Morpholinyl, piperazinyl, oxazepanyl and diazepanyl O-glycoprotein-2-acetamido-2-deoxy-3-D-glucopyranosidase inhibitors

Abstract

As used herein, the compound represented by formula (I) TIFF2022510430000188.tif3681 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 , m, n, and p are as defined herein.

Description

[Technical field]

[0001] Related Applications This application claims priority under 35 U.S.C. §119(e) to the filing date of U.S. Provisional Application No. 62 / 775,558, filed December 5, 2018, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] A wide range of cellular proteins in both the nucleus and cytoplasm are post-translationally modified by the addition of the monosaccharide 2-acetamido-2-deoxy-β-D-glucopyranoside (β-N-acetylglucosamine) attached via an O-glycosidic bond. This monosaccharide is commonly referred to as O-linked N-acetylglucosamine or O-GlcNAc. The enzyme that post-translationally attaches 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 liberate the protein, resulting in a dynamic cycle of O-GlcNAc modification that occurs several times during the life of a protein.

[0003] O-GlcNAc-modified proteins regulate a wide range of important cellular functions, including, for example, transcription, proteasomal degradation, and cell signaling. O-GlcNAc is also found in many structural proteins, including the cytoskeletal protein "tau," which is involved in stabilizing a critical cellular network of microtubules that is 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 and 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 consist of abnormal forms of tau. In AD patients, tau becomes hyperphosphorylated, thereby disrupting its normal function, forming PHFs and ultimately aggregating to form NFTs.

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

[0006] It has recently been shown that increased phosphorylation levels result in decreased O-GlcNAc levels, and conversely, increased O-GlcNAc levels correlate with decreased phosphorylation levels. Reduced glucose availability in the brain has been shown to result in hyperphosphorylation of tau. A progressive impairment of glucose transport and metabolism leads to a decrease in O-GlcNAc and hyperphosphorylation of tau (and other proteins). Thus, inhibition of O-GlcNAcase, which prevents tau hyperphosphorylation by preventing the removal of O-GlcNAc from tau, should compensate for impaired glucose metabolism in the brain with aging in healthy individuals and in 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 numerous functionally related enzymes in higher eukaryotic tissues. Thus, the use of nonselective inhibitors in studying the cellular and organismal physiological role of a particular enzyme is complicated by the complex phenotypes that result from the simultaneous inhibition of such functionally related enzymes. In the case of β-N-acetylglucosaminidase, existing compounds that act to block O-GlcNAcase function are nonspecific and act potently to inhibit lysosomal β-hexosaminidase.

[0008] Considering the aforementioned technical challenges, and given the potential of modulating O-GlcNAcase to treat AD, tauopathy and other neurological diseases, there remains a need to develop 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 modified by O-GlcNAcase.

[0010] A first embodiment of the compound of the present invention has the following structural formula: [ka] or a pharma- ceutically acceptable salt thereof, Ar is an optionally substituted 5-10 membered aryl or an optionally substituted 5-10 membered heteroaryl, provided that when the sum of m and p is 1, Ar is not a 9 membered bicyclic heteroaryl having 1-4 nitrogen atoms; W is O or -NR d and; X is -CR 2 R 2 , -(CR 2 R 2 )2, -(CR 2 R 2)O- or -O(CR 2 R 2 )-and; Y 1 and Y 2 are 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; m is 1 or 2; p is 0 or 1, unless the sum of m and p is 3; n is 0 or an integer from 1 to 9; R if n is nonzero 1 are each independently halo, -C1-C4 alkyl, -C1-C4 haloalkyl, or -C1-C4 alkoxy; R 2 are each independently -H, halo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C 10 Cycloalkyl, or -C3-C 10 halocycloalkyl; Or, two R's 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; and R 4 is -H, -C1-C4 alkyl, -C1-C4 haloalkyl, or -C3-C6 cycloalkyl; Or, R 3 and R 4together with their intervening atoms form an optionally substituted 5- to 7-membered heterocyclyl.

[0011] Provided 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 excipient.

[0012] Also provided is a method for treating a subject having 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 are methods 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- 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.

[0014] Also provided is a method for treating a disease or condition characterized by hyperphosphorylation of tau in the brain, comprising administering to a 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 that are 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 has the following structural formula (I): [ka] or a pharma- ceutically acceptable salt thereof, in which the variables are as defined above in the Summary for the compounds represented by formula (IA) or a pharma- ceutically acceptable salt thereof.

[0017] In a second embodiment, the compound of the present invention has one of the following structural formulas (IIA), (IIB), (IIB') or (IIC): [ka] or a pharma- ceutically acceptable salt thereof; 1 is halo or -C1-C4 alkyl, and the remainder of the variables are as defined in the first embodiment.

[0018] In a third embodiment, the compound of the present invention has one of the following structural formulas (IIIA), (IIIB), and (IIIB'): [ka] or a pharma- ceutically acceptable salt thereof; 2 are each independently -H or C1-C4 alkyl; the remaining variables are as defined in the first or second embodiment.

[0019] In a fourth embodiment, the compound of the present invention has one of the following structural formulas (IIIC-1) and (IIIC-2): [ka] or a pharma- ceutically acceptable salt thereof; d is -H, -C1-C4 alkyl, or -C(=O)C1-C4 alkyl; R 1 is -C1-C4 alkyl; R 2are each independently -H or C1-C4 alkyl; the remaining variables are as defined in the first or second embodiment.

[0020] In a fifth embodiment, the compound of the present invention has the following structural formula (IVA): [ka] or a pharma- ceutically acceptable salt thereof; 1 is -C1-C4 alkyl, R 2 is -H, -CH3, or -CH2CH3; the remainder of the variables are as defined in the first, second, or third embodiment.

[0021] In a sixth embodiment, the compound of the present invention has the following structural formula (IVA'): [ka] or a pharma- ceutically acceptable salt thereof; 1 is -C1-C4 alkyl, R 2 is -H, -CH3, or -CH2CH3; the remainder of the variables are as defined in the first, second, or third embodiment.

[0022] In a seventh embodiment, the compound of the present invention has one of the following structural formulas (IVB) and (IVB'): [ka] or a pharma- ceutically acceptable salt thereof; in which Ar is as defined in the first, second or third embodiment.

[0023] In an eighth embodiment, the compound of the present invention has one of the following structural formulas (IVC-1) and (IVC-2): [ka] or a pharma- ceutically acceptable salt thereof; dis -H, -CH3, -CH2CH3, or -C(=O)CH3; the remainder of the variables are as defined in the first, second, or fourth embodiment.

[0024] In a ninth embodiment, the compounds of the present invention have the following structural formulas (VA), (VA-1), (VA-2), (VA-3), (VC-1) and (VC-2): [ka] or a pharma- ceutically acceptable salt thereof; 1 is -CH3; R 2 is -H or -CH3; and Ar is as defined in the first, second, fourth, or eighth embodiment.

[0025] In a tenth embodiment, the compound of the present invention has one of the following structural formulas (VA'), (VA'-1), (VA'-2), (VA'-3): [ka] or a pharma- ceutically acceptable salt thereof; 1 is -CH3; R 2 is -H or -CH3; Ar is as defined in the first or second embodiment.

[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 5- or 6-membered monocyclic heteroaryl.

[0027] In a twelfth embodiment, in a compound of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh embodiment, or a pharma- ceutically acceptable salt thereof, Ar is an optionally substituted 6-membered monocyclic heteroaryl containing one or more nitrogen atoms.

[0028] In a thirteenth embodiment, in the 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 an optionally substituted pyridinyl, an optionally substituted pyrimidinyl, or an optionally substituted pyrazinyl.

[0029] In a fourteenth 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 monocyclic heteroaryl containing one or more nitrogen atoms.

[0030] In a fifteenth embodiment, in the compound of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment, or a pharma- ceutically acceptable salt thereof, Ar is pyridinyl, an optionally substituted pyrimidinyl, or an optionally substituted pyrazinyl.

[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, or fourteenth embodiment, or a pharma- ceutically acceptable salt thereof, Ar is [ka] It is.

[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, or fifteenth embodiment, or a pharma- ceutically acceptable salt thereof, Ar is [ka] It is.

[0033] In an eighteenth embodiment, in the compound of the invention according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth or seventeenth embodiment or a pharma- ceutically acceptable salt 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 , optionally substituted with one or more (e.g., 2, 3, 4, etc.) groups selected from phenyl and monocyclic heteroaryl; During the ceremony, The C1-C4 alkyl group substituents on 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 , 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 group substituents on Ar are optionally and independently selected from C1-C4 alkyl, C1-C4 haloalkyl, 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 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 Replaced with; Each R x and each R y is independently -H, C1-C4 alkyl, or C3-C8 cycloalkyl; R x or R y 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 zis -H, C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, or C3-C8 heterocyclyl; R z 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); and i is 0, 1, or 2.

[0034] In a nineteenth 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, sixteenth, seventeenth or eighteenth embodiment, or a pharma- ceutically acceptable salt thereof, Ar is C1-C4 alkyl, C1-C4 haloalkyl, halo, -CN, -OR z , and -NR x R y is optionally substituted with one or more groups selected from

[0035] In a twentieth 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, sixteenth, seventeenth, or eighteenth embodiment, or a pharma- ceutically acceptable salt thereof, Ar is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, -F, -Cl, -CN, and -OR. z R z is a C1-C4 alkyl optionally substituted with one or more halo groups.

[0036] In a twenty-first 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, sixteenth, seventeenth, eighteenth, or nineteenth embodiment, or a pharma- ceutically acceptable salt thereof, Ar is optionally substituted with one or more (e.g., two, three, four, etc.) groups selected from -CH3, -CF3, -CHF2, -F, -OCH3, -OCHF2, -OCH2CH3, -OCH(CH3)2, and -OCH2CF3.

[0037] In another embodiment, the compound of the present invention is selected from the compounds set forth in the exemplified embodiments herein, including pharma- ceutically acceptable salts and neutral forms thereof.

[0038] Another embodiment of the present invention is a compound selected from the group consisting of: (R)—N-(5-((2-((5-fluoropyrimidin-2-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide; (R)—N-(5-((2-((2-methoxypyridin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide; (R)—N-(5-((2-((2-methoxy-3-methylpyridin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide; (R)-N-(5-((2-(4-fluoro-3-methoxybenzyl)morpholino)methyl)thiazol-2-yl)acetamide; (R)-N-(5-((2-((2-methoxypyrimidin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide; (R)-N-(5-((2-((6-methoxypyrimidin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide; (R)—N-(5-((2-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide; (R)—N-(5-((2-((2-ethoxypyridin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide; (R)—N-(5-((2-((2-isopropoxypyridin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide; (R)—N-(5-((2-((2-(difluoromethyl)pyridin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide; (R)-N-(5-((2-((2-methylpyrimidin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide; (R)—N-(5-((2-((3-fluoro-2-methoxypyridin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide; (R)—N-(5-((2-((5-methylpyridin-2-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide; (R)—N-(5-((2-((2-(difluoromethoxy)pyridin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide; (R)—N-(5-((2-((5-fluoro-4-methylpyridin-2-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide; (R)—N-(5-((2-((6-methylpyridin-3-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide; (R)—N-(5-((2-((2-methylpyridin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide; (R)—N-(5-((2-((2,6-dimethylpyridin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide; N-(5-((R)-1-((R)-2-((5-fluoropyrimidin-2-yl)methyl)morpholino)ethyl)thiazol-2-yl)acetamide; N-(5-((S)-1-((R)-2-((5-fluoropyrimidin-2-yl)methyl)morpholino)ethyl)thiazol-2-yl)acetamide; N-(5-(((R)-2-((R)-1-(5-fluoropyrimidin-2-yl)ethyl)morpholino)methyl)thiazol-2-yl)acetamide; N-(5-(((R)-2-((S)-1-(5-fluoropyrimidin-2-yl)ethyl)morpholino)methyl)thiazol-2-yl)acetamide; N-(5-(((S)-2-((S)-1-(5-fluoropyrimidin-2-yl)ethyl)morpholino)methyl)thiazol-2-yl)acetamide; N-(5-(((S)-2-((R)-1-(5-fluoropyrimidin-2-yl)ethyl)morpholino)methyl)thiazol-2-yl)acetamide; N-(5-(((2R,5S)-2-((5-fluoropyrimidin-2-yl)methyl)-5-methylmorpholino)methyl)thiazol-2-yl)acetamide; N-(5-(((2S,5S)-2-((5-fluoropyrimidin-2-yl)methyl)-5-methylmorpholino)methyl)thiazol-2-yl)acetamide; N-(5-(((2R,5S)-2-((2,6-dimethylpyridin-4-yl)methyl)-5-methylmorpholino)methyl)thiazol-2-yl)acetamide; N-(5-(((2R,5S)-5-methyl-2-((2-methylpyridin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide; N-(5-(((2R,5S)-5-methyl-2-((6-methylpyridin-3-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide; N-(5-(((cis)-2-((5-fluoropyrimidin-2-yl)methyl)-6-methylmorpholino)methyl)thiazol-2-yl)acetamide; N-(5-(((2R,6S)-2-((5-fluoropyrimidin-2-yl)methyl)-6-methylmorpholino)methyl)thiazol-2-yl)acetamide; N-(5-(((2S,6R)-2-((5-fluoropyrimidin-2-yl)methyl)-6-methylmorpholino)methyl)thiazol-2-yl)acetamide; N-(5-((2-((2,6-dimethylpyridin-4-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide; (S)—N-(5-((2-((2,6-dimethylpyridin-4-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide; (R)—N-(5-((2-((2,6-dimethylpyridin-4-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide; N-(5-((2-((5-fluoropyrimidin-2-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide; (S)—N-(5-((2-((5-fluoropyrimidin-2-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide; (R)—N-(5-((2-((5-fluoropyrimidin-2-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide; N-(5-((2-((2-methoxypyridin-4-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide; (S)—N-(5-((2-((2-methoxypyridin-4-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide; (R)—N-(5-((2-((2-methoxypyridin-4-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide; N-(5-((6-((2,6-dimethylpyridin-4-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide; (S)—N-(5-((6-((2,6-dimethylpyridin-4-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide; (R)—N-(5-((6-((2,6-dimethylpyridin-4-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide; N-(5-((6-((5-fluoropyrimidin-2-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide; (S)—N-(5-((6-((5-fluoropyrimidin-2-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide; (R)—N-(5-((6-((5-fluoropyrimidin-2-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide; N-(5-((6-((2-methoxypyridin-4-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide; (S)—N-(5-((6-((2-methoxypyridin-4-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide; (R)—N-(5-((6-((2-methoxypyridin-4-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide; (R)—N-(4-fluoro-5-((2-((6-methylpyridin-3-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide; N-(4-fluoro-5-(((2R,5S)-5-methyl-2-((6-methylpyridin-3yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide; N-(5-(((2S,5R)-2-methyl-5-((2-methylpyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide; N-(5-(((2S,5R)-2,4-dimethyl-5-((2-methylpyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide; N-(5-(((2S,5R)-4-ethyl-2-methyl-5-((2-methylpyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide; N-(5-(((2S,5R)-5-((5-fluoropyrimidin-2-yl)methyl)-2-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide; N-(5-(((2S,5R)-5-((5-fluoropyrimidin-2-yl)methyl)-2,4-dimethylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide; N-(5-(((2S,5R)-5-((2,6-dimethylpyridin-4-yl)methyl)-2-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide; N-(5-(((2S,5R)-2-methyl-5-((6-methylpyridin-3-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide; N-(5-(((2S,5R)-5-((2,6-dimethylpyridin-4-yl)methyl)-2,4-dimethylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide; N-(5-(((2S,5R)-2,4-dimethyl-5-((6-methylpyridin-3-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide; N-(5-(((2S,5R)-4-ethyl-2-methyl-5-((6-methylpyridin-3-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide; N-(5-(((2S,5R)-5-((2,6-dimethylpyrimidin-4-yl)methyl)-2-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide; N-(5-(((2S,5R)-5-((2-methoxypyridin-4-yl)methyl)-2-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide; N-(5-(((2S,5R)-5-((2,6-dimethylpyrimidin-4-yl)methyl)-2,4-dimethylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide; N-(5-(((2S,5R)-5-((2-methoxypyridin-4-yl)methyl)-2,4-dimethylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide; N-(5-((3-((5-fluoropyrimidin-2-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide; N-(5-((3-((2-methoxypyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide; N-(5-(((2S,5S)-5-(((2,6-dimethylpyridin-4-yl)oxy)methyl)-2-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide; N-(5-(((2S,5S)-5-(((2,6-dimethylpyridin-4-yl)oxy)methyl)-2,4-dimethylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide; N-(5-(((2S,5S)-2-(((2,6-dimethylpyridin-4-yl)oxy)methyl)-5 methylmorpholino)methyl)thiazol-2-yl)acetamide; N-(5-(((2S,5S)-2-(((2,6-dimethylpyridin-4-yl)oxy)methyl)-5 methylmorpholino)methyl)thiazol-2-yl)acetamide; (S)—N-(5-((3-((2,6-dimethylpyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide hydrochloride; (S)—N-(5-((3-((2,6-dimethylpyridin-4-yl)methyl)-4-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide; N-(5-((3-(4-fluoro-3-methoxybenzyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide; (R)—N-(5-((3-((2-methylpyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide; (S)—N-(5-((3-((2-methylpyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide; and (S)—N-(5-((4-methyl-3-((2-methylpyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide; or a pharma- ceutically acceptable salt thereof.

[0039] 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.

[0040] As used herein, the term "alkoxy" refers to the group -OR, where R is alkyl or cycloalkyl, as that term is 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.

[0041] As used herein, the terms "aryl", "aryl group", "aryl ring", "aromatic group" and "aromatic ring" are used interchangeably and refer to an aromatic 5- to 12-membered monocyclic or bicyclic carbocyclic ring system. Examples of monocyclic aryl systems include, but are not limited to, cyclopenta-1,3-dien-1-yl, phenyl, naphthyl, and the like.

[0042] The number of carbon atoms in a group is indicated herein by the prefix "C x-xx ", where x and xx are integers. For example, "C 1-4 "Alkyl" is an alkyl group having 1 to 4 carbon atoms.

[0043] As used herein, the term "halogen" or "halo" can be fluoro, chloro, bromo or iodo.

[0044] As used herein, the term "haloalkyl" refers to an alkyl, as defined herein, substituted by one or more halo groups, as defined herein.

[0045] 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 (e.g., fused) ring system having 3 to 12 ring members, particularly 3 to 6 ring members or 5 to 7 ring members, at least one of which is a heteroatom and up to four (e.g., 1, 2, 3 or 4) of which may be heteroatoms, the heteroatoms being independently selected from O, S and N, where C can be oxidized (e.g., C(=O)) and N can be oxidized (e.g., N(O)) or quaternized (e.g., N +), where S can be optionally oxidized to sulfoxide and sulfone. Examples of non-aromatic heterocyclyls 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 non-aromatic heterocyclic ring systems include benzo[1,3]dioxolyl, tetrahydroindolyl, and 2-azaspiro[3.3]heptanyl.

[0046] As used herein, the terms "heteroaryl", "heteroaryl group", "heteroaromatic" and "heteroaromatic ring" are used interchangeably and refer to an aromatic 5-12 membered monocyclic or bicyclic 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 heteroaromatic groups fused to a phenyl group or a non-aromatic heterocycle, e.g., tetrahydrofuran, pyran, pyrrolidine, piperidine, and the like. As used herein, the heteroaryl group Ar can be attached to the remainder of the compound of the invention at any ring that has an open valence. Examples of heteroaryl include pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl, tetrazinyl, 1-oxo-pyridyl, thienyl, azaindolyl, benzimidazolyl, benzofuryl, benzoisoxazolyl, benzoisothiazolyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriaryl, and benzotriaryl. Examples of the pyrimidinyl group include azolyl, benzoxadiazolyl, benzoxazolyl, cyclopentaimidazolyl, cyclopentatriazolyl, imidazo[1,2-a]pyridyl, indazolyl, indolizinyl, indolyl, isoquinolinyl, oxalopyridinyl, purinyl, pyrazolo[3,4]pyrimidinyl, pyridopyrazinyl, pyridopyrimidinyl, pyrrolo[2,3]pyrimidinyl, pyrrolopyrazolyl, pyrroloimidazolyl, pyrrolotriazolyl, quinazolinyl, quinolinyl, thiazolopyridinyl, and naphthyridyl.

[0047] 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.

[0048] As used herein, the term "halocycloalkyl" refers to a cycloalkyl, as defined herein, that is substituted by one or more halo groups, as defined herein.

[0049] A substituted alkyl, phenyl, heteroaryl, non-aromatic heterocyclyl, or heterocyclyl group is an alkyl, phenyl, heteroaryl, non-aromatic heterocyclyl, or heterocyclyl group that bears one or more substituents. Suitable substituents are those that do not significantly reduce the O-GlcNAcase inhibitory activity of a compound of formula (I), (IIA), (IIB), (IIB'), (IIC), (IIIA), (IIIB), (IIIB'), (IIIC-1), (IIIC-2), (IVA), (IVA'), (IVB), (IVB'), (IVC-1), (IVC-2), (VA), (VA'), (VA-1), (VA'-1), (VA-2), (VA'-2), (VA-3), (VA'-3), (VC-1), or (VC-2) (hereinafter collectively referred to as a compound of any one of formulas (I) through (VC-2)), or a pharma- ceutically acceptable salt thereof. Examples of suitable substituents for alkyl, phenyl, heteroaryl, non-aromatic heterocyclyl or heterocyclyl groups include C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 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)Ry , -NRx(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 groups include, but are not limited to, -CN, -NO2, -OR, -C1-C4 alkyl groups, -C2-C4 alkyl groups include, but are not limited to ... 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 Ry , -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 substituents on the C3-C6 cycloalkyl, phenyl and monocyclic heteroaryl groups are optionally and independently selected from 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; 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; 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.

[0050] 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 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.

[0051] Pharmaceutically acceptable salts may be obtained, for example, by reacting a sufficiently basic compound, such as an amine, with a suitable acid to provide a physiologically acceptable anion, using standard procedures well known in the art. Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids may also be made.

[0052] 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.

[0053] Some of the disclosed compounds, or pharma- ceutically acceptable salts thereof, contain one or more asymmetric centers in the molecule. It is to be understood that any structure that does not specify stereochemistry according to the present disclosure encompasses all the various stereoisomers (e.g., diastereomers and enantiomers) in pure or substantially pure form, and mixtures thereof (e.g., racemic mixtures, or enantiomerically enriched mixtures). Methods for preparing such optically active forms (e.g., by resolution of racemates by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases) are well known in the art. The disclosed compounds may exist in tautomeric forms and mixtures, and separate individual tautomers are contemplated. Some compounds may also exhibit polymorphism.

[0054] When a particular stereoisomer (e.g., enantiomer, diastereomer, etc.) of a compound used in the disclosed methods is represented 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 % by weight of the desired stereoisomer based on the combined weight of all stereoisomers.

[0055] When the stereochemistry of a disclosed compound is named or depicted by a structure, and the named or depicted structure encompasses multiple stereoisomers (e.g., as a diastereomeric pair), it is understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. 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.

[0056] As used herein, the term "Peak 1" refers to the first eluting peak during separation of enantiomers and / or diastereomers, followed by the subsequently eluted "Peak 2," and optionally "Peak 3," and "Peak 4."

