Compounds with O-GlcNAcase inhibitory activity and their uses

Abstract

The present invention provides a compound having O-GlcNAcase inhibitory activity and capable of reducing tau protein phosphorylation in vivo, and a pharmaceutical composition comprising the compound for treating or preventing diseases caused by tau protein hyperphosphorylation.

Description

Technical Field

[0001] This invention relates to a novel compound with O-GlcNAcase inhibitory activity and its uses. Background Technology

[0002] Microtubule-associated protein tau (MAPT) is an inherently unstructured protein that can be formed through various reactions such as glycosylation and phosphorylation. Tau proteins aggregate sequentially through hyperphosphorylation to form paired helical filaments (PHFs), which then form neurofibrillary tangles (NFTs). The resulting NFTs are one of the main pathological features of Alzheimer's disease (AD) and tau-related diseases, a broader neurodegenerative disorder. The normal function of phosphorylated tau proteins is to promote and stabilize microtubule assembly. In healthy individuals, tau protein contains an average of 1.9 phosphate groups per molecule, but in the brains of pathologically confirmed AD patients, soluble tau protein contains an average of 2.6 phosphate groups per molecule, and tau protein purified from PHFs contains an average of 6 to 8 phosphate groups per molecule. In AD patients, this means that the degree of phosphorylation is increased by 3 to 4 times compared to tau protein isolated from healthy brain tissue. Tau protein hyperphosphorylation not only promotes its own aggregation, but also reduces microtubule stability by interfering with the binding of tau protein to microtubules.

[0003] According to a study conducted 10 years ago, bovine tau protein undergoes extensive post-translational modifications via O-GlcNAc binding, and this modification has also been observed in human tau protein. O-GlcNAc is found on the hydroxyl side chains of serine and threonine residues in various nucleoproteins and cytoplasmic proteins, and in some cases, it occurs on known phosphorylated protein residues. Like phosphorylation, O-GlcNAc glycosylation is a dynamic modification that can be transferred to and removed from the protein multiple times throughout the polypeptide backbone's lifecycle. This dynamic cycling of O-GlcNAc is mediated by two enzymes. Uridine diphosphate N-acetyl-D-glucosamine polypeptidyltransferase (OGT) converts UDP-GlcNAc to GlcNAc by targeting the hydroxyl group of the receptor protein. The hydrolytic cleavage of O-GlcNAc from modified proteins is catalyzed by glycosidases called O-GlcNAcas e or OGA.

[0004] Tau protein phosphorylation and O-GlcNAc glycosylation were reversed in cultured or metabolically active mouse brain slices. This interaction suggests that tau protein phosphorylation and O-GlcNAc glycosylation are in dynamic equilibrium. The presence of phosphorylated and O-GlcNAc glycosylated serine or threonine residues allows these residues to exist in one of three distinct states (phosphorylation, glycosylation, or free hydroxylation). The formation of these states is regulated by appropriate enzymes. Furthermore, soluble tau protein in the brains of diseased individuals retains less O-GlcNAc, while insoluble tau protein aggregates appear to be completely lacking in O-GlcNAc. Since O-GlcNAc is sensitive to glucose availability, these reductions and defects are hypothesized to be due to impaired brain glucose metabolism found in AD patients. Tau protein hyperphosphorylation can be attributed to a reduction in O-GlcNAc due to decreased hexosamine biosynthetic pathway (HBSP), resulting in reduced availability of UDP-GlcNAc. Decreased OGT activity or uncontrolled O-GlcNAc may lead to reduced O-GlcNAc levels in tau protein, thus causing tau protein hyperphosphorylation. The gene encoding O-GlcNAc is located at a site on chromosome 10q24.1 associated with an increased risk of late-onset AD, consistent with the last hypothesis described above. Regardless of the source of reduced O-GlcNAc in the AD brain, increasing O-GlcNAc levels in tau protein could co-activate the possibility of blocking tau protein hyperphosphorylation and preventing the accumulation of toxic tau protein species.

[0005] Reduced tau protein phosphorylation is believed to offer a pathway to slow or halt disease progression in Alzheimer's disease (AD), hence much current effort focuses on developing therapeutically effective kinase inhibitors. Given that AD patients exhibit lower O-GlcNAc levels in the brain compared to normal brains, an alternative approach could be considered: utilizing the dynamic balance between GlcNAc glycosylation and phosphorylation to limit tau protein phosphorylation. By inhibiting O-GlcNAc ase in vivo, O-GlcNAc levels should increase, while tau protein phosphorylation levels should decrease.

[0006] Although several highly effective O-GlcNAcase inhibitors have been discovered, they have some limitations compared to function-related eukaryotic enzymes for eukaryotic O-GlcNAcase. These limitations include moderate selectivity and chemical stability. Furthermore, one limitation is the need for relatively large quantities to obtain the desired amount. One class of inhibitors, GlcNAcstatin, has shown picomolar efficacy against O-GlcNAcase bacterial homologues from *Clostridium perfringens*, but has not yet been tested against any eukaryotic O-GlcNAcase. However, gluco-nagstatin, a structure-related inhibitor, has been found to be active against human O-GlcNAcase with a Ki of 420 nM. The reciprocal properties of O-GlcNAc and tau protein phosphorylation, and the possibility of utilizing this relationship in vivo to limit tau protein phosphorylation, is a topic of considerable interest, as it could lead to strategies for limiting tau protein hyperphosphorylation in AD.

[0007] In vitro studies using the inhibitor O-(2-acetamido-2-deoxy-D-glycopyranosylidene)amino-N-phenylcarbamate (PU GNAc) have shown that this is achievable, but it is not selective and does not cross the blood-brain barrier. Therefore, a highly stable and selective inhibitor that readily crosses the blood-brain barrier and is stronger than existing compounds is needed. Early studies of human O-GlcNAcase showed that the enzyme uses a catalytic mechanism involving the transient formation of a non-covalently bound oxazoline intermediate facilitated by a substrate of the 2-acetamido group. Superficially similar to this intermediate, NAG-thiazoline is a potent O-GlcNAcase inhibitor due to its geometric similarity in the transition state. By altering most of the thiazoline substituents, potent (Ki1 / 4600 nM) inhibitors of O-GlcNAcase exhibit 800-fold greater selectivity for human O-GlcNAcase at pH 7.4 than for human lysosomal β-hexosaminidase. These thiazolines demonstrate excellent selectivity and reasonable efficacy, but exhibit limited chemical stability in solution over extended periods ranging from days to weeks.

[0008] Related existing technologies:

[0009] Korean Patent No. 10-2054744 Summary of the Invention

[0010] Technical issues

[0011] To address the problems described above, the inventors confirmed the O-GlcNAcase inhibitory activity of the novel compound and discovered that it inhibits tau protein phosphorylation, thus completing this invention.

[0012] Solution to the problem

[0013] To achieve the objectives described above, the present invention provides a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof:

[0014] Chemical Formula 1:

[0015]

[0016] In the above chemical formula,

[0017] D is a ring selected from the group consisting of substituted C3 to C10 cycloalkyl groups, substituted 5-membered unsaturated or aromatic rings, substituted 6-membered unsaturated or aromatic rings, substituted 5-membered unsaturated or aromatic heterocycles, and substituted 6-membered unsaturated or aromatic heterocycles, or a polycyclic ring formed by the fusion of two or more rings selected from the above group.

[0018] X1 is C, N, O, or S.

[0019] X2 is N or O.

[0020] R1, R2, and R3 are each independently hydrogen or C1 to C5 alkyl groups.

[0021] L is a direct bond or a C1 to C12 alkylene bond.

[0022] n is an integer from 0 to 3.

[0023] Furthermore, the present invention provides a pharmaceutical composition comprising the above-described compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient for treating or preventing diseases caused by hyperphosphorylation of tau protein.

[0024] The effects of the invention

[0025] The novel compounds of this invention have potent eukaryotic O-GlcNAcase inhibitory efficacy and can effectively reduce tau protein phosphorylation in vivo, thus providing multiple uses as therapeutic agents for tau protein-related diseases. Attached Figure Description

[0026] Figure 1The graphs show the inhibitory effects of compounds A-34S and A-34R, which are enantiomers of compound A-34 prepared in Example 1, on human OGA enzyme at different concentrations. Detailed Implementation

[0027] Embodiments of the present invention will now be described in detail with reference to the accompanying drawings. In the following description, detailed descriptions of techniques well-known to those skilled in the art may be omitted. Furthermore, in describing the present invention, detailed descriptions may be omitted if it is determined that a specific description of a related notification function or structure might unnecessarily obscure the spirit of the invention. In addition, the terminology used in this specification is for appropriately expressing preferred embodiments of the present invention and may vary according to the intent of the user or operator or the conventions of the art to which this invention pertains.

