23% yield) as a yellow oil. LCMS (ESI): [M+H] 282. 1 HNMR: (500 MHz, CDCl3) δ 8.38 (s, 1H), 6.08 (s, 1H), 5.30-5.33 (m, 1H), 4.29-4.32 (m, 2H), 3.95-4.12 (m, 2H), 3.95 (s, 3H), 1.44 (s, 9H).

[0093] Intermediate 5 [ka] 4-(azetidin-3-yloxy)-6-methoxypyrimidine: To a solution of tert-butyl 3-((6-methoxypyrimidin-4-yl)oxy)azetidine-1-carboxylate (450 mg, 1.60 mmol) in DCM (10 mL) was added TFA (1 mL). The mixture was stirred at 30 °C for 2 h. TLC (petroleum ether:ethyl acetate = 1:1) showed complete consumption of the starting material. The reaction was concentrated to give the product. H2O (2 mL) was added and the aqueous layer was extracted with CHCl2 (3 × 4 mL). The aqueous phase was adjusted to pH 8 by adding NH3·H2O and then concentrated to give 4-(azetidin-3-yloxy)-6-methoxypyrimidine (200 mg, 69% yield), which was used in the next step without purification.

[0094] Example 2-1 [ka] N-(5-((3-((6-Methoxypyrimidin-4-yl)oxy)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: A solution of 4-(azetidin-3-yloxy)-6-methoxypyrimidine (220 mg, 1.21 mmol, 1 equiv) and N-(5-formylthiazol-2-yl)acetamide (206 mg, 1.21 mmol, 1 equiv) in MeOH (15 mL) was stirred at 50° C. for 0.5 h. Sodium cyanoborohydride (228 mg, 3.63 mmol, 3 equiv) was added to the mixture. The reaction was stirred at 50° C. for 12 h. LCMS showed the desired product was detected. The reaction was concentrated to give the crude product, which was purified by preparative HPLC (Column: Waters Xbridge Prep OBD C18 150*30 5u, Conditions: Water (0.04% NH3H2O+10mM NH4HCO3)-ACN, Start B: 15; End B: 45, Gradient time (min): 10, 100%B hold time (min): 2, Flow rate (ml / min): 25) to give N-(5-((3-((6-methoxypyrimidin-4-yl)oxy)azetidin-1-yl)methyl)thiazol-2-yl)acetamide (90 mg, 22% yield) as a white solid. LCMS (ESI): [M+H] 335.9.1 HNMR: (400 MHz, DMSO) δ : 11.86 (br s, 1H), 8.41 (s, 1H), 7.24 (s, 1H), 6.24 (s, 1H), 5.11-5.17 (m, 1H), 3.85 (s, 3H), 3.71 (s, 2H), 3.61-3.65 (m, 2H), 3.03-3.07 (m, 2H), 2.08 (s. 3H).

[0095] Example 2-2 [ka] N-(5-((3-((5-fluoropyrimidin-2-yl)oxy)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 2-bromo-5-fluoropyrimidine, tert-butyl 3-hydroxyazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 2. LCMS (ESI): [M+H] 324. 1 HNMR: (400 MHz, CDCl3) δ 11.64 (br s, 1H), 8.35 (s, 2H), 7.22 (s, 1H), 5.17-5.24 (m, 1H), 3.88 (dd, J=6.0, 8.8 Hz, 2H), 3.82 (s, 2H), 3.19 (dd, J=6.0, 9.2 Hz, 2H), 2.30 (s, 3H).

[0096] Example 2-3 [ka] N-(5-((3-((2-Methoxypyridin-4-yl)oxy)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 4-bromo-2-methoxypyridine, tert-butyl 3-hydroxyazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 2. LCMS (ESI): [M+H] 335.1 HNMR: (400 MHz, CDCl3) δ : 10.87 (s, 1H), 7.96 (d, J=6.0 Hz,1H), 7.22 (s, 1H), 6.37 (d, J=6.0 Hz, 1H), 5.99 (s, 1H), 4.77-4.83 (m, 1H), 3.90 (s, 3H), 3.82-3.85 (m, 4H), 3.16-3.20 (m, 2H), 2.29 (s, 3H).

[0097] Examples 2-4 [ka] N-(5-((3-((3-Methylpyridin-2-yl)oxy)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 2-chloro-3-methylpyridine, tert-butyl 3-hydroxyazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 2. LCMS (ESI): [M+H] 319. 1 HNMR: (400 MHz, D2O) δ8.25 (d, J=6.0 Hz, 1H), 8.19 (d, J=7.2 Hz, 1H), 7.57 (s, 1H), 7.43 (t, J=6.8 Hz, 1H), 5.72-5.79 (m, 1H), 5.18-5.42 (m, 1H), 4.81-4.85 (m, 1H), 4.52-4.61 (m, 2H), 3.60-3.71 (m, 2H), 2.35 (s, 3H), 2.26 (s, 3H).

[0098] Examples 2-5 [ka] N-(5-((3-((5-cyanopyridin-2-yl)oxy)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 6-chloronicotinonitrile, tert-butyl 3-hydroxyazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 2. LCMS (ESI): [M+H] 323. 1 HNMR: (400 MHz, CDCl3) δ 10.69 (s, 1H), 8.42 (s, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.22 (s, 1H), 6.83 (d, J=8.8 Hz, 1H), 5.28-5.36 (m, 1H), 3.82-3.85 (m, 4H), 3.20-3.23 (m, 2H), 2.29 (s, 3H).

[0099] Examples 2-6 [ka] N-(5-(((2R,3R)-3-((2-methoxypyridin-4-yl)oxy)-2-methylazetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 4-bromo-2-methoxypyridine, tert-butyl 3-hydroxy-2-methylazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that of Scheme 2. The diastereomers were separated by preparative HPLC (mobile phase: water (0.05% ammonium hydroxide)-ACN; column: water xbridge prep OBD C). 18 150*30mm*5um; detection. Wavelength: 220nm). LCMS (ESI): [M+H] 349. 1HNMR: (400 MHz, CD3OD) δ 7.91 (d, J=6.0 Hz, 1H), 7.28 (s, 1H), 6.54 (dd, J=6.0 Hz, 2.4 Hz, 1H), 6.17 (s, 1H), 4.92-5.00 (m, 1H), 3.91-3.92 (m, 1H), 3.80 (s, 3H), 3.76-3.78 (m, 2H), 3.38-3.44 (m, 2H), 2.18 (s, 3H), 1.10 (s, 3H).

[0100] Examples 2-7 [ka] N-(5-(((2R,3S)-3-((2-methoxypyridin-4-yl)oxy)-2-methylazetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 4-bromo-2-methoxypyridine, tert-butyl 3-hydroxy-2-methylazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that of Scheme 2. The diastereomers were separated by preparative HPLC (mobile phase: water (0.05% ammonium hydroxide)-ACN; column: water xbridge prep OBD C). 18 150*30mm*5um; detection. Wavelength: 220nm). LCMS (ESI): [M+H] 349. 1 HNMR: (400 MHz, CD3OD) δ 7.91 (d, J=6.0 Hz, 1H), 7.28 (s, 1H), 6.50 (dd, J=6.0 Hz, 2.5 Hz, 1H), 6.18 (s, 1H), 4.44-4.45 (m, 1H), 3.95-3.96 (m, 1H), 3.83-3.85 (m, 4H), 3.77-3.80 (m, 1H), 3.38-3.41 (m, 1H), 2.86-2.89 (m, 1H), 2.20 (s, 3H), 1.24 (s, 3H).