[0057] In one embodiment, any position occupied by hydrogen is meant to include enrichment with deuterium in excess of the natural abundance of deuterium. For example, one or more hydrogen atoms are replaced with deuterium at an abundance of at least 3340 times the natural abundance of deuterium (0.015% (i.e., at least 50.1% deuterium incorporation)), at least 3500 times (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 times (60% deuterium incorporation), at least 4500 times (67.5% deuterium incorporation), at least 5000 times (75% deuterium), at least 5500 times (82.5% deuterium incorporation), at least 6000 times (90% deuterium incorporation), at least 6333.3 times (95% deuterium incorporation), at least 6466.7 times (97% deuterium incorporation), at least 6600 times (99% deuterium incorporation), or at least 6633.3 times (99.5% deuterium incorporation). In one embodiment, hydrogen is present at all positions at its natural abundance. The compounds described herein, or pharma- ceutically acceptable salts thereof, may exist in tautomeric forms and mixtures, and the individual tautomers are contemplated separately.

[0058] One aspect of the invention includes a method of inhibiting glycosidases and / or glycosidase signaling pathways in a cell, the method comprising contacting the cell with an effective amount of a compound of any one of formulae (I)-(VC-2), or a pharma- ceutically acceptable salt thereof. The glycosidase is preferably a glycoside hydrolase, more preferably a family 84 glycoside hydrolase, 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 the compound to a subject.

[0059] One aspect of the present invention includes a method of inhibiting glycosidases and / or glycosidase signaling pathways in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I)-(VC-2), or a pharma- ceutically acceptable salt thereof, thereby activating glycosidases in the subject. The glycosidase is preferably a glycoside hydrolase, more preferably a Family 84 glycoside hydrolase, even more preferably an O-glycoprotein-2-acetamido-2-deoxy-3-D-glucopyranosidase (O-GlcNAcase or OGA), and most preferably a mammalian O-GlcNAcase.

[0060] One aspect of the present invention includes a method for 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 Formulae (I) to (VC-2), or a pharma- ceutically acceptable salt thereof, thereby promoting survival or extending the lifespan of the eukaryotic cell.

[0061] One aspect of the present invention includes a method for treating a disease or condition caused, mediated, and / or propagated by O-GlcNAcase activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of Formulae (I)-(VC-2), or a pharma- ceutically acceptable salt thereof. Preferably, the disease or condition is a neurological disorder, diabetes, cancer, or stress. More preferably, the disease or condition is a neurological disorder. 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), 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, Guadeloupe-type parkinsonism, Hallervorden-Spatz disease (neurodegeneration with brain iron accumulation type 1), ischemic stroke, One or more tauopathies selected from mild cognitive impairment (MCI), multiple system atrophy, myotonic dystrophy, Niemann-Pick disease (type C), pallidopontine-nigral degeneration, Guam type Parkinsonism-dementia syndrome, Pick's disease (PiD), postencephalitic parkinsonism (PEP), prion diseases (including Creutzfeldt-Jakob disease (GJD)), variant Creutzfeldt-Jakob disease (vCJD), fatal familial insomnia, kuru, progressive transcortical gliosis, progressive supranuclear palsy (PSP), Steele-Richardson-Olszewski syndrome, subacute sclerosing panencephalitis, neurofibrillary tangle 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.

[0062] One aspect of the invention includes a method for treating a disease or condition characterized by tau hyperphosphorylation in a subject (e.g., tau hyperphosphorylation in the brain), the method comprising administering to the subject a therapeutically effective amount of a compound of any one of Formulas (I)-(VC-2), or a pharma- ceutically acceptable salt thereof. In one embodiment, the disease or condition 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), 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, Guadeloupe-type parkinsonism, Hallervorden-Spatz disease (neurodegeneration with brain iron accumulation type 1). , ischemic stroke, mild cognitive impairment (MCI), multiple system atrophy, myotonic dystrophy, Niemann-Pick disease (type C), pallidopontine-nigral degeneration, Guam type Parkinsonism-dementia syndrome, Pick's disease (PiD), postencephalitic parkinsonism (PEP), prion diseases (including Creutzfeldt-Jakob disease (GJD)), variant Creutzfeldt-Jakob disease (vCJD), fatal familial insomnia, kuru, progressive transcortical gliosis, progressive supranuclear palsy (PSP), Steele-Richardson-Olszewski syndrome, subacute sclerosing panencephalitis, neurofibrillary tangle dementia, Huntington's disease, and Parkinson's disease. 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, stroke, mild cognitive impairment (MCI), Huntington's disease, and Parkinson's disease. In yet another embodiment, the disease or condition is Alzheimer's disease.

[0063] As used herein, the terms "subject" and "patient" are 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.

[0064] As used herein, the term "treating" or "treatment" refers to obtaining a desired pharmacological and / or physiological effect. The effect is therapeutic and includes partially or substantially achieving one or more of the following results: reducing the severity of a disease, disorder or syndrome; improving or ameliorating clinical symptoms or indicators associated with a disorder; delaying, inhibiting, or reducing the likelihood of progression of a disease, disorder, or syndrome.

[0065] The term "effective amount" refers to an amount of any one of the compounds of formula (I)-(VC-2) or a pharma- ceutically acceptable salt thereof, e.g., 0.1 mg to 1000 mg / kg body weight, that, when administered to a subject, produces a clinical effect, i.e., reverses, alleviates, inhibits, reduces or delays the progression of a disease or condition treatable by any one of the compounds of formula (I)-(VC-2) or a pharma- ceutically acceptable salt thereof, or reduces the likelihood of developing a disease or condition treatable by any one of the compounds of formula (I)-(VC-2), or one or more symptoms, e.g., as determined by clinical symptoms, compared to a control. The expression "effective amount" also encompasses an amount effective for increasing normal physiological function, e.g., 0.01 mg / kg per day to 500 mg / kg per day.

[0066] 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.

[0067] Also included herein is the use of any one of the compounds of formulae (I)-(VC-2), 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 formulae (I)-(VC-2), or a pharma- ceutically acceptable salt thereof, optionally 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 pharmaceutical composition comprising any one of the compounds of formulae (I)-(VC-2), or a pharma- ceutically acceptable salt thereof, optionally with a pharma- ceutically acceptable carrier, 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 formulae (I)-(VC-2), or a pharma- ceutically acceptable salt thereof, optionally with a pharma- ceutically acceptable carrier, for use in treating one or more of the diseases or conditions described herein.

[0068] 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 to be formulated and is safe for human use.The pharmaceutical acceptable carrier that can be used in the composition of the present disclosure includes, but is 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, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, 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, polyacrylate, wax, polyethylene-polyoxypropylene block polymer, polyethylene glycol and wool fat.

[0069] 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 is described in Handbook of Pharmaceutical Excipients (5th Ed., a Pharmaceutical Press (2005)). Those skilled in the art will know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003, 20th edition) and The United States Pharmacopeia: The National Formulary published in 1999 (USP24 NF19).

[0070] A compound of any one of formulas (I)-(VC-2), or a pharma- ceutically acceptable salt thereof, or a composition of the present disclosure may be administered, for example, orally, parenterally, sublingually, topically, rectally, nasally, bucally, vaginally, transdermally, via a patch, pump administration, or via an implanted reservoir, and the pharmaceutical composition is formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, pulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0071] 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.

[0072] The useful dose 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 extrapolating effective doses in mice and other animals to humans are known in the art; see, for example, U.S. Patent No. 4,938,949, which is incorporated by reference in its entirety. EXAMPLES

[0073] Common methods Silica gel chromatography was performed using either Teledyne ISCO Combiflash RF or a Grace Reveleris X2 with ELSD purification system, using 20-40uM (particle size), 250-400 mesh, or 400-632 mesh silica gel.

[0074] Analytical HPLC Acidic HPLC: performed using a Shimadzu 20A instrument equipped with an Ultimate C18 3.0×50 mm, 3 um column eluted with 2.75 mL / 4 L TFA in water (solvent A) and 2.5 mL / 4 L TFA in acetonitrile (solvent B) according to the following method: Method A: Use the following elution gradient: 0% to 60% (solvent B) for 6 min, hold at 60% for 2 min, with a flow rate of 1.2 ml / min. Wavelengths: UV 220 nm, 215 nm and 254 nm. Method B: Use the following elution gradient: 10% to 80% (solvent B) for 6 min, hold at 60% for 2 min, at a flow rate of 1.2 ml / min. Wavelengths: UV 220 nm, 215 nm and 254 nm. Method C: Use the following elution gradient: 30% to 90% (solvent B) for 6 min, hold at 60% for 2 min, at a flow rate of 1.2 ml / min. Wavelengths: UV 220 nm, 215 nm and 254 nm. Basic HPLC: performed using a Shimadzu 20A instrument equipped with an Xbridge Shield RP-18, 5um, 2.1x50mm column eluted with 2mL / 4L aqueous NH3H2O ​​(solvent A) and acetonitrile (solvent B) according to the following method: Method D: Use the following elution gradient: 0% to 60% (solvent B) for 4.0 min, hold at 60% for 2 min, at a flow rate of 1.2 ml / min. Method E: Use the following elution gradient: 10% to 80% (solvent B) for 4.0 min, hold at 60% for 2 min, at a flow rate of 1.2 ml / min. Method F: Use the following elution gradient: 30% to 90% (solvent B) for 4.0 min, hold at 60% for 2 min, at a flow rate of 1.2 ml / min.

[0075] 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 (2.1 mm x 30 mm, 3.0 mm or 2.1 mm x 50 mm, C18, 1.7 um) eluted with 1.5 mL / 4 L TFA in water (solvent A) and 0.75 mL / 4 L TFA in acetonitrile (solvent B) using the following method: 1.5 minute method: General method: Use the following elution gradient: 5% to 95% (solvent B) for 0.7 min, hold at 95% for 0.4 min, at a flow rate of 1.5 ml / min. Wavelength: UV 220 nm and 254 nm.

[0076] 2 minute method: Method A: Use the following elution gradient: 0% to 60% (solvent B) for 0.9 min, hold at 60% for 0.6 min, with a flow rate of 1.2 ml / min. Wavelength: UV 220 nm and 254 nm. Method B: Use the following elution gradient: 10% to 80% (solvent B) for 0.9 min, hold at 60% for 0.6 min, at a flow rate of 1.2 ml / min. Wavelength: UV 220 nm and 254 nm. Method C: Use the following elution gradient: 30% to 90% (solvent B) for 0.9 min, hold at 60% for 0.6 min, with a flow rate of 1.2 ml / min. Wavelength: UV 220 nm and 254 nm.

[0077] 3.5 Minute Method: Initial conditions, solvent A-95%:solvent B-5%; 0.0–0.1 min, hold initial value; 0.1–3.25 min, linear ramp to solvent A-5%:solvent B-95%; 3.25–3.5 min, hold solvent A-5%:solvent B-95%; diode array / MS detection.

[0078] 4 minute method: Method A: Use the following elution gradient: 0% to 60% (solvent B) for 3 min, hold at 60% for 0.5 min, at a flow rate of 0.8 ml / min. Wavelength: UV 220 nm and 254 nm. Method B: Use the following elution gradient: 10% to 80% (solvent B) for 3 min, hold at 60% for 0.5 min, at a flow rate of 0.8 ml / min. Wavelength: UV 220 nm and 254 nm. Method C: Use the following elution gradient: 30% to 90% (solvent B) for 3 min, hold at 60% for 0.5 min, at a flow rate of 0.8 ml / min. Wavelength: UV 220 nm and 254 nm.

[0079] 7 Minute Method: Method A: Use the following elution gradient: 0% to 60% (solvent B) for 6 min, hold at 60% for 0.5 min, at a flow rate of 0.8 ml / min. Wavelength: UV 220 nm and 254 nm. Method B: Use the following elution gradient: 10% to 80% (solvent B) for 6 min, hold at 60% for 0.5 min, at a flow rate of 0.8 ml / min. Wavelength: UV 220 nm and 254 nm. Method C: Use the following elution gradient: 30% to 900% (solvent B) for 6 min, hold at 60% for 0.5 min, at a flow rate of 0.8 ml / min. Wavelength: UV 220 nm and 254 nm.

[0080] Basic LCMS: 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 i.d.) or a 2.1mm x 50mm, C18, 1.7um column eluting with 2mL / 4L aqueous NH3·H2O (solvent A) and acetonitrile (solvent B) using the following method: 3 minute method: Method A: Use the following elution gradient: 0% to 60% (solvent B) for 2 min, hold at 60% for 0.48 min, at a flow rate of 1 ml / min. Wavelength: UV 220 nm and 254 nm. Method B: Use the following elution gradient: 10% to 80% (solvent B) for 2 min, hold at 60% for 0.48 min, at a flow rate of 1 ml / min. Wavelength: UV 220 nm and 254 nm. Method C: Use the following elution gradient: 30% to 90% (solvent B) for 2 min, hold at 60% for 0.48 min, at a flow rate of 1 ml / min. Wavelength: UV 220 nm and 254 nm.

[0081] 3.5 Minute Method: Initial conditions, solvent A-95%:solvent B-5%; 0.0–0.1 min, hold initial value; 0.1–3.25 min, linear ramp to solvent A-5%:solvent B-95%; 3.25–3.5 min, hold solvent A-5%:solvent B-95%; diode array / MS detection.

[0082] 7 Minute Method: Method A: Use the following elution gradient: 0% to 60% (solvent B) for 6 min, hold at 60% for 0.5 min, at a flow rate of 0.8 ml / min. Wavelength: UV 220 nm and 254 nm. Method B: Use the following elution gradient: 10% to 80% (solvent B) for 6 min, hold at 60% for 0.5 min, at a flow rate of 0.8 ml / min. Wavelength: UV 220 nm and 254 nm. Method C: Use the following elution gradient: 30% to 90% (solvent B) for 6 min, hold at 60% for 0.5 min, at a flow rate of 0.8 ml / min. Wavelengths: UV 220 nm and 254 nm.

[0083] SFC analysis separation Instrument: Waters UPC2 analytical SFC (SFC-H). Column: ChiralCel OJ, 150 x 4.6 mm ID, 3 μm. Mobile phase: A for CO2, B for ethanol (0.05% DEA). Gradient: B 40%. Flow rate: 2.5 mL / min. Back pressure: 100 bar. Column temperature: 35°C. Wavelength: 220 nm.

[0084] Preparative HPLC purification General Methods: Preparative HPLC was performed on a Gilson UV / VIS-156 equipped with 220 / 254 nm UV detection and a Gilson 281 autocollection. Acidic conditions: Two acid grade series used: hydrochloric acid and formic acid. Method A: Hydrochloride: YMC-Actus Triart C18 150 x 30 mm x 5 um, gradient was 0-100% acetonitrile with water and corresponding acid (0.05% HCl). Method B: Formic Acid: Phenomenex Synergi C18 150 x 30 mm x 4 um, gradients used 0-100% acetonitrile with water and 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 was used 0-100% (water (10 mM NH4HCO3)-ACN), gradient shape was optimized for each separation. Basic conditions: Waters Xbridge Prep OBD C18 150x30 10um, gradient 0-100% water (0.04% NH3H2O ​​+ 10mM NH4HCO3)-acetonitrile, gradient shape optimized for each individual separation.

[0085] 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 Concentration gradient characteristics: 12 min run: initial conditions: A-95%:B-5%; 0.0-0.5 min, hold at initial value; 0.5-7.5 min, linear ramp from A-5% to variable B-% (normal range is B-40% to B-75%); 7.5-8.0 min, linear ramp from B-% to B-95%; 8.0-10.0 min, hold at A-5%:B-95%; End of DAD / MS detection; 10.0-10.5 min, linear ramp down to initial conditions and hold at initial conditions for 1.5 min. Mobile phase: Acid: A: 0.1% trifluoroacetic acid in water (v / v); Mobile phase B: 0.1% trifluoroacetic acid in acetonitrile (v / v). Base: A: 0.1% ammonia in water (v / v); Mobile phase B: 0.1% ammonia in acetonitrile (v / v).

[0086] Preparative SFC purification Instrument: MGIII preparative SFC (SFC-1). Column: ChiralCel OJ, 250 x 30 mm ID, 5 μm. Mobile phase: A for CO2, B for 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.

[0087] 1 H-NMR NMR spectra were recorded on a Bruker Avance III HD 500MHz, Bruker Avance III 500MHz, Bruker Avance III 400MHz, Varian-400 VNMRS, or 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 (single), d (double), t (triplet), dd (double doublet), dt (double triplet), dq (double quartet), m (multiplet), br (broad).

[0088] The following general reaction schemes 1, 2, 3, and 4 provide useful details for preparing the present compounds. The necessary intermediates are in some cases commercially available or can be prepared according to literature procedures. The exemplary reaction schemes are not limited by the compounds listed or by the particular substituents used for illustrative purposes, and the substituent labels (i.e., R groups) shown in the reaction schemes do not necessarily correlate with the substituents used in the claims, and in many cases, for clarity, a single substituent is shown attached to compounds where multiple substituents are permitted under the definition of formula (I) above.

[0089] Scheme 1 [ka]

[0090] Intermediate 1 [ka] tert-Butyl (R)-2-((5-fluoropyrimidin-2-yl)methyl)morpholine-4-carboxylate: A solution of NiCl2(glyme) (0.039 g, 0.178 mmol), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (0.048 g, 0.178 mmol), and Ir{dF(CF3)ppy}2(dtbpy)PF6 (0.020 g, 0.018 mmol) in DME (8.9 mL) was sparged with N2 for 15 min. The nickel solution was added to a mixture of tert-butyl (S)-2-(bromomethyl)morpholine-4-carboxylate (0.499 g, 1.78 mmol), 2-bromo-5-fluoro-pyrimidine (0.315 g, 1.78 mmol), tris(trimethylsilyl)silane (0.575 g, 2.31 mmol, 0.71 mL), and lithium hydroxide (0.170 g, 7.12 mmol). The mixture was flushed with N2 (15 min) and then the reaction was irradiated overnight with a blue LED (48 watts, 450 hv). Celite was added to the reaction and the mixture was diluted with EtOAc and filtered. The organic layer was washed with NH4Cl(aq), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc:heptane) to give the title compound (0.10 g, 19% yield). LCMS(ESI):[M+H(-t-Bu)]242.

[0091] Intermediate 2 [ka]

[0092] (R)-2-((5-fluoropyrimidin-2-yl)methyl)morpholine hydrochloride: A solution of HCl in dioxane (4.0 M, 0.840 mL, 3.36 mmol) was added to a solution of tert-butyl (R)-2-((5-fluoropyrimidin-2-yl)methyl)morpholine-4-carboxylate (0.100 g, 0.336 mmol) in CHCl (1.68 mL). After 2 h, the mixture was concentrated in vacuo to give the title compound (0.078 g, 99% yield). LCMS (ESI): [M+H] 198.

[0093] Example 1-1 [ka] (R)-N-(5-((2-((5-fluoropyrimidin-2-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide: To a suspension of (R)-2-((5-fluoropyrimidin-2-yl)methyl)morpholine hydrochloride (0.039 g, 0.198 mmol) and N-[5-(chloromethyl)thiazol-2-yl]acetamide (0.040 g, 0.208 mmol) in acetonitrile (1.0 mL) was added triethylamine (0.082 mL, 0.593 mmol) and the mixture was warmed to 55 °C overnight. The reaction was cooled to room temperature and the mixture was diluted with EtOAc and washed with saturated NH4Cl(aq). The organics were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (10-70% EtOAc:ethanol (3:1 v / v) / heptane) to give the title compound (0.030 g, 43% yield). LCMS: [M+H] 352. 1HNMR: (500 MHz, CDCl3) 12.09 (br s, 1H), 8.54 (s, 2H), 7.23 (s, 1H), 4.10-4.17 (m, 1H), 3.80-3.88 (m, 1H), 3.67-3.71 (m, 2H), 3.58-3.67 (m, 1H), 3.16 (dd, J=7.94, 14.04 Hz, 1H), 3.04 (dd, J=4.27, 14.04 Hz, 1H), 2.90 (br d, J=10.99 Hz, 1H), 2.71 (br d, J=10.99 Hz, 1H), 2.33 (s, 3H), 2.24 (dt, J=2.75, 11.14 Hz, 1H), 2.10 (br t, J=10.38 Hz, 1H).

[0094] Example 1-2 [ka] (S)-N-(5-((2-((5-fluoropyrimidin-2-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared from tert-butyl (R)-2-(bromomethyl)morpholine-4-carboxylate, 2-bromo-5-fluoro-pyrimidine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide in a manner similar to that in Scheme 1. LCMS (ESI): [M+H] 352. 1HNMR: (500 MHz, CDCl3) δ 11.87 (br s, 1H), 8.54 (s, 2H), 7.22 (s, 1H), 4.08-4.20 (m, 1H), 3.81-3.88 (m, 1H), 3.68 (s, 2H), 3.62 (dt, 2.65-2.74 (m, 1H), 2.32 (s, 3H), 2.23 (dt, J=3.36, 11.14 Hz, 1H), 2.08 (t, J=10.38 Hz, 1H).

[0095] Examples 1-3 [ka] (R)-N-(5-((2-((2-Methoxypyridin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared from tert-butyl (S)-2-(bromomethyl)morpholine-4-carboxylate, 4-bromo-2-methoxypyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide in a manner similar to that in Scheme 1. LCMS (ESI): [M+H] 363. 1 HNMR: (500 MHz, CDCl3) δ 11.87 (s, 1H), 8.06 (d, J=5.27 Hz, 1H), 7.20 (s, 1H), 6.75 (dd, J=1.51, 5.27 Hz, 1H), 6.60 (s, 1H), 3.92 (s, 3H), 3.82-3.88 (m, 1H), 3.73-3.81 (m, 1H), 3.54-3.71 (m, 3H), 2.73-2.82 (m, 2H), 2.70 (br d, J=11.04 Hz, 1H), 2.57-2.66 (m, 1H), 2.32 (s, 3H), 2.20 (dt, J=3.26, 11.17 Hz, 1H), 1.91-2.01 (m, 1H).

[0096] Examples 1-4 [ka] (S)-N-(5-((2-((2-Methoxypyridin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner as in Scheme 1 from tert-butyl (R)-2-(bromomethyl)morpholine-4-carboxylate, 4-bromo-2-methoxypyridine, and N-[5-(chloromethyl)]thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 363. 1 HNMR: (500 MHz, CDCl3) δ 11.59 (br s, 1H), 8.06 (d, J=5.49 Hz, 1H), 7.20 (s, 1H), 6.75 (dd, J=1.22, 4.88 Hz, 1H), 6.60 (s, 1H), 3.92 (s, 3H), 3.82-3.87 (m, 1H), 3.75-3.81 (m, 1H), 3.59-3.69 (m, 3H), 2.73-2.81 (m, 2H), 2.70 (br d, J=10.99 Hz, 1H), 2.62 (dd, J=5.49, 14.04 Hz, 1H), 2.31 (s, 3H), 2.20 (dt, J=3.36, 11.14 Hz, 1H), 1.97 (t, J=10.38 Hz, 1H).

[0097] Examples 1-5 [ka] (R)-N-(5-((2-((2-Methoxy-3-methylpyridin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 1 from tert-butyl (S)-2-(bromomethyl)morpholine-4-carboxylate, 4-bromo-2-methoxy-3-methylpyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 377.1 HNMR: (500 MHz, CDCl3) δ 12.19 (br s, 1H), 7.90 (d, J=5.49 Hz, 1H), 7.20 (s, 1H), 6.70 (d, J=4.88 Hz, 1H), 3.94 (s, 3H), 3.81-3.88 (m, 1H), 3.72-3.80 (m, 1H), 3.56-3.71 (m, 3H), 2.83 (dd, J=7.33, 14.04 Hz, 1H), 2.75 (br d, J=10.99 Hz, 1H), 2.61-2.71 (m, 2H), 2.32 (s, 3H), 2.17-2.24 (m, 1H), 2.15 (s, 3H), 2.02 (t, J=10.38 Hz, 1H).