[0028] Therefore, the definitions of these terms should be based on the entire contents of this specification. Throughout this specification, when a section "includes" a structural element, unless otherwise stated, it means that it may further include other structural elements without excluding them.

[0029] Throughout the specification, the term "aromatic ring" refers to a ring containing at least one aromatic ring, and "aromatic heterocycle" refers to a ring containing at least one aromatic ring and at least one heterocycle.

[0030] Throughout the specification, the term "heterogeneous element" refers to an element other than carbon and hydrogen, such as, but not limited to, elements selected from the group consisting of N, O, S, and P.

[0031] The active ingredient of this invention can be used in the form of a pharmaceutically acceptable salt, which is an acid addition salt formed from a pharmaceutically acceptable free acid. The term "pharmaceutically acceptable salt" refers to a concentration that is effective and relatively non-toxic to the patient, and refers to any organic or inorganic addition salt of the base compound of the active ingredient, without diminishing the beneficial effect of the base compound due to side effects caused by the salt. Among these salts, inorganic and organic acids can be used as free acids; hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid, phosphoric acid, etc., can be used as inorganic acids; citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, mesylic acid, glycolic acid, succinic acid, tartaric acid, galacturonic acid, primic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) malic acid, maleic acid, mesylic acid, ethanesulfonic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid, or malonic acid, etc., can be used as organic acids. Furthermore, these salts also include alkali metal salts (sodium salts, potassium salts, etc.) and alkaline earth metal salts (calcium salts, magnesium salts, etc.). For example, acid addition salts may include acetates, aspartates, benzoates, benzenesulfonates, bicarbonates / carbonates, bisulfates / sulfates, borates, camphorsulfonates, citrates, ethanesulfonates, ethanesulfonates, formates, fumarates, gluconate, glucuronide, glucuronide, hexafluorophosphate, hydroxybenzoates, hydrochlorides / chlorides, hydrobromates / bromates, hydroiodates / iodates, hydroxyethanesulfonates, lactates, malates, maleates, malonates, and so on. Sulfonates, methyl sulfates, naphthalates, 2-naphthalenesulfonates, nicotinates, nitrates, orotates, oxalates, palmitates, dihydroxynaphthalates, phosphates / hydrogen phosphates / dihydrogen phosphates, glycosides, stearates, succinates, tartrates, toluenesulfonates, trifluoroacetates, aluminum, arginine, benzathine penicillin, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, zinc salts, etc., with hydrochloride or trifluoroacetate being preferred.

[0032] The acid addition salt of the present invention can be prepared by conventional methods, such as dissolving the active substance in organic solvents such as methanol, ethanol, acetone, dichloromethane, and acetonitrile, and filtering and drying the precipitate formed by adding organic or inorganic acids, or drying after vacuum distillation of the solvent and excess acid, or crystallizing in an organic solvent.

[0033] Furthermore, pharmaceutically acceptable metal salts can be prepared using alkalis. Alkali metal salts or alkaline earth metal salts can be obtained, for example, by dissolving the compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare sodium, potassium, or calcium salts as metal salts. Additionally, the corresponding silver salts can be obtained by reacting the alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0034] Furthermore, the present invention includes not only the active substance and its pharmaceutically acceptable salt, but also possible solvates, hydrates, isomers, optical isomers, etc. that can be prepared therefrom.

[0035] This invention provides a compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof:

[0036] Chemical Formula 1:

[0037]

[0038] In the above chemical formula,

[0039] D is a ring selected from the group consisting of substituted C3 to C10 cycloalkyl groups, substituted 5-membered unsaturated or aromatic rings, substituted 6-membered unsaturated or aromatic rings, substituted 5-membered unsaturated or aromatic heterocycles, and substituted 6-membered unsaturated or aromatic heterocycles, or a polycyclic ring formed by the fusion of two or more rings selected from the above group.

[0040] X1 is C, N, O, or S.

[0041] X2 is N or O.

[0042] R1, R2, and R3 are each independently hydrogen or C1 to C5 alkyl groups.

[0043] L is a direct bond or a C1 to C12 alkylene bond.

[0044] n is an integer from 0 to 3.

[0045] In one embodiment of the present invention, the compound of Formula 1 described above can be prepared by chemical covalent bonding of lipoic acid and naringenin through a linker. Specifically, various novel compounds with different binding sites can be prepared by selectively reacting one of the hydroxyl groups in naringenin that react with lipoic acid. In particular, various compound structures can be prepared by using various linkers such as ethers and amides in a multi-step reaction.

[0046] In one embodiment of the present invention, the compound of chemical formula 1 may include compounds represented by chemical formulas 2 to 4:

[0047] Chemical formula 2:

[0048]

[0049] Chemical formula 3:

[0050]

[0051] Chemical formula 4:

[0052]

[0053] In the above chemical formula,

[0054] A, B, and C are each independently a ring selected from the group consisting of substituted C3 to C10 cycloalkyl groups, substituted 5-membered unsaturated or aromatic rings, substituted 6-membered unsaturated or aromatic rings, substituted 5-membered unsaturated or aromatic heterocycles, and substituted 6-membered unsaturated or aromatic heterocycles, or a polycyclic ring formed by the fusion of two or more rings selected from the above group.

[0055] R1, R2, R3, and n are as defined in the above chemical formula 1.

[0056] In one embodiment of the present invention, in the above chemical formula 2, A can be selected from the following substituents, but is not limited thereto:

[0057] A:

[0058]

[0059] In one embodiment of the present invention, the compound of chemical formula 2 may include, but is not limited to, the following compounds:

[0060]

[0061]

[0062]

[0063]

[0064]

[0065] Preferably, the above-mentioned compound A-34 can be an enantiomer of the (S) configuration, which is compound A-34S represented by the following chemical formula 5.

[0066] Chemical formula 5:

[0067]

[0068] In one embodiment of the present invention, in the above chemical formula 3, B can be selected from the following substituents, but is not limited thereto.

[0069] B:

[0070]

[0071] In one embodiment of the present invention, the compound of chemical formula 3 may include, but is not limited to, the following compounds:

[0072]

[0073]

[0074]

[0075] In one embodiment of the present invention, in the above chemical formula 4, C can be selected from the following substituents, but is not limited thereto.

[0076] C:

[0077]

[0078] In one embodiment of the present invention, the compound of chemical formula 4 may include, but is not limited to, the following compounds:

[0079]

[0080]

[0081] In one embodiment of the present invention, the above-mentioned compound may have O-GlcNAcase inhibitory activity, but is not limited thereto.

[0082] Furthermore, the present invention provides a pharmaceutical composition comprising the above-described compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient for treating or preventing diseases caused by hyperphosphorylation of tau protein.

[0083] In one embodiment of the present invention, the aforementioned diseases may include stroke, memory loss, memory impairment, dementia, amnesia, Parkinson's disease, Alzheimer's disease, Pick's disease, Creutzfeld-Kacob disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), progressive supranuclear palsy (PSAP), corticobasal degeneration (CBD), and Lou Gehrig's disease, but are not limited thereto.

[0084] In the pharmaceutical compositions of the present invention, the compounds of the present invention can be administered together with carriers and diluents known in the art in a suitable dosage form, which, depending on the desired method, can be for oral or parenteral administration, such as intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, suppositories, etc.

[0085] The above dosage forms can be prepared by conventional methods using suitable excipients, fillers, binders, wetting agents, disintegrants, lubricants, surfactants, dispersants, buffers, preservatives, solubilizers, disinfectants, sweeteners, flavorings, analgesics, stabilizers, isotonic solutions, etc., commonly used in pharmaceutical compositions.

[0086] Each of the above dosage forms may contain a pharmaceutically acceptable carrier or additive. Specific examples of such carriers or additives include water, pharmaceutically acceptable organic solvents, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyethylene polymers, sodium alginate, water-soluble dextran, sodium carboxymethyl starch, pectin, xanthan gum, gum arabic, casein, gelatin, agar, glycerin, propylene glycol, polyethylene glycol, petrolatum, paraffin, stearyl alcohol, stearic acid, human serum albumin, mannitol, sorbitol, and lactic acid, etc. One or more additives may be selected or appropriately combined depending on the formulation. Furthermore, as a method of administration for cell therapy agents, in addition to conventional systemic administration such as intravenous and intra-arterial administration, local administration to target cells is also possible, and administration methods combined with catheter technology and surgery can be used.