[0101] Examples 2-8 [ka] N-(5-(((2R,3R)-3-((5-fluoropyridin-2-yl)oxy)-2-methylazetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 2-bromo-5-fluoropyridine, tert-butyl 3-hydroxy-2-methylazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a similar manner to that of Scheme 2. The diastereomers were separated by preparative HPLC (Column: Xtimate C18 150*25mm*5um; Conditions: Water (10mM NH4HCO3)-ACN; Start B: 36; End B: 66; Gradient Time (min): 10; 100%B Retention Time (min): 2; Flow Rate (ml / min): 25). LCMS (ESI): [M+H] 337. 1 HNMR: (400 MHz, CD3OD) δ 7.96 (d, J=2.8 Hz, 1H), 7.47-7.53 (m, 1H), 7.29 (s, 1H), 6.77-6.80 (m, 1H), 4.75-4.80 (m, 1H), 3.93-3.97 (m, 1H), 3.78-3.86 (m, 2H), 3.34-3.38 (m, 1H), 2.91-2.95 (m, 1H), 2.20 (s, 3H), 1.26 (d, J=6.0 Hz, 3H).

[0102] Examples 2-9 [ka] N-(5-(((2R,3S)-3-((5-fluoropyridin-2-yl)oxy)-2-methylazetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 2-bromo-5-fluoropyridine, tert-butyl 3-hydroxy-2-methylazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a similar manner to that of Scheme 2. The diastereomers were separated by preparative HPLC (Column: Xtimate C18 150*25mm*5um; Conditions: Water (10mM NH4HCO3)-ACN; Start B: 36; End B: 66; Gradient Time (min): 10; 100%B Retention Time (min): 2; Flow Rate (ml / min): 25). LCMS (ESI): [M+H] 337. 1 HNMR: (400 MHz, CD3OD) δ 7.94 (d, J=2.8 Hz, 1H), 7.49-7.54 (m, 1H), 7.29 (s, 1H), 6.86-6.89 (m, 1H), 5.30-5.34 (m, 1H), 3.88-3.92 (m, 1H), 3.70-3.81 (m, 2H), 3.43 (d, J=4.0 Hz, 2H), 2.19 (s, 3H), 1.07 (d, J=6.8 Hz, 3H).

[0103] Example 2-10 [ka] N-(5-(((2R,3R)-3-((6-Methoxypyrimidin-4-yl)oxy)-2-methylazetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 4-chloro-6-methoxypyrimidine, tert-butyl 3-hydroxy-2-methylazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 2. LCMS (ESI): [M+H] 349. 1HNMR: (400 MHz, CD3OD) δ 8.09 (s, 1H), 7.26 (s, 1H), 5.86 (s, 1H), 3.85-3.89 (m, 5H), 3.71-3.74 (m, 1H), 3.60-3.63 (m, 1H), 3.41-3.43 (m, 1H), 3.26-3.39 (m, 1H), 2.19 (s, 3H), 0.97 (d, J=6.4 Hz, 3H).

[0104] Example 2-11 [ka] N-(5-((3-((5-cyanopyridin-2-yl)oxy)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 4-bromo-6-methoxypyrimidine, tert-butyl 3-aminoazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 2. LCMS (ESI): [M+H] 335. 1 HNMR: (500 MHz, CDCl3) δ 11.86 (s, 1H), 8.27 (s, 1H), 7.22 (s, 1H), 6.86 (s, 1H), 5.52 (s, 1H), 4.18-4.19 (m, 1H), 3.91 (s, 3H), 3.79 (s, 2H), 3.71 (t, J=6.5 Hz, 2H), 3.05-3.08 (m, 2H), 2.29 (s, 3H).

[0105] Example 2-12 [ka] N-(5-((3-((2-Methoxypyridin-4-yl)amino)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 4-bromo-2-methoxypyridine, tert-butyl 3-aminoazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 2. LCMS (ESI): [M+H] 335. 1 HNMR: (500 MHz, CDCl3) δ 11.86 (s, 1H), 8.27 (s, 1H), 7.22 (s, 1H), 6.86 (s, 1H), 5.52 (s, 1H), 4.18-4.19 (m, 1H), 3.91 (s, 3H), 3.79 (s, 2H), 3.71 (t, J=6.5 Hz, 2H), 3.05-3.08 (m, 2H), 2.29 (s, 3H).

[0106] Example 2-13 [ka] N-(5-((3-((5-cyanopyridin-2-yl)amino)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 6-chloronicotinonitrile, tert-butyl 3-aminoazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 2. LCMS (ESI): [M+H] 329. 1 HNMR: (500 MHz, CD3OD) δ 11.97 (br s, 1H), 8.40 (s, 1H), 8.06 (d, J = 6.5 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 6.55 (d, J = 9.0 Hz, 1H), 4.43-4.44 (m, 1H), 3.71 (s, 2H), 3.57-3.59 (m, 2H), 2.92-2.95 (m, 2H), 2.14 (s, 3H).

[0107] Intermediate 6 [ka] tert-Butyl (1-((2-acetamidothiazol-5-yl)methyl)azetidin-3-yl)carbamate: tert-Butyl azetidin-3-ylcarbamate (5.0 g, 29.03 mmol, 1 equiv) and N-(5-formylthiazol-2-yl)acetamide (4.9 g, 29.03 mmol, 1 equiv) in MeOH (100 mL) were stirred at 50° C. for 0.5 h, after which sodium cyanoborohydride (5.5 g, 87.09 mmol, 3 equiv) was added to the mixture. The reaction was stirred at 50° C. for 1 h. LCMS showed the desired product was detected. The reaction was quenched with HO (5 mL) and purified by column chromatography (ethyl acetate) to give tert-butyl (1-((2-acetamidothiazol-5-yl)methyl)azetidin-3-yl)carbamate (7 g, 74% yield) as a brown solid. LCMS (ESI): [M+H] 327. 1 HNMR: (400 MHz, CD3OD) δ 7.27 (s, 1H), 4.18-4.23 (m, 1H), 3.84 (s, 2H), 3.68-3.69 (m, 2H), 3.08-3.11 (m, 2H), 2.19 (s, 3H), 1.41(s, 9H).

[0108] Intermediate 7 [ka] N-(5-((3-aminoazetidin-1-yl)methyl)thiazol-2-yl)acetamide: To a solution of tert-butyl (1-((2-acetamidothiazol-5-yl)methyl)azetidin-3-yl)carbamate (2 g, 6.13 mmol, 1 equiv) in DCM (30 mL) was added TFA (5 mL). The mixture was stirred at 50° C. for 2 h. TLC (ethyl acetate) showed that the starting material was completely consumed. The reaction was concentrated to give the product. To the mixture was added HO (8 mL) and the aqueous layer was extracted with DCM (4 mL). The aqueous phase was adjusted to pH 8 by adding NH3·H2O, then concentrated to give a residue which was purified by preparative HPLC (Column: Waters Xbridge Prep OBD C18 100*19 5u, Conditions: Water (0.04%NH3H2O+10mM NH4HCO3)-ACN, Start B: 0; End B: 30, Gradient time (min): 10, 100%B hold time (min): 2, Flow rate (ml / min): 25) to give N-(5-((3-aminoazetidin-1-yl)methyl)thiazol-2-yl)acetamide (300 mg, 22% yield) as a white solid. LCMS (ESI): [M+H] 227. 1 HNMR: (400 MHz, CD3OD) δ 7.24 (s, 1H), 3.76 (s, 2H), 3.52-3.62 (m, 3H), 2.85-2.89 (m, 2H), 2.19 (s, 3H).

[0109] Example 2-14 [ka] N-(5-((3-((5-fluoropyridin-2-yl)amino)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: To a solution of N-(5-((3-aminoazetidin-1-yl)methyl)thiazol-2-yl)acetamide (150 mg, 662.84 umol) and 2-chloro-5-fluoropyridine (110 mg, 835.18 umol, 84.51 uL) in DMF (10 mL) was added Pd2(dba)3 (60 mg, 66.28 umol, 0.1 equiv), sodium tert-butoxide (127 mg, 1.33 mmol, 2 equiv), and XPhos (63 mg, 132.57 umol, 0.2 equiv). The reaction was degassed with N2 three times and stirred at 110 °C for 3 h. LCMS showed that the desired product was detected. The reaction was quenched with H2O (10 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed with HO (20 mL) and brine (20 mL), dried over NaSO, filtered, and the filtrate was concentrated to give the crude product, which was purified by preparative HPLC ((Column: Waters Xbridge Prep OBD C18 100*19 5u, Conditions: water (0.04% NHHO+10 mM NHHCO)-ACN, Start B: 11; End B: 41, Gradient Time (min): 10, 100% B Retention Time (min): 2, Flow Rate (ml / min): 25)) to give N-(5-((3-((5-fluoropyridin-2-yl)amino)azetidin-1-yl)methyl)thiazol-2-yl)acetamide (42.90 mg, 133.49 umol, 20% yield) as a pale yellow solid.