[0098] Examples 1-6 [ka] (R)-N-(5-((2-(4-Fluoro-3-methoxybenzyl)morpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 1 from tert-butyl (S)-2-(bromomethyl)morpholine-4-carboxylate, 4-bromo-1-fluoro-2-methoxybenzene, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 380. 1 HNMR: (500 MHz, CDCl3) δ 1H NMR (500 MHz, CDCl3) δ 11.88 (br s, 1H), 7.20 (s, 1H), 6.97 (dd, J=7.94, 10.99 Hz, 1H), 6.82 (dd, J=1.83, 7.94 Hz, 1H), 6.68-6.73 (m, 1H), 3.88 (s, 3H), 3.84-3.87 (m, 1H), 3.70-3.79 (m, 1H), 3.59-3.67 (m, 3H), 2.74-2.83 (m, 2H), 2.66-2.73 (m, 1H), 2.63 (dd, J=5.49, 14.04 Hz, 1H), 2.31 (s, 3H), 2.20 (dt, J=3.05, 11.29 Hz, 1H), 1.91-2.01 (m, 1H).

[0099] Examples 1-7 [ka] (R)-N-(5-((2-((2-Methoxypyrimidin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 1 from tert-butyl (S)-2-(bromomethyl)morpholine-4-carboxylate, 4-chloro-2-methoxypyrimidine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 364. 1 HNMR: (500 MHz, CDCl3) δ 1H NMR (500 MHz, CDCl3) δ 11.22 (br s, 1H), 8.39 (d, J=4.88 Hz, 1H), 7.21 (s, 1H), 6.86 (d, J=4.88 Hz, 1H), 4.00-4.07 (m, 1H), 3.99 (s, 3H), 3.79-3.88 (m, 1H), 3.67 (s, 2H), 3.61-3.66 (m, 1H), 2.82-2.93 (m, 2H), 2.74-2.80 (m, 1H), 2.71 (br d, J=10.99 Hz, 1H), 2.31 (s, 3H), 2.22 (dt, J=3.36, 11.14 Hz, 1H), 1.96-2.09 (m, 1H).

[0100] Examples 1-8 [ka] (R)-N-(5-((2-((6-Methoxypyrimidin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 1 from tert-butyl (S)-2-(bromomethyl)morpholine-4-carboxylate, 4-chloro-6-methoxypyrimidine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 364. 1 HNMR: (500 MHz, CDCl3) δ 11.59 (br s, 1H), 8.70 (s, 1H), 7.21 (s, 1H), 6.65 (s, 1H), 3.93-4.01 (m, 4H), 3.79-3.89 (m, 1H), 3.67 (d, 2.70 (br d, J=11.60 Hz, 1H), 2.31 (s, 3H), 2.21 (dt, J=3.36, 11.14 Hz, 1H), 2.04 (t, J=10.38 Hz, 1H).

[0101] Examples 1-9 [ka] (R)-N-(5-((2-((2-(trifluoromethyl)pyrimidin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 1 from tert-butyl (S)-2-(bromomethyl)morpholine-4-carboxylate, 4-chloro-2-(trifluoromethyl)pyrimidine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 402. 1 HNMR: (500 MHz, CDCl3) δ 12.66 (br s, 1H), 8.75 (d, J=4.88 Hz, 1H), 7.44 (d, J=4.88 Hz, 1H), 7.21 (s, 1H), 3.94-4.03 (m, 1H), 3.80 (dd, J=1.53, 9.46 Hz, 1H), 3.64-3.73 (m, 2H), 3.60 (dt, J=2.44, 11.29 Hz, 1H), 2.91-3.03 (m, 2H), 2.88 (br d, J=10.99 Hz, 1H), 2.71 (br d, J=11.60 Hz, 1H), 2.33 (s, 3H), 2.22 (dt, J=3.36, 11.14 Hz, 1H), 1.97-2.08 (m, 1H).

[0102] Examples 1-10 [ka] (R)-N-(5-((2-((2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 1 from tert-butyl (S)-2-(bromomethyl)morpholine-4-carboxylate, 4-bromo-2-(2,2,2-trifluoroethoxy)pyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 431. 1 HNMR: (500 MHz, CDCl3) δ 11.55 (br s, 1H), 8.03 (d, J=4.88 Hz, 1H), 7.21 (s, 1H), 6.84 (dd, J=1.22, 5.49 Hz, 1H), 6.73 (s, 1H), 4.74 (q, 3.83-3.89 (m, 1H), 3.75-3.82 (m, 1H), 3.59-3.71 (m, 3H), 2.74-2.83 (m, 2H), 2.71 (br d, J=10.99 Hz, 1H), 2.62-2.68 (m, 1H), 2.31 (s, 3H), 2.21 (dt, J=3.05, 11.29 Hz, 1H), 1.98 (t, J=10.38 Hz, 1H).

[0103] Examples 1-11 [ka]

[0104] (R)-N-(5-((2-((2-ethoxypyridin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 1 from tert-butyl (S)-2-(bromomethyl)morpholine-4-carboxylate, 4-bromo-2-ethoxypyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 377. 1HNMR: (500 MHz, CDCl3) δ 11.47 (br s, 1H), 8.04 (d, J=4.88 Hz, 1H), 7.20 (s, 1H), 6.73 (dd, J=1.22, 5.49 Hz, 1H), 6.58 (s, 1H), 4.34 (q, 3.83-3.92 (m, 1H), 3.74-3.82 (m, 1H), 3.58-3.70 (m, 3H), 2.73-2.83 (m, 2H), 2.70 (br d, J=10.99 Hz, 1H), 2.61 (dd, J=5.49, 14.04 Hz, 1H), 2.31 (s, 3H), 2.19 (dt, J=3.05, 11.29 Hz, 1H), 1.97 (t, J=10.38 Hz, 1H), 1.39 (t, J=7.02 Hz, 3H).

[0105] Examples 1-12 [ka] (R)-N-(5-((2-((2-isopropoxypyridin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 1 from tert-butyl (S)-2-(bromomethyl)morpholine-4-carboxylate, 4-bromo-2-isopropoxypyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 391. 1HNMR: (500 MHz, CDCl3) δ 11.50 (br s, 1H), 8.03 (d, J=5.49 Hz, 1H), 7.20 (s, 1H), 6.70 (dd, J=1.22, 5.49 Hz, 1H), 6.54 (s, 1H), 5.27 (spt, J=6.10 Hz, 1H), 3.83-3.89 (m, 1H), 3.75-3.81 (m, 1H), 3.59-3.71 (m, 3H), 2.67-2.82 (m, 3H), 2.60 (dd, J=5.49, 14.04 Hz, 1H), 2.31 (s, 3H), 2.19 (dt, J=3.66, 11.29 Hz, 1H), 1.97 (t, J=10.68 Hz, 1H), 1.34 (d, J=6.10 Hz, 6H).

[0106] Examples 1-13 [ka] (R)-N-(5-((2-((2-(difluoromethyl)pyridin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 1 from tert-butyl (S)-2-(bromomethyl)morpholine-4-carboxylate, 4-bromo-2-(difluoromethyl)pyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 383. 1HNMR: (500 MHz, CDCl3) δ 11.62 (br s, 1H), 8.55 (d, J=4.88 Hz, 1H), 7.49 (s, 1H), 7.27-7.30 (m, 1H), 7.21 (s, 1H), 6.63 (t, J=54.33 Hz, 1H), 3.83-3.89 (m, 1H), 3.77-3.83 (m, 1H), 3.67 (s, 2H), 3.62 (dt, J=2.44, 11.29 Hz, 1H), 2.82-2.89 (m, 1H), 2.69-2.81 (m, 3H), 2.32 (s, 3H), 2.22 (dt, J=3.05, 11.29 Hz, 1H), 1.96-2.02 (m, 1H).

[0107] Examples 1-14 [ka] (R)-N-(5-((2-((2-methylpyrimidin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 1 from tert-butyl (S)-2-(bromomethyl)morpholine-4-carboxylate, 4-chloro-2-methylpyrimidine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 348.

[0108] Examples 1-15 [ka] (R)-N-(5-((2-((3-fluoro-2-methoxypyridin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 1 from tert-butyl (S)-2-(bromomethyl)morpholine-4-carboxylate, 4-bromo-3-fluoro-2-methoxypyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 381. 1HNMR: (500 MHz, CDCl3) δ 11.83 (br s, 1H), 7.82 (d, J=4.88 Hz, 1H), 7.21 (s, 1H), 6.79 (t, J=4.58 Hz, 1H), 4.01 (s, 3H), 3.75-3.89 (m, 2H), 3.58-3.72 (m, 3H), 2.73-2.88 (m, 3H), 2.69 (dd, J=1.53, 11.29 Hz, 1H), 2.32 (s, 3H), 2.20 (dt, J=3.36, 11.14 Hz, 1H), 2.01 (t, J=10.38 Hz, 1H).

[0109] Examples 1-16 [ka] (R)-N-(5-((2-((5-Methylpyridin-2-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner as in Scheme 1 from tert-butyl (S)-2-(bromomethyl)morpholine-4-carboxylate, 2-bromo-5-methylpyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 347. 1 HNMR: (500 MHz, CDCl3) δ 11.45 (br s, 1H), 8.33 (d, J=1.83 Hz, 1H), 7.44 (dd, J=2.44, 7.94 Hz, 1H), 7.20 (s, 1H), 7.09 (d, J=7.94 Hz, 1H), 3.84 (br d, J=11.60 Hz, 1H), 3.67-3.75 (m, 1H), 3.65 (d, J=3.05 Hz, 2H), 3.57-3.63 (m, 1H), 2.72-2.82 (m, 2H), 2.69 (br d, J=11.60 Hz, 1H), 2.62-2.67 (m, 1H), 2.53 (s, 3H), 2.31 (s, 3H), 2.19 (dt, J=3.05, 11.29 Hz, 1H), 1.97 (t, J=10.38 Hz, 1H).

[0110] Examples 1-17 [ka] (R)-N-(5-((2-((2-(difluoromethoxy)pyridin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 1 from tert-butyl (S)-2-(bromomethyl)morpholine-4-carboxylate, 4-bromo-2-(difluoromethoxy)pyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 399. 1 HNMR: (500 MHz, CDCl3) δ 11.21 (br s, 1H), 8.08 (d, J=5.49 Hz, 1H), 7.45 (t, J=72.60 Hz, 1H), 7.21 (s, 1H), 6.96 (dd, J=1.53, 5.19 Hz, 1H), 6.77 (s, 1H), 3.82-3.90 (m, 1H), 3.74-3.81 (m, 1H), 3.66 (s, 2H), 3.62 (dt, J=2.44, 11.29 Hz, 1H), 2.66-2.85 (m, 4H), 2.31 (s, 3H), 2.22 (dt, J=3.66, 11.29 Hz, 1H), 1.98 (dd, J=9.77, 10.99 Hz, 1H).

[0111] Examples 1-18 [ka] (R)-N-(5-((2-((5-Fluoro-4-methylpyridin-2-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 1 from tert-butyl (S)-2-(bromomethyl)morpholine-4-carboxylate, 2-chloro-5-fluoro-4-methylpyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 365.

[0112] Examples 1-19 [ka] (R)-N-(5-((2-((6-Methylpyridin-3-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner as in Scheme 1 from tert-butyl (S)-2-(bromomethyl)morpholine-4-carboxylate, 5-bromo-2-methylpyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 347. 1 HNMR: (500 MHz, CDCl3) 12.03 (br s, 1H), 8.33 (d, J=1.83 Hz, 1H), 7.44 (dd, J=2.44, 7.94 Hz, 1H), 7.20 (s, 1H), 7.08 (d, J=7.94 Hz, 1H), 3.80-3.88 (m, 1H), 3.67-3.75 (m, 1H), 3.64 (d, J=2.44 Hz, 2H), 3.57-3.63 (m, 1H), 2.72-2.83 (m, 2H), 2.69 (dd, J=1.22, 10.99 Hz, 1H), 2.62-2.67 (m, 1H), 2.52 (s, 3H), 2.31 (s, 3H), 2.18 (dt, J=3.05, 11.29 Hz, 1H), 1.91-2.01 (m, 1H).

[0113] Examples 1-20 [ka] (R)-N-(5-((2-((2-methylpyridin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner as in Scheme 1 from tert-butyl (S)-2-(bromomethyl)morpholine-4-carboxylate, 4-bromo-2-methylpyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 347. 1 HNMR: (500 MHz, CDCl3) δ 11.60 (br s, 1H), 8.39 (d, J=4.88 Hz, 1H), 7.20 (s, 1H), 7.01 (s, 1H), 6.95 (d, J=4.88 Hz, 1H), 3.83-3.90 (m, 1H), 3.75-3.81 (m, 1H), 3.59-3.69 (m, 3H), 2.67-2.83 (m, 3H), 2.63 (dd, J=4.88, 14.04 Hz, 1H), 2.53 (s, 3H), 2.31 (s, 3H), 2.21 (dt, J=3.36, 11.14 Hz, 1H), 1.97 (t, J=10.38 Hz, 1H).

[0114] Examples 1-21 [ka] (R)-N-(5-((2-((2,6-dimethylpyridin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 1 from tert-butyl (S)-2-(bromomethyl)morpholine-4-carboxylate, 4-bromo-2,6-dimethylpyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 361. 1HNMR: (500 MHz, CDCl3) δ 11.39 (br s, 1H), 7.20 (s, 1H), 6.82 (s, 2H), 3.82-3.91 (m, 1H), 3.75-3.80 (m, 1H), 3.59-3.69 (m, 3H), 2.67-2.79 (m, 3H), 2.58 (dd, J=5.49, 14.04 Hz, 1H), 2.49 (s, 6H), 2.31 (s, 3H), 2.21 (dt, J=3.36, 11.14 Hz, 1H), 1.97 (dd, J=9.77, 10.99 Hz, 1H).

[0115] Examples 1-22 [ka] N-(5-(-1-((R)-2-((5-fluoropyrimidin-2-yl)methyl)morpholino)ethyl)thiazol-2-yl)acetamide: The title compound was prepared in a manner similar to Scheme 1 from tert-butyl (S)-2-(bromomethyl)morpholine-4-carboxylate, 2-bromo-5-fluoro-pyrimidine, and N-(5-(1-chloroethyl)thiazol-2-yl)acetamide.

[0116] Examples 1-23 [ka] The mixture of diastereomers obtained from Examples 1-22, i.e. N-(5-((R)-1-((R)-2-((5-fluoropyrimidin-2-yl)methyl)morpholino)ethyl)thiazol-2-yl)acetamide and N-(5-((S)-1-((R)-2-((5-fluoropyrimidin-2-yl)methyl)morpholino)ethyl)thiazol-2-yl)acetamide, were separated using the following conditions: Column: CHIRALPAK AD-H 30×250 mm, 5 um. Method: 30% isopropanol with 0.1% diethylamine in CO2 (flow rate: 100 mL / min), ABPR 120 bar, MBPR 60 psi: Peak 1: LCMS (ESI): [M+H] 366. LCMS (ESI): [M+H] 366. Peak 2: LCMS (ESI): [M+H] 366.

[0117] Intermediate 3 [ka]

[0118] tert-Butyl 2-(1-hydroxyethyl)morpholine-4-carboxylate: To a solution of tert-butyl 2-acetylmorpholine-4-carboxylate (1.01 g, 4.40 mmol) in ethanol (22.00 mL) was added sodium borohydride (0.250 mg, 6.60 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water. The mixture was treated with 5% aqueous sodium hydrogen sulfate and extracted with ethyl acetate. The extract was washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (1.00 g, 98% yield).

[0119] Intermediate 4 [ka]

[0120] tert-Butyl 2-(1-bromoethyl)morpholine-4-carboxylate: To a stirred solution of tert-butyl 2-(1-hydroxyethyl)morpholine-4-carboxylate (1.00 g, 4.40 mmol), triphenylphosphine (2.54 g, 9.68 mmol), and pyridine (1.74 g, 22.0 mmol) in acetonitrile (22.0 mL) was added a solution of tetrabromomethane (3.21 g, 9.68 mmol) in acetonitrile (22.0 mL). The resulting reaction mixture was stirred at room temperature for 16 h. Et2O (100 mL) was added to the reaction mixture and the resulting precipitate was removed by filtration. The filtrate was washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified on SiO2 (0-50% EtOAc:heptane) to give the title compound (0.54 g, 41% yield). LCMS (ESI): [M+H (-tBu)] 238.

[0121] Examples 1-24 [ka] N-(5-((2-(1-(5-fluoropyrimidin-2-yl)ethyl)morpholino)methyl)thiazol-2-yl)acetamide; The title compound was prepared in a manner similar to Scheme 1 from tert-butyl 2-(1-bromoethyl)morpholine-4-carboxylate, 2-bromo-5-fluoro-pyrimidine, and N-[5-(chloromethyl)]thiazol-2-yl]acetamide.

[0122] Examples 1-25 [ka] The mixture of diastereomers and enantiomers obtained from Examples 1-24, i.e. N-(5-(((R)-2-((R)-1-(5-fluoropyrimidin-2-yl)ethyl)morpholino)methyl)thiazol-2-yl)acetamide, N-(5-(((R)-2-((S)-1-(5-fluoropyrimidin-2-yl)ethyl)morpholino)methyl)thiazol-2-yl)acetamide, N-(5-(((S)-2-((S)-1-(5-fluoropyrimidin-2-yl)ethyl)morpholino)methyl)thiazol-2-yl)acetamide and N-(5-(((S)-2-((R)-1-(5-fluoropyrimidin-2-yl)ethyl)morpholino)methyl)thiazol-2-yl)acetamide, were separated using the following conditions: Column: CHIRALPAK AD-H 30×250mm, 5um. Method: 30% isopropanol with 0.1% diethylamine in CO2 (flow rate: 100mL / min), ABPR 120 bar, MBPR 60psi: Peak 1: LCMS (ESI): [M+H] 366. 1 H NMR: (500 MHz, methanol-d4) δ 8.64 (s, 2H), 7.16 (s, 1H), 3.88 (ddd, J=1.83, 3.36, 11.29 Hz, 1H), 3.81-3.86 (m, 1H), 3.60-3.66 (m, 1H), 3.60 (d, J=1.22 Hz, 2H), 3.11-3.21 (m, 1H), 2.66-2.71 (m, 1H), 2.41-2.46 (m, 1H), 2.19 (s, 3H), 2.14-2.18 (m, 1H), 1.92 (dd, J=9.77, 11.60 Hz, 1H), 1.36 (d, J=7.33 Hz, 3H). Peak 2: LCMS (ESI): [M+H] 366. 1H NMR: (500 MHz, methanol-d4) δ 8.64 (s, 2H), 7.16 (s, 1H), 3.86-3.91 (m, 1H), 3.81-3.86 (m, 1H), 3.58-3.66 (m, 3H), 3.15 (dd, J=7.02, 8.24 Hz, 1H), 2.64-2.73 (m, 1H), 2.41-2.46 (m, 1H), 2.19 (s, 3H), 2.13-2.22 (m, 1H), 1.92 (dd, J=9.77, 11.60 Hz, 1H), 1.36 (d, J=7.33 Hz, 3H). Peak 3: LCMS (ESI): [M+H] 366. 1 H NMR: (500 MHz, methanol-d4) δ 8.65 (s, 2H), 7.26 (s, 1H), 3.89-3.93 (m, 1H), 3.65-3.79 (m, 3H), 3.48 (dt, J=2.44, 11.29 Hz, 1H), 3.15-3.25 (m, 1H), 2.98-3.05 (m, 1H), 2.67 (dd, J=1.83, 10.99 Hz, 1H), 2.20 (s, 3H), 2.14-2.20 (m, 1H), 2.05 (dd, J=10.07, 11.29 Hz, 1H), 1.22 (d, J=7.33 Hz, 3H). Peak 4: LCMS (ESI): [M+H] 366. 1 H NMR: (500 MHz, methanol-d4) δ 8.65 (s, 2H), 7.26 (s, 1H), 3.88-3.96 (m, 1H), 3.66-3.79 (m, 3H), 3.48 (dt, J=2.44, 11.29 Hz, 1H), 3.15-3.24 (m, 1H), 3.02 (d, J=10.99 Hz, 1H), 2.67 (dd, J=1.83, 11.60 Hz, 1H), 2.20 (s, 3H), 2.14-2.19 (m, 1H), 2.05 (dd, J=9.77, 10.99 Hz, 1H), 1.22 (d, J=7.33 Hz, 3H).

[0123] Intermediate 5 [ka] ((2S,5S)-4-benzyl-5-methylmorpholin-2-yl)methanol: (S)-2-(benzylamino)propan-1-ol (3.0 g) was dissolved in toluene (57.6 mL) and (2R)-2-(chloromethyl)oxirane (2.50 g, 27.1 mmol, 2.12 mL) was added. Lithium perchlorate (2.88 g, 27.1 mmol) was added and the mixture was stirred at room temperature for 16 h. NaOH (2.14 g, 53.6 mmol) was dissolved in methanol (30 mL) and the mixture was added slowly and stirred at room temperature for 36 h. The reaction was concentrated, dissolved in CHCl and water was added. The layers were separated and the organic layer was dried over NaSO and concentrated in vacuo. The residue was purified by silica gel chromatography (0-5% CHCl:MeOH) to give the title compound (3.70 g, 92% yield). LCMS (ESI): [M+H] 222. 1 HNMR: (500 MHz, CDCl3) δ 7.24-7.35 (m, 5H), 3.75-3.83 (m, 1H), 3.51-3.63 (m, 2H), 3.30-3.49 (m, 5H), 2.58 (dd, J=11.6, 2.4 Hz, 1H), 2.40 (ddd, J=9.9, 6.3, 3.4 Hz, 1H), 1.09 (d, J=6.1 Hz, 3H).

[0124] Intermediate 6 [ka] tert-Butyl (2S,5S)-2-(hydroxymethyl)-5-methylmorpholine-4-carboxylate: ((2S,5S)-4-benzyl-5-methylmorpholin-2-yl)methanol (3.70 g, 16.72 mmol) was dissolved in methanol (100.0 mL). Palladium hydroxide on carbon (1.88 g, 2.68 mmol, 20% w / w) was added followed by Boc anhydride (3.65 g, 16.7 mmol). The reaction was stirred under an atmosphere of H for 16 h. The reaction was filtered through Celite and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% CH2Cl2:MeOH) to give the title compound (2.32 g, 59% yield). 1 HNMR: (500 MHz, CDCl3) δ 4.03 (br d, J=6.7 Hz, 1H), 3.78-3.94 (m, 3H), 3.65 (dd, J=14.0, 2.4 Hz, 1H), 3.56 (s, 1H), 3.33-3.48 (m, 3H), 1.45-1.47 (m, 9H), 1.24 (d, J=6.7 Hz, 3H).