[0087] The compositions of the present invention may comprise a pharmaceutically effective amount of the compound of the present invention and a pharmaceutically acceptable carrier.

[0088] In this invention, a "pharmaceuticalally effective amount" refers to the amount of the active ingredient that exhibits alleviating, suppressing, improving, and / or curing effects on the treated immune rejection disease. The dosage of the compounds of this invention varies depending on the patient's weight, age, sex, health status, diet, administration time, method of administration, and disease severity. For example, the therapeutically effective dosage can be preliminarily determined using in vitro analytical methods via cell culture. The therapeutically effective dosage can be determined without excessive experimentation in the art, and such information can be used to more accurately determine the dosage useful to humans. For example, the compounds of this invention can be administered as the active ingredient at doses ranging from 0.1 mg / kg / day to 100 mg / kg / day.

[0089] The term "food" as used above refers to natural products or processed products containing one or more nutrients, preferably products that can be consumed directly after a certain degree of processing. In a traditional sense, it refers to food, food additives, functional foods, and beverages.

[0090] Foods for which food-grade compositions can be added include, for example, various food products, beverages, chewing gum, tea, vitamin complexes, and functional foods. This also includes, but is not limited to, special nutritional foods (such as formula milk, infant food, and toddler food), processed meat products, fish products, tofu, jelly, noodles (such as ramen and wheat noodles), bread, health products, condiments (such as soy sauce, miso, chili sauce, and mixed sauces), sauces, biscuits (such as pastries), candies, chocolates, chewing gum, ice cream, dairy products (such as fermented milk and cheese), other processed foods, pickles, preserved foods (various types of pickles and preserved vegetables), beverages (such as fruit juices, vegetable drinks, soy milk, and fermented beverages), and natural seasonings (such as ramen soup base). The aforementioned foods, beverages, or food additives can be prepared using conventional methods.

[0091] Furthermore, the present invention provides a method for the prevention or treatment of diseases caused by hyperphosphorylation of tau protein, comprising administering to an individual a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the present invention.

[0092] The individuals mentioned above can be mammals, such as humans, but are not limited to them.

[0093] Implementation of the invention

[0094] The present invention will now be described in detail through embodiments. However, these embodiments are only used to illustrate the present invention more specifically, and the scope of the present invention is not limited to these embodiments.

[0095] Example

[0096] Example 1

[0097] Preparation of compounds of chemical formula 2

[0098] The compound of chemical formula 2 below was prepared by the following process.

[0099]

[0100] Option 1. Synthesis of A-1 to A-41

[0101]

[0102] A:

[0103]

[0104] Reagents and conditions: (i) paraformaldehyde, AcOH, 100℃, 4h; (ii) TFA, DCM, rt, overnight; (iii) TEA, DCM, 0℃-rt, 4h; (iv) NaH, iodomethane, DMF, 0℃-rt, 1h; (v) Amine compounds, K2CO3, acetonitrile, rt, overnight.

[0105] Synthesis of Scheme 2.1c

[0106]

[0107] Reagents and conditions: (i) di-tert-butyl dicarbonate, DCM, 0℃-rt, 4h

[0108]

[0109] tert-butyl 3-methylpiperazine-1-carboxylate (1c): Di-tert-butyl dicarbonate (761 mg, 3.49 mmol) was added dropwise to a solution of 2-methylpiperazine (349 mg, 3.49 mmol) in DCM (20 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 4 hours. DCM was evaporated under vacuum. The resulting residue was purified by column chromatography (DCM:MeOH = 20:1) to give a pale yellow oily intermediate 1c (166 mg, 83%). 1 HNM R (400MHz, CDCl3) δ: 3.93 (s, 2H), 2.98-2.68 (m, 5H), 2.46-2.31 (m, 1H), 1.46 (s, 9H), 1.05 (d, J = 6.3Hz, 3H).

[0110]

[0111] 4-((2-acetamidothiazol-5-yl)methyl)piperazine-1-carboxylate (tert-butyl 4-((2-acetamidothiazol-5-yl)methyl)piperazine-1-carboxylate)(2b): Paraformaldehyde (3.10 g, 104.69 mmol) was added to a stirred solution of 2-acetamidothiazole (5.50 g, 31.74 mmol) and 1-(tert-butoxycarbonyl)piperazine (3.90 g, 21.16 mmol) in acetic acid (50 mL) at 100 °C. The reaction mixture was stirred at 100 °C for 4 hours. Acetic acid was evaporated under vacuum. The final residue was purified by column chromatography (n-hexane: EtOAc = 2:1) to give a pale yellow solid 2b (6.65 g, 93%). 1 HNMR (400MHz, CDCl3) δ: 11.68 (s, 1H), 7.20 (s, 1H), 3.68 (s, 2H), 3.43 (t, J=5.0Hz, 4H), 2.43 (t, J=5.0Hz, 4H), 2.31 (s, 3H), 1.45 (s, 9H).

[0112]

[0113] 4-((2-acetamidothi azol-5-yl)methyl)-3-methylpiperazine-1-carboxylate (tert-butyl 4-((2-acetamidothi azol-5-yl)methyl)-3-methylpiperazine-1-carboxylate)(2c): Following the same synthesis process as 2b, 2-acetamidothi azol (618 mg, 4.35 mmol), intermediate 1c (166 mg, 2.90 mmol), and paraformaldehyde (435 mg, 14.50 mmol) in acetic acid (20 mL) were purified by column chromatography (DCM:MeOH = 30:1) to obtain a pale yellow solid intermediate 2c (873 mg, 85%). 1HNMR (400MHz, CDCl3) δ: 7.14 (s, 1H), 3.97 (d, J=14.6H z, 1H), 3.67 (dd, J=18.7, 13.8Hz, 4H), 3.48 (q, J=7.0Hz, 1H), 3.12 (d, J=10.5Hz, 1H), 2.7 0 (dt, J=11.5, 3.7Hz, 1H), 2.46 (s, 1H), 2.11 (s, 3H), 1.44 (s, 9H), 1.12 (d, J=6.2Hz, 3H).

[0114]

[0115] N-(5-(piperazin-1-ylmethyl)thiazol-2-yl)acetamide and 2,2,2-trifluoroacetaldehyde (1:1) (3b): Intermediate 2b was dissolved in DCM (50 mL), and the reaction mixture was stirred overnight at room temperature. The DCM was then evaporated under vacuum to give a pale yellow solid 3b (6.61 g, quantitative yield). 1 HNMR (400MHz, DMSO-d6) δ: 12.31 (s, 1H), 9.20 (s, 2H), 7.61 (s, 1H), 4.55 (s, 2H), 2.17 (s, 3H).

[0116]

[0117] N-(5-((2-methylpiperazin-1-yl)methyl)thiazol-2-yl)acetamide (3c): Using intermediate 2c (873 mg, 2.90 mmol) in DCM (20 mL) and TFA (3.32 g, 29.10 mmol), a pale yellow solid intermediate 3c (633 mg, 86%) was obtained by the synthetic method in 3b. 1H NMR (400MHz, DMSO-d6) δ: 12.02 (s, 1H), 7.31 (s, 1H), 4.00 (d, J = 14.7Hz, 1H), 3.72 (d, J = 14.7Hz, 1H), 3.15 (dd, J = 10.8, 2.5Hz, 2H), 2.94 -2.87 (m, 1H), 2.82 (dt, J=12.8, 3.2Hz, 1H), 2.71-2.58 (m, 2H), 2.38 (ddd, J=13.0, 11.3, 2.9Hz, 1H), 2.12 (s, 3H), 1.13 (d, J=6.0Hz, 3H).

[0118]

[0119] 2-Chloro-N-phenylacetamide (5a1): At 0°C, add to DCM (30 mL)

[0120] Aniline (1.00 g, 10.74 mmol) and trimethylamine in DCM (30 mL)

[0121] Chloroacetyl chloride (1.33 g, 11.81 mmol) was added dropwise to (1.20 g, 11.81 mmol), and the reaction mixture was stirred at room temperature for 4 hours. DCM was evaporated under vacuum. The final residue was purified by column chromatography (n-hexane:EtOAc = 2:1) to give a pale red solid intermediate 5a1 (1.80 g, 99%). 1 HNMR (400M Hz, CDCl3) δ: 8.22 (s, 1H), 7.58-7.52 (m, 2H), 7.40-7.33 (m, 2H), 7.21-7.15 (m, 1H), 4.20 (s, 2H).