[0110] Example 2-15 [ka] N-(5-(((2R,3R)-3-((5-fluoropyridin-2-yl)amino)-2-methylazetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 2-chloro-5-fluoropyridine, tert-butyl 3-amino-2-methylazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 3. LCMS (ESI): [M+H] 335.9. 1 HNMR: (500 MHz, CD3OD) δ 7.80 (d, J=3.0 Hz, 1H), 7.29-7.33 (m, 2H), 6.61-6.63 (m, 1H), 4.44-4.47 (m, 1H), 3.91 (d, J=13.5 Hz, 1H), 3.77 (d, J=13.5 Hz, 1H), 3.64-3.70 (m, 1H), 3.46 (t, J=8.0 Hz, 1H), 3.27-3.30 (m, 1H), 2.22 (s, 3H), 1.00 (d, J=6.5 Hz, 3H).

[0111] Example 2-16 [ka] N-(5-(((2R,3R)-3-((2-methoxypyridin-4-yl)amino)-2-methylazetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 4-bromo-2-methoxypyridine, tert-butyl 3-amino-2-methylazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a similar manner to that of Scheme 3. The diastereomers were separated by preparative HPLC (Column: Xtimate C18 150*25mm*5um; Condition: Water (10mM NH4HCO3)-ACN; Start B: 11; End B: 41; Gradient Time (min): 10; 100% B Retention Time (min): 2; Flow Rate (ml / min): 25). LCMS (ESI): [M+H] 348. 1HNMR: (400 MHz, CDCl3) δ11.54 (s, 1H), 7.78 (d, J=6.4 Hz, 1H), 7.20 (s, 1H), 6.13-6.15 (m, 1H), 5.75 (s, 1H), 4.74 (d, J=8.4 Hz, 1H), 4.04-4.06 (m, 1H), 3.83-3.87 (m, 4H), 3.63-3.67 (m, 1H), 3.54-3.56 (m, 1H), 3.29-3.31 (m, 1H), 3.21-3.23 (m, 1H), 2.30 (s, 3H), 1.03(d, J=6.4 Hz, 3H).

[0112] Example 2-17 [ka] N-(5-(((2R,3S)-3-((2-Methoxypyridin-4-yl)amino)-2-methylazetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 4-bromo-2-methoxypyridine, tert-butyl 3-amino-2-methylazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a similar manner to that of Scheme 3. The diastereomers were separated by preparative HPLC (Column: Xtimate C18 150*25mm*5um; Condition: Water (10mM NH4HCO3)-ACN; Start B: 11; End B: 41; Gradient Time (min): 10; 100%B Retention Time (min): 2; Flow Rate (ml / min): 25). LCMS (ESI): [M+H] 347.9. 1 HNMR: (400 MHz, CDCl3) δ12.10 (s, 1H), 7.78 (d, J=6.0 Hz, 1H), 7.20 (s, 1H), 6.09 (d, J=5.6 Hz, 1H), 5.79 (s, 1H), 4.26 (d, J=7.2 Hz, 1H), 3.82-3.86 (m, 4H), 3.80-3.83 (m, 1H), 3.65-3.71 (m, 2H), 2.99-3.02 (m, 1H), 2.59-2.62 (m, 1H), 2.30 (s, 3H), 1.27(d, J=5.6 Hz, 3H).

[0113] Example 2-18 [ka] N-(5-(((2R,3R)-3-((5-cyanopyridin-2-yl)amino)-2-methylazetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 6-chloronicotinonitrile, tert-butyl 3-amino-2-methylazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a similar manner to that of Scheme 3. The diastereomers were separated at intermediate 1 by preparative HPLC (column: Xtimate C18 150*25mm*5um; condition: water (10mM NH4HCO3)-ACN; start B: 11; end B: 41; gradient time (min): 10; 100% B retention time (min): 2; flow rate (ml / min): 25). LCMS (ESI): [M+H] 342.9. 1 HNMR: (400 MHz, CDCl3) δ : 11.01 (s, 1H), 8.33 (s, 1H), 7.55 (d, J=5.2 Hz, 1H), 7.23 (s, 1H), 6.41 (d, J=8.4 Hz, 1H), 5.84 (br s,1H), 4.52-4.53 (m, 1H), 3.85-3.89 (m, 1H), 3.58-3.59 (m, 1H), 3.52-3.56 (m, 1H), 3.31-3.35 (m, 1H), 3.24-3.26 (m, 1H), 2.29 (s, 3H), 1.01 (d, J=6.0 Hz, 3H).

[0114] Example 2-19 [ka] N-(5-(((2R,3S)-3-((5-cyanopyridin-2-yl)amino)-2-methylazetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 6-chloronicotinonitrile, tert-butyl 3-amino-2-methylazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a similar manner to that of Scheme 3. The diastereomers were separated at intermediate 1 by preparative HPLC (column: Xtimate C18 150*25mm*5um; condition: water (10mM NH4HCO3)-ACN; start B: 11; end B: 41; gradient time (min): 10; 100% B retention time (min): 2; flow rate (ml / min): 25). LCMS (ESI): [M+H] 342.9. 1 HNMR: (400 MHz, CDCl3) δ : 10.86 (br s, 1H), 8.34 (s, 1H), 7.58-7.60 (m, 1H), 7.21-7.22 (m, 1H), 6.34-6.36 (m,1H), 5.42 (br s, 1H), 3.68-4.00 (m, 4H), 3.06-3.07 (m, 1H), 2.67-2.68 (m, 1H), 2.28 (s, 3H), 1.27 (d, J=6.0 Hz, 3H).

[0115] Example 2-20 [ka] N-(5-((3-(((2,6-dimethylpyridin-4-yl)oxy)methyl)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 4-bromo-2,6-dimethylpyridine, tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 2. LCMS (ESI): [M+H] 347. 1HNMR: (400 MHz, CD3OD) δ 11.45 (s, 1H), 7.20 (s, 1H), 6.90 (s, 2H), 4.35 (s, 2H), 4.19-4.24 (m, 1H), 3.77 (s, 2H), 3.63-3.67 (m, 2H), 3.00-3.04 (m, 2H), 2.51 (s, 6H), 2.29 (s, 3H).

[0116] Example 2-21 [ka] N-(5-((3-(((2,6-dimethylpyrimidin-4-yl)oxy)methyl)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 4-chloro-2,6-dimethylpyrimidine, tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 2. LCMS (ESI): [M+H] 348. 1 HNMR: (400 MHz, CD3OD) δ 7.27 (s, 1H), 6.55 (s, 1H), 4.46 (d, J = 6.4 Hz, 2H), 3.81 (s, 2H), 3.47 (t, J = 8.0 Hz, 2H), 3.19 (t, J = 8.0 Hz, 2H), 2.89-2.96 (m, 1H), 2.51 (s, 3H), 2.38 (s, 3H), 2.19 (s, 3H).

[0117] Example 2-22 [ka] N-(5-((3-(((5-fluoropyridin-2-yl)oxy)methyl)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 2-chloro-5-fluoropyridine, tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 2. LCMS (ESI): [M+H] 337. 1 HNMR: (400 MHz, CDCl3) δ 10.96-11.03 (m, 1H), 7.96 (d, J=2.4 Hz, 1H), 7.20-7.35 (m, 2H), 6.67-6.71 (m, 1H), 4.36 (d, J=6.4 Hz, 2H), 3.74 (s, 2H), 3.45-3.48 (m, 2H), 3.11-3.14 (m, 2H), 2.90-2.95 (m, 1H), 2.30 (s, 3H).