[0125] Intermediate 7 [ka] tert-Butyl (2S,5S)-2-(bromomethyl)-5-methylmorpholine-4-carboxylate: tert-Butyl (2S,5S)-2-(hydroxymethyl)-5-methylmorpholine-4-carboxylate (939 mg, 4.06 mmol) was dissolved in CHCl (16.2 mL). The mixture was cooled to 0° C. and triphenylphosphine (polymer support) (3.19 g, 12.2 mmol) was added, followed by carbon tetrabromide (2.69 g, 8.12 mmol). The reaction was allowed to reach ambient temperature and stirred at room temperature for 16 h. The reaction was filtered through a pad of silica and Celite and concentrated in vacuo. The residue was purified by silica gel chromatography (0-50% EtOAc:heptane) to give the title compound (405 mg, 33% yield). LCMS (ESI): [M-Boc)] 194. 1HNMR: (500 MHz, CDCl3) δ 4.08 (dt, J=6.9, 3.6 Hz, 1H), 3.89-4.00 (m, 2H), 3.83 (dd, J=11.9, 4.0 Hz, 1H), 3.47-3.55 (m, 2H), 3.37-3.42 (m, 2H), 1.46-1.49 (m, 9H), 1.24 (d, J=6.7 Hz, 3H)

[0126] Intermediate 8 [ka] tert-Butyl (2R,5R)-2-(bromomethyl)-5-methylmorpholine-4-carboxylate: The title compound was prepared from (2S)-2-(benzylamino)propan-1-ol and (2S)-2-(chloromethyl)oxirane in a manner similar to that of Intermediate 7. LCMS (ESI): [M-Boc)] 194. 1 HNMR: (500 MHz, CDCl3) δ 4.08 (dt, J=6.7, 3.4 Hz, 1H), 3.96-4.00 (m, 1H), 3.92 (d, J=1.8 Hz, 1H), 3.90 (d, J=1.8 Hz, 1H), 3.83 (dd, J=11.9, 4.0 Hz, 1H), 3.47-3.54 (m, 2H), 3.37-3.41 (m, 2H), 1.46-1.55 (m, 9H), 1.24 (d, J=7.3 Hz, 3H).

[0127] Intermediate 9 [ka] tert-Butyl (2R,5S)-2-(bromomethyl)-5-methylmorpholine-4-carboxylate: The title compound was prepared from (2S)-2-(benzylamino)propan-1-ol and (2S)-2-(chloromethyl)oxirane in a manner similar to that of Intermediate 7. LCMS (ESI): [M-Boc)] 194. 1HNMR: (500 MHz, CDCl3) δ 4.12 (br d, J=7.3 Hz, 1H), 3.81-4.03 (m, 2H), 3.66-3.77 (m, 2H), 3.46-3.60 (m, 1H), 3.35-3.42 (m, 2H), 1.59 (s, 1H), 1.44-1.49 (m, 9H), 1.19-1.34 (m, 3H).

[0128] Intermediate 10 [ka] tert-Butyl (2S,5R)-2-(bromomethyl)-5-methylmorpholine-4-carboxylate: The title compound was prepared from (2R)-2-(benzylamino)propan-1-ol and (2R)-2-(chloromethyl)oxirane in a manner similar to that of Intermediate 7. LCMS (ESI): [M-Boc)] 194. 1 HNMR: (500 MHz, CDCl3) δ 4.12 (br d, J=7.3 Hz, 1H), 3.99 (br s, 1H), 3.67-3.86 (m, 2H), 3.56 (br s, 1H), 3.35-3.41 (m, 2H), 2.86 (br s, 1H), 1.59 (s, 1H), 1.55 (s, 1H), 1.45-1.51 (m, 9H), 1.23 (d, J=6.7 Hz, 3H).

[0129] Examples 1-26 [ka] N-(5-(((2R,5S)-2-((5-fluoropyrimidin-2-yl)methyl)-5-methylmorpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared from tert-butyl (2S,5S)-2-(bromomethyl)-5-methylmorpholine-4-carboxylate, 2-bromo-5-fluoro-pyrimidine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide in a manner similar to that in Scheme 1. LCMS (ESI): [M+H] 366. 1 HNMR: (500 MHz, CDCl3) δ 10.95 (br s, 1H), 8.51 (s, 2H), 7.27-7.38 (m, 1H), 7.20 (s, 1H), 5.30 (s, 1H), 4.05-4.13 (m, 2H), 3.68 (dd, J=11.0, 3.1 Hz, 1H), 3.58-3.63 (m, 1H), 3.23 (t, J=11.0 Hz, 1H), 3.09 (dd, J=14.0, 8.5 Hz, 1H), 2.99 (dd, J=14.3, 4.6 Hz, 1H), 2.83 (dd, J=11.3, 2.1 Hz, 1H), 2.44 (ddd, J=9.9, 6.3, 3.4 Hz, 1H), 2.31 (s, 3H), 2.12-2.17 (m, 1H), 1.56 (s, 1H), 1.04-1.09 (m, 4H).

[0130] Examples 1-27 [ka] N-(5-(((2R,5R)-2-((5-fluoropyrimidin-2-yl)methyl)-5-methylmorpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared from tert-butyl (2S,5R)-2-(bromomethyl)-5-methylmorpholine-4-carboxylate, 2-bromo-5-fluoro-pyrimidine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide in a manner similar to that in Scheme 1. LCMS (ESI): [M+H] 366. 1HNMR: (500 MHz, methanol-d4) δ 8.65 (s, 2H), 7.24 (s, 1H), 4.17 (dd, J=4.9, 3.7 Hz, 1H), 3.79-3.84 (m, 1H), 3.73-3.78 (m, 1H), 3.58-3.70 (m, 3H), 3.25 (dd, J=14.0, 7.9 Hz, 1H), 3.07 (dd, J=14.0, 5.5 Hz, 1H), 2.77-2.82 (m, 1H), 2.53-2.61 (m, 2H), 2.21 (s, 3H), 1.30 (s, 1H), 1.11 (d, J=6.7 Hz, 3H).

[0131] Examples 1-28 [ka] N-(5-(((2S,5S)-2-((5-fluoropyrimidin-2-yl)methyl)-5-methylmorpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to that in Scheme 1 from tert-butyl (2R,5S)-2-(bromomethyl)-5-methylmorpholine-4-carboxylate, 2-bromo-5-fluoro-pyrimidine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 366. 1 HNMR: (500 MHz, CDCl3) δ 10.76 (br s, 1H), 8.52 (s, 2H), 7.20 (s, 1H), 5.30 (s, 1H), 4.10-4.17 (m, 1H), 3.61-3.77 (m, 4H), 3.24-3.43 (m, 1H), 3.02 (dd, J=14.0, 4.3 Hz, 1H), 2.77-2.84 (m, 1H), 2.53-2.58 (m, 2H), 2.29 (s, 3H), 2.04 (s, 1H), 1.55 (s, 1H), 1.26 (t, J=7.0 Hz, 1H), 1.08 (d, J=6.7 Hz, 3H).

[0132] Examples 1-29 [ka] N-(5-(((2S,5R)-2-((5-fluoropyrimidin-2-yl)methyl)-5-methylmorpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared from tert-butyl (2R,5R)-2-(bromomethyl)-5-methylmorpholine-4-carboxylate, 2-bromo-5-fluoro-pyrimidine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide in a manner similar to that in Scheme 1. LCMS (ESI): [M+H] 366. 1 HNMR: (500 MHz, CDCl3) δ 11.44 (br s, 1H), 8.51 (s, 2H), 7.20 (s, 1H), 4.05-4.14 (m, 2H), 3.68 (dd, J=11.3, 3.4 Hz, 1H), 3.60 (d, J=14.0 Hz, 1H), 3.20-3.26 (m, 1H), 3.09 (dd, J=14.0, 8.5 Hz, 1H), 2.99 (dd, J=14.0, 4.3 Hz, 1H), 2.84 (dd, J=11.6, 1.8 Hz, 1H), 2.40-2.47 (m, 1H), 2.32 (s, 3H), 2.14 (dd, J=11.6, 10.4 Hz, 1H), 2.04 (s, 1H), 1.58 (br s, 1H), 1.22-1.32 (m, 2H), 1.05 (d, J=6.1 Hz, 3H)

[0133] Examples 1-30 [ka] N-(5-(((2R,5S)-2-((2-Methoxypyridin-4-yl)methyl)-5-methylmorpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared from tert-butyl (2S,5S)-2-(bromomethyl)-5-methylmorpholine-4-carboxylate, 4-bromo-2-methoxypyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide in a manner similar to that in Scheme 1. LCMS (ESI): [M+H] 377. 1 HNMR: (500 MHz, CDCl3) δ 11.57 (br s, 1H), 8.03 (d, J=5.5 Hz, 1H), 7.17-7.25 (m, 1H), 6.74 (d, J=5.4 Hz, 1H), 6.59 (s, 1H), 3.89-3.94 (m, 3H), 3.62-3.81 (m, 6H), 2.77-2.85 (m, 2H), 2.67 (dd, J=14.3, 5.2 Hz, 1H), 2.38-2.46 (m, 2H), 2.29 (s, 3H), 1.06 (d, J=6.7 Hz, 3H)

[0134] Examples 1-31 [ka] N-(5-(((2R,5S)-2-((2,6-dimethylpyridin-4-yl)methyl)-5-methylmorpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared from tert-butyl (2S,5S)-2-(bromomethyl)-5-methylmorpholine-4-carboxylate, 4-bromo-2,6-dimethylpyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide in a manner similar to that in Scheme 1. LCMS (ESI): [M+H] 375. 1HNMR: (500 MHz, CDCl3) δ 12.12-12.33 (m, 1H), 7.19 (s, 1H), 6.79 (s, 2H), 4.06 (d, J=14.7 Hz, 1H), 3.74-3.79 (m, 1H), 3.60 (d, J=14.7 Hz, 1H), 3.24 (t, J=10.7 Hz, 1H), 2.62-2.75 (m, 2H), 2.50-2.60 (m, 1H), 2.47 (s, 6H), 2.34-2.45 (m, 1H), 2.32 (s, 3H), 2.01-2.08 (m, 2H), 1.06 (d, J=6.1 Hz, 3H)

[0135] Examples 1-32 [ka] N-(5-(((2R,5S)-5-Methyl-2-((2-methylpyridin-4-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared from tert-butyl (2S,5S)-2-(bromomethyl)-5-methylmorpholine-4-carboxylate, 4-bromo-2-methylpyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide in a manner similar to that in Scheme 1. LCMS (ESI): [M+H] 361. 1HNMR: (500 MHz, CDCl3) δ 12.06 (br s, 1H), 8.23 ​​(d, J=5.5 Hz, 1H), 7.05 (s, 1H), 6.85 (s, 1H), 6.79 (d, J=4.9 Hz, 1H), 3.91-4.01 (m, 1H), 3.59-3.66 (m, 1H), 3.57 (dd, J=11.6, 3.1 Hz, 1H), 3.46 (d, J=14.7 Hz, 1H), 3.10 (t, J=10.7 Hz, 1H), 2.50-2.64 (m, 2H), 2.41-2.50 (m, 1H), 2.37 (s, 3H), 2.29 (ddd, J=9.9, 6.3, 3.4 Hz, 1H), 2.19 (s, 3H), 1.83-1.98 (m, 2H), 1.04-1.21 (m, 1H), 0.93 (d, J=6.1 Hz, 3H)

[0136] Examples 1-33 [ka] N-(5-(((2R,5S)-5-Methyl-2-((6-methylpyridin-3-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared from tert-butyl (2S,5S)-2-(bromomethyl)-5-methylmorpholine-4-carboxylate, 5-bromo-2-methylpyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide in a manner similar to that in Scheme 1. LCMS (ESI): [M+H] 361. 1HNMR: (500 MHz, CDCl3) δ 2.33 (br s, 1H), 12.27 (br s, 1H), 8.30 (d, J=2.4 Hz, 1H), 7.41 (dd, J=7.9, 2.4 Hz, 1H), 7.19 (s, 1H), 7.06 (d, J=7.9 Hz, 1H), 4.05 (d, J=14.7 Hz, 1H), 3.66-3.72 (m, 2H), 3.60 (d, J=14.7 Hz, 1H), 3.21 (t, J=11.0 Hz, 1H), 2.58-2.75 (m, 3H), 2.50-2.55 (m, 3H), 2.38-2.45 (m, 1H), 2.29-2.38 (m, 3H), 2.01-2.09 (m, 2H), 1.05 (d, J=6.1 Hz, 3H)

[0137] Intermediate 11 [ka] tert-Butyl cis-2-(hydroxymethyl)-6-methylmorpholine-4-carboxylate: cis-4-(tert-butoxycarbonyl)-6-methylmorpholine-2-carboxylic acid (0.75 g, 3.06 mmol) was dissolved in THF (10.0 mL) and cooled to 0° C. A solution of BH3-THF (1.0 M, 5.51 mL) was added dropwise over 25 min. The reaction was allowed to warm to room temperature and quenched with MeOH:acetic acid (9:1, 5 mL). The mixture was concentrated under reduced pressure and carried on to the next transformation. LCMS (ESI): [M+H (-tBu)] 176. 1 H NMR (CDCl3) δ: 3.77-3.99 (m, 2H), 3.68 (br d, J=8.5 Hz, 2H), 3.57 (br d, J=6.7 Hz, 2H), 2.64 (br s, 1H), 2.48 (br s, 1H), 1.69 (br s, 1H), 1.42-1.48 (m, 9H), 1.18 (d, J=6.7 Hz, 3H).

[0138] Intermediate 12 [ka] tert-Butyl (cis)-2-(bromomethyl)-6-methylmorpholine-4-carboxylate: The title compound was prepared from tert-butyl cis-2-(hydroxymethyl)-6-methylmorpholine-4-carboxylate in a similar manner to intermediate 7. LCMS (ESI): [M] * 293. 1 H NMR (CDCl3) δ: 4.08 (dt, J=6.9, 3.6 Hz, 1H), 3.89-4.00 (m, 2H), 3.83 (dd, J=11.9, 4.0 Hz, 1H), 3.47-3.55 (m, 2H), 3.37-3.42 (m, 2H), 1.46-1.49 (m, 9H), 1.24 (d, J=6.7 Hz, 3H).

[0139] Examples 1-34 [ka] N-(5-(((cis)-2-((5-fluoropyrimidin-2-yl)methyl)-6-methylmorpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 1 from tert-butyl (cis)-2-(bromomethyl)-6-methylmorpholine-4-carboxylate, 2-bromo-5-fluoro-pyrimidine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 366. 1HNMR: (500 MHz, CDCl3) δ 11.18 (br s, 1H), 8.53 (s, 2H), 7.32 (s, 1H), 7.20 (s, 1H), 4.11-4.18 (m, 1H), 3.60-3.70 (m, 3H), 3.19 (dd, J=14.3, 7.0 Hz, 1H), 3.03 (dd, J=14.0, 6.7 Hz, 1H), 2.85 (br d, J=10.4 Hz, 1H), 2.73 (br d, J=11.0 Hz, 1H), 2.29-2.31 (m, 3H), 1.98 (t, J=10.7 Hz, 1H), 1.80 (t, J=10.4 Hz, 1H), 1.25 (d, J=7.3 Hz, 1H), 1.08 (d, J=6.1 Hz, 3H).

[0140] Examples 1-35 [ka] The mixture of enantiomers of Examples 1-34, i.e. N-(5-(((2R,6S)-2-((5-fluoropyrimidin-2-yl)methyl)-6-methylmorpholino)methyl)thiazol-2-yl)acetamide and N-(5-(((2S,6R)-2-((5-fluoropyrimidin-2-yl)methyl)-6-methylmorpholino)methyl)thiazol-2-yl)acetamide, was separated using the following conditions: Column: CHIRALPAK IC 30×250 mm, 5 um. Method: 40% MeOH with 0.1% diethylamine in CO2 (flow rate: 100 mL / min), ABPR 120 bar, MBPR 40 psi: Peak 1: LCMS (ESI): [M+H] 366. 1H NMR: (500 MHz, メタノール-d4) δ 8.65 (s, 2H), 7.23 (s, 1H), 4.14-4.19 (m, 1H), 3.69 (s, 2H), 3.58-3.66 (m, 1H), 3.04-3.13 (m, 1H), 2.95-3.04 (m, 1H), 2.87 (d, J=11.6 Hz, 1H), 2.69-2.81 (m, 3H), 2.07-2.25 (m, 3H), 1.93 (t, J=10.7 Hz, 1H), 1.79 (t, J=10.7 Hz, 1H), 1.18 (t, J=7.3 Hz, 3H), 1.05 (d, J=6.1 Hz, 3H) ピーク2: LCMS (ESI): [M+H] 366. 1 H NMR: (500 MHz, メタノール-d4) δ 8.65 (s, 2H), 7.23 (s, 1H), 4.14-4.21 (m, 1H), 3.69 (s, 2H), 3.58-3.67 (m, 1H), 2.96-3.17 (m, 2H), 2.83-2.92 (m, 1H), 2.71-2.83 (m, 3H), 2.16-2.28 (m, 3H), 1.93 (t, J=10.7 Hz, 1H), 1.79 (t, J=10.7 Hz, 1H), 1.13-1.27 (m, 3H), 1.05 (d, J=6.1 Hz, 3H)

[0141] Intermediate 13

change

[0142] Examples 1-36 [ka] N-(5-((2-((2,6-dimethylpyridin-4-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 1 from tert-butyl 2-(bromomethyl)-1,4-oxazepan-4-carboxylate, 4-bromo-2,6-dimethylpyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 375. 1HNMR: (500 MHz, CDCl3) δ 11.95 (br s, 1H), 7.17 (s, 1H), 6.78 (s, 2H), 3.81-3.90 (m, 2H), 3.79 (d, J=3.66 Hz, 2H), 3.66-3.74 (m, 1H), 2.83-2.90 (m, 2H), 2.69 (dd, J=7.94, 14.04 Hz, 1H), 2.63 (ddd, J=4.27, 8.55, 12.82 Hz, 1H), 2.52 (dd, J=5.80, 13.73 Hz, 1H), 2.47 (s, 6H), 2.43 (dd, J=9.16, 13.43 Hz, 1H), 2.31 (s, 3H), 1.89-1.97 (m, 1H), 1.83-1.89 (m, 1H).

[0143] Examples 1-37 [ka] The mixture of enantiomers of Examples 1-36, i.e. (S)-N-(5-((2-((2,6-dimethylpyridin-4-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide and (R)-N-(5-((2-((2,6-dimethylpyridin-4-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide, was separated using the following conditions: Column: CHIRALPAK AD-H 30x250mm, 5um. Method: 0.1% diethylamine in 30% IPA w / CO2 (Flow rate: 100mL / min, ABPR 120 bar, MBPR 60psi, as peak 1 and peak 2.

[0144] Examples 1-38 [ka] N-(5-((2-((5-fluoropyrimidin-2-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 1 from tert-butyl 2-(bromomethyl)-1,4-oxazepan-4-carboxylate, 2-bromo-5-fluoro-pyrimidine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 366. 1 HNMR: (500 MHz, CDCl3) δ 11.67 (br s, 1H), 8.51 (s, 2H), 7.19 (s, 1H), 4.26 (q, J=7.33 Hz, 1H), 3.77-3.91 (m, 3H), 3.67-3.75 (m, 1H), 3.13 (dd, J=7.94, 14.04 Hz, 1H), 2.87-3.02 (m, 3H), 2.62-2.70 (m, 1H), 2.55 (dd, J=8.85, 13.12 Hz, 1H), 2.32 (s, 3H), 1.90-2.01 (m, 1H), 1.80-1.88 (m, 1H).

[0145] Examples 1-39 [ka] The mixture of enantiomers of Examples 1-38, namely (S)-N-(5-((2-((5-fluoropyrimidin-2-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide and (R)-N-(5-((2-((5-fluoropyrimidin-2-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide, was separated using the following conditions: Column: CHIRALPAK IC 30x250mm, 5um. Method: 40% EtOH with 0.1% diethylamine in CO2 (flow rate: 100mL / min), ABPR 120 bar, MBPR 40psi, as peak 1 and peak 2.

[0146] Examples 1-40 [ka] N-(5-((2-((2-Methoxypyridin-4-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 1 from tert-butyl 2-(bromomethyl)-1,4-oxazepan-4-carboxylate, 4-bromo-2-methoxypyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 377. 1 HNMR: (500 MHz, CDCl3) δ 12.10 (br s, 1H), 8.03 (d, J=4.88 Hz, 1H), 7.17 (s, 1H), 6.72 (dd, J=1.22, 5.49 Hz, 1H), 6.56 (s, 1H), 3.90 (s, 3H), 3.83-3.88 (m, 2H), 3.80 (s, 2H), 3.65-3.73 (m, 1H), 2.80-2.91 (m, 2H), 2.72 (dd, J=7.94, 14.04 Hz, 1H), 2.60-2.67 (m, 1H), 2.56 (dd, J=5.49, 14.04 Hz, 1H), 2.45 (dd, J=8.85, 13.12 Hz, 1H), 2.32 (s, 3H), 1.80-1.96 (m, 2H).

[0147] Examples 1-41 [ka] The mixture of enantiomers of Examples 1-40, namely (S)-N-(5-((2-((2-methoxypyridin-4-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide and (R)-N-(5-((2-((2-methoxypyridin-4-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide, was separated using the following conditions: Column: CHIRALPAK AD-H 30×250 mm, 5 um. Method: 35% IPA with 0.1% diethylamine in CO2 (flow rate: 100 mL / min), ABPR 120 bar, MBPR 60 psi, as peak 1 and peak 2.

[0148] Intermediate 14 [ka] tert-Butyl 6-(bromomethyl)-1,4-oxazepane-4-carboxylate: To a solution of tert-butyl 6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (3.18 g, 13.7 mmol) in CHCl (65 mL) at 0° C. was added triphenylphosphine (polymer support) (10.82 g, 41.2 mmol) followed by carbon tetrabromide (9.12 g, 27.5 mmol). The mixture was allowed to warm to room temperature and stirred for 72 h. The mixture was filtered through Celite and concentrated in vacuo. The residue was purified by silica gel chromatography (0-20% EtOAc:heptane) to give the title compound (2.71 g, 67% yield). 1 HNMR: (500 MHz, CDCl3) δ 3.56-3.79 (m, 6H), 3.31-3.45 (m, 4H), 2.35-2.47 (m, 1H), 1.61 (d, J=4.3 Hz, 1H), 1.48 ppm (br d, J=10.4 Hz, 9H).

[0149] Examples 1-42 [ka] N-(5-((6-((2,6-dimethylpyridin-4-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner as in Scheme 1 from tert-butyl 6-(bromomethyl)-1,4-oxazepan-4-carboxylate, 4-bromo-2-methoxypyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 375. 1 HNMR: (500 MHz, methanol-d4) δ 7.16 (s, 1H), 6.79 (s, 2H), 3.86-3.94 (m, 1H), 3.68-3.82 (m, 5H), 3.42-3.51 (m, 1H), 2.76-2.91 (m, 1H), 2.69 (dq, J=12.9, 3.6 Hz, 2H), 2.45-2.56 (m, 1H), 2.42 (s, 6H), 2.27-2.39 (m, 3H), 2.24 (s, 3H).

[0150] Examples 1-43 [ka] The mixture of enantiomers of Examples 1-42, i.e. (S)-N-(5-((6-((2,6-dimethylpyridin-4-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide and (R)-N-(5-((6-((2,6-dimethylpyridin-4-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide, was separated using the following conditions: Column: CHIRALPAK AD-H 30x250mm, 5um. Method: 40% IPA with 0.1% diethylamine in CO2 (flow rate: 100mL / min), ABPR 120 bar, MBPR 40psi, as peak 1 and peak 2.

[0151] Examples 1-44 [ka] N-(5-((6-((5-fluoropyrimidin-2-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 1 from tert-butyl 6-(bromomethyl)-1,4-oxazepan-4-carboxylate, 2-bromo-5-fluoro-pyrimidine and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 366. 1 HNMR: (500 MHz, methanol-d4) δ 8.53 (s, 2H), 7.15 (s, 1H), 3.97 (dd, J=11.9, 5.8 Hz, 1H), 3.67-3.84 (m, 5H), 3.49-3.58 (m, 1H), 2.79-2.87 (m, 2H), 2.60-2.77 (m, 5H), 2.46 (dd, J=13.1, 7.6 Hz, 1H), 2.20-2.28 (m, 4H).