[0122]

[0123] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-phenylacetamide (A-1): Intermediate 5a1 (79 mg, 0.46 mmol) was added to a suspension of intermediate 3b (190 mg, 0.55 mmol) and K2CO3 (152 mg, 1.10 mmol) in acetonitrile (30 mL). The reaction mixture was stirred overnight at room temperature. The acetonitrile was evaporated under vacuum. The final residue was purified by column chromatography (DCM:MeOH = 20:1) to give a white solid A-1 (100 mg, 58%). Mp: 190–192 °C. 1 HNMR (400MHz, CDCl3) δ: 10.25 (s, 1H), 9.09 (s, 1H), 7.58-7.54 (m, 2H), 7.33 (dd, J=8.5, 7.4Hz, 2H ), 7.14-7.08 (m, 1H), 3.72 (d, J=1.0Hz, 2H), 3.14 (s, 2H), 2.66 (s, 4H), 2.58 (s, 4H), 2.29 (s, 3H).

[0124]

[0125] 2-Chloroacetate (5a2): After the synthesis of 5a1 using phenol (750 mg, 7.97 mmol), triethylamine (887 mg, 0.47 mmol), and chloroacetyl chloride (990 mg, 8.77 mmol) from DCM, the intermediate 5a2 (1.03 g, 76%) was purified by column chromatography (n-hexane / EtOAc = 1:1) to obtain a colorless oily intermediate 5a2. 1 HNMR (400MHz, CDCl3) δ: 7.44-7.37 (m, 2H), 7.30-7.26 (m, 1H), 7.16-7.09 (m, 2H), 4.31 (s, 2H).

[0126]

[0127] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)acetate (A-2): Following the synthesis of compound A-1 using intermediates 3b (623 mg, 1.75 mmol) and 5a2 (200 mg, 1.17 mmol) from acetonitrile, and K₂CO₃ (486 mg, 3.52 mmol), the product was purified by column chromatography (DCM:MOH = 20:1) to give a white solid compound A-2 (103 mg, 23%). Mp: 185-194 °C. 1 HNMR (400MHz, CDCl3) δ: 10.91 (s, 1H), 7.37 (dd, J=8.4, 7.4Hz, 2H), 7.25-7.22 (m, 1H), 7.21 ( s, 1H), 7.11-7.07 (m, 2H), 3.69 (s, 2H), 3.48 (s, 2H), 2.71 (s, 4H), 2.60 (s, 4H), 2.29 (s, 3H).

[0128]

[0129] 2-Chloro-N-(p-tolyl)acetamide (5a3): After the synthesis of 5a1 using p-toluidine (500 mg, 4.67 mmol), triethylamine (519 mg, 5.13 mmol), and chloroacetyl chloride (579 mg, 5.13 mmol) from DCM, the intermediate 5a3 (950 mg, 99%) was purified by column chromatography (n-hexane / EtOAc = 2:1) to obtain a colorless oily intermediate 5a3. 1 HNMR (400MHz, CDCl3) δ: 8.16 (s, 1H), 7.46-7.38 (m, 2H), 7.18-7.14 (m, 2H), 4.19 (s, 2H), 2.33 (s, 3H).

[0130]

[0131] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(p-tolyl)acetamide (2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(p-tolyl)acetamide)(A-3): Compound A-3 was synthesized using intermediates 5a3 (200 mg, 1.09 mmol) and 3b (314 mg, 1.31 mmol) from acetonitrile and K2CO3 (181 mg, 1.31 mmol). The resulting product was purified by column chromatography (DCM:MOH = 20:1) to give a white solid compound A-3 (113 mg, 26%). Mp: 213-217 °C. 1 HNMR (400MHz, CDCl3) δ: 9.82 (s, 1H), 9.00 (s, 1H), 7.43 (d, J = 8.5Hz, 2H), 7.21 (d, J = 0.9Hz, 1H), 7.13 (d , J=8.1Hz, 2H), 3.71 (d, J=1.0Hz, 2H), 3.12 (s, 2H), 2.65 (s, 4H), 2.58 (s, 4H), 2.32 (s, 3H), 2.28 (s, 3H).

[0132]

[0133] 2-Chloro-N-(o-tolyl)acetamide (5a4): Following the synthesis of 5a1 using m-toluidine (500 mg, 4.67 mmol), triethylamine (519 mg, 5.13 mmol), and chloroacetyl chloride (579 mg, 5.13 mmol) from DCM, the intermediate 5a4 (867 mg, 77%) was purified by column chromatography (n-hexane / EtOAc = 1:1) to obtain a colorless oily intermediate 5a4. 1 HNMR (400MHz, CDCl3) δ: 8.22 (s, 1H), 7.90-7.86 (m, 1H), 7.26-7.19 (m, 2H), 7.12 (td, J=7.4, 1.3Hz, 1H), 4.24 (s, 2H), 2.31 (s, 3H).

[0134]

[0135] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(o-tolyl)acetamide (2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(o-tolyl)acetamide)(A-4): Compound A-4 was synthesized using intermediates 5a4 (296 mg, 1.62 mmol) and 3b (467 mg, 1.94 mmol) from acetonitrile and K2CO3 (268 mg, 1.94 mmol). The resulting product was purified by column chromatography (DCM:MOH = 20:1) to give a pale yellow solid, A-4 (15 mg, 3%). Mp: 194-196 °C. 1 HNMR (400MHz, CDCl3) δ: 9.24 (s, 1H), 8.93 (s, 1H), 8.12 (dd, J=8.0, 1.2Hz, 1H), 7.95 (d, J=7.9Hz, 1H), 7.32 (s, 1H), 7.13 (d , J=7.3Hz, 1H), 7.06-7.04 (m, 1H), 3.72 (d, J=1.0Hz, 2H), 3.18 (s, 2H), 2.70 (s, 4H), 2.58 (s, 4H), 2.27 (s, 3H), 2.12 (s, 3H).

[0136]

[0137] 2-Chloro-N-(m-tolyl)acetamide (5a5): Following the synthesis of 5a1 using m-tolylamine (500 mg, 4.67 mmol) and triethylamine (519 mg, 5.13 mmol) from DCM, the intermediate 5a5 (741 mg, 86%) was purified by column chromatography (n-hexane / EtOAc = 5:1) to obtain a colorless oily intermediate 5a5. 1 HNMR (400MHz, CDCl3) δ: 8.26 (s, 1H), 7.41-7.32 (m, 2H), 7.27 (s, 1H), 6.99 (ddd, J=7.6, 1.9, 1.0Hz, 1H), 4.20 (s, 2H), 2.36 (s, 3H).

[0138]

[0139] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(m-tolyl)acetamide (2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(m-tolyl)acetamide)(A-5): Compound A-5 was synthesized using intermediates 5a5 (200 mg, 1.09 mmol) and 3b (463 mg, 1.31 mmol) from acetonitrile and K2CO3 (434 mg, 1.31 mmol). The resulting product was purified by column chromatography (DCM:MOH = 20:1) to give a pale yellow solid, A-5 (259 mg, 61%). Mp: 202-204 °C. 1 HNMR (400MHz, CDCl3) δ: 11.24 (s, 1H), 9.02 (s, 1H), 7.39 (t, J=1.8Hz, 1H), 7.35-7.33 (m, 1H), 7.23-7.19 (m, 2H), 6.93 (ddt, J=7.6, 1.9, 0.9Hz, 1H), 3.72 (d, J=1.0Hz, 2H), 3.13 (s, 2H), 2.65 (s, 4H), 2.59 (s, 4H), 2.35 (s, 3H), 2.30 (s, 3H).

[0140]

[0141] 2-Chloro-N-(4-isopropylphenyl)acetamide (5a6): Following the synthesis of 5a1 using 4-isopropylaniline (500 mg, 3.70 mmol), triethylamine (411 mg, 4.07 mmol), and chloroacetyl chloride (459 mg, 4.07 mmol) from DCM, the product was purified by column chromatography (n-hexane / EtOAc = 1:1) to give a white solid intermediate 5a6 (741 mg, 95%). 1 HNMR (400MHz, CDCl3) δ: 8.17 (s, 1H), 7.48-7.41 (m, 2H), 7.24-7.19 (m, 2H), 4.19 (s, 2H), 2.90 (p, J = 6.9Hz, 1H), 1.25 (s, 3H), 1.23 (s, 3H).