[0118] Example 2-23 [ka] N-(5-((3-(((2-Methoxypyridin-4-yl)oxy)methyl)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 4-bromo-2-methoxypyridine, tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 2. LCMS (ESI): [M+H] 349. 1HNMR: (400 MHz, CDCl3) δ 11.86 (br s, 1H), 7.96 (d, J=6.0 Hz, 1H), 7.20 (s, 1H), 6.46 (d, J=6.0 Hz, 1H), 6.17 (d, J=2.0 Hz, 1H), 4.09 (d, J=7.0 Hz, 2H), 3.91 (s, 3H), 3.74 (s, 2H), 3.43 (t, J=7.5 Hz, 2H), 3.11-3.14 (m, 2H), 2.88-2.92 (m, 1H), 2.30 (s, 3H).

[0119] Example 2-24 [ka] N-(5-((3-(((2,6-dimethylpyridin-4-yl)amino)methyl)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 4-bromo-2,6-dimethylpyridine, tert-butyl 3-(aminomethyl)azetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 2. LCMS (ESI): [M+H] 346. 1 HNMR: (400 MHz, CD3OD) δ 7.26 (s, 1H), 6.36 (s, 2H), 3.77 (s, 2H), 3.37-3.45 (m, 4H), 3.05-3.08 (m, 2H), 2.73-2.77 (m, 1H), 2.35 (s, 6H), 2.20 (s, 3H).

[0120] Example 2-25 [ka] N-(5-((3-(((2-Methoxypyridin-4-yl)amino)methyl)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 4-bromo-2-methoxypyridine, tert-butyl 3-(aminomethyl)azetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 2. LCMS (ESI): [M+H] 348. 1 HNMR: (400 MHz, CDCl3) δ 11.82 (br s, 1H), 7.78 (d, J=6.0 Hz, 1H), 7.18 (s, 1H), 6.16-6.14 (m, 1H), 5.81 (s, 1H), 4.70-4.73 (m, 1H), 3.87 (s, 3H), 3.71 (s, 2H), 3.33-3.37 (m, 2H), 3.28-3.31 (m, 2H), 3.06-3.09 (m, 2H), 2.67-2.70 (m, 2H), 2.29 (s, 3H).

[0121] Example 2-26 [ka] N-(5-((3-(((2,6-dimethylpyrimidin-4-yl)amino)methyl)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 4-chloro-2,6-dimethylpyrimidine, tert-butyl 3-(aminomethyl)azetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 2. LCMS (ESI): [M+H] 347. 1HNMR: (400 MHz, CD3OD) δ 10.27 (br s, 1H), 7.19 (s, 1H), 6.04 (s, 1H), 5.24 (s, 1H), 3.71 (s, 2H), 3.45-3.53 (m, 2H), 3.35 (t, J=7.5 Hz, 2H), 3.05-3.08 (m, 2H), 2.67-2.71 (m, 1H), 2.47 (s, 3H), 2.33 (s, 3H), 2.27 (s, 3H).

[0122] Example 2-27 [ka] N-(5-(((2R,3S)-3-((6-Methoxypyrimidin-4-yl)oxy)-2-methylazetidin-1-yl)methyl)thiazol-2-yl)acetamide: A solution of 4-methoxy-6-(((2R,3S)-2-methylazetidin-3-yl)oxy)pyrimidine (66 mg, 338.08 umol, 1 eq) and N-(5-formylthiazol-2-yl)acetamide (58 mg, 338.08 umol, 1 eq) in MeOH (4 mL) was stirred at 50° C. for 0.5 h. Sodium cyanoborohydride (64 mg, 1.01 mmol, 3 eq) was added to the mixture. The reaction was stirred at 50° C. for 1 h. LCMS showed the desired product was detected. The reaction was concentrated to give the crude product, which was purified by preparative HPLC (Column: Waters Xbridge Prep OBD C18 100*19 5u, Conditions: Water (0.04% NH3H2O+10mM NH4HCO3)-ACN, Start B: 15; End B: 45, Gradient time (min): 10, 100%B hold time (min): 2, Flow rate (ml / min): 25) to give N-(5-(((2R,3S)-3-((6-methoxypyrimidin-4-yl)oxy)-2-methylazetidin-1-yl)methyl)thiazol-2-yl)acetamide (19.3 mg, 16% yield) as a white solid. LCMS (ESI): [M+H] 350. 1HNMR: (400 MHz, CD3OD) δ 8.34 (s, 1H), 7.28 (s, 1H), 6.14 (s, 1H), 4.82-4.85 (m, 1H), 3.90-3.92 (m, 4H), 3.89 (s, 3H), 3.76-3.83 (m, 2H), 3.32-3.38 (m, 1H), 2.92 (t, J = 7.2 Hz, 1H), 2.19 (s, 3H), 1.24 (d, J = 6.4 Hz, 3H).

[0123] Example 2-28 [ka] N-(5-(((2R,3R)-3-((6-Methoxypyrimidin-4-yl)oxy)-2-methylazetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 4-chloro-6-methoxypyrimidine, tert-butyl 3-hydroxy-2-methylazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 3. LCMS (ESI): [M+H] 350. 1 HNMR: (400 MHz, CD3OD) δ 8.33 (s, 1H), 7.28 (s, 1H), 6.22 (d, J = 0.8 Hz, 1H), 5.36-5.40 (m, 1H), 3.87-3.93 (m, 4H), 3.41-3.79 (m, 2H), 3.42 (d, J = 5.2 Hz, 2H), 2.19 (s, 3H), 1.06 (d, J = 6.8 Hz, 3H).

[0124] Example 2-29 [ka] N-(5-(((2R,3R)-3-((5-fluoropyrimidin-2-yl)oxy)-2-methylazetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 2-bromo-5-fluoropyrimidine, tert-butyl 3-hydroxy-2-methylazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 3. LCMS (ESI): [M+H] 338. 1 HNMR: (400 MHz, CDCl3) δ 11.62 (br s, 1H), 8.34 (s, 2H), 7.23 (s, 1H), 5.23-5.27 (m, 1H), 3.85-3.88 (m, 1H), 3.73-3.78 (m, 2H), 3.52-3.53 (m, 1H), 3.39-3.42 (m, 1H), 2.30 (s, 3H), 1.17 (d, J=6.0 Hz, 3H).

[0125] Example 2-30 [ka] N-(5-(((2R,3S)-3-((5-fluoropyrimidin-2-yl)oxy)-2-methylazetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 2-bromo-5-fluoropyrimidine, tert-butyl 3-hydroxy-2-methylazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 3. LCMS (ESI): [M+H] 338. 1 HNMR: (400 MHz, CDCl3) δ11.39 (br s, 1H), 8.35 (s, 2H), 7.22 (s, 1H), 4.79-4.84 (m, 1H), 3.87-3.94 (m, 2H), 3.71-3.75 (m, 1H), 3.33-3.38 (m, 1H), 2.90 (t, J=7.2 Hz, 1H), 2.30 (s, 3H), 1.29 (d, J=6.4 Hz, 3H).

[0126] Example 2-31 [ka] N-(5-(((2R,3R)-3-((5-cyanopyridin-2-yl)oxy)-2-methylazetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 6-chloronicotinonitrile, tert-butyl 3-hydroxy-2-methylazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 3. LCMS (ESI): [M+H] 344. 1 HNMR: (400 MHz, CD3OD) δ : 8.50 (s, 1H), 7.96 (dd, J=8.8, 2.4 Hz, 1H), 7.28 (s, 1H), 6.91 (d, J=8.8 Hz, 1H), 3.92-3.96 (m,1H), 3.77-3.85 (m, 2H), 3.36-3.47 (m, 2H), 2.92-2.96 (m, 1H), 2.19 (s, 3H), 1.26 (d, J=6.4 Hz, 3H).