[0152] Examples 1-45 [ka] The mixture of enantiomers of Examples 1-44, namely (S)-N-(5-((6-((5-fluoropyrimidin-2-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide and (R)-N-(5-((6-((5-fluoropyrimidin-2-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide, was separated using the following conditions: Column: CHIRALPAK AD-H 30x250mm, 5um. Method: 40% IPA with 0.1% diethylamine in CO2 (flow rate: 100mL / min), ABPR 120 bar, MBPR 60psi, as peak 1 and peak 2.

[0153] Examples 1-46 [ka] N-(5-((6-((2-Methoxypyridin-4-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 1 from tert-butyl 6-(bromomethyl)-1,4-oxazepan-4-carboxylate, 4-bromo-2-methoxypyridine, and N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 377. 1 HNMR: (500 MHz, methanol-d4) δ 7.93 (d, J=4.9 Hz, 1H), 7.17 (s, 1H), 6.71 (dd, J=5.5, 1.2 Hz, 1H), 6.54 (s, 1H), 3.88-3.93 (m, 1H), 3.86-3.88 (m, 3H), 3.70-3.81 (m, 4H), 3.49 (dd, J=12.2, 7.9 Hz, 1H), 2.78-2.84 (m, 1H), 2.67-2.75 (m, 2H), 2.49-2.56 (m, 1H), 2.40-2.47 (m, 2H), 2.28-2.35 (m, 1H), 2.24 (s, 3H).

[0154] Examples 1-47 [ka] The mixture of enantiomers of Examples 1-46, namely (S)-N-(5-((6-((2-methoxypyridin-4-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide and (R)-N-(5-((6-((2-methoxypyridin-4-yl)methyl)-1,4-oxazepan-4-yl)methyl)thiazol-2-yl)acetamide, was separated using the following conditions: Column: CHIRALPAK IC 30×250 mm, 5 um. Method: 40% IPA with 0.1% diethylamine in CO2 (flow rate: 100 mL / min), ABPR 120 bar, MBPR 40 psi, as peak 1 and peak 2.

[0155] Scheme 2 [ka]

[0156] Intermediate 15 [ka] 1-Benzyl 4-(tert-butyl)(2S,5S)-5-methyl-2-(((methylsulfonyl)oxy)methyl)-piperazine-1,4-dicarboxylate: Methanesulfonyl chloride (6.0 g, 53 mmol, 4.1 mL) was added dropwise to a solution of 1-benzyl 4-(tert-butyl)(2S,5S)-2-(hydroxymethyl)-5-methylpiperazine-1,4-dicarboxylate (16 g, 43.9 mmol) and triethylamine (9.1 g, 90 mmol, 12.5 mL) in ether (200 mL) at 0° C. The reaction was then stirred at room temperature for 2 hours. The reaction solution was washed with water, brine, then dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to give the title compound, which was used in the next step without further purification. LCMS (ESI): [M+Na] 465 (M+Na).

[0157] Intermediate 16 [ka] 1-Benzyl 4-(tert-butyl)(2S,5S)-2-(bromomethyl)-5-methylpiperazine-1,4-dicarboxylate: To a solution of 1-benzyl 4-(tert-butyl)(2S,5S)-5-methyl-2-(((methylsulfonyl)oxy)methyl)-piperazine-1,4-dicarboxylate (19 g, 42.9 mmol) in THF (200 mL) was added LiBr (29.8 g, 343.4 mmol). The reaction was heated to reflux for 3 h. After 3 h, an additional 5 g of LiBr was added. The mixture was heated to reflux for 1 h, after which an additional 5 g was added. The reaction was maintained at reflux for an additional 1 h. The mixture was cooled to room temperature, the solids were filtered off, and the filtrate was concentrated in vacuo and purified by silica gel chromatography (0-100% EtOAc:heptane) to give the title compound (12.5 g, 68% yield). LCMS (ESI): [M+H] not observed, 327 & 329 (M-Boc) observed. 1 H NMR (400 MHz, CDCl3) δ 7.29-7.43 (m, 5H), 5.09-5.26 (m, 2H), 3.99-4.62 (m, 3H), 3.69-3.92 (m, 1H), 3.33-3.58 (m, 2H), 3.10-3.30 (m, 2H), 1.48 (s, 9H), 1.07-1.21 (m, 3H).

[0158] Intermediate 17 [ka] 1-Benzyl 4-(tert-butyl)(2R,5S)-5-methyl-2-((2-methylpyridin-4-yl)methyl)piperazine-1,4-dicarboxylate: A mixture of NiCl2glyme (17.9 mg, 81.4 umol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (18 mg, 16.3 umol) and BBBPY (21.8 mg, 81.4 umol) in DME (20 ml) was purged with nitrogen for 10 minutes. In a separate vial, a mixture of 4-bromo-2-methyl-pyridine (280 mg, 1.6 mmol), 1-benzyl 4-(tert-butyl)(2S,5S)-2-(bromomethyl)-5-methylpiperazine 1,4-dicarboxylate (696 mg, 1.6 mmol), lithium hydroxide (156 mg, 6.5 mmol) and bis(trimethylsilyl)silyl-trimethyl-silane (810 mg, 3.3 mmol, 1.0 mL) in DME (6 ml) was purged with nitrogen for 10 min. The first solution was added to the second solution under nitrogen. The reaction mixture was then irradiated with 2× blue Kessel Lamps at 40° C. overnight. The reaction mixture was treated with charcoal, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (10-100% EtOAc:heptane) to give the title compound (323 mg, 45% yield). LCMS (ESI): [M+H] 440. 1 H NMR (400 MHz, CDCl3) δ 8.21-8.61 (m, 1H), 7.34-7.48 (m, 3H), 7.29 (br d, J=2.51 Hz, 2H), 7.16-7.26 (m, 1H), 6.84-7.13 (m, 1H), 4.86-5.19 (m, 2H), 4.17-4.61 (m, 2H), 3.56-4.00 (m, 2H), 3.27 (br d, J=12.80 Hz, 1H), 3.06-3.21 (m, 1H), 2.82-3.00 (m, 2H), 2.65-2.81 (m, 2H), 2.52-2.63 (m, 1H), 2.01 (s, 3H), 1.49 (br d, J=13.30 Hz, 9H), 1.17 (br dd, J=6.78, 19.32 Hz, 3H).

[0159] Intermediate 18 [ka] Benzyl (2R,5S)-5-methyl-2-((2-methylpyridin-4-yl)methyl)piperazine-1-carboxylate: To a solution of 1-benzyl 4-(tert-butyl)(2R,5S)-5-methyl-2-((2-methylpyridin-4-yl)-methyl)piperazine-1,4-dicarboxylate (320 mg, 0.728 mmol) in CHCl (5.0 mL) was added a solution of HCl in dioxane (4 M, 0.910 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and used in the next step without purification. LCMS (ESI): [M+H] 340.

[0160] Intermediate 19 [ka] Benzyl (2R,5S)-4-((2-acetamidothiazol-5-yl)methyl)-5-methyl-2-((2-methylpyridin-4-yl)methyl)piperazine-1-carboxylate: To a mixture of benzyl (2R,5S)-5-methyl-2-[(2-methyl-4-pyridyl)methyl]piperazine-1-carboxylate (270 mg, 0.718 mmol, hydrochloride salt) and N-[5-(chloromethyl)thiazol-2-yl]acetamide (164 mg, 0.862 mmol) in acetonitrile (5.0 mL) was added diisopropylethylamine (0.557 g, 4.3 mmol, 0.753 mL). The reaction was stirred at room temperature for 1 h and concentrated in vacuo. The residue was purified by silica gel chromatography (0-80% EtOAc-EtOH (3:1 v / v 2% NH4OH):heptane) to give the title compound (316 mg, 89% yield). LCMS (ESI): [M+H] 494; 1H NMR (400 MHz, methanol-d4) δ 8.12 (br s, 1H), 7.28-7.39 (m, 3H), 7.16-7.27 (m, 3H), 6.97 (br s, 1H), 5.00 (br s, 2H), 4.35 (br s, 1H), 3.75-3.89 (m, 2H), 3.65 (d, J=14.05 Hz, 1H), 3.49 (dd, J=3.39, 13.18 Hz, 1H), 3.18 (br s, 1H), 3.01 (br s, 2H), 2.66 (br dd, J=3.64, 11.92 Hz, 1H), 2.36 (br s, 4H), 2.21 (s, 3H), 1.00 (d, J=6.53 Hz, 3H).

[0161] Examples 1-48 [ka] (R)-N-(4-Fluoro-5-((2-((6-methylpyridin-3-yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared from tert-butyl (S)-2-(bromomethyl)morpholine-4-carboxylate, 5-bromo-2-methylpyridine, and N-(4-fluoro-5-formylthiazol-2-yl)acetamide in a manner similar to Scheme 1 and Intermediate 26 (prepared according to literature procedures described in WO2018 / 140299A1). LCMS (ESI): [M+H] 364. 1HNMR: (500 MHz, CDCl3) δ 8.62 (d, J=2.44 Hz, 1 H) 8.41 (dd, J=8.24, 2.14 Hz, 1 H) 7.89 (d, J=8.55 Hz, 1 H) 4.51 (s, 2 H) 4.12 (dd, J=13.43, 3.05 Hz, 1 H) 3.97 - 4.06 (m, 2 H) 3.70 - 3.79 (m, 1 H) 3.62 - 3.69 (m, 1 H) 3.50 (br d, J=12.21 Hz, 1 H) 3.10 - 3.21 (m, 2 H) 2.97 - 3.08 (m, 3H) 2.79 (s, 3 H) 2.23 - 2.25 (m, 3 H).

[0162] Examples 1-49 [ka] N-(4-Fluoro-5-(((2R,5S)-5-methyl-2-((6-methylpyridin-3yl)methyl)morpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared from tert-butyl (2S,5S)-2-(bromomethyl)-5-methylmorpholine-4-carboxylate, 5-bromo-2-methylpyridine, and N-(4-fluoro-5-formylthiazol-2-yl)acetamide in a manner similar to Scheme 1 and Intermediate 26 (prepared according to literature procedures described in WO2018 / 140299A1). LCMS (ESI): [M+H] 378.1. 1 HNMR: (500 MHz, CDCl3) δ 11.67 (br s, 1 H) 8.33 (s, 1 H) 7.46 (dd, J=7.94, 1.83 Hz, 1 H) 7.08 (d, J=7.94 Hz, 1 H) 3.56 - 3.75 (m, 5 H) 2.75 - 2.88 (m, 2 H) 2.70 (dd, J=14.34, 5.19 Hz, 1 H) 2.57 (s, 1 H) 2.52 (s, 3 H) 2.41 - 2.49 (m, 2 H) 2.30 (s, 3 H) 1.07 (d, J=6.71 Hz, 3 H)

[0163] Example 2-1 [ka] N-(5-(((2S,5R)-2-Methyl-5-((2-methylpyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide: A mixture of benzyl (2R,5S)-4-[(2-acetamidothiazol-5-yl)methyl]-5-methyl-2-[(2-methyl-4-pyridyl)methyl]piperazine-1-carboxylate (300 mg, 0.607 mmol) and HBr (33% in HOAc, 1.0 mL) was stirred at room temperature for 4 h. The mixture was diluted with ether and the resulting precipitate was filtered, washed with ether and then dried under vacuum to give the title compound (282 mg, 105% yield, HBr salt). LCMS (ESI): [M+H] 360. 1 H NMR (400 MHz, methanol-d4) δ 8.69 (d, J=6.27 Hz, 1H), 8.03 (s, 1H), 7.96 (d, J=6.02 Hz, 1H), 7.79 (s, 1H), 4.84 (br s, 1H), 4.60 (d, J=14.81 Hz, 1H), 4.38 (br d, J=8.53 Hz, 1H), 3.65-3.88 (m, 3H), 3.37-3.53 (m, 4H), 2.82 (s, 3H), 2.28 (s, 3H), 1.59 (d, J=6.27 Hz, 3H).

[0164] Example 2-2 [ka] N-(5-(((2S,5R)-2,4-Dimethyl-5-((2-methylpyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide: To a mixture of N-[5-[[(2S,5R)-2-methyl-5-[(2-methyl-4-pyridyl)methyl]piperazin-1-yl]methyl]thiazol-2-yl]acetamide (50 mg, 0.114 mmol, hydrobromide salt), sodium triacetoxyborohydride (48 mg, 0.227 mmol) and formaldehyde (37% in water, 1.00 mL) was added triethylamine (23 mg, 0.227 mmol, 31 uL). The reaction solution was then heated in a microwave at 80° C. for 20 minutes. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (24 mg, 43% yield, TFA salt). (ESI): [M+H] 374. 1 H NMR (400 MHz, methanol-d4) δ 8.61 (d, J=6.27 Hz, 1H), 7.81 (s, 1H), 7.77 (br d, J=6.02 Hz, 1H), 7.23-7.30 (m, 1H), 4.13-4.27 (m, 1H), 3.85 (d, J=14.81 Hz, 1H), 3.60 (br d, J=11.29 Hz, 2H), 3.47 (d, J=10.04 Hz, 1H), 3.00-3.23 (m, 2H), 2.84-2.99 (m, 5H), 2.75 (s, 3H), 2.40-2.53 (m, 1H), 2.21 (s, 3H), 1.26-1.35 (m, 3H).

[0165] Example 2-3 [ka] N-(5-(((2S,5R)-4-Ethyl-2-methyl-5-((2-methylpyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide: To a mixture of N-[5-[[(2S,5R)-2-methyl-5-[(2-methyl-4-pyridyl)methyl]piperazin-1-yl]methyl]thiazol-2-yl]acetamide (50 mg, 0.114 mmol, hydrobromide salt), sodium triacetoxyborohydride (48 mg, 0.227 mmol), acetaldehyde (0.3 mL) and water (0.6 mL) was added triethylamine (57 mg, 0.568 mmol, 79 uL). The reaction solution was then heated in a microwave at 80° C. for 20 minutes. The mixture was concentrated in vacuo and purified by HPLC to give the title product (19 mg, 33% yield, TFA salt). LCMS (ESI): [M+H] 388. 1 H NMR (400 MHz, methanol-d4) δ 8.62 (d, J=6.27 Hz, 1H), 7.84 (s, 1H), 7.79 (d, J=6.27 Hz, 1H), 7.26 (s, 1H), 4.18 (br d, J=14.81 Hz, 1H), 3.85 (d, J=14.56 Hz, 1H), 3.72-3.81 (m, 1H), 3.65 (br dd, J=4.27, 14.05 Hz, 1H), 3.45-3.60 (m, 2H), 3.06-3.26 (m, 2H), 2.95 (br d, J=9.54 Hz, 2H), 2.89 (dd, J=3.01, 13.30 Hz, 1H), 2.75 (s, 3H), 2.54 (dd, J=10.54, 13.30 Hz, 1H), 2.22 (s, 3H), 1.37 (t, J=7.28 Hz, 3H), 1.33 (d, J=5.52 Hz, 3H).

[0166] Examples 2-4 [ka] N-(5-(((2S,5R)-4-Acetyl-2-methyl-5-((2-methylpyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide: To a solution of N-[5-[[(2S,5R)-2-methyl-5-[(2-methyl-4-pyridyl)methyl]piperazin-1-yl]methyl]thiazol-2-yl]acetamide (50 mg, 0.114 mmol, hydrobromide salt) in CHCl (1.0 mL) was added acetic anhydride (116 mg, 1.1 mmol, 107 uL), and triethylamine (57 mg, 0.567 mmol, 79 uL). The reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and purified by HPLC to give the title compound (34 mg, 58% yield, TFA salt). LCMS (ESI): [M+H] 402. 1 H NMR (400 MHz, methanol-d4) δ 8.53 (br d, J=5.77 Hz, 1H), 7.72-7.82 (m, 2H), 7.54 (s, 1H), 5.12 (br s, 1H), 4.24-4.48 (m, 2H), 3.82-4.06 (m, 2H), 3.69 (br d, J=6.78 Hz, 1H), 3.37-3.58 (m, 1H), 3.25 (br s, 1H), 3.08 (br d, J=12.55 Hz, 1H), 2.72 (s, 3H), 2.23 (s, 3H), 1.99 (br s, 3H), 1.81-1.96 (m, 1H), 1.19-1.43 (m, 3H).

[0167] Examples 2-5 [ka] N-(5-(((2S,5R)-5-((5-fluoropyrimidin-2-yl)methyl)-2-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 2-bromo-5-fluoropyrimidine, 1-benzyl 4-(tert-butyl)(2S,5S)-2-(bromomethyl)-5-methylpiperazine-1,4-dicarboxylate and N-(5-(chloromethyl)thiazol-2-yl)acetamide. LCMS (ESI): [M+H] 365. 1 H NMR (400 MHz, methanol-d4) δ 8.74 (s, 2H), 7.81 (s, 1H), 4.96 (d, J=14.81 Hz, 1H), 4.69 (d, J=14.56 Hz, 1H), 4.34-4.46 (m, 1H), 3.76-3.93 (m, 3H), 3.41-3.60 (m, 4H), 2.28 (s, 3H), 1.67 (d, J=6.27 Hz, 3H).

[0168] Examples 2-6 [ka] N-(5-(((2S,5R)-5-((5-fluoropyrimidin-2-yl)methyl)-2,4-dimethylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from N-(5-(((2S,5R)-5-((5-fluoropyrimidin-2-yl)methyl)-2-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide in a manner similar to Example 2-2. LCMS (ESI): [M+H] 379. 1H NMR (400 MHz, methanol-d4) δ 8.68 (d, J=0.75 Hz, 2H), 7.25 (s, 1H), 4.21 (d, J=14.56 Hz, 1H), 3.71-3.91 (m, 2H), 3.35-3.52 (m, 3H), 3.02-3.12 (m, 2H), 2.98 (s, 3H), 2.82 (br s, 1H), 2.46 (dd, J=11.29, 13.30 Hz, 1H), 2.21 (s, 3H), 1.30 (d, J=6.27 Hz, 3H).

[0169] Examples 2-7 [ka] N-(5-(((2S,5R)-4-Acetyl-5-((5-fluoropyrimidin-2-yl)methyl)-2-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from N-(5-(((2S,5R)-5-((5-fluoropyrimidin-2-yl)methyl)-2-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide in a manner similar to Example 2-4. LCMS (ESI): [M+H] 407. 1 H NMR (400 MHz, methanol-d4) δ 8.61 (br s, 2H), 7.61 (s, 1H), 5.06-5.44 (m, 1H), 4.57 (s, 2H), 3.93 (br s, 1H), 3.79 (br d, J=6.78 Hz, 1H), 3.33-3.63 (m, 5H), 2.24 (s, 3H), 2.01-2.14 (m, 3H), 1.32-1.54 (m, 3H).

[0170] Examples 2-8 [ka] N-(5-(((2S,5R)-5-((2,6-dimethylpyridin-4-yl)methyl)-2-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 4-bromo-2,6-dimethylpyridine, 1-benzyl 4-(tert-butyl)(2S,5S)-2-(bromomethyl)-5-methylpiperazine-1,4-dicarboxylate and N-(5-(chloromethyl)thiazol-2-yl)acetamide. LCMS (ESI): [M+H] 373. 1 H NMR (400 MHz, methanol-d4) δ 7.84 (s, 1H), 7.78 (s, 2H), 4.92-4.97 (m, 1H), 4.68 (d, J=14.81 Hz, 1H), 4.33-4.45 (m, 1H), 3.82-3.93 (m, 1H), 3.71-3.81 (m, 2H), 3.44-3.54 (m, 2H), 3.39 (d, J=7.03 Hz, 2H), 2.77 (s, 6H), 2.29 (s, 3H), 1.62 (d, J=6.53 Hz, 3H).

[0171] Examples 2-9 [ka] N-(5-(((2S,5R)-2-Methyl-5-((6-methylpyridin-3-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 5-bromo-2-methylpyridine, 1-benzyl 4-(tert-butyl)(2S,5S)-2-(bromomethyl)-5-methylpiperazine-1,4-dicarboxylate and N-(5-(chloromethyl)thiazol-2-yl)acetamide. LCMS (ESI): [M+H] 360. 1H NMR (400 MHz, methanol-d4) δ 8.86 (d, J=1.76 Hz, 1H), 8.57 (dd, J=2.01, 8.28 Hz, 1H), 7.96 (d, J=8.28 Hz, 1H), 7.84 (s, 1H), 4.91-4.96 (m, 1H), 4.67 (d, J=14.56 Hz, 1H), 4.30-4.43 (m, 1H), 3.70-3.95 (m, 3H), 3.43-3.57 (m, 2H), 3.41 (d, J=7.53 Hz, 2H), 2.81 (s, 3H), 2.29 (s, 3H), 1.62 (d, J=6.53 Hz, 3H).

[0172] Example 2-10 [ka] N-(5-(((2S,5R)-5-((2,6-dimethylpyridin-4-yl)methyl)-2,4-dimethylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from N-(5-(((2S,5R)-5-((2,6-dimethylpyridin-4-yl)methyl)-2-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide in a manner similar to Example 2-2. LCMS (ESI): [M+H] 388. 1 H NMR (400 MHz, methanol-d4) δ 7.61 (s, 2H), 7.26 (s, 1H), 4.19 (br d, J=15.06 Hz, 1H), 3.83 (d, J=14.81 Hz, 1H), 3.43-3.66 (m, 3H), 2.83-3.04 (m, 7H), 2.70 (s, 6H), 2.39-2.53 (m, 1H), 2.21 (s, 3H), 1.30 (d, J=6.02 Hz, 3H).

[0173] Example 2-11 [ka] N-(5-(((2S,5R)-2,4-dimethyl-5-((6-methylpyridin-3-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from N-(5-(((2S,5R)-2-methyl-5-((6-methylpyridin-3-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide in a manner similar to Example 2-2. LCMS (ESI): [M+H] 374. 1 H NMR (400 MHz, methanol-d4) δ 8.67 (d, J=2.01 Hz, 1H), 8.35 (dd, J=2.01, 8.53 Hz, 1H), 7.84 (d, J=8.53 Hz, 1H), 7.26 (s, 1H), 4.19 (d, J=14.56 Hz, 1H), 3.86 (d, J=14.81 Hz, 1H), 3.40-3.60 (m, 3H), 2.84-3.08 (m, 6H), 2.76 (s, 3H), 2.49 (dd, J=10.79, 13.05 Hz, 1H), 2.21 (s, 3H), 1.29 (d, J=5.77 Hz, 3H).

[0174] Example 2-12 [ka] N-(5-(((2S,5R)-4-ethyl-2-methyl-5-((6-methylpyridin-3-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from N-(5-(((2S,5R)-2-methyl-5-((6-methylpyridin-3-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide in a manner similar to Example 2-3. LCMS (ESI): [M+H] 388. 1H NMR (400 MHz, methanol-d4) δ 8.67 (d, J=1.76 Hz, 1H), 8.35 (dd, J=2.01, 8.28 Hz, 1H), 7.84 (d, J=8.53 Hz, 1H), 7.24 (s, 1H), 4.15 (br d, J=14.56 Hz, 1H), 3.84 (d, J=14.81 Hz, 1H), 3.45-3.73 (m, 4H), 3.21 (q, J=7.28 Hz, 2H), 2.97-3.09 (m, 1H), 2.85-2.96 (m, 2H), 2.76 (s, 3H), 2.49 (dd, J=10.42, 13.18 Hz, 1H), 2.21 (s, 3H), 1.38 (t, J=7.28 Hz, 3H), 1.31-1.34 (m, 3H).