[0142]

[0143] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(4-isopropylphenyl)acetamide (A-6): Compound A-6 was synthesized using intermediates 5a6 (250 mg, 1.18 mmol) and 3b (340 mg, 1.42 mmol) from acetonitrile and K2CO3 (196 mg, 1.42 mmol). The resulting product was purified by column chromatography (DCM:MOH = 20:1) to give a white solid, A-6 (86 mg, 18%). Mp: 173-176 °C. 1 HNMR (400MHz, CDCl3) δ: 10.51 (s, 1H), 9.00 (s, 1H), 7.47-7.45 (m, 2H), 7.22 (s, 1H), 7.19 (d, J=8.4Hz, 2H), 3. 72 (s, 2H), 3.13 (s, 2H), 2.88 (p, J=6.9Hz, 1H), 2.65 (s, 4H), 2.58 (s, 4H), 2.29 (s, 3H), 1.23 (d, J=6.9Hz, 6H).

[0144]

[0145] 2-Chloro-N-(4-methoxyphenyl)acetamide (5a7): Following the synthesis of 5a1 using p-anisidine (500 mg, 406 mmol), triethylamine (452 ​​mg, 4.47 mmol), and chloroacetyl chloride (504 mg, 4.47 mmol) from DCM, the product was purified by column chromatography (n-hexane / EtOAc = 1:1) to give a white solid intermediate 5a7 (802 mg, 99%). 1 HNMR (400MHz, CDCl3) δ: 8.26 (s, 1H), 7.48-7.43 (m, 2H), 6.92-6.86 (m, 2H), 4.20 (s, 2H), 3.80 (s, 3H).

[0146]

[0147] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(4-methoxyphenyl)acetamide (A-7): Compound A-7 was synthesized using intermediates 5a7 (200 mg, 1.00 mmol) and 3b (426 mg, 1.20 mmol) from acetonitrile and K2CO3 (331 mg, 2.40 mmol). The resulting product was purified by column chromatography (DCM:MOH = 20:1) to give a pale yellow solid, A-7 (135 mg, 33%). Mp: 217-220 °C. 1 HNMR (400MHz, CDCl3) δ: 10.82 (s, 1H), 8.95 (s, 1H), 7.47 7.45 (m, 2H), 7.22 (t, J=0.9Hz, 1H), 6.88 6.86 (m, 2H), 3.79 (s, 3H), 3.71 (d, J=1.0Hz, 2H), 3.13 (s, 2H), 2.65 (s, 4H), 2.58 (s, 4H), 2.30 (s, 3H).

[0148]

[0149] 2-Chloro-N-(4-methoxyphenethyl)acetamide (5a8): Purified by column chromatography (n-hexane / EtOAc = 1:1) using 2-(4-methoxyphenyl)ethylamine (500 mg, 3.30 mmol), triethylamine (367 mg, 3.63 mmol), and chloroacetyl chloride (410 mg, 3.63 mmol) from DCM to give a pale yellow oily intermediate 5a8 (751 mg, 63%). 1 HNMR (400MHz, CDCl3) δ: 7.15-7.10 (m, 2H), 6.89-6.84 (m, 2H), 6.58 (s, 1H), 4 .02 (s, 2H), 3.80 (s, 3H), 3.53 (td, J=7.0, 5.9Hz, 2H), 2.79 (t, J=7.0Hz, 2H).

[0150]

[0151] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(4-methoxyphenethyl)acetamide (A-8): Compound A-1 was synthesized using intermediates 5a8 (200 mg, 0.88 mmol) and 3b (375 mg, 1.06 mmol) from acetonitrile and K2CO3 (166 mg, 1.06 mmol). The resulting product was purified by column chromatography (DCM:MOH = 30:1) to give A-8 (117 mg, 31%) as a pale yellow solid. Mp: 177-179 °C. 1 HNMR (400MHz, CDCl3) δ: 11.21 (s, 1H), 7.20 (d, J=1.0Hz, 1H), 7.13-7.09 (m, 2H), 6.85-6.83 (m, 2H), 3.79 (s, 3H), 3.64 (d, J=1.0Hz, 2H), 3.52 (q, J=6.6Hz, 2H), 2.95 (s, 2H), 2.77 (t, J=6.8Hz, 2H), 2.44 (d, J=4.4Hz, 4H), 2.39 (s, 4H), 2.30 (s, 3H).

[0152]

[0153] 2-Chloro-N-(3-methoxyphenyl)acetamide (5a9): Following the synthesis of 5a1 using m-anisidine (500 mg, 4.06 mmol), triethylamine (452 ​​mg, 4.47 mmol), and chloroacetyl chloride (504 mg, 4.47 mmol) from DCM, the product was purified by column chromatography (n-hexane / EtOAc = 1:1) to give a white solid intermediate 5a9 (802 mg, 99%). 1 HNMR (400MHz, CDCl3) δ: 8.24 (s, 1H), 7.29 (t, J=2.3Hz, 1H), 7.24 (d, J=8.1Hz, 1H), 7.04 ( ddd, J=8.0, 2.0, 0.9Hz, 1H), 6.73 (ddd, J=8.3, 2.5, 0.9Hz, 1H), 4.19 (s, 2H), 3.82 (s, 3H).

[0154]

[0155] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(3-methoxyphenyl)acetamide (A-9): Compound A-9 was synthesized using intermediates 5a9 (200 mg, 1.00 mmol) and 3b (426 mg, 1.20 mmol) from acetonitrile and K2CO3 (331 mg, 2.40 mmol). The resulting product was purified by column chromatography (DCM:MOH = 30:1) to give a pale yellow solid, A-9 (137 mg, 34%). Mp: 210-212 °C. 1 HNMR (400MHz, CDCl3) δ: 9.84 (s, 1H), 9.07 (s, 1H), 7.34 (t, J=2.3Hz, 1H), 7.24-7.20 (m, 2H), 7.02-6.99 (m, 1H), 6.67 ( ddd, J=8.3, 2.5, 0.9Hz, 1H), 3.82 (s, 3H), 3.71 (d, J=0.9Hz, 2H), 3.13 (s, 2H), 2.65 (s, 4H), 2.58 (s, 4H), 2.28 (s, 3H).

[0156]

[0157] 2-Chloro-N-(3,4-dimethoxyphenyl)acetamide (5a10): 5a1 was synthesized using 3,4-dimethoxyaniline (500 mg, 3.26 mmol), triethylamine (363 mg, 3.59 mmol), and chloroacetyl chloride (405 mg, 3.59 mmol) from DCM. The resulting product was purified by column chromatography (n-hexane / EtOAc = 1:1) to give a white solid intermediate 5a10 (742 mg, 99%). 1 HNMR (400MHz, CDCl3) δ: 8.14 (s, 1H), 7.28 (d, J=2.5Hz, 1H), 6.96 (dd, J=8.6, 2.5Hz, 1H), 6.84 (d, J=8.6Hz, 1H), 4.19 (s, 2H), 3.90 (s, 3H), 3.88 (s, 3H).

[0158]

[0159] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(3,4-dimethoxyphenyl)acetamide (A-10): Compound A-10 was synthesized using intermediates 5a11 (280 mg, 1.22 mmol) and 3b (518 mg, 1.46 mmol) from acetonitrile and K2CO3 (404 mg, 2.93 mmol). The resulting product was purified by column chromatography (DCM:MOH = 40:1) to give a pale yellow solid, A-10 (172 mg, 32%). Mp: 182-184 °C. 1 HNMR (400MHz, CDCl3) δ: 9.75 (s, 1H), 8.96 (s, 1H), 7.42 (d, J = 2.4Hz, 1H), 7.21 (d, J = 2.7Hz, 1H), 6.87 (dd, J = 8.6, 2.4Hz, 1H), 6.81 (d, J=8.6Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.72 (s, 2H), 3.13 (s, 2H), 2.66 (s, 4H), 2.58 (s, 4H), 2.28 (s, 3H).

[0160]

[0161] 2-Chloro-N-(4-fluorophenyl)acetamide (5a11): 5a1 was synthesized using 4-fluoroaniline (500 mg, 4.50 mmol), triethylamine (500 mg, 4.95 mmol), and chloroacetyl chloride (559 mg, 4.95 mmol) from DCM. The resulting product was purified by column chromatography (n-hexane / EtOAc = 1:1) to give a pale yellow solid intermediate, 5a11 (835 mg, 99%). 1 HNMR (400MHz, CDCl3) δ: 8.22 (s, 1H), 7.55-7.46 (m, 2H), 7.11-7.00 (m, 2H), 4.20 (s, 2H).