[0127] Example 2-32 [ka] N-(5-(((2R,3S)-3-((6-methoxypyrimidin-4-yl)oxy)-2-methylazetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 6-chloronicotinonitrile, tert-butyl 3-hydroxy-2-methylazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 3. LCMS (ESI): [M+H] 349. 1HNMR: (400 MHz, CD3OD) δ 8.09 (s, 1H), 7.26 (s, 1H), 5.86 (s, 1H), 3.85-3.89 (m, 5H), 3.71-3.74 (m, 1H), 3.60-3.63 (m, 1H), 3.41-3.43 (m, 1H), 3.26-3.39 (m, 1H), 2.19 (s, 3H), 0.97 (d, J=6.4 Hz, 3H).

[0128] Example 2-33 [ka] N-(5-(((2R,3S)-3-((5-fluoropyrimidin-2-yl)oxy)-2-methylazetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 2-bromo-5-fluoropyrimidine, tert-butyl 3-hydroxy-2-methylazetidine-1-carboxylate, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 3. LCMS (ESI): [M+H] 338. 1 HNMR: (400 MHz, CDCl3) δ11.39 (br s, 1H), 8.35 (s, 2H), 7.22 (s, 1H), 4.79-4.84 (m, 1H), 3.87-3.94 (m, 2H), 3.71-3.75 (m, 1H), 3.33-3.38 (m, 1H), 2.90 (t, J=7.2 Hz, 1H), 2.30 (s, 3H), 1.29 (d, J=6.4 Hz, 3H).

[0129] Scheme 3 [ka]

[0130] Intermediate 8 [ka] tert-Butyl 3-((2,6-dimethylpyridin-4-yl)methyl)amino)azetidine-1-carboxylate: A mixture of 2,6-dimethylisonicotinaldehyde (500 mg, 2.90 mmol, 1 eq) and tert-butyl 3-aminoazetidine-1-carboxylate (431 mg, 3.19 mmol, 1.1 eq) in MeOH (12 mL) was stirred for 30 min, then sodium cyanoborohydride (547 mg, 8.70 mmol, 3 eq) was added. The mixture was stirred at 30° C. for 2 h. LCMS showed that the desired product was observed. The solvent was removed to give a residue, which was purified by silica gel column chromatography (EtOAc / MeOH=5 / 1) to give tert-butyl 3-((2,6-dimethylpyridin-4-yl)methyl)amino)azetidine-1-carboxylate (331.0 mg, 39% yield) as a yellow solid. LCMS (ESI): [M+H] 292. 1 HNMR: (500 MHz, CDCl3) δ 6.91 (s, 2H), 4.07-4.10 (m, 2H), 3.64-3.66 (m, 4H), 3.58-3.61 (m, 1H), 2.51 (s, 6H), 1.4 (s, 9H).

[0131] Intermediate 9 [ka] N-((2,6-dimethylpyridin-4-yl)methyl)azetidin-3-amine: To a solution of tert-butyl 3-((2,6-dimethylpyridin-4-yl)methyl)amino)azetidine-1-carboxylate (200 mg, 686.37 umol, 1 eq) in DCM (10 mL) was added TFA (1 mL). The mixture was stirred at 25° C. for 2.0 h. LCMS showed that the desired product was observed. The mixture was adjusted to pH 8-9 with ammonia. The mixture was concentrated to give N-((2,6-dimethylpyridin-4-yl)methyl)azetidin-3-amine (110 mg, crude) as a yellow solid. LCMS (ESI): [M+H] 192.

[0132] Example 3-1 [ka] N-(5-((3-(((2,6-dimethylpyridin-4-yl)methyl)amino)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: A mixture of N-((2,6-dimethylpyridin-4-yl)methyl)azetidin-3-amine (80 mg, 418.26 umol, 1 eq) and N-(5-formylthiazol-2-yl)acetamide (142 mg, 836.51 umol, 2 eq) with MeOH (10 mL) was stirred for 30 min, then sodium cyanoborohydride (78.9 mg, 1.25 mmol, 3 eq) was added. The mixture was stirred at 30° C. for 2 h. LCMS showed that the desired product was observed. The mixture was purified by preparative HPLC (Column: Xtimate C18 150*25mm*5um; Condition: Water (10mM NH4HCO3)-ACN; Start B: 11; End B: 41; Gradient time (min): 10; 100% B retention time (min): 2; Flow rate (ml / min): 25) to give N-(5-((3-(((2,6-dimethylpyridin-4-yl)methyl)amino)azetidin-1-yl)methyl)thiazol-2-yl)acetamide (18.7mg, 13% yield) as a yellow solid. LCMS (ESI): [M+H] 346. 1 HNMR: (500 MHz, CDCl3) δ 11.56 (br s, 1H), 7.19 (s, 1H), 6.90 (s, 2H), 3.74 (s, 2H), 3.65 (s, 2H), 3.58-3.61 (m, 2H), 3.47-3.52 (m, 1H), 2.86-2.89 (m, 2H), 2.50 (s, 6H), 2.29 (s, 3H).

[0133] Example 3-2 [ka] N-(5-((3-(((2-Methoxypyridin-4-yl)methyl)amino)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 2-methoxyisonicotinaldehyde and tert-butyl 3-aminoazetidine-1-carboxylate and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Scheme 4. LCMS (ESI): [M+H] 348. 1 HNMR: (500 MHz, CDCl3) δ 12.13 (br s, 1H), 8.08 (d, J = 4.0 Hz, 1H), 7.18 (s, 1H), 6.80-6.82 (m, 1H), 6.67 (s, 1H), 3.91 (s, 3H), 3.72 (s, 2H), 3.68 (s, 2H), 3.56-3.59 (m, 2H), 3.47-3.51 (m, 1H), 2.82-2.85 (m, 2H), 2.29 (s, 3H).

[0134] Example 3-3 [ka] N-(5-((3-(((5-Methyl-1,2,4-oxadiazol-3-yl)methyl)amino)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from tert-butyl 3-(((5-methyl-1,2,4-oxadiazol-3-yl)methyl)amino)azetidine-1-carboxylate and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that of Scheme 4. LCMS (ESI): [M+H] 348. 1 HNMR: (500 MHz, CD3OD) δ 7.27 (s, 1H), 6.55 (s, 1H), 4.46 (d, J = 6.4 Hz, 2H), 3.81 (s, 2H), 3.47 (t, J=8.0 Hz, 2H), 3.19 (t, J=7.6 Hz, 2H), 2.89-2.96 (m, 1H), 2.51 (s, 3H), 2.38 (s, 3H), 2.19 (s, 3H).

[0135] Scheme 4 [ka]

[0136] Intermediate 10 [ka] tert-Butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine-1-carboxylate: A solution of 2,2,6,6-tetramethylpiperidine (2.6 g, 18.63 mmol, 3.13 mL) in THF (30 mL) was cooled to 0° C. n-BuLi (2.05 M, 10.92 mL) was added and the mixture was stirred for 10 min. A solution of 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolane (5 g, 18.63 mmol) in THF (6 mL) was added and the mixture was stirred for 15 min. The solution was cooled to -78 °C in a dry ice bath and a solution of tert-butyl 3-oxoazetidine-1-carboxylate (2.68 g, 15.66 mmol) in THF (15 mL) was added. The reaction was allowed to reach ambient temperature and stirred for 16 h. The reaction was quenched with 30% K2CO3, extracted with ethyl acetate, dried over sodium sulfate, and concentrated. The crude organic material was purified on silica eluting with heptane / ethyl acetate (8:2) to give tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine-1-carboxylate (1.28 g) in 28% yield. LCMS (ESI): [Mt-Butyl] 240. 1 HNMR: (500 MHz, CDCl3) δ = 4.64 (q, J=3.1 Hz, 2H), 4.48-4.57 (m, 2H), 1.47 (s, 9H), 1.25 ppm (s, 12H).

[0137] Intermediate 11 [ka] tert-Butyl 3-((2-ethoxypyridin-4-yl)methylene)azetidine-1-carboxylate: A vessel was charged with tert-butyl 3-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]azetidine-1-carboxylate (216 mg, 731.76 umol), 4-bromo-2-ethoxy-pyridine (148 mg, 731.76 umol), potassium carbonate (303 mg, 2.20 mmol), Pd(dppf)Cl2·DCM adduct (59.76 mg, 73.18 umol), dioxane (3 mL) and water (1 mL). The mixture was heated to 100 °C and stirred for 16 h. The reaction was filtered through a silica / celite pad and concentrated. The crude organic material was passed through silica / celite and used directly in the next step without further purification: LCMS (ESI): [M+H] 291.