[0175] Example 2-13 [ka] N-(5-(((2S,5R)-5-((2,6-dimethylpyrimidin-4-yl)methyl)-2-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 4-bromo-2,6-dimethylpyrimidine, 1-benzyl 4-(tert-butyl)(2S,5S)-2-(bromomethyl)-5-methylpiperazine-1,4-dicarboxylate and N-(5-(chloromethyl)thiazol-2-yl)acetamide. LCMS (ESI): [M+H] 375. 1 H NMR (400 MHz, methanol-d4) δ 7.80 (s, 1H), 7.73 (s, 1H), 4.78-4.84 (m, 1H), 4.49-4.61 (m, 1H), 4.37 (br s, 1H), 3.83 (br d, J=13.05 Hz, 1H), 3.63-3.78 (m, 2H), 3.37-3.53 (m, 3H), 3.32-3.37 (m, 1H), 2.87 (s, 3H), 2.75 (s, 3H), 2.26 (s, 3H), 1.58 (d, J=6.27 Hz, 3H).

[0176] Example 2-14 [ka] N-(5-(((2S,5R)-5-((2-methoxypyridin-4-yl)methyl)-2-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 4-bromo-2-methoxypyridine, 1-benzyl 4-(tert-butyl)(2S,5S)-2-(bromomethyl)-5-methylpiperazine-1,4-dicarboxylate and N-(5-(chloromethyl)thiazol-2-yl)acetamide. LCMS (ESI): [M+H] 376. 1 H NMR (400 MHz, methanol-d4) δ 8.34 (d, J=6.27 Hz, 1H), 7.63-7.75 (m, 2H), 7.49 (dd, J=1.38, 6.15 Hz, 1H), 4.77 (br d, J=14.81 Hz, 1H), 4.44-4.54 (m, 1H), 4.21-4.42 (m, 4H), 3.55-3.73 (m, 3H), 3.33-3.44 (m, 3H), 3.19-3.29 (m, 1H), 2.27 (s, 3H), 1.56 (d, J=6.27 Hz, 3H).

[0177] Example 2-15 [ka] N-(5-(((2S,5R)-4-Acetyl-5-((2,6-dimethylpyridin-4-yl)methyl)-2-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from N-(5-(((2S,5R)-5-((2,6-dimethylpyridin-4-yl)methyl)-2-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide in a manner similar to that of Example 2-4. LCMS (ESI): [M+H] 416. 1H NMR (400 MHz, methanol-d4) δ 7.55 (d, J=4.27 Hz, 3H), 5.09 (br s, 1H), 4.56 (br s, 1H), 4.26-4.47 (m, 2H), 3.80-3.98 (m, 2H), 3.71 (br d, J=6.02 Hz, 1H), 3.13-3.28 (m, 2H), 3.06 (br d, J=12.55 Hz, 1H), 2.67 (s, 6H), 2.23 (s, 3H), 1.92-2.10 (m, 3H), 1.22-1.44 (m, 3H).

[0178] Example 2-16 [ka] N-(5-(((2S,5R)-4-Acetyl-2-methyl-5-((6-methylpyridin-3-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from N-(5-(((2S,5R)-2-methyl-5-((6-methylpyridin-3-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide in a manner similar to Example 2-4. LCMS (ESI): [M+H] 402. 1 H NMR (400 MHz, methanol-d4) δ 8.60 (d, J=1.76 Hz, 1H), 8.32 (dd, J=2.01, 8.28 Hz, 1H), 7.78 (br d, J=8.03 Hz, 1H), 7.48 (s, 1H), 5.04 (br s, 1H), 4.13-4.37 (m, 2H), 3.72-3.96 (m, 2H), 3.57 (br s, 1H), 3.35-3.48 (m, 1H), 3.06-3.25 (m, 2H), 2.99 (br d, J=12.80 Hz, 1H), 2.74 (s, 3H), 2.23 (s, 3H), 1.99 (s, 3H), 1.14-1.39 (m, 3H).

[0179] Example 2-17 [ka] N-(5-(((2S,5R)-5-((2,6-dimethylpyrimidin-4-yl)methyl)-2,4-dimethylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from N-(5-(((2S,5R)-5-((2,6-dimethylpyrimidin-4-yl)methyl)-2-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide in a manner similar to Example 2-2. LCMS (ESI): [M+H] 389. 1 H NMR (400 MHz, methanol-d4) δ 7.61 (s, 2H), 7.26 (s, 1H), 4.19 (br d, J=15.06 Hz, 1H), 3.83 (d, J=14.81 Hz, 1H), 3.43-3.66 (m, 3H), 2.83-3.04 (m, 7H), 2.70 (s, 6H), 2.39-2.53 (m, 1H), 2.21 (s, 3H), 1.30 (d, J=6.02 Hz, 3H).

[0180] Example 2-18 [ka] N-(5-(((2S,5R)-5-((2-methoxypyridin-4-yl)methyl)-2,4-dimethylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from N-(5-(((2S,5R)-5-((2-methoxypyridin-4-yl)methyl)-2-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide in a manner similar to Example 2-2. LCMS (ESI): [M+H] 390. 1H NMR (400 MHz, methanol-d4) δ 8.01 (d, J=5.27 Hz, 1H), 7.18 (s, 1H), 6.81 (dd, J=1.38, 5.40 Hz, 1H), 6.68 (s, 1H), 4.16 (d, J=14.31 Hz, 1H), 3.88 (s, 3H), 3.68 (d, J=14.56 Hz, 1H), 3.42-3.57 (m, 2H), 3.36 (br dd, J=3.89, 13.68 Hz, 1H), 2.92-3.04 (m, 4H), 2.81 (dd, J=2.89, 13.43 Hz, 2H), 2.59-2.72 (m, 1H), 2.18-2.31 (m, 4H), 1.27 (d, J=6.27 Hz, 3H).

[0181] Intermediate 20 [ka] 1-Benzyl 4-(tert-butyl) 2-(hydroxymethyl)piperazine-1,4-dicarboxylate: To a mixture of 1-((benzyloxy)carbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (3.05 g, 8.37 mmol) in THF (50.0 mL), borane dimethylsulfide complex (10 M, 1.67 mL) was added dropwise at 0° C., and then the mixture was stirred at 70° C. for 1 h. The mixture was cooled to 0° C., quenched with MeOH, and stirred at 70° C. for an additional 2 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc=3 / 1) to give the title compound (1.01 g, 34% yield). 1 H NMR (500 MHz, CDCl3) δ 7.31-7.37 (m, 5H), 5.10-5.17 (m, 2H), 4.17-4.33 (m, 1H), 3.92-4.02 (m, 2H), 3.62-3.73 (m, 2H), 2.75-3.34 (m, 4H), 1.46 (s, 9H).

[0182] Intermediate 21 [ka] 1-Benzyl 4-(tert-butyl) 2-(((methylsulfonyl)oxy)methyl)piperazine-1,4-dicarboxylate: The title compound was prepared in a similar manner to Intermediate 15. The resulting crude material was used in the next step without further purification.

[0183] Intermediate 22 [ka] 1-Benzyl 4-(tert-butyl) 2-(bromomethyl)piperazine-1,4-dicarboxylate: The title compound was prepared in a similar manner to Intermediate 16. 1 H NMR (500 MHz, CDCl3) δ 7.32-7.39 (m, 5H), 5.14-5.18 (m, 2H), 4.22-4.48 (m, 2H), 3.83-4.01 (m, 2H), 3.35-3.47 (m, 2H), 2.82-3.07 (m, 3H), 1.47 (s, 9H).

[0184] Example 2-19 [ka] N-(5-((3-((5-fluoropyrimidin-2-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 2-bromo-5-fluoropyrimidine, 1-benzyl 4-(tert-butyl) 2-(bromomethyl)piperazine-1,4-dicarboxylate and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that of Scheme 2.

[0185] Example 2-20 [ka] The mixture of enantiomers of Example 2-19, namely (R)-N-(5-((3-((5-fluoropyrimidin-2-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide and (S)-N-(5-((3-((5-fluoropyrimidin-2-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide, was separated. Optical separation method: SFC, Column: CHIRALPAK IC 250x30mm, 10um; 0.1% NH3H2O ​​EtOH, Flow rate (ml / min): 80. The product was: Peak 1: LCMS (ESI): [M+H] 351. 1 H NMR (400 MHz, D2O) δ 8.65 (s, 2H), 7.30 (s, 1H), 3.70-3.80 (m, 2H), 3.24-3.26 (m, 1H), 3.00-3.02 (m, 3H), 2.87-2.95 (m, 1H), 2.76-2.84 (m, 2H), 2. 25 (s, 3H), 2.20-2.23 (m, 1H), 1.95-2.00 (m, 1H). Peak 2: LCMS (ESI): [M+H] 351. 1 H NMR (400 MHz, D2O) δ 8.65 (s, 2H), 7.30 (s, 1H), 3.70-3.80 (m, 2H), 3.24-3.26 (m, 1H), 3.00-3.02 (m, 3H), 2.87-2.95 (m, 1H), 2.76-2.84 (m, 2H), 2. 25 (s, 3H), 2.20-2.23 (m, 1H), 1.95-2.00 (m, 1H).

[0186] Intermediate 23 [ka] 2-((4-((benzyloxy)carbonyl)-1-(tert-butoxycarbonyl)piperazin-2-yl)methoxy)-2-oxoacetic acid: A round-bottom flask was charged with 4-benzyl 1-(tert-butyl) 2-(hydroxymethyl)piperazine-1,4-dicarboxylate (8.0 g, 22.83 mmol), followed by diethyl ether (35.0 mL). The solution was cooled to 0 °C. Oxalyl chloride (5.8 g, 45.66 mmol, 2.0 equiv.) was added dropwise. The homogeneous reaction mixture was warmed to 28 °C and stirred for 18 h. The reaction was cooled to 0 °C and quenched by the slow addition of H2O (90 mL). After stirring at 25 °C for 1 h, the resulting mixture was transferred to a separatory funnel and the aqueous mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (3.0 g, 31% yield). LCMS (ESI): [M-Boc+H] 323.

[0187] Intermediate 24 [ka] 4-Benzyl 1-(tert-butyl) 2-((2-methoxypyridin-4-yl)methyl)piperazine-1,4-dicarboxylate: 4-bromo-2-methoxypyridine (50.0 mg, 0.265 mmol) and 2-((4-((benzyloxy)carbonyl)-1-(tert-butoxycarbonyl)piperazin-2-yl)methoxy)-2-oxo in dioxane (16.0 mL) and DMSO (4.0 mL). To a suspension of acetic acid (112.3 mg, 0.265 mmol, 1.0 equiv) was added NiCl2 glyme (5.8 mg, 26.59 umol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (3.0 mg, 2.66 umol), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (10.7 mg, 39.89 umol) and CsHCO3 (154.7 mg, 797.79 umol). The mixture was stirred and irradiated with a blue LED at 60 °C under N2 for 60 h. The reaction mixture was concentrated and the residue was treated with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phase was washed with water (2 x 20 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (petroleum ether: EtOAc = 3:1) to give 20 mg of impure product, which was purified by preparative HPLC ((0.04% NH3·H2O + 10 mM NH4HCO3); mobile phase B: acetonitrile; column: water Xbridge Prep OBD C18 150 × 30 × 5 um; detection wavelength: 220 nm) to give the title compound (5.0 mg, yield 4.26%). 1 H NMR (400 MHz, CDCl3) δ 8.07-7.93 (m, 1H), 7.36-7.33 (m, 5H), 6.74-6.53 (m, 2H), 5.29-5.11 (m, 2H), 4.11-3.92 (m, 4H), 3.92 (s, 3H), 3.08-2.95 (m, 3H), 2.72-2.71 (m, 2H), 1.43 (s, 9H).

[0188] Intermediate 25 [ka] tert-Butyl 2-((2-methoxypyridin-4-yl)methyl)piperazine-1-carboxylate: To a solution of 4-benzyl 1-(tert-butyl) 2-((2-methoxypyridin-4-yl)methyl)piperazine-1,4-dicarboxylate (80.0 mg, 0.181 mmol) in MeOH (5.0 mL) was added Pd / C (28.9 mg, 0.271 mmol). The reaction mixture was stirred under 40 psi of H2(g) at 30° C. for 3 h. The reaction mixture was filtered and concentrated in vacuo to give the title compound (50.0 mg, 89% yield). LCMS (ESI): [M+H] 308.

[0189] Intermediate 26 [ka] tert-Butyl-4-((2-acetamidothiazol-5-yl)methyl)-2-((2-methoxypyridin-4-yl)methyl)piperazine-1-carboxylate: A solution of tert-butyl 2-((2-methoxypyridin-4-yl)methyl)piperazine-1-carboxylate (50.0 mg, 0.162 mmol) and N-(5-formylthiazol-2-yl)acetamide (41.52 mg, 0.244 mmol) in MeOH (5.0 mL) was stirred at 50° C. for 0.5 h. Sodium cyanoborohydride (25.6 mg, 0.406 mmol) was added and the mixture was stirred at 50° C. for 16 h. The reaction mixture was purified by preparative TLC (petroleum ether / EtOAc=1 / 1) to give the title compound (70.0 mg, 93% yield). LCMS (ESI): [M+H] 462.

[0190] Example 2-21 [ka] N-(5-((3-((2-Methoxypyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide: To a solution of tert-butyl 4-((2-acetamidothiazol-5-yl)methyl)-2-((2-methoxypyridin-4-yl)methyl)piperazine-1-carboxylate (70.0 mg, 0.151 mmol) in DCM (10.0 mL) was added TFA (1.0 mL). The reaction mixture was stirred at 30 °C for 1 h. The reaction mixture was concentrated and basified to pH 9 with NH3·H2O. The residue was purified by preparative HPLC (mobile phase: water (10 mM NH4HCO3)-ACN; column: xtimate prep OBD C). 18 150×25 mm×5 um; detection wavelength: 220 nm) to give the title compound (30.0 mg, 54% yield). LCMS (ESI): [M+H] 362. The resulting enantiomers were separated using chiral SFC.

[0191] Example 2-22 [ka] The mixture of enantiomers of Example 2-21, i.e. (R)-N-(5-((3-((2-methoxypyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide and (S)-N-(5-((3-((2-methoxypyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide, was separated. Optical separation method: SFC, Column: DAICEL CHIRALPAK AD (250mm x 30mm, 10um); Ethanol (0.1% NH3·H2O) in CO2. The products were: Peak 1: LCMS (ESI): [M+H] 351. 1H NMR (400 MHz, D2O) δ 8.65 (s, 2H), 7.30 (s, 1H), 3.70-3.80 (m, 2H), 3.24-3.26 (m, 1H), 3.00-3.02 (m, 3H), 2.87-2.95 (m, 1H), 2.76-2.84 (m, 2H), 2. 25 (s, 3H), 2.20-2.23 (m, 1H), 1.95-2.00 (m, 1H). Peak 2: LCMS (ESI): [M+H] 351. 1 H NMR (400 MHz, D2O) δ 8.65 (s, 2H), 7.30 (s, 1H), 3.70-3.80 (m, 2H), 3.24-3.26 (m, 1H), 3.00-3.02 (m, 3H), 2.87-2.95 (m, 1H), 2.76-2.84 (m, 2H), 2. 25 (s, 3H), 2.20-2.23 (m, 1H), 1.95-2.00 (m, 1H).

[0192] Intermediate 27 [ka] 1-Benzyl 4-(tert-butyl) 2-methyl 1,4-diazepane-1,2,4-tricarboxylate: To a stirred solution of 1-(tert-butyl) 3-methyl 1,4-diazepane-1,3-dicarboxylate (5.00 g, 19.36 mmol) and triethylamine (4.11 g, 41 mmol, 5.6 mL) in dichloromethane (120 mL) was added benzyl carbonochloridate (3.63 g, 21.3 mmol, 3.0 mL) dropwise at 0° C. The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 1 h. The reaction was then quenched by the addition of water. The organic layer was washed with water and then with brine. The organic layer was then separated, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in heptane) to give the title compound (6.80 g, 89% yield). LCMS (ESI): [M-Boc] 293. 1H NMR (400 MHz, methanol-d4) δ 7.23-7.43 (m, 5H), 5.15-5.25 (m, 1H), 4.99-5.13 (m, 2H), 4.15-4.32 (m, 1H), 3.84-4.07 (m, 2H), 3.65-3.77 (m, 3H), 3.11-3.29 (m, 2H), 2.72-3.02 (m, 1H), 1.69-1.89 (m, 1H), 1.51-1.67 (m, 1H), 1.33-1.45 (m, 9H).

[0193] Intermediate 28 [ka] 1-Benzyl 4-(tert-butyl) 2-(hydroxymethyl)-1,4-diazepane-1,4-dicarboxylate: To a solution of 1-benzyl 4-(tert-butyl) 2-methyl 1,4-diazepane-1,2,4-tricarboxylate (1.00 g, 2.55 mmol) in methanol (10 mL) at 0° C. was added sodium borohydride (145 mg, 3.82 mmol) in portions. The reaction was stirred at room temperature for 2 h. Sodium borohydride (50 mg) was then added. The reaction was stirred for 30 min. An additional amount of sodium borohydride (50 mg) was added. Stirred for an additional 30 min. The reaction was quenched with brine. The mixture was concentrated in vacuo, the residue was diluted with ethyl acetate, washed with brine, dried, and the residue was purified by silica gel chromatography (0-100% EtOAc in heptane) to give the title compound (855 mg, 92% yield). LCMS (ESI): [M+Na] 387. 1H NMR (400 MHz, methanol-d4) δ 7.22-7.42 (m, 5H), 5.03-5.23 (m, 2H), 4.45-4.69 (m, 1H), 3.88-4.10 (m, 3H), 3.51-3.65 (m, 2H), 3.16-3.27 (m, 1H), 2.97-3.14 (m, 1H), 2.71-2.93 (m, 1H), 1.76 (br s, 1H), 1.48-1.61 (m, 1H), 1.33-1.45 (m, 9H).

[0194] Intermediate 29 [ka] 1-Benzyl 4-(tert-butyl) 2-(((methylsulfonyl)oxy)methyl)-1,4-diazepane-1,4-dicarboxylate: To a solution of 1-benzyl 4-(tert-butyl) 2-(hydroxymethyl)-1,4-diazepane-1,4-dicarboxylate (850 mg, 2.33 mmol) and triethylamine (589 mg, 5.83 mmol, 807 uL) in ether (10 mL) was added methanesulfonyl chloride (320 mg, 2.80 mmol, 216 uL) dropwise at 0° C. The reaction was then allowed to warm to room temperature. After 2 hours the reaction was diluted with ethyl acetate, washed with brine, dried over MgSO4 and evaporated to give the title compound (880 mg, 85% yield), which was used in the next step without further purification. LCMS (ESI): [M+Na] 465; 1 H NMR (400 MHz, methanol-d4) δ 7.22-7.50 (m, 5H), 5.01-5.28 (m, 2H), 4.15-4.47 (m, 2H), 3.79-4.12 (m, 3H), 3.38-3.79 (m, 1H), 3.14-3.26 (m, 1H), 2.95-3.12 (m, 3H), 2.72-2.94 (m, 1H), 1.73-1.94 (m, 1H), 1.51-1.65 (m, 1H), 1.28-1.50 (m, 9H).

[0195] Intermediate 30 [ka] 1-Benzyl 4-(tert-butyl) 2-(bromomethyl)-1,4-diazepane-1,4-dicarboxylate: To a solution of 1-benzyl 4-(tert-butyl) 2-(((methylsulfonyl)oxy)methyl)-1,4-diazepane-1,4-dicarboxylate (870 mg, 1.97 mmol) in tetrahydrofuran (15 mL) was added lithium bromide (1.37 g, 15.76 mmol). The reaction mixture was then heated at 50° C. for 6 h, cooled to room temperature, and subsequently concentrated in vacuo. The residue was diluted with dichloromethane, causing a white precipitate to form and be removed by filtration. The eluent was concentrated and purified by silica gel chromatography (0-100% EtOAc in heptane) to give the title compound (125 mg, 15% yield). LCMS (ESI): [M+Na] 449 / 451. 1 H NMR (400 MHz, chloroform-d) δ 7.29-7.45 (m, 5H), 5.06-5.26 (m, 2H), 4.57-4.89 (m, 1H), 3.91-4.25 (m, 3H), 3.29-3.58 (m, 2H), 2.64-3.27 (m, 3H), 1.67-2.00 (m, 2H), 1.36-1.53 ​​(m, 9H).

[0196] Intermediate 31 [ka] 1-Benzyl 4-(tert-butyl) 2-((5-fluoropyrimidin-2-yl)methyl)-1,4-diazepane-1,4-dicarboxylate: The title compound was prepared from 2-bromo-5-fluoropyrimidine and 1-benzyl 4-(tert-butyl) 2-(bromomethyl)-1,4-diazepane-1,4-dicarboxylate in a similar manner to intermediate 1. LCMS (ESI): [M+H] 445. 1H NMR (400 MHz, methanol-d4) δ 8.31-8.51 (m, 2H), 7.09-7.44 (m, 5H), 4.88-5.10 (m, 2H), 4.68-4.80 (m, 1H), 3.84-4.12 (m, 3H), 3.12-3.26 (m, 1H), 2.93-3.08 (m, 3H), 2.76-2.92 (m, 1H), 1.73-1.93 (m, 1H), 1.58 (br s, 1H), 1.33-1.44 (m, 9H).

[0197] Intermediate 32 [ka] Benzyl 2-((5-fluoropyrimidin-2-yl)methyl)-1,4-diazepane-1-carboxylate hydrochloride: The title compound was prepared from 1-benzyl 4-(tert-butyl) 2-((5-fluoropyrimidin-2-yl)methyl)-1,4-diazepane-1,4-dicarboxylate in a similar manner to intermediate 2. LCMS (ESI): [M+H] 345.

[0198] Intermediate 33 [ka] Benzyl 4-((2-acetamidothiazol-5-yl)methyl)-2-((5-fluoropyrimidin-2-yl)methyl)-1,4-diazepane-1-carboxylate: The title compound was prepared from benzyl 2-[(5-fluoropyrimidin-2-yl)methyl]-1,4-diazepane-1-carboxylate hydrochloride and N-[5-(chloromethyl)thiazol-2-yl]acetamide in a similar manner to intermediate 19. LCMS (ESI): [M+H] 499; 1H NMR (400 MHz, methanol-d4) δ 8.27-8.46 (m, 2H), 7.26-7.41 (m, 4H), 7.14-7.24 (m, 2H), 4.96-5.07 (m, 1H), 4.89-4.94 (m, 0.5H), 4.73-4.79 (m, 0.5H), 4.49-4.66 (m, 1H), 3.72-3.92 (m, 3H), 3.07-3.21 (m, 2H), 2.81-3.05 (m, 3H), 2.51-2.69 (m, 2H), 2.20 (d, J=2.76 Hz, 3H), 1.77-1.97 (m, 1H), 1.63 (br d, J=10.54 Hz, 1H).

[0199] Example 2-23 [ka] N-(5-((3-((5-fluoropyrimidin-2-yl)methyl)-1,4-diazepan-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from benzyl 4-((2-acetamidothiazol-5-yl)methyl)-2-((5-fluoropyrimidin-2-yl)methyl)-1,4-diazepane-1-carboxylate in a manner similar to that of Example 2-1. LCMS (ESI): [M+H] 365. 1 H NMR (400 MHz, methanol-d4) δ 8.67 (s, 2H), 7.73 (s, 1H), 4.69-4.80 (m, 2H), 4.58 (br s, 1H), 4.00 (dd, J=8.53, 15.31 Hz, 1H), 3.74-3.87 (m, 2H), 3.48-3.70 (m, 5H), 2.40-2.56 (m, 2H), 2.26 (s, 3H).