[0162]

[0163] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(4-fluorophenyl)acetamide (2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(4-fluorophenyl)acetamide (A-11): Compound A-1 was synthesized using intermediates 5a11 (400 mg, 2.13 mmol) in acetonitrile, intermediate 3b (907 mg, 2.56 mmol), and K2CO3 (353 mg, 2.56 mmol). The resulting product was purified by column chromatography (DCM:MOH = 40:1) to give a pale yellow solid, A-11 (145 mg, 17%). Mp: 212-215 °C. 1 HNMR (400MHz, CDCl3) δ: 10.56 (s, 1H), 9.06 (s, 1H), 7.54-7.50 (m, 2H), 7.22 (s, 1H), 7.00-7.0 0 (m, 2H), 3.72 (d, J=1.0Hz, 2H), 3.14 (s, 2H), 2.65 (d, J=4.7Hz, 4H), 2.58 (s, 4H), 2.29 (s, 3H).

[0164]

[0165] 2-Chloro-N-(4-chlorophenyl)acetamide (5a12): 5a1 was synthesized using 4-chloroaniline (552 mg, 4.33 mmol), triethylamine (481 mg, 4.76 mmol), and chloroacetyl chloride (537 mg, 4.76 mmol) from DCM. The resulting product was purified by column chromatography (n-hexane / EtOAc = 1:1) to give a pale yellow solid intermediate 5a12 (727 mg, 82%). 1 HNMR (400MHz, CDCl3) δ: 8.22 (s, 1H), 7.55-7.46 (m, 2H), 7.37-7.29 (m, 2H), 4.19 (s, 2H).

[0166]

[0167] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(4-chlorophenyl)acetamide (A-12): Compound A-1 was synthesized using intermediates 5a12 (230 mg, 1.13 mmol) in acetonitrile, intermediate 3b (478 mg, 1.35 mmol), and K2CO3 (374 mg, 2.71 mmol). The resulting product was purified by column chromatography (DCM:MOH = 40:1) to give a pale yellow solid, A-12 (97 mg, 24%). Mp: 232-236 °C. 1 HNMR (400MHz, CDCl3) δ: 10.02 (s, 1H), 9.11 (s, 1H), 7.53-7.50 (m, 2H), 7.31-7.27 (m, 2H), 7.2 2 (s, 1H), 3.72 (d, J=1.0Hz, 2H), 3.13 (s, 2H), 2.65 (d, J=4.6Hz, 4H), 2.58 (s, 4H), 2.28 (s, 3H).

[0168]

[0169] N-(2-bromo-4-chlorophenyl)-2-chloroacetamide (5a13): 5a1 was synthesized using 2-bromo-4-chloroaniline (500 mg, 2.42 mmol), triethylamine (269 mg, 2.66 mmol), and chloroacetyl chloride (300 mg, 2.66 mmol) from DCM. The resulting product was purified by column chromatography (n-hexane / EtOAc = 1:1) to give a pale yellow solid intermediate, 5a13 (684 mg, 82%). 1 HNMR (400MHz, Chloroform-d) δ 8.90 (s, 1H), 8.33 (d, J=8.9Hz, 1H), 7.58 (d, J=2.3Hz, 1H), 7.33 (ddd, J=8.9, 2.3, 0.5Hz, 1H), 4.23 (s, 2H).

[0170]

[0171] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(2-bromo-4-chlorophenyl)acetamide (A-13): Compound A-1 was synthesized using intermediates 5a13 (200 mg, 0.71 mmol) in acetonitrile, intermediate 3b (298 mg, 0.85 mmol), and K2CO3 (117 mg, 0.85 mmol). The resulting product was purified by column chromatography (DCM:MOH = 40:1) to give a pale yellow solid, A-13 (110 mg, 32%). Mp: 212-213 °C. 1 HNMR (400MHz, CDCl3) δ: 11.25 (s, 1H), 9.94 (s, 1H), 8.44 (d, J = 8.8Hz, 1H), 7.53 (d, J = 2.3Hz, 1H), 7.29 (dd, J=8.9, 2.4Hz, 1H), 7.22 (s, 1H), 3.72 (d, J=0.9Hz, 2H), 3.18 (s, 2H), 2.69 (s, 4H), 2.63 (s, 4H), 2.31 (s, 3H).

[0172]

[0173] N-(4-acetamidophenyl)-2-chloroacetamide (5a14): 5a1 was synthesized using 4'-aminoacetanilide (500 mg, 3.33 mmol), triethylamine (370 mg, 3.66 mmol), and chloroacetyl chloride (413 mg, 3.66 mmol) from DCM. The resulting product was purified by column chromatography (n-hexane / EtOAc = 1:1) to give a white solid intermediate 5a14 (747 mg, 99%). 1 HNMR (400MHz, DMSO-d6) δ: 10.24 (s, 1H), 9.92 (s, 1H), 7.54-7.47 (m, 4H), 4.22 (s, 2H), 2.02 (d, J = 2.6Hz, 3H).

[0174]

[0175] N-(4-acetamidophenyl)-2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)acetamide (A-14): Compound A-1 was synthesized using intermediates 5a14 (227 mg, 1.00 mmol) in acetonitrile, intermediate 3b (425 mg, 1.20 mmol), and K2CO3 (231 mg, 2.40 mmol). The resulting product was purified by column chromatography (DCM:MOH = 50:1) to give a white solid, A-14 (207 mg, 48%). Mp: 234-237 °C. 1 HNMR (400MHz, DMSO-d6) δ: 11.93 (s, 1H), 9.85 (s, 1H), 9.57 (s, 1H), 7.52-7.47 (m, 4H), 7 .25 (d, J=0.8Hz, 1H), 3.63 (s, 2H), 3.08 (s, 2H), 2.46 (s, 4H), 2.11 (s, 3H), 2.01 (s, 3H). 13C NMR (101MHz, DMSO-d6) δ: 206.98, 168.36, 136.15, 135.45, 134.26, 120.31, 119.7 3, 65.40, 62.15, 55.36, 53.96, 53.23, 52.53, 49.07, 31.14, 24.33, 22.88, 15.63.

[0176]

[0177] 2-Chloro-N-(pyridin-2-yl)acetamide (5a15): 5a1 was synthesized using 2-aminopyridine (500 mg, 5.31 mmol), triethylamine (591 mg, 5.84 mmol), and chloroacetyl chloride (660 mg, 5.84 mmol) from DCM. The resulting product was purified by column chromatography (n-hexane / EtOAc = 1:1) to give a white solid intermediate 5a15 (475 mg, 52%). 1HNMR (400MHz, CDCl3) δ: 8.84 (s, 1H), 8.32 (ddd, J=4.9, 1.9, 1.0Hz, 1H), 8.20 (d, J=8.4Hz , 1H), 7.74 (ddd, J=8.3, 7.3, 1.9Hz, 1H), 7.11 (ddd, J=7.4, 4.9, 1.0Hz, 1H), 4.20 (s, 2H).

[0178]

[0179] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(pyridin-2-yl)acetamide (2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(pyridin-2-yl)acetamide)(A-15): Following the synthesis of compound A-1, intermediates 5a15 (200 mg, 1.17 mmol), 3b (623 mg, 1.75 mmol), and K2CO3 (486 mg, 3.52 mmol) were added to acetonitrile to obtain compound A-15, which was purified by column chromatography (DCM:MOH = 30:1) to give a white solid (78 mg, 18%). Mp: 211-217 °C. 1 HNMR (400MHz, CDCl3) δ: 11.17 (s, 1H), 9.54 (s, 1H), 8.30 (ddd, J=5.0, 1.9, 0.9Hz, 1H), 8.24 (dt, J=8.4, 1.1Hz, 1H), 7.70 (ddd, J=8.6, 7.2 , 1.9Hz, 1H), 7.21 (s, 1H), 7.04 (ddd, J=7.3, 4.9, 1.1Hz, 1H), 3.71 (d, J=1.0Hz, 2H), 3.17 (s, 2H), 2.65 (s, 4H), 2.61 (s, 4H), 2.30 (s, 3H).