[0138] Intermediate 12 [ka] tert-Butyl 3-((2-ethoxypyridin-4-yl)methyl)azetidine-1-carboxylate: A vessel was charged with tert-butyl 3-[(2-ethoxy-4-pyridyl)methylene]azetidine-1-carboxylate (212 mg, 730.13 umol), MeOH (5.00 mL), and Pd / C (78 mg, 73.01 umol, 10% purity). A balloon of H2 was bubbled through the solution with air and the reaction was stirred under H2 for 16 hours at room temperature. Upon completion, the reaction was filtered through Celite and concentrated to give tert-butyl 3-((2-ethoxypyridin-4-yl)methyl)azetidine-1-carboxylate (212 mg, 730.13 umol), which was carried on directly to the next step without purification. LCMS (ESI): [M+H] 292.

[0139] Intermediate 13 [ka] 4-(Azetidin-3-ylmethyl)-2-ethoxy-pyridine: tert-Butyl 3-((2-ethoxypyridin-4-yl)methyl)azetidine-1-carboxylate (212 mg, 730.13 umol) was dissolved in DCM (5 mL) and TFA (166 mg, 1.46 mmol, 111.50 uL) was added. The reaction was stirred at room temperature for 16 hours and then concentrated to give the title compound (222.4 mg, 730.13 umol). LCMS (ESI): [M+H] 192.

[0140] Example 4-1 [ka] N-(5-((3-((2-ethoxypyridin-4-yl)methyl)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: 4-(azetidin-3-ylmethyl)-2-ethoxy-pyridine was dissolved in MeOH (3 mL) and N-(5-formylthiazol-2-yl)acetamide (18 mg, 1.09 mmol) was added followed by sodium cyanoborohydride (92 mg, 1.46 mmol) and the mixture was stirred at 50° C. for 16 h. The mixture was filtered through Celite and purified on silica gel eluting with [EtOAc / EtOH (3:1)] / EtOAc (0→20→50%). LCMS (ESI): [M+H] 347. 1 HNMR: (500 MHz, CD3OD) δ = 7.98 (d, J=5.5 Hz, 1H), 7.51-7.59 (m, 1H), 7.27 (s, 1H), 6.78 (d, J=5.4 Hz, 1H), 6.60 (s, 1H), 4.28 (q,J=7.3 Hz, 2H), 3.78 (s, 2H), 3.40-3.51 (m, 2H), 3.02 (dd, J=8.2, 6.4 Hz, 2H), 2.84-2.88 (m, 2H), 2.77-2.84 (m, 1H), 2.18-2.25 (m, 3H), 2.05 (s, 1H), 1.35-1.40 ppm (m, 3H).

[0141] Example 4-2 [ka] N-(5-((3-benzylazetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from tert-butyl 3-oxoazetidine-1-carboxylate and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that of Example 5-1. LCMS (ESI): [M+H] 302. 1 HNMR: (500 MHz, CD3OD) δ 7.29 (s, 1H), 7.03-7.41 (m, 5H), 3.84 (d, J=0.75 Hz, 2H), 3.43-3.55 (m, 2H), 3.10 (dd, J=6.78, 8.28 Hz, 2H), 2.71-2.90 (m, 3H), 2.21 (s, 3H).

[0142] Scheme 5 [ka]

[0143] Intermediate 14 [ka]

[0144] Intermediate 15 [ka] 2-(azetidin-3-yl)-5-fluoropyrimidine: tert-Butyl 3-(5-fluoropyrimidin-2-yl)azetidine-1-carboxylate (131 mg, 517 umol) was treated with a solution of HCl in dioxane (18 mg, 517 ul, 4 M). The reaction was stirred for 16 hours and the solvent was removed under reduced pressure to give the title compound.

[0145] Example 5-1 [ka] N-(5-((3-(5-Fluoropyrimidin-2-yl)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: N-[5-(cyclomethyl)thiazol-2-yl]acetamide (106 mg, 553.74 umol) was added to a solution of 2-(azetidin-3-yl)-5-fluoro-pyrimidine (105 mg, 553.74 umol, hydrochloride salt) and Hunig's base (357 mg, 2.77 mmol, 483.55 uL) in DMF (2 mL). After 2 hours, the solvent was removed under reduced pressure. The residue was dissolved in DCM, washed (NaHCO3), dried over sodium sulfate and concentrated. The residue was purified on silica gel eluting with DCM / MeOH (8.5:1.5) to give the title compound as an off-white solid. LCMS (ESI): [M+H] 307. 1 HNMR: (500 MHz, CDCl3) δ 12.07 (br s 1 H), 8.47 - 8.64 (m, 2 H), 7.25 (t, J=1.1 Hz, 1 H), 4.03 (quin, J=7.7 Hz, 1 H), 3.84 (s, 2 H), 3.81 (t, J=7.8 Hz, 2 H), 3.52 (t, J=7.5 Hz, 2 H), 2.28 - 2.34 (m, 3 H).

[0146] Example 5-2 [ka] N-(5-((3-(thieno[2,3-d]pyrimidin-4-yl)azetidin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine, 4-bromothieno[2,3-d]pyrimidine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide in a manner similar to that of Example 6-1. LCMS (ESI): [M+H] 292. 1HNMR: (500 MHz, (CD3)2SO) δ 11.94 (s, 1 H), 9.06 (s, 1 H), 7.94 (d, J=6.0 Hz, 1 H), 7.64 (d, J=6.1 Hz, 1 H), 7.28 (s, 1 H), 4.37 (quintet, J=7.9 Hz, 2 H), 3.70 - 3.78 (m, 6 H), 3.44 (t, J=7.6 Hz, 3 H), 2.11 (s, 4 H).

[0147] Biological Data

[0148] Biochemical assay for inhibition of OGA enzyme

[0149] Recombinant full-length human OGA enzyme was purchased from Origene. 4-MUGlCNAc substrate was purchased from Sigma. All other reagents were purchased from Sigma or Fisher. The assay buffer consisted of McIlvaine buffer system pH 6.4 (0.2 M Na2HPO4 mixed with 0.1 M citric acid) and 0.01% BSA. Reactions contained 1 nM OGA, 100 μM 4-MUGlcNAc (K m ), and compound in a final volume of 10 μl. Reactions were incubated for 90 min at room temperature, quenched with 40 μl 3M glycine, pH 10, and read on a Perkin Elmer Envision plate reader (Ex: 355 nm / Em: 460 nm). Compounds were tested in a 10-point dose response starting at 20 μM with 4-fold dilutions. Data were fitted using GraphPad Prism using a 4-parameter fit with variable slope. [Table 1]

[0150] Having described a number of embodiments of the present disclosure, it will be apparent that the basic examples may be modified to produce other embodiments that utilize the compounds and methods of the present disclosure. It will therefore be apparent that the scope of the present disclosure is to be defined by the appended claims rather than by the specific embodiments that have been presented by way of example.