[0200] Example 2-24 [ka] N-(5-((3-((5-fluoropyrimidin-2-yl)methyl)-4-methyl-1,4-diazepan-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Example 2-2 from N-[5-[[3-[(5-fluoropyrimidin-2-yl)methyl]-1,4-diazepan-1-yl]methyl]thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 379. 1 H NMR (400 MHz, methanol-d4) δ 8.59 (s, 2H), 7.15 (s, 1H), 3.92 (br s, 1H), 3.78-3.88 (m, 2H), 3.52-3.63 (m, 2H), 3.40 (d, J=6.78 Hz, 2H), 3.01-3.11 (m, 5H), 2.80-2.97 (m, 2H), 2.08-2.27 (m, 5H).

[0201] Example 2-25 [ka] N-(5-((3-((2-Methoxypyridin-4-yl)methyl)-1,4-diazepan-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 4-bromo-2-methoxypyridine, 1-benzyl 4-(tert-butyl) 2-(bromomethyl)-1,4-diazepane-1,4-dicarboxylate and N-(5-(chloromethyl)thiazol-2-yl)acetamide. LCMS (ESI): [M+H] 376. 1H NMR (400 MHz, methanol-d4) δ 8.32 (d, J=6.02 Hz, 1H), 7.79 (s, 1H), 7.71 (s, 1H), 7.59 (d, J=5.77 Hz, 1H), 4.70 (s, 2H), 4.31 (s, 3H), 3.94-4.05 (m, 1H), 3.76 (br dd, J=6.65, 13.43 Hz, 1H), 3.56-3.72 (m, 3H), 3.44-3.56 (m, 3H), 3.36-3.43 (m, 1H), 2.52 (br t, J=8.91 Hz, 1H), 2.36-2.45 (m, 1H), 2.27 (s, 3H).

[0202] Example 2-26 [ka] N-(5-((4-acetyl-3-((2-methoxypyridin-4-yl)methyl)-1,4-diazepan-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from N-(5-((3-((2-methoxypyridin-4-yl)methyl)-1,4-diazepan-1-yl)methyl)thiazol-2-yl)acetamide hydrobromide in a manner similar to that of Example 2-4. LCMS (ESI): [M+H] 418. 1 H NMR (400 MHz, methanol-d4) δ 7.90-8.02 (m, 1H), 7.11-7.23 (m, 1H), 6.72-6.78 (m, 1H), 6.59 (d, J=7.53 Hz, 1H), 4.54-4.74 (m, 1H), 3.99-4.19 (m, 1H), 3.86 (d, J=2.01 Hz, 3H), 3.67-3.84 (m, 2H), 3.14 (dd, J=6.40, 15.18 Hz, 1H), 2.85-3.03 (m, 2H), 2.45-2.80 (m, 3H), 2.20 (d, J=1.76 Hz, 3H), 1.92-2.16 (m, 4H), 1.77-1.90 (m, 1H), 1.58 (br d, J=12.55 Hz, 1H).

[0203] Example 2-27 [ka] N-(5-((3-((2-Methylpyridin-4-yl)methyl)-1,4-diazepan-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 4-bromo-2-methylpyridine, 1-benzyl 4-(tert-butyl) 2-(bromomethyl)-1,4-diazepane-1,4-dicarboxylate and N-(5-(chloromethyl)thiazol-2-yl)acetamide. LCMS (ESI): [M+H] 360. 1 H NMR (400 MHz, methanol-d4) δ 8.67 (d, J=6.02 Hz, 1H), 8.13 (s, 1H), 8.01 (br d, J=6.02 Hz, 1H), 7.70 (s, 1H), 4.64-4.76 (m, 2H), 4.01 (dd, J=9.03, 15.56 Hz, 1H), 3.70-3.79 (m, 1H), 3.59-3.70 (m, 2H), 3.40-3.59 (m, 5H), 2.83 (s, 3H), 2.46-2.60 (m, 1H), 2.34-2.45 (m, 1H), 2.26 (s, 3H).

[0204] Example 2-28 [ka] N-(5-((3-((2,6-dimethylpyridin-4-yl)methyl)-1,4-diazepan-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from 4-bromo-2,6-dimethylpyridine, 1-benzyl 4-(tert-butyl) 2-(bromomethyl)-1,4-diazepane-1,4-dicarboxylate and N-(5-(chloromethyl)thiazol-2-yl)acetamide. LCMS (ESI): [M+H] 374. 1H NMR (400 MHz, methanol-d4) δ 7.86 (s, 2H), 7.73 (s, 1H), 4.78-4.85 (m, 1H), 4.72 (s, 2H), 4.03 (dd, J=8.91, 15.43 Hz, 1H), 3.77 (br dd, J=6.53, 13.55 Hz, 1H), 3.64 (dt, J=3.01, 7.03 Hz, 2H), 3.45-3.59 (m, 3H), 3.33-3.39 (m, 1H), 2.77 (s, 6H), 2.48-2.64 (m, 1H), 2.33-2.46 (m, 1H), 2.25-2.32 (m, 3H).

[0205] Example 2-29 [ka] N-(5-((4-acetyl-3-((2,6-dimethylpyridin-4-yl)methyl)-1,4-diazepan-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from N-(5-((3-((2,6-dimethylpyridin-4-yl)methyl)-1,4-diazepan-1-yl)methyl)thiazol-2-yl)acetamide in a manner similar to that of Example 2-4. LCMS (ESI): [M+H] 416. 1 H NMR (400 MHz, methanol-d4) δ 7.16 (d, J=18.57 Hz, 1H), 6.91 (d, J=19.58 Hz, 2H), 4.00-4.69 (m, 1H), 3.63-3.93 (m, 3H), 2.91-3.16 (m, 2H), 2.65-2.91 (m, 2H), 2.41-2.61 (m, 9H), 2.20 (s, 3H), 2.01-2.15 (m, 3H), 1.78-1.90 (m, 2H).

[0206] Example 2-30 [ka]

[0207] N-(5-((3-((2,6-dimethylpyridin-4-yl)methyl)-4-methyl-1,4-diazepan-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 2 from N-(5-((3-((2,6-dimethylpyridin-4-yl)methyl)-1,4-diazepan-1-yl)methyl)thiazol-2-yl)acetamide. LCMS (ESI): [M+H] 388.

[0208] Scheme 3 [ka]

[0209] Intermediate 34 [ka] 1-Benzyl 4-(tert-butyl)(2S,5S)-2-(((2,6-dimethylpyridin-4-yl)oxy)methyl)-5-methylpiperazine-1,4-dicarboxylate: To a mixture of 2,6-dimethylpyridin-4-ol (255 mg, 2.1 mmol, 193 uL) and K2CO3 (572 mg, 4.2 mmol) in DMF (2 mL) was added a solution of 1-benzyl 4-(tert-butyl)(2S,5S)-2-(bromomethyl)-5-methylpiperazine-1,4-dicarboxylate (885 mg, 2.1 mmol) in DMF (2 mL). The reaction mixture was then heated at 80 °C for 2 h. Remove all solvent under vacuum. The residue was purified by silica gel chromatography (0-100% EtOAc:heptane) to give the title product (116 mg, 12% yield). LCMS (ESI): [M+H] 470. 1H NMR (400 MHz, methanol-d4) δ 7.25-7.44 (m, 5H), 6.50-6.75 (m, 2H), 5.04-5.24 (m, 2H), 4.43-4.70 (m, 1H), 4.21-4.42 (m, 1H), 4.14-4.21 (m, 1H), 3.93-4.07 (m, 1H), 3.81 (br, d, =13.55 Hz, 1H), 3.33-3.40 (m, 1H), 3.21-3.30 (m, 1H), 2.40 (br, d, =15.56 Hz, 6H), 1.29-1.51(m, 9H), 1.17 (t, =7.53 Hz, 3H).

[0210] Intermediate 35 [ka] Benzyl (2S,5S)-2-(((2,6-dimethylpyridin-4-yl)oxy)methyl)-5-methylpiperazine-1-carboxylate: The title compound was prepared in a similar manner to Scheme 3 from 1-benzyl 4-(tert-butyl)(2S,5S)-2-(((2,6-dimethylpyridin-4-yl)oxy)methyl)-5-methylpiperazine-1,4-dicarboxylate. LCMS (ESI): [M+H] 370.

[0211] Intermediate 36 [ka] Benzyl (2S,5S)-4-((2-acetamidothiazol-5-yl)methyl)-2-(((2,6-dimethylpyridin-4-yl)oxy)methyl)-5-methylpiperazine-1-carboxylate: The title compound was prepared in a similar manner to Scheme 3 from benzyl (2S,5S)-2-(((2,6-dimethylpyridin-4-yl)oxy)methyl)-5-methylpiperazine-1-carboxylate and N-(5-(chloromethyl)thiazol-2-yl)acetamide. LCMS (ESI): [M+H] 524.

[0212] Example 3-1 [ka] N-(5-(((2S,5S)-5-(((2,6-dimethylpyridin-4-yl)oxy)methyl)-2-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 3 from benzyl (2S,5S)-4-((2-acetamidothiazol-5-yl)methyl)-2-(((2,6-dimethylpyridin-4-yl)oxy)methyl)-5-methylpiperazine-1-carboxylate. LCMS (ESI): [M+H] 390. 1 H NMR (400 MHz, methanol-d4) δ 7.74 (s, 1H), 7.36 (s, 2H), 4.82 (br d, J=14.56 Hz, 1H), 4.58-4.72 (m, 2H), 4.46 (br d, J=14.56 Hz, 1H), 4.26 (br d, J=8.78 Hz, 1H), 3.73 (dt, J=3.01, 13.43 Hz, 3H), 3.33-3.51 (m, 2H), 2.69 (s, 6H), 2.27 (s, 3H), 1.59 (d, J=6.27 Hz, 3H).

[0213] Example 3-2 [ka] N-(5-(((2S,5S)-5-(((2,6-dimethylpyridin-4-yl)oxy)methyl)-2,4-dimethylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from N-(5-(((2S,5S)-5-(((2,6-dimethylpyridin-4-yl)oxy)methyl)-2-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide in a manner similar to Example 2-2. LCMS (ESI): [M+H] 404. 1 H NMR (400 MHz, methanol-d4) δ.

[0214] Example 3-3 [ka] N-(5-(((2S,5S)-4-Acetyl-5-(((2,6-dimethylpyridin-4-yl)oxy)methyl)-2-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from N-(5-(((2S,5S)-5-(((2,6-dimethylpyridin-4-yl)oxy)methyl)-2-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide in a manner similar to Example 2-4. LCMS (ESI): [M+H] 432. 1 H NMR (400 MHz, methanol-d4) δ.

[0215] Examples 3-4 [ka] N-(5-(((2S,5S)-2-(((2,6-dimethylpyridin-4-yl)oxy)methyl)-5-methylmorpholino)methyl)thiazol-2-yl)acetamide: The title compound was prepared in a similar manner to Scheme 3 from (2S,5S)-2-(((2,6-dimethylpyridin-4-yl)oxy)methyl)-5-methylmorpholine N-[5-(chloromethyl)thiazol-2-yl]acetamide. LCMS (ESI): [M+H] 391. 1 H NMR (400 MHz, methanol-d4) δ.

[0216] Intermediate 37 [ka] N-(5-((6-(hydroxymethyl)-4-methyl-1,4-diazepan-1-yl)methyl)thiazol-2-yl)acetamide: To a mixture of (1-methyl-1,4-diazepan-6-yl)methanol (1.0 g, 6.6 mmol) and N-[5-(chloromethyl)thiazol-2-yl]acetamide (1.26 g, 6.6 mmol) in acetonitrile (20 mL) and DMF (1.0 mL) was added Hunig's base (1.70 g, 13.18 mmol, 2.30 mL). The reaction was stirred at room temperature for 4 h. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (50-100% EtOAc-EtOH 3:1, 2% NH4OH in heptane) to give the title compound (1.2 g, 55% yield). LCMS (ESI): [M+H] 299. 1 H NMR (400 MHz, methanol-d4) δ 7.23 (s, 1H), 3.82 (s, 2H), 3.36-3.45 (m, 2H), 2.81-2.92 (m, 3H), 2.61-2.80 (m, 4H), 2.56 (dd, J=8.78, 12.55 Hz, 1H), 2.47 (s, 3H), 2.20 (s, 3H), 2.06-2.16 (m, 1H).

[0217] Examples 3-5 [ka] N-(5-((6-(((5-fluoropyrimidin-2-yl)oxy)methyl)-4-methyl-1,4-diazepan-1-yl)methyl)thiazol-2-yl)acetamide: To a solution of N-[5-[[6-(hydroxymethyl)-4-methyl-1,4-diazepan-1-yl]methyl]thiazol-2-yl]acetamide (100 mg, 335 umol) and 2-bromo-5-fluoro-pyrimidine (59 mg, 335 umol) in THF (2.00 mL) and DMF (0.5 mL) was added NaH (20.11 mg, 503 umol, 60% purity). The mixture was stirred at room temperature overnight. Methanol was added to the mixture followed by concentration in vacuo. The residue was purified by HPLC to give the title compound (8 mg, 5% yield) as the trifluoroacetate salt. LCMS (ESI): [M+H] 395. 1 H NMR (400 MHz, methanol-d4) δ 8.53 (s, 2H), 7.39 (s, 1H), 4.26-4.42 (m, 2H), 4.15 (s, 2H), 3.51-3.65 (m, 3H), 3.38-3.48 (m, 1H), 3.15-3.27 (m, 3H), 2.96-3.06 (m, 4H), 2.73-2.84 (m, 1H), 2.21 (s, 3H).

[0218] Scheme 4 [ka]

[0219] Intermediate 38 [ka] 4-Benzyl 1-(tert-butyl) 2-methylpiperazine-1,2,4-tricarboxylate: To a solution of 1-(tert-butyl) 2-methylpiperazine-1,2-dicarboxylate (10.0 g, 40.9 mmol) and Et3N (4.56 g, 45.0 mmol) in DCM (100.0 mL) under N2 at 0 °C was added Cbz-Cl (7.68 g, 45.0 mmol) dropwise. Upon addition the solution became cloudy and the mixture was stirred at 0 °C for 30 min. The reaction was warmed to 30 °C for 10 h. The reaction was quenched with aqueous NH4Cl (20 mL) and extracted with EtOAc (3 x 60 mL). The combined organics were washed with brine (2 x 50 mL) and dried over Na2SO4. Then the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / EtOAc=5 / 1) to give the title compound (10.5 g, yield 67.79%). 1 H NMR (500MHz, CDCl3) δ 7.31-7.36 (m, 5H), 5.07-5.17 (m, 2H), 4.56-4.76 (m, 3H), 3.59-3.87 (m, 4H), 3.28-2.90 (m, 3H), 1.47 (s, 9H).

[0220] Intermediate 39 [ka] 4-Benzyl 1-(tert-butyl) 2-(hydroxymethyl)piperazine-1,4-dicarboxylate: To a solution of 4-benzyl 1-(tert-butyl) 2-methylpiperazine-1,2,4-tricarboxylate (7.0 g, 18.5 mmol) in THF (30.0 mL) and EtOH (30.0 mL) was added CaCl2 (3.29 g, 29.6 mmol) and stirred at 30 °C until the salt dissolved. The resulting mixture was cooled to 0 °C and NaBH4 (3.5 g, 92.5 mmol) was added. The reaction was stirred at 0 °C for 30 min, then warmed to 30 °C and stirred for 4 h. The reaction was quenched with HCl (2 M, 10 mL) and stirred until effervescence ceased. The mixture was then extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (2×30 mL), dried over Na 2 SO 4 , concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / EtOAc=1 / 1) to give the title compound (5.12 g, 79% yield). 1 H NMR (400MHz, CDCl3) δ 7.29-7.39 (m, 5H), 5.16 (s, 2H), 3.85-4.19 (m, 4H), 3.59 (br s, 2H), 3.00 (br s, 3H), 1.46 (s, 9H).

[0221] Intermediate 40 [ka] 4-Benzyl 1-(tert-butyl) 2-formylpiperazine-1,4-dicarboxylate: To a solution of (COCl)2 (17.39 g, 137.00 mmol) in DCM (120 mL) was added DMSO (16.06 g, 205.5 mmol) dropwise at -70°C and stirred for 30 min. A solution of 4-benzyl 1-(tert-butyl) 2-(hydroxymethyl)piperazine-1,4-dicarboxylate (12.0 g, 34.25 mmol) in DCM (100 mL) was added dropwise and the mixture was stirred at -70°C for 1 h. Et3N (27.7 g, 274.0 mmol) was added dropwise at -70°C and the mixture was stirred at -70°C for 1 h, then warmed to 0°C and stirred for an additional 1 h. The reaction was slowly quenched with water (200 mL) and extracted with DCM (2 x 200 mL). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on a silica gel column (petroleum ether / EtOAc = 10 / 1 to 5 / 1) to give the title compound (8.20 g, 68% yield). 1 HNMR (400 MHz, CDCl3) δ 9.57 (brs, 1H), 7.32-7.36 (m, 5H), 5.12 (s, 2H), 4.48-4.64 (m, 2H), 3.94-4.09 (m, 2H), 2.98-3.21 (m, 3H), 1.47 (s, 9H).

[0222] Intermediate 41 [ka] 4-Benzyl 1-(tert-butyl) 2-((2-tosylhydrazinelidene)methyl)piperazine-1,4-dicarboxylate: To a solution of 4-benzyl 1-(tert-butyl) 2-formylpiperazine-1,4-dicarboxylate (8.20 g, 23.54 mmol) in MeOH (150 mL) was added TsNHNH2 (4.34 g, 23.54 mmol). The mixture was stirred at 25 °C for 16 h. The solvent was removed and the residue was purified on a silica gel column (petroleum ether / EtOAc = 10:1 to 5:1, then 3:1) to give the title compound (11.50 g, 95% yield). LCMS (ESI): [M+H (-Boc)] 417.

[0223] Intermediate 42 [ka]

[0224] 4-Benzyl 1-(tert-butyl) 2-((2,6-dimethylpyridin-4-yl)methyl)piperazine-1,4-dicarboxylate: To a solution of 4-benzyl 1-(tert-butyl) 2-((2-tosylhydrazinelidene)methyl)piperazine-1,4-dicarboxylate (1.00 g, 1.94 mmol) in dioxane (10.0 mL) was added (2,6-dimethylpyridin-4-yl)boronic acid (292.23 mg, 1.94 mmol) and K2CO3 (802.60 mg, 5.81 mmol). The mixture was stirred at 110 °C for 5 h. The solvent was removed and the residue was treated with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column (petroleum ether / EtOAc = 3 / 1 to 1 / 1) to give the title compound (500.0 mg, yield 59%). 1HNMR (500 MHz, CDCl3) δ 7.34-7.36 (m, 5H), 6.75-6.80 (m, 2H), 5.18 (s, 2H), 3.93-4.20 (m, 4H), 2.95-3.15 (m, 3H), 2.43-2.48 (m, 2H), 2.27-2.38 (m, 6H), 1.46 (s, 9H).

[0225] Intermediate 43 [ka] tert-Butyl 2-((2,6-dimethylpyridin-4-yl)methyl)piperazine-1-carboxylate: The title compound was prepared in a similar manner to Intermediate 25.

[0226] Intermediate 44 [ka] tert-Butyl 4-((2-acetamidothiazol-5-yl)methyl)-2-((2,6-dimethylpyridin-4-yl)methyl)piperazine-1-carboxylate: The title compound was prepared in a similar manner to Intermediate 26. The resulting enantiomers were separated using chiral SFC.

[0227] Intermediate 45 [ka] The mixture of enantiomers of intermediate 44, i.e., tert-butyl (R)-4-((2-acetamidothiazol-5-yl)methyl)-2-((2,6-dimethylpyridin-4-yl)methyl)piperazine-1-carboxylate and tert-butyl (S)-4-((2-acetamidothiazol-5-yl)methyl)-2-((2,6-dimethylpyridin-4-yl)methyl)piperazine-1-carboxylate, was separated by SFC (column: REGIS(s,s)WHELK-O1 (250 mm×30 mm, 5 um); condition: 0.1% NH3H2O ​​EtOH) to give the title compound (100.0 mg, yield 31, Rt=4.56 min) as peak 1 and peak 2.

[0228] Example 4-1 [ka]

[0229] (R)-N-(5-((3-((2,6-dimethylpyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide hydrochloride: tert-Butyl (R)-4-((2-acetamidothiazol-5-yl)methyl)-2-((2,6-dimethylpyridin-4-yl)methyl)piperazine-1-carboxylate; To intermediate 45 (100.0 mg, 0.217 mmol) was added a solution of HCl in dioxane (0.217 mmol, 1.00 mL) and the mixture was stirred at 25° C. for 2 h. The mixture was concentrated and the residue was treated with water (5 mL) and lyophilized to give the title compound (80.0 mg, hydrochloride salt). LCMS (ESI): [M+H] 360. 1 HNMR: (500 MHz, MeOD) δ 7.76 (s, 2H), 7.70 (s, 1H), 4.57 (s, 2H), 4.20-4.22 (m, 1H), 3.62-3.71 (m, 3H), 3.50-3.55 (m, 1H), 3.33-3.41 (m, 4H), 2.76 (s, 6H), 2.25 (s, 3H).

[0230] Example 4-2 [ka] (S)-N-(5-((3-((2,6-dimethylpyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide hydrochloride: tert-butyl (S)-4-((2-acetamidothiazol-5-yl)methyl)-2-((2,6-dimethylpyridin-4-yl)methyl)piperazine-1-carboxylate; the title compound was prepared in a manner similar to Example 4-1 from Intermediate 46. LCMS (ESI): [M+H] 360. 1 HNMR: (500 MHz, MeOD) δ 7.76 (s, 2H), 7.71 (s, 1H), 4.58 (s, 2H), 4.20-4.23 (m, 1H), 3.64-3.72 (m, 3H), 3.50-3.56 (m, 1H), 3.35-3.41 (m, 4H), 2.76 (s, 6H), 2.26 (s, 3H).

[0231] Example 4-3 [ka] (R)-N-(5-((3-((2,6-dimethylpyridin-4-yl)methyl)-4-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide: (R)-N-(5-((3-((2,6-dimethylpyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide hydrochloride; The title compound was prepared from Example 4-1 in a manner similar to Example 2-2. LCMS (ESI): [M+H] 374. 1 HNMR: (500 MHz, CDCl3) δ 12.01 (s, 1H), 7.14 (s, 1H), 6.76 (s, 2H), 3.48-3.64 (m, 2H), 2.93-2.96 (m, 1H), 2.77-2.79 (m, 1H), 2.63-2.66 (m, 1H), 2.33-2.53 (m, 14H), 2.29 (s, 3H), 2.08-2.01 (m, 1H).

[0232] Example 4-4 [ka] (S)-N-(5-((3-((2,6-dimethylpyridin-4-yl)methyl)-4-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide: (S)-N-(5-((3-((2,6-dimethylpyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide hydrochloride; The title compound was prepared in a manner similar to Example 2-2 from Example 4-2. LCMS (ESI): [M+H] 374. 1 HNMR: (500 MHz, CDCl3) δ 12.23 (s, 1H), 7.13 (s, 1H), 6.75 (s, 2H), 3.48-3.64 (m, 2H), 2.93-2.95 (m, 1H), 2.76-2.79 (m, 1H), 2.63-2.66 (m, 1H), 2.32-2.53 (m, 14H), 2.28 (s, 3H), 2.01-2.08 (m, 1H).

[0233] Intermediate 47 [ka] tert-Butyl 4-((2-acetamidothiazol-5-yl)methyl)-2-(4-fluoro-3-methoxybenzyl)piperazine-1-carboxylate: The title compound was prepared from 4-benzyl 1-(tert-butyl) 2-((2-tosylhydrazinelidene)methyl)piperazine-1,4-dicarboxylate, (4-fluoro-3-methoxyphenyl)boronic acid, and N-(5-formylthiazol-2-yl)acetamide in a similar manner as intermediate 26. LCMS (ESI): [M+H] 479.