[0180]

[0181] 2-Chloro-N-(6-methylpyridin-2-yl)acetamide (5a16): Following the synthesis of 5a1, 2-amino-6-methylpyridine (500 mg, 4.62 mmol), triethylamine (514 mg, 5.09 mmol), and chloroacetyl chloride (574 mg, 5.13 mmol) were placed in DCM to obtain intermediate 5a16, which was purified by column chromatography (n-hexane / EtOAc = 1:1) to give a white solid (853 mg, 91%). 1 HNMR (400MHz, CDCl3) δ: 8.94 (s, 1H), 8.00 (d, J=8.2Hz, 1H), 7.63 (dd, J=8.2, 7.5Hz, 1H), 6.96 (d, J=7.5Hz, 1H), 4.19 (s, 2H), 2.48 (s, 3H).

[0182]

[0183] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(6-methylpyridin-2-yl)acetamide (2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(6-methylpyridin-2-yl)acetamide)(A-16): Compound A-1 was synthesized using intermediates 5a16 (200 mg, 1.08 mmol) in acetonitrile, intermediate 3b (460 mg, 1.30 mmol), and K2CO3 (180 mg, 1.30 mmol). The resulting product was purified by column chromatography (DCM:MOH = 20:1) to give a pale yellow solid, A-16 (134 mg, 32%). Mp: 224-228 °C. 1 HNMR (400MHz, CDCl3) δ: 10.91 (s, 1H), 9.37 (s, 1H), 8.03 (d, J = 8.3Hz, 1H), 7.58 (t, J = 7.9Hz, 1H), 7.22 (s , 1H), 6.89 (d, J=7.4Hz, 1H), 3.71 (d, J=1.0Hz, 2H), 3.15 (s, 2H), 2.63 (s, 8H), 2.47 (s, 3H), 2.30 (s, 3H).

[0184]

[0185] 2-Chloro-N-(5-methylpyridin-2-yl)acetamide (5a17): Following the synthesis of 5a1 using 2-amino-5-methylpyridine (500 mg, 4.62 mmol), triethylamine (514 mg, 5.09 mmol), and chloroacetyl chloride (574 mg, 5.13 mmol) from DCM, the product was purified by column chromatography (n-hexane / EtOAc = 1:1) to give a white solid intermediate 5a17 (852 mg, 91%). 1 HNMR (400MHz, CDCl3) δ: 9.32 (s, 1H), 8.18-8.07 (m, 2H), 7.59 (ddq, J=8.5, 2.2, 0.7Hz, 1H), 4.19 (s, 2H), 2.33 (d, J=0.8Hz, 3H).

[0186]

[0187] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(5-methylpyridin-2-yl)acetamide (2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(5-methylpyridin-2-yl)acetamide)(A-17): Compound A-1 was synthesized using intermediates 5a17 (200 mg, 1.08 mmol) in acetonitrile, intermediate 3b (460 mg, 1.30 mmol), and K2CO3 (180 mg, 1.30 mmol). The resulting product was purified by column chromatography (DCM:MOH = 20:1) to give a pale yellow solid, A-17 (100 mg, 24%). Mp: 224-230 °C. 1 HNMR (400MHz, CDCl3) δ: 11.45 (s, 1H), 9.46 (s, 1H), 8.13 (d, J=8.4Hz, 1H), 8.11 (d, J=2.3Hz, 1H), 7.51 (dd, J=8.5, 2.4H z, 1H), 7.21 (d, J=1.1Hz, 1H), 3.70 (d, J=0.9Hz, 2H), 3.15 (s, 2H), 2.64 (s, 4H), 2.60 (s, 4H), 2.31 (s, 3H), 2.29 (s, 3H).

[0188]

[0189] 2-Chloro-N-(4-methylpyridin-2-yl)acetamide (5a18): Following the synthesis of 5a1 using 2-amino-4-methylpyridine (500 mg, 4.62 mmol), triethylamine (514 mg, 5.09 mmol), and chloroacetyl chloride (574 mg, 5.13 mmol) from DCM, the product was purified by column chromatography (n-hexane / EtOAc = 1:1) to give a white solid intermediate 5a18 (725 mg, 85%). 1 HNMR (400MHz, CDCl3) δ: 8.86 (s, 1H), 8.17 (dd, J=5.1, 0.8Hz, 1H), 8.04 (s, 1H), 6.93 (ddd, J=5.2, 1.6, 0.8Hz, 1H), 4.19 (s, 2H), 2.39 (d, J=0.7Hz, 3H).

[0190]

[0191] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(4-methylpyridin-2-yl)acetamide (A-18): Compound A-1 was synthesized using intermediates 5a18 (200 mg, 1.08 mmol) in acetonitrile, intermediate 3b (460 mg, 1.30 mmol), and K2CO3 (180 mg, 1.30 mmol). The resulting product was purified by column chromatography (DCM:MOH = 10:1) to give a pale yellow solid, A-18 (73 mg, 20%). Mp: 210-211 °C. 1 HNMR (400MHz, CDCl3) δ: 10.22 (s, 1H), 9.48 (s, 1H), 8.15 (dd, J=5.1, 0.8Hz, 1H), 8.08 (dt, J=1.6, 0.8Hz, 1H), 7.21 (s, 1H), 6.87 (ddd, J=5.1, 1.5, 0.7Hz, 1H), 3.70 (d, J=1.0Hz, 2H), 3.15 (s, 2H), 2.64 (s, 4H), 2.60 (s, 4H), 2.36 (d, J=0.7Hz, 3H), 2.28 (s, 3H).

[0192]

[0193] 2-Chloro-N-(pyrazin-2-yl)acetamide (5a19): Following the synthesis of 5a1 using 2-aminopyrazine (500 mg, 5.26 mmol), triethylamine (585 mg, 5.78 mmol), and chloroacetyl chloride (664 mg, 5.78 mmol) from DCM, the product was purified by column chromatography (n-hexane / EtOAc = 1:1) to give a white solid intermediate 5a19 (476 mg, 53%). 1 HNMR (400MHz, CDCl3) δ: 9.54 (d, J=1.5Hz, 1H), 8.76 (s, 1H), 8.43 (d, J=2.6Hz, 1H), 8.31 (dd, J=2.6, 1.6Hz, 1H), 4.24 (s, 2H).

[0194]

[0195] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(pyrazin-2-yl)acetamide (2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(pyrazin-2-yl)acetamide)(A-19): Compound A-1 was synthesized using intermediates 5a19 (257 mg, 1.50 mmol) in acetonitrile, intermediate 3b (350 mg, 1.00 mmol), and K2CO3 (276 mg, 2.00 mmol). The resulting product was purified by column chromatography (DCM:MOH = 10:1) to give a white solid, A-19 (74 mg, 15%). Mp: 224-226 °C. 1 HNMR (400MHz, CDCl3) δ: 10.24 (s, 1H), 9.58 (s, 1H), 9.57 (d, J = 1.5Hz, 1H), 8.34 (d, J = 2.6Hz, 1H), 8.26 (dd, J=2.6, 1.5Hz, 1H), 7.21 (s, 1H), 3.71 (d, J=1.0Hz, 2H), 3.20 (s, 2H), 2.67 (s, 4H), 2.61 (s, 4H), 2.29 (s, 3H).

[0196]

[0197] 2-Chloro-N-cyclohexylacetamide (5a20): Following the synthesis of 5a1 using cyclohexylamine (500 mg, 5.00 mmol), triethylamine (561 mg, 5.55 mmol), and chloroacetyl chloride (626 mg, 5.55 mmol) from DCM, the intermediate 5a20 (225 mg, 45%) was purified by column chromatography (n-hexane / EtOAc = 2:1) to obtain an oily intermediate. 1 HNMR (400MHz, CDCl3) δ: 6.43 (s, 1H), 4.03 (d, J=2.8Hz, 2H), 3.79 (tdt, J=10.6, 8.1, 3.8Hz, 1H), 1.93 ( dd, J=12.8, 3.8Hz, 2H), 1.73 (dt, J=13.2, 3.9Hz, 4H), 1.64 (dd, J=12.6, 3.7Hz, 2H), 1.23-1.18 (m, 2H).

[0198]

[0199] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-cyclohexylacetamide (A-20): Compound A-1 was synthesized using intermediates 5a20 (225 mg, 2.27 mmol) in acetonitrile, intermediate 3b (1.20 g, 3.41 mmol), and K2CO3 (1.41 g, 10.24 mmol). The resulting product was purified by column chromatography (DCM:MOH = 40:1) to give a white solid, A-20 (74 mg, 15%). Mp: 198-200 °C. 1 HNMR (400MHz, CDCl3) δ: 10.25 (s, 1H), 7.20 (s, 1H), 7.02 (s, 1H), 3.83-3.78 (m, 1H), 3.69 (d, J=1.0Hz, 2H), 2.97 (s, 2H), 2. 54 (s, 8H), 2.28 (s, 3H), 1.87 (dd, J=12.9, 4.0Hz, 2H), 1.70-1.67 (m, 2H), 1.41-1.34 (m, 2H), 1.16 (dd, J=12.1, 8.9Hz, 4H).