[0151] The contents of all references cited throughout this application (including literature references, issued patents, published patent applications, and co-pending patent applications) are expressly incorporated herein in their entirety by reference. Unless otherwise defined, all technical and scientific terms used herein are given the meaning commonly known to one of ordinary skill in the art. In one aspect, the present invention may be as follows. [Aspect 1] A compound represented by the following structural formula: [ka] or a pharma- ceutical acceptable salt thereof, wherein: Ar is an optionally substituted 6- to 10-membered aryl or an optionally substituted 5- to 10-membered heteroaryl, with the proviso that when X is not present, Ar is not phenyl; X is absent or -CR 2 R 2 -, -(CR 2 R 2 )2-, -O-, -(CR 2 R 2 )O-, -O(CR 2 R 2 )-, -NR d -, -NR d (CR 2 R 2 )- or -(CR 2 R 2 )NR d - and Y 1 and Y 2 are respectively CR c or N and Y 1 or Y 2 At least one of is N; Z is -CR 2 R 2 -, -C(=O)-, -(CR 2 R 2 )2-, or -CH2C(=O)-, R c is -H, halo, -C1-C4 alkyl, or -C1-C4 haloalkyl; R d is -H, -C1-C4 alkyl, -C1-C4 haloalkyl, or -C(=O)C1-C4 alkyl; n is 0 or an integer from 1 to 5; When n is nonzero, R 1 is independently at each occurrence halo, -C1-C4 alkyl, -C1-C4 haloalkyl, or -C1-C4 alkoxy; R 2 is independently at each occurrence -H, halo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C 10 Haloalkyl, or -C3-C 10 is an alkoxy; or alternatively, two R 2 together with the carbon atom to which they are attached, C3-C 10 Forming a cycloalkyl, R 3 is -H, or -C1-C4 alkyl; R 4 is -H, -C1-C4 alkyl, -C1-C4 haloalkyl, or -C3-C6 cycloalkyl; Or alternatively, R 3 and R 4 taken together with their intervening atoms form an optionally substituted 5- to 7-membered heterocyclyl, or a pharma- ceutically acceptable salt thereof. [Aspect 2] The compound according to aspect 1, wherein the compound is represented by the following structural formula: [ka] or a pharma- ceutically acceptable salt thereof. [Aspect 3] The compound according to any one of Aspects 1 and 2, wherein the compound is represented by the following structural formula: [ka] or a pharma- ceutically acceptable salt thereof. [Aspect 4] The compound according to any one of aspects 1 to 3, wherein the compound is represented by one of the following structural formulas: [ka] or a pharma- ceutically acceptable salt thereof. [Aspect 5] The compound according to any one of Aspects 1 to 4, wherein the compound is represented by the following structural formula: [ka] or a pharma- ceutically acceptable salt thereof. [Aspect 6] X is -CR 2 R 2 -, -(CR 2 R 2 )O-, -NR d -, or -NR d (CR 2 R 2 )-, wherein R d is -H or -C1-C4 alkyl, 10. The compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof. [Aspect 7] R c is -H or halo, and R 4 A compound according to any one of aspects 1 and 2, wherein is -H and -C1-C4 alkyl, or a pharma- ceutically acceptable salt thereof. [Aspect 8] The compound according to any one of Aspects 1 to 7, wherein Ar is an optionally substituted 5- to 10-membered heteroaryl. [Aspect 9] The compound according to any one of Aspects 1 to 8, wherein Ar is an optionally substituted 5- or 6-membered monocyclic heteroaryl. [Aspect 10] The compound according to any one of Aspects 1 to 9, wherein Ar is an optionally substituted 6-membered monocyclic heteroaryl. [Aspect 11] A compound according to any one of Aspects 1 to 10, wherein Ar is an optionally substituted pyridinyl, an optionally substituted pyrimidinyl, or an optionally substituted pyrazinyl, or a pharma- ceutically acceptable salt thereof. [Aspect 12] Ar is optionally substituted [ka] Arbitrarily substituted [ka] Arbitrarily substituted [ka] Arbitrarily substituted [ka] Arbitrarily substituted [ka] Arbitrarily substituted [ka] or optionally substituted [ka] or a pharma- ceutically acceptable salt thereof. [Aspect 13] Ar is optionally substituted [ka] or optionally substituted [ka] 13. The compound according to any one of aspects 1 to 12, wherein: [Aspect 14] Ar is C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, halo, -CN, -NO2, -ORz , -NR x R y , -S(O) i R x , -NR x S(O) i R y , -S(O) i NR x R y , -C(=O)OR x , -OC(=O)OR x , -C(=S)OR y , -O(C=S)R x , -C(=O)NR x R y , -NR x C(=O)R y , -C(=S)NR x R y , -NR x C(=S)R y , -NR x (C=O)OR y , -O(C=O)NR x R y , -NR x (C=S)OR y , -O(C=S)NR x R y , -NR x (C=O)NR x R y , -NR x (C=S)NR x R y , -C(=S)R x , -C(=O)R x , phenyl, and monocyclic heteroaryl; During the ceremony, The C1-C4 alkyl substituents of Ar are -CN, -NO2, -OR z , -NR x R y , -S(O) i R x , -NR x S(O) i R y , -S(O) i NR x R y , -C(=O)OR x, -OC(=O)OR x , -C(=S)OR x , -O(C=S)R x , -C(=O)NR x R y , -NR x C(=O)R y , -C(=S)NR x R y , -NR x C(=S)R y , -NR x (C=O)OR y , -O(C=O)NR x R y , -NR x (C=S)OR y , -O(C=S)NR x R y , -NR x (C=O)NR x R y , -NR x (C=S)NR x R y , -C(=S)R x , and -C(=O)R y , C3-C6 cycloalkyl (- optionally substituted with one or more groups selected from: -CH3, halomethyl, halo, methoxy, and halomethoxy; monocyclic heteroaryl (optionally substituted with one or more groups selected from: -CH3, halomethyl, halo, methoxy, or halomethoxy); and phenyl (optionally substituted with one or more groups selected from: -CH3, halomethyl, halo, methoxy, and halomethoxy); The C3-C6 cycloalkyl, C3-C6 heterocyclyl, phenyl, and monocyclic heteroaryl substituents of Ar are C1-C4 alkyl, C1-C4 haloalkyl, halo, -CN, -NO2, -OR. z , -NR x R y , -S(O) i R x , -NR x S(O) i R y , -S(O) i NR x Ry , -C(=O)OR x , -OC(=O)OR x , -C(=S)OR x , -O(C=S)R y , -C(=O)NR x R y , -NR x C(=O)R y , -C(=S)NR x R y , -NR x C(=S)R y , -NR x (C=O)OR y , -O(C=O)NR x R y , -NR x (C=S)OR y , -O(C=S)NR x R y , -NR x (C=O)NR x R y , -NR x (C=S)NR x R y , -C(=S)R x , and -C(=O)R x is optionally and independently substituted with Each R x and each R y are independently -H, C1-C4 alkyl or C3-C8 cycloalkyl; R x or R y wherein the C1-C4 alkyl or C3-C8 cycloalkyl represented by the formula: is optionally substituted with one or more substituents selected from halo, hydroxyl, C3-C6 cycloalkyl, and phenyl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy, or halomethoxy); R z is -H, C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, or C3-C8 heterocyclyl; R zC1-C4 alkyl or C3-C8 cycloalkyl represented by the formula: is optionally substituted with one or more substituents selected from -CN, halo, hydroxyl, C1-C4 alkyl, C1-C4, C3-C6 cycloalkyl, and phenyl (optionally substituted with one or more groups selected from -CH3, halomethyl, halo, methoxy, and halomethoxy); 14. A compound according to any one of aspects 1 to 13, wherein i is 0, 1 or 2, or a pharma- ceutically acceptable salt thereof. [Aspect 15] Ar is C1-C4 alkyl, C1-C4 haloalkyl, halo, -CN, -NO2, -OR z , -SR z , -NR x S(O) i R y , -C(=O)OR x , -OC(=O)OR x , -C(=S)OR y , -O(C=S)R x , -C(=O)NR x R y , -C(=S)NR x R y , -NR x C(=S)R y , -NR x (C=O)OR y , -O(C=O)NR x R y , -NR x (C=S)OR y , -O(C=S)NR x R y , -NR x (C=O)NR x R y , -NR x (C=S)NR x R y , -C(=S)R x , and -C(=O)R x wherein each R x , each R y , and R zis each independently -H or C1-C4 alkyl; or a pharma- ceutically acceptable salt thereof. [Aspect 16] Ar is C1-C4 alkyl, C1-C4 haloalkyl, halo, -CN, -OR z , and -C(=O)NR x R y 16. A compound according to any one of aspects 1 to 15, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more groups selected from: [Aspect 17] A compound according to any one of Aspects 1 to 16, or a pharma- ceutically acceptable salt thereof, wherein Ar is optionally substituted with one or more groups selected from -CH3, -F, -CN, and -OCH3. [Aspect 18] A pharmaceutical composition comprising the compound according to any one of Aspects 1 to 17 or a pharma- ceutically acceptable salt thereof and a pharma- ceutical acceptable carrier or diluent. [Aspect 19] A method for treating a subject suffering from a disease or condition selected from a neurodegenerative disease, a tauopathy, diabetes, cancer, and stress, the method comprising administering to the subject an effective amount of a compound according to any one of Aspects 1 to 17, or an effective amount of a pharmaceutical composition according to Aspect 18. [Aspect 20] The disease or condition is selected from the group consisting of acute ischemic stroke (AIS), Alzheimer's disease, dementia, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), argyrophilic grain dementia, Bluit's disease, corticobasal degeneration (CBP), kogakuka dementia, diffuse neurofibrillary tangle disease with calcifications, Down's syndrome, epilepsy, familial British dementia, familial Danish dementia, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Gerstmann-Sträussler-Scheinker disease, Guadalcanalicular encephalopathy, and glaucoma. 20. The method of embodiment 19, wherein the disease is selected from progressive parkinsonism, Hallervorden-Spatz disease (neurodegenerative disease with cerebral iron deposition type 1), ischemic stroke, mild cognitive impairment (MCI), multiple system atrophy, myotonic dystrophy, Niemann-Pick disease (type C), pallidopontonigral degeneration, Parkinsonism-Dementia Complex of Guam, Pick's disease (PiD), post-encephalitic Parkinsonism (PEP), prion diseases (including Creutzfeldt-Jakob disease (GJD), variant Creutzfeldt-Jakob disease (vCJD)), fatal familial insomnia, kuru, progressive supercortical gliosis, progressive supranuclear palsy (PSP), Steele-Richardson-Olszewski syndrome, subacute sclerosing panencephalitis, neurofibrillary senile dementia, Huntington's disease, and Parkinson's disease. [Aspect 21] The method according to any one of aspects 19 and 20, wherein the disease or condition is selected from acute ischemic stroke (AIS), Alzheimer's disease, dementia, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), argyrophilic grain dementia, epilepsy, ischemic stroke, mild cognitive impairment (MCI), Huntington's disease, and Parkinson's disease. [Aspect 22] A method according to any one of aspects 19 to 21, wherein the disease or condition is Alzheimer's disease. [Aspect 23] A method for inhibiting O-GlcNAcase in a subject in need of inhibition of O-GlcNAcase, comprising: The method comprises administering to the subject an effective amount of a compound according to any one of aspects 1 to 17, or an effective amount of a pharmaceutical composition according to aspect 18. [Aspect 24] A method for treating a disease or condition characterized by hyperphosphorylation of tau in the brain, the method comprising administering to the subject an effective amount of a compound described in any one of aspects 1 to 17, or an effective amount of a pharmaceutical composition described in aspect 18.