[0234] Examples 4-5 [ka] N-(5-((3-(4-Fluoro-3-methoxybenzyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide: To a solution of tert-butyl 4-((2-acetamidothiazol-5-yl)methyl)-2-(4-fluoro-3-methoxybenzyl)piperazine-1-carboxylate (80.0 mg, 0.167 mmol) in DCM (5.0 mL) was added TFA (2.98 g, 2.0 mL). The reaction mixture was stirred at 28 °C for 1 h. The mixture was adjusted to pH 8 with NH3·H2O. Water (5 mL) was added and extracted with DCM (10 mL × 2). The combined organic phase was dried over Na2SO4, filtered and concentrated. The resulting enantiomers were separated by SFC (column: Chiralpak AD-3 150×4.6 mm ID, 3 um mobile phase: A: CO2 B: ethanol (0.05% DEA)) to give Examples 4-6.

[0235] Examples 4-6 [ka] The mixture of enantiomers of Examples 4-5, i.e., (R)-N-(5-((3-(4-fluoro-3-methoxybenzyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide and (S)-N-(5-((3-(4-fluoro-3-methoxybenzyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide, was separated as follows. Peak 1: LCMS (ESI): [M+H] 379. 1 HNMR: (500 MHz, methanol-d4) δ 7.20 (s, 1H), 6.96-6.98 (m, 1H), 6.88-6.90 (m, 1H), 6.70-6.71 (m, 1H), 3.83 (s, 3H), 3.77(s, 2H), 2.92-2.96 (m, 2H), 2.76-2.79 (m, 3H), 2.61-2.65 (m, 2H), 2.18 (s, 3H), 2.17-2.18 (m, 1H), 1.82-1.87 (m, 1H). Peak 2: LCMS (ESI): [M+H] 379. 1HNMR: (500 MHz, methanol-d4) δ 7.22 (s, 1H), 6.91-6.99 (m, 2H), 6.72-6.75 (m, 1H), 3.88 (s, 3H), 3.71 (s, 2H), 3.10-3.13 (m, 2H), 2.83-2.96 (m, 3H), 2.72-2.74 (m, 2H), 2.25-2.35 (m, 1H), 2.19 (s, 3H), 1.98-2.03 (m, 1H).

[0236] Examples 4-7 [ka] The title compound was prepared from 4-benzyl 1-(tert-butyl) 2-((2-tosylhydrazinelidene)methyl)piperazine-1,4-dicarboxylate, (2-methylpyridin-4-yl)boronic acid, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that of Example 4-6.

[0237] Examples 4-8 [ka] The mixture of enantiomers obtained in Examples 4-7, i.e., (R)-N-(5-((3-((2-methylpyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide and (S)-N-(5-((3-((2-methylpyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide, was purified by SFC (column: DAICEL CHIRALPAK AD-H (250 mm x 30 mm, 5 um), condition: 0.1% NH3H2O ​​EtOH, flow rate (ml / min): 50): Peak 1: LCMS (ESI): [M+H] 346. 1HNMR: (500 MHz, CDCl3) δ 10.61 (br s, 1H), 8.39 (d, J=5.0 Hz, 1H), 7.18 (s, 1H), 7.00 (s, 1H), 6.94 (d, J=5.0 Hz, 1H), 3.66 (s, 2H), 2.96-3.05 (m, 1H), 2. 83-2.85 (m, 1H), 2.78-2.81 (m, 3H), 3.66-2.67 (m, 2H), 2.65 (s, 3H), 2.52 (s, 3H), 2.18-2.29 (m, 1H), 1.96-1.98 (m, 1H). Peak 2: LCMS (ESI): [M+H] 346. 1 HNMR: (500 MHz, CDCl3) δ 10.95 (s, 1H), 8.38 (d, J=5.0 Hz, 1H), 7.18 (s, 1H), 7.00 (s, 1H), 6.94 (d, J=5.0 Hz, 1H), 3.66 (s, 2H), 2.96-3.05 (m, 1H), 2.83-2.85 (m, 1H), 2.78-2.81 (m, 3H), 3.66-2.67 (m, 2H), 2.65 (s, 3H), 2.52 (s, 3H), 2.18-2.29 (m, 1H), 1.95-1.98 (m, 1H).

[0238] Examples 4-9 [ka] (R)-N-(5-((4-Methyl-3-((2-methylpyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide: (R)-N-(5-((3-((2-methylpyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide; The title compound was prepared in a similar manner to Example 2-2 from Example 4-8. LCMS (ESI): [M+H] 360. 1HNMR: (400 MHz, methanol-d4) δ 8.21 (d, J = 5.2 Hz, 1H), 7.15 (s, 1H), 7.10 (s, 1H), 7.04 (d, J = 4.8 Hz, 1H), 3.59-3.64 (m, 2H), 3.08-3.11 (m, 1H), 2.85-2.86 (m, 1H), 2.83-2.84 (m, 1H), 2.68-2.69 (m, 2H), 2.44-2.55 (m, 9H), 2.42 (s, 3H), 1.99-2.19 (m, 1H).

[0239] Examples 4-10 [ka] (S)-N-(5-((4-Methyl-3-((2-methylpyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide: (S)-N-(5-((3-((2-methylpyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide; The title compound was prepared in a similar manner to Example 2-2 from Example 4-9. LCMS (ESI): [M+H] 360. 1 HNMR: (400 MHz, methanol-d4) δ 8.21 (d, J = 5.6 Hz, 1H), 7.15 (s, 1H), 7.12 (s, 1H), 7.04 (d, J = 4.8 Hz, 1H), 3.55-3.64 (m, 2H), 3.09-3.12 (m, 1H), 2.85-2.86 (m, 1H), 2.83-2.84 (m, 1H), 2.68-2.69 (m, 2H), 2.44-2.54 (m, 9H), 2.42 (s, 3H), 1.99-2.19 (m, 1H).

[0240] Example 4-11 [ka] N-(5-((3-((2-methoxypyridin-4-yl)methyl)-4-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 4-benzyl 1-(tert-butyl) 2-((2-tosylhydrazinelidene)methyl)piperazine-1,4-dicarboxylate, (2-methoxypyridin-4-yl)boronic acid, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that of Example 4-10.

[0241] Example 4-12 [ka] The mixture of enantiomers obtained from Example 4-12, i.e. (R)-N-(5-((3-((2-methoxypyridin-4-yl)methyl)-4-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide and (S)-N-(5-((3-((2-methoxypyridin-4-yl)methyl)-4-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide, was separated by (column: DAICEL CHIRALPAK IC (250mm×30mm, 10um), condition: 0.1% NH3·H2O EtOH): Peak 1: LCMS (ESI): [M+H] 376. 1 HNMR: (500 MHz, methanol-d4) δ 8.94 (d, J = 5.2 Hz, 1H), 7.15 (s, 1H), 6.78 (d, J = 4.8 Hz, 1H), 6.61 (s, 1H), 3.85 (s, 3H), 3.55-3.66 (s, 2H), 3.06-3.08 (m, 1H), 2.84-2.85 (m, 1H), 2.81-2.83 (m, 1H), 2.40-2.60 (m, 8H), 2.19 (s, 3H), 1.99-2.02 (m, 1H). Peak 2: LCMS (ESI): [M+H] 376. 1HNMR: (500 MHz, methanol-d4) δ 7.95 (d, J = 5.6 Hz, 1H), 7.15 (s, 1H), 6.80 (d, J = 5.2 Hz, 1H), 6.61 (s, 1H), 3.85 (s, 3H), 3.56-3.69 (m, 2H), 3.07-3.09 (m, 1H), 2.85-2.89 (m, 1H), 2.69-2.72 (m, 1H), 2.44-2.60 (m, 8H), 2.19 (s, 3H), 1.99-2.02 (m, 1H).

[0242] Example 4-13 [ka] N-(5-((3-((6-methylpyridin-3-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from 4-benzyl 1-(tert-butyl) 2-((2-tosylhydrazinelidene)methyl)piperazine-1,4-dicarboxylate, (2-methylpyridin-4-yl)boronic acid, and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that in Example 4-6.

[0243] Example 4-14 [ka] The mixture of enantiomers obtained from Examples 4-14, i.e. (R)-N-(5-((3-((6-methylpyridin-3-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide and (S)-N-(5-((3-((6-methylpyridin-3-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide, was separated by SFC (DAICEL CHIRALPAK AD-H (250mm x 30mm, 5um); Start B: 45%; End B: 45%; Flow rate (ml / min: 50): Peak 1: LCMS (ESI): [M+H] 346. 1HNMR: (500 MHz, methanol-d4) δ 8.80 (s, 1H), 8.51-8.52 (m, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.60 (s, 1H), 4.38 (s, 2H), 4.05-4.06 (m, 1H), 3.31-3.65 (m, 6H), 3.16-3.17 (m, 2H), 2.81 (s, 3H), 2.25 (s, 3H). Peak 2: LCMS (ESI): [M+H] 346. 1 HNMR: (500 MHz, methanol-d4) δ 8.83 (s, 1H), 8.55 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.73 (s, 1H), 4.61 (s, 2H), 4.19-4.18 (m, 1H), 3.66-3.69 (m, 3H), 3.38-3.52 (m, 5H), 2.81 (s, 3H), 2.26 (s, 3H).

[0244] Example 4-15 [ka] (R)-N-(5-((4-Methyl-3-((6-methylpyridin-3-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide: (R)-N-(5-((3-((6-methylpyridin-3-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide; The title compound was prepared in a similar manner to Example 2-2 from Example 4-14. LCMS (ESI): [M+H] 360. 1HNMR: (400 MHz, methanol-d4) δ 8.21 (s, 1H), 7.55 (dd, J = 8.0, 2.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 3.60 (s, 2H), 3.10-3.13 (m, 1H), 2.86 (d, J = 11.6 Hz, 1H), 2.72 (d, J = 9.2 Hz, 1H), 2.34-2.50 (m, 11H), 2.19 (s, 3H), 1.94-1.97 (m, 1H).

[0245] Example 4-16 [ka] (S)-N-(5-((4-Methyl-3-((6-methylpyridin-3-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide: (S)-N-(5-((3-((6-methylpyridin-3-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide; The title compound was prepared in a similar manner to Example 2-2 from Example 4-15. LCMS (ESI): [M+H] 360. 1 HNMR: (400 MHz, methanol-d4) δ 8.21 (s, 1H), 7.54-7.57 (m, 1H), 7.16-7.21 (m, 2H), 3.60 (s, 2H), 3.12 (d, J = 11.6 Hz, 1H), 2.85-2.88 (m, 1H), 2.72 (d, J = 9.6 Hz, 1H), 2.34-2.54 (m, 11H), 2.19 (s, 3H), 1.98-1.97 (m, 1H).

[0246] Intermediate 48 [ka] 4-Benzyl 1-(tert-butyl)(Z)-2-((3-fluoro-2-methoxypyridin-4-yl)methylene)piperazine-1,4-dicarboxylate: To a solution of 4-benzyl 1-(tert-butyl)(Z)-2-((2-tosylhydrazinelidene)methyl)piperazine-1,4-dicarboxylate (1.0 g, 1.94 mmol) and 4-bromo-3-fluoro-2-methoxypyridine (0.599 g, 2.91 mmol) in dioxane (10.0 mL) was added Pd2(dba)3 (0.177 g, 0.194 mmol), XPhos (0.092 g, 0.194 mmol) and lithium 2-methylpropan-2-olate (0.465 g, 5.82 mmol). The mixture was stirred at 80 °C under N2 for 2 h. The reaction was concentrated and purified by silica gel column chromatography (petroleum ether / EtOAc=5 / 1) to give the title compound (118 mg, 13% yield). LCMS (ESI): [M+H] 458.

[0247] Intermediate 49 [ka] tert-Butyl 2-((3-fluoro-2-methoxypyridin-4-yl)methyl)piperazine-1-carboxylate: To a solution of 4-benzyl 1-(tert-butyl)(Z)-2-((3-fluoro-2-methoxypyridin-4-yl)methylene)piperazine-1,4-dicarboxylate (94 mg, 0.205 mmol) in MeOH (5.0 mL) was added Pd(OH)2 / C (29 mg, 0.021 mmol, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (40 Psi) at 30 °C for 2 h. The mixture was filtered and the eluent was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 2) to give the title compound (32.0 mg, 48% yield). LCMS (ESI): [M+H] 326.

[0248] Example 4-17 [ka] N-(5-((3-((3-fluoro-2-methoxypyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide: The title compound was prepared from tert-butyl 2-((3-fluoro-2-methoxypyridin-4-yl)methyl)piperazine-1-carboxylate (Intermediate X; above) and N-(5-formylthiazol-2-yl)acetamide in a manner similar to that of Example 2-22.

[0249] Example 4-18 [ka] The mixture of enantiomers obtained from Example 4-18, i.e. (R)-N-(5-((3-((3-fluoro-2-methoxypyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide and (S)-N-(5-((3-((3-fluoro-2-methoxypyridin-4-yl)methyl)piperazin-1-yl)methyl)thiazol-2-yl)acetamide, was separated by SFC (apparatus: SFC-14; condition: 0.1% NH3H2O ​​IPA); column: DAICEL CHIRALPAK AD-H (250mm x 30mm, 5um); start B: 35%; end B: 35%; flow rate (ml / min): 50): Peak 1: LCMS (ESI): [M+H] 380. 1 HNMR: (400 MHz, methanol-d4) δ 7.80 (d, J = 5.2 Hz, 1H), 7.22 (s, 1H), 6.83 (t, J = 4.8 Hz, 1H), 3.96 (s, 3H), 3.69-3.72 (m, 2H), 3.04-3.08 (m, 1H), 2.95-2.98 (m, 1H), 2.75-2.84 (m, 5H), 2.20 (s, 3H), 2.14-2.19 (m, 1H), 1.91-1.96 (m, 1H). Peak 2: LCMS (ESI): [M+H] 380. 1HNMR: (400 MHz, methanol-d4) δ 7.86 (d, J = 4.8 Hz, 1H), 7.24 (s, 1H), 6.86 (t, J = 4.8 Hz, 1H), 3.98 (s, 3H), 3.73-3.81 (m, 2H), 3.46-3.47 (m, 1H), 3.25-3.26 (m, 1H), 3.07-3.10 (m, 1H), 2.93-2.97 (m, 4H), 2.24-2.38 (m, 1H), 2.21-2.23 (m, 1H), 2.20 (s, 3H).

[0250] Biological Data

[0251] OGA enzyme inhibition biochemical assay 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 consisted of 1 nM OGA, 100 μM 4-MUGlcNAc (K m ), and compound in a final volume of 10 μl. Reactions were incubated at room temperature for 90 min, quenched with 40 μl of 3 M 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 in 4-fold dilutions. Data were fitted using a 4-parameter fit with variable slope using GraphPad Prism. [Table 1] [Table 2] [Table 3]

[0252] Although several embodiments have been described, it will be apparent that the basic examples may be modified to provide other embodiments that utilize the compounds and methods of the present disclosure. It will therefore be appreciated that the scope of the present disclosure is defined by the appended claims rather than the specific embodiments shown by way of example.

[0253] 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 by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one of ordinary skill in the art.

Claims

1. A compound represented by the following structural formula: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, wherein: Ar is an optionally substituted 5-10 membered aryl or an optionally substituted 5-10 membered heteroaryl, and when Ar is the sum of m and p is 1, it is not a 9 membered bicyclic heteroaryl having 1-4 nitrogen atoms; W is O or -NR ｄ and X is -CR ２ R ２ , -(CR ２ R ２ ) ２ , -(CR ２ R ２ )O- or -O(CR ２ R ２ )—wherein Y １ and Y ２ However, 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 -CH ２ C(=O); R ｃ But, -H, halo, -C １ -C ４ Alkyl, or -C １ -C ４ is haloalkyl, R ｄ But -H, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, or -C(=O)C １ -C ４ is alkyl; m is 1 or 2; p is 0 or 1, unless the sum of m and p is 3; n is 0 or an integer from 1 to 9; When n is other than 0, R １ each independently represents halo, -C １ -C ４ Alkyl, -C １ -C ４ Haloalkyl, or -C １ -C ４ is alkoxy; R ２ each independently represents -H, halo, -C １ -C ４ Alkyl, -C １ -C ４ Haloalkyl, -C ３ -C １０ cycloalkyl, or -C ３ -C １０ halocycloalkyl; Or, two R ２ together with the carbon atom to which they are attached, -C ３ -C １０ Forming a cycloalkyl; R ３ is -H or -C １ -C ４ is alkyl; and R ４ But -H, -C １ -C ４ Alkyl, -C １ -C ４ Haloalkyl, or -C ３ -C ６ is cycloalkyl; Or, R ３ and R ４ taken together with their intervening atoms form an optionally substituted 5- to 7-membered heterocyclyl; The compound or a pharma- ceutically acceptable salt thereof.

2. The compound has the following structural formula: 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof; １ is halo or -C １ -C ４ The compound of claim 1 , wherein the aryl group is an alkyl group.

3. The compound has the following structural formula: 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof; ２ are each independently -H or -C １ -C ４ 3. The compound of claim 1 or 2, which is alkyl.

4. The compound has the following structural formula: 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof; １ Ga-C １ -C ４ alkyl, R ２ is -H, -CH ３ or -CH ２ CH ３ The compound according to any one of claims 1 to 3,

5. The compound comprising: 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof; １ Ga-CH ３ and R ２ is -H or -CH ３ The compound according to any one of claims 1 to 3,

6. The compound has the following structural formula: 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof; １ Ga-C １ -C ４ alkyl, R ２ is -H, -CH ３ or -CH ２ CH ３ The compound according to any one of claims 1 to 3,

7. The compound comprising: 【Chemistry 7】 or a pharma- ceutically acceptable salt thereof; １ Ga-CH ３ and R ２ is -H or -CH ３ The compound according to any one of claims 1 to 3,

8. The compound has the following structural formula: 【Chemistry 8】 or a pharma- ceutically acceptable salt thereof; １ is halo or -C １ -C ４ The compound of claim 1 , wherein the aryl group is an alkyl group.

9. The compound has one of the following structural formulas: 【Chemistry 9】 or a pharma- ceutically acceptable salt thereof; R ｄ But -H, -C １ -C ４ Alkyl, or -C(=O)C １ -C ４ is alkyl; R １ But, -C １ -C ４ is alkyl; R ２ are each independently -H or C １ -C ４ is alkyl, A compound according to any one of claims 1 to 8.

10. R Ｃ But, halo, -C １ -C ４ Alkyl, or -C １ -C ４ 10. The compound of any one of claims 1, 2, 3, 8, and 9, which is a haloalkyl.

11. The compound has one of the following structural formulas: 【Chemistry 10】 or a pharma- ceutically acceptable salt thereof; ｄ is -H, -CH ３ , -CH ２ CH ３ or -C(=O)CH ３ 10. The compound according to any one of claims 1, 8 and 9,

12. The compound has one of the following structural formulas: 【Chemistry 11】 11. The compound according to any one of claims 1 and 8 to 10, represented by:

13. During the ceremony, (i) Ar is an optionally substituted 5- or 6-membered monocyclic heteroaryl; (ii) Ar is an optionally substituted 6-membered monocyclic heteroaryl containing one or more nitrogen atoms; (iii) Ar is optionally substituted pyridinyl, optionally substituted pyrimidinyl, or optionally substituted pyrazinyl; (iv) Ar is 【Chemistry 12】 or (v) Ar is 【Chemistry 13】 and Optionally, Ar in (i)-(v) is C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, C ３ -C ６ Cycloalkyl, C ３ -C ６ Heterocyclyl, halo, -CN, -NO ２ , -OR ｚ , -NR ｘ R ｙ , -S(O) ｉ R ｘ , -NR ｘ S (O) ｉ R ｙ , -S(O) ｉ N.R. 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 C on Ar １ -C ４ The alkyl group substituent is -CN, -NO ２ , -OR ｚ , -NR ｘ R ｙ , -S(O) ｉ R ｘ , -NR ｘ S (O) ｉ R ｙ , -S(O) ｉ N.R. 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 , C ３ -C ６ Cycloalkyl (-CH ３ , halomethyl, halo, methoxy, and halomethoxy), monocyclic heteroaryl (-CH ３ , halomethyl, halo, methoxy, or halomethoxy), and phenyl (—CH ３ , optionally substituted with one or more groups selected from halomethyl, halo, methoxy, and halomethoxy; The C on Ar ３ -C ６ Cycloalkyl, C ３ -C ６ The heterocyclyl, phenyl and monocyclic heteroaryl group substituents are optionally and independently selected from the group consisting of C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, halo, -CN, -NO ２ , -OR ｚ , -NR ｘ R ｙ , -S(O) ｉ R ｘ , -NR ｘ S (O) ｉ R ｙ , -S(O) ｉ N.R. 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 replaced by; Each R ｘ And each R ｙ are independently -H, C １ -C ４ Alkyl, or C ３ -C ８ is cycloalkyl; R ｘ Or R ｙ The C represented by １ -C ４ Alkyl or C ３ -C ８ Cycloalkyl is halo, hydroxyl, C ３ -C ６ Cycloalkyl and phenyl (-CH ３ , halomethyl, halo, methoxy, or halomethoxy; R ｚ But -H, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C ３ -C ８ Cycloalkyl, or C ３ -C ８ heterocyclyl; R ｚ The C represented by １ -C ４ Alkyl or C ３ -C ８ Cycloalkyl groups include -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 i is 0, 1, or 2; A compound according to any one of claims 1 to 12.

14. During the ceremony, (i) Ar is C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, halo, -CN, -OR ｚ , and -NR ｘ R ｙ Optionally substituted with one or more groups selected from: (ii) Ar is C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, -F, -Cl, -CN, and -OR ｚ and R ｚ C optionally substituted with one or more halo groups １ -C ４ is alkyl; or (iii), Ar is -CH ３ , -CF ３ , -CHF ２ , -F, -OCH ３ , -OCHF ２ , -OCH ２ CH ３ , -OCH(CH ３ ) ２ , and -OCH ２ CF ３ Optionally substituted with one or more groups selected from 14. The compound of claim 13 or a pharma- ceutically acceptable salt thereof.

15. The compound is 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 2. The compound of claim 1, selected from the group consisting of:

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or diluent.

17. A compound according to any one of claims 1 to 15 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, for the treatment of a subject having a disease or condition selected from a neurodegenerative disease, a tauopathy, diabetes, cancer and stress, optionally comprising (i) 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 calcification, Down's syndrome, epilepsy, familial British dementia, familial Danish dementia, frontotemporal dementia linked to chromosome 17 and parkinsonism (FTDP-17), Gerstmann-Sträussler-Scheinker disease, Guadeloupe-type parkinsonism, Hallervorden-Spatz disease (neurodegeneration with brain iron accumulation type 1), ischemic stroke, and glaucoma. selected from hemorrhagic stroke, mild cognitive impairment (MCI), multiple system atrophy, myotonic dystrophy, Niemann-Pick disease (Type C), pallidal-pontine-nigral degeneration, Guam type Parkinsonism-dementia complex, Pick's disease (PiD), postencephalitic parkinsonism (PEP), prion diseases (including Creutzfeldt-Jakob disease (GJD)), variant Creutzfeldt-Jakob disease (vCJD), fatal familial insomnia, kuru, progressive transcortical gliosis, progressive supranuclear palsy (PSP), Steele-Richardson-Olszewski syndrome, subacute sclerosing panencephalitis, neurofibrillary tangle dementia, Huntington's disease, and Parkinson's disease; (ii) 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; or (iii) the disease or condition is Alzheimer's disease; The compound or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition.

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