Claims

1. A compound represented by the following structural formula: 【Chemistry 1】 (IV-A) or a pharma- ceutical acceptable salt thereof, wherein: Ar is an optionally substituted 6- to 10-membered aryl or an optionally substituted 5- to 10-membered heteroaryl, and Ar is １ -C ４ Alkyl, C １ -C ４ Haloalkyl, halo, -CN, -OR ｚ and -C(=O)NR ｘ R ｙ and optionally substituted with one or more groups selected from Each R ｘ And each R ｙ are independently -H, C １ -C ４ Alkyl, or C ３ -C ８ cycloalkyl, R ｘ Or R ｙ The C represented by １ -C ４ Alkyl or C ３ -C ８ Cycloalkyl is optionally selected from halo, hydroxyl, C ３ -C ６ Cycloalkyl and phenyl (-CH ３ , halomethyl, halo, methoxy, or halomethoxy; R ｚ H, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C ３ -C ８ Cycloalkyl, or C ３ -C ８ heterocyclyl, R ｚ Represented by C １ -C ４ Alkyl or C ３ -C ８ Cycloalkyl is -CN, halo, hydroxyl, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C ３ -C ６ Cycloalkyl, and phenyl (-CH ３ , halomethyl, halo, methoxy and halomethoxy; and The compound or a pharma- ceutically acceptable salt thereof, wherein R 1 is halo, -C 1 -C 4 alkyl, -C 1 -C 4 haloalkyl, or -C 1 -C 4 alkoxy.

2. The compound of claim 1 , wherein the compound is represented by the following structural formula: 【Chemistry 2】 (IV-B) or a pharma- ceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound is represented by the following structural formula: 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof.

4. The compound of any one of claims 1 to 3, wherein Ar is an optionally substituted 5-10 membered heteroaryl.

5. The compound of any one of claims 1 to 3, wherein Ar is an optionally substituted 5- or 6-membered monocyclic heteroaryl.

6. The compound of any one of claims 1 to 3, wherein Ar is an optionally substituted 6-membered monocyclic heteroaryl.

7. 4. The compound of any one of claims 1 to 3, wherein Ar is an optionally substituted pyridinyl, an optionally substituted pyrimidinyl, or an optionally substituted pyrazinyl, or a pharma- ceutically acceptable salt thereof.

8. Ar is an optionally substituted 【Chemistry 4】 Arbitrarily substituted 【Chemistry 5】 Arbitrarily substituted 【Chemistry 6】 Arbitrarily substituted 【Chemistry 7】 Arbitrarily substituted 【Chemistry 8】 Arbitrarily substituted 【Chemistry 9】 or optionally substituted 【Chemistry 10】 4. The compound according to any one of claims 1 to 3, wherein:

9. Ar is an optionally substituted 【Chemistry 11】 or optionally substituted 【Chemistry 12】 4. The compound according to any one of claims 1 to 3, wherein:

10. Ar is -CH ３ , -F, -CN, and -OCH ３ 10. The compound of any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more groups selected from:

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or diluent.

12. 11. A pharmaceutical composition for treating a subject suffering from a disease or condition selected from a neurodegenerative disease, a tauopathy, diabetes, cancer and stress, said pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 10.

13. The disease or condition is selected from the group consisting of acute ischemic stroke (AIS), Alzheimer's disease, dementia, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), argyrophilic grain dementia, Bluit's disease, corticobasal degeneration (CBP), martial dementia, diffuse neurofibrillary tangle disease with calcifications, Down's syndrome, epilepsy, familial British dementia, familial Danish dementia, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Gerstmann-Sträussler-Scheiker disease, Guadeloupe type Parkinsonism, Hallervorden-Spatz disease (neurodegenerative disease type 1 with cerebral iron deposition), ischemic stroke, mild cognitive impairment (MCI), multiple system atrophy, myotonic dystrophy, Niemann-Pick disease (type C), pallidopontinigral degeneration, Parkinsonism-Dementia Complex of Guam, Pick's disease (PiD), postencephalitic Parkinsonism (PEP), prion diseases (including Creutzfeldt-Jakob disease (GJD) and variant Creutzfeldt-Jakob disease (vCJD)), fatal familial insomnia, kuru, progressive epicortical gliosis (progressive 13. The pharmaceutical composition according to claim 12, wherein the disease is selected from the group consisting of acute myelopathy, chronic myelopathy, progressive supranuclear palsy (PSP), Steele-Richardson-Olszewski syndrome, subacute sclerosing panencephalitis, neurofibrillary senile dementia, Huntington's disease, and Parkinson's disease.

14. 14. The pharmaceutical composition of any one of claims 12 and 13, wherein the disease or condition is selected from acute ischemic stroke (AIS), Alzheimer's disease, dementia, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis with cognitive impairment (ALSci), argyrophilic grain dementia, epilepsy, ischemic stroke, mild cognitive impairment (MCI), Huntington's disease, and Parkinson's disease.

15. The pharmaceutical composition according to any one of claims 12 to 14, wherein the disease or condition is Alzheimer's disease.

16. 1. A pharmaceutical composition for inhibiting O-GlcNAcase in a subject in need thereof, comprising: The pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 10.

17. A pharmaceutical composition for the treatment of a disease or condition characterized by hyperphosphorylation of tau in the brain, said pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 10.

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