[0200]

[0201] 2-Chloro-N-(thiazol-2-yl)acetamide (5a21): Following the synthesis of 5a1 using 2-aminothiazole (500 mg, 4.99 mmol), triethylamine (559 mg, 5.49 mmol), and chloroacetyl chloride (620 mg, 5.49 mmol) from DCM, the product was purified by column chromatography (n-hexane / EtOAc = 2:1) to give a white solid intermediate 5a21 (562 mg, 64%). 1 HNMR (400MHz, CDCl3) δ: 10.06 (s, 1H), 7.51 (d, J=3.5Hz, 1H), 7.05 (d, J=3.5Hz, 1H), 4.29 (s, 2H).

[0202]

[0203] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide (A-21): Following the synthetic method of compound A-1 derived from intermediates 5a21 (200 mg, 1.13 mmol) in acetonitrile, intermediate 3b (661 mg, 1.69 mmol), and K2CO3 (469 mg, 3.40 mmol), the compound was purified by column chromatography (DCM:MOH = 40:1) to give a white solid compound A-21 (156 mg, 41%). Mp: 237-240 °C. 1 HNMR (400MHz, CDCl3) δ: 11.02 (s, 1H), 10.37 (s, 1H), 7.45 (d, J=3.5Hz, 1H), 7.22 (s, 1H), 6.99 (d, J=3.5Hz, 1H), 3.71 (d, J=1.0Hz, 2H), 3.26 (s, 2H), 2.66 (s, 4H), 2.59 (s, 4H), 2.31 (s, 3H).

[0204]

[0205] 2-chloro-N-(quinolin-6-yl)acetamide (5a22): Following the synthesis of 5a1 using 6-aminoquinoline (500 mg, 3.47 mmol), triethylamine (385 mg, 3.81 mmol), chloroacetyl chloride (430 mg, 3.81 mmol), and DCM, the product was purified by column chromatography (DCM / MeOH = 20:1) to give a red solid compound 5a22 (193 mg, 64%). 1 HNMR (400MHz, CDCl3) δ: 8.88 (d, J=3.9Hz, 1H), 8.45 (s, 1H), 8.35 (d, J=2.4Hz, 1H), 8.1 8-8.07 (m, 2H), 7.65 (dd, J=9.0, 2.4Hz, 1H), 7.42 (dd, J=8.3, 4.2Hz, 1H), 4.27 (s, 2H).

[0206]

[0207] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(quinolin-6-yl)acetamide (A-22): Compound A-1 was synthesized using intermediates 5a22 (200 mg, 0.91 mmol) in acetonitrile, intermediate 3b (480 mg, 1.36 mmol), and K2CO3 (187 mg, 1.36 mmol). The resulting product was purified by column chromatography (DCM:MOH = 40:1) to give a white solid, A-22 (155 mg, 40%). Mp: 248-250 °C. 1 HNMR (400MHz, CDCl3) δ: 10.79 (s, 1H), 9.36 (s, 1H), 8.83 (dd, J=4.2, 1.7Hz, 1H), 8.41 (d, J=2.4Hz, 1H), 8.14 (dd, J=8.0, 1.2Hz, 1H), 8.06 (d, J=9.0Hz, 1H), 7.59 (dd, J=9.0, 2.4Hz, 1H), 7.39 (dd, J=8.3, 4.2Hz, 1H), 7.24 (s, 1H), 3.75 (d, J=1.0Hz, 2H), 3.21 (s, 2H), 2.70 (s, 4H), 2.63 (s, 4H), 2.30 (s, 3H).

[0208]

[0209] 2-Chloro-N-(quinoxalin-6-yl)acetamide (5a23): Compound A-1 was synthesized using 6-aminoquinoxaline (500 mg, 3.44 mmol), triethylamine (385 mg, 3.79 mmol), and chloroacetyl chloride (427 mg, 3.79 mmol) from DCM. The resulting product was purified by column chromatography (DCM / MeOH = 20:1) to give a brown solid intermediate 5a23 (629 mg, 88%). 1 HNMR (400MHz, CDCl3) δ: 8.41 (d, J=2.4Hz, 1H), 8.12 (d, J=9.1Hz, 1H), 7.96 (dd, J=9.1, 2.4Hz, 1H), 7.89 (d, J=8.9Hz, 1H), 7.23-7.12 (m, 2H), 4.28 (s, 2H).

[0210]

[0211] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(quinoxalin-6-yl)acetamide (A-23): Compound A-1 was synthesized using intermediates 5a23 (222 mg, 1.00 mmol) in acetonitrile, intermediate 3b (425 mg, 1.20 mmol), and K2CO3 (331 mg, 2.40 mmol). The resulting product was purified by column chromatography (DCM:MOH = 30:1) to give a white solid, A-23 (272 mg, 64%). Mp: 234-235 °C. 1 HNMR (400MHz, CDCl3) δ: 10.60 (s, 1H), 9.52 (s, 1H), 8.81 (d, J=1.8Hz, 1H), 8.76 (d, J=1.9Hz, 1H), 8.30 (dd, J=2.0, 0. 9Hz, 1H), 8.07-8.06 (m, 2H), 7.24 (s, 1H), 3.75 (d, J=1.0Hz, 2H), 3.22 (s, 2H), 2.71 (s, 4H), 2.63 (s, 4H), 2.30 (s, 3H).

[0212]

[0213] 2-Chloro-N-(naphthalen-1-yl)acetamide (5a24): Following the synthesis of 5a1 using 1-naphthylamine (500 mg, 3.49 mmol), triethylamine (388 mg, 3.84 mmol), and chloroacetyl chloride (434 mg, 3.84 mmol) from DCM, the product was purified by column chromatography (n-hexane / EtOAc = 2:1) to give a white solid intermediate 5a24 (350 mg, 45%). 1 HNMR (400MHz, CDCl3) δ: 8.77 (s, 1H), 8.00 (d, J=7.5Hz, 1H), 7.89 (t, J=9.4Hz, 2H), 7.76 (d, J=8.2Hz, 1H), 7.60-7.49 (m, 3H), 4.36 (s, 2H).

[0214]

[0215] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(naphthalen-1-yl)acetamide (A-24): Compound A-1 was synthesized using intermediates 5a24 (220 mg, 1.00 mmol) in acetonitrile, intermediate 3b (425 mg, 1.20 mmol), and K2CO3 (331 mg, 2.40 mmol). The resulting product was purified by column chromatography (DCM:MOH = 40:1) to give a white solid, A-24 (246 mg, 58%). Mp: 257-258 °C. 1 HNMR (400MHz, CDCl3) δ: 10.72 (s, 1H), 9.90 (s, 1H), 8.24 (dd, J=7.6, 1.1Hz, 1H), 7.89-7.86 (m, 1H), 7.84-7.82 (m, 1H), 7.66 (d, J= 8.2Hz, 1H), 7.57-7.47 (m, 3H), 7.25 (d, J=0.9Hz, 1H), 3.77 (d, J=1.0Hz, 2H), 3.30 (s, 2H), 2.79 (s, 4H), 2.68 (s, 4H), 2.30 (s, 3H).

[0216]

[0217] 2-Chloro-N-(1H-indol-5-yl)acetamide (5a25): Following the synthesis of 5a1 using 5-aminoindole (500 mg, 3.78 mmol), triethylamine (420 mg, 4.16 mmol), and chloroacetyl chloride (470 mg, 4.16 mmol) from DCM, the product was purified by column chromatography (n-hexane / EtOAc = 2:1) to give a white solid intermediate 5a25 (470 mg, 60%). 1 HNMR (400MHz, CDCl3) δ: 8.26 (s, 1H), 8.19 (s, 1H), 7.87 (d, J=2.1Hz, 1H), 7.36 (dt, J=8.6, 0.8Hz , 1H), 7.27 (d, J=2.1Hz, 1H), 7.25-7.22 (m, 1H), 6.54 (ddd, J=3.1, 2.0, 0.9Hz, 1H), 4.22 (s, 2H).

[0218]

[0219] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(1H-indol-5-yl)acetamide (A-25): Compound A-1 was synthesized using intermediates 5a25 (210 mg, 1.00 mmol) and 3b (425 mg, 1.20 mmol) from acetonitrile, and K2CO3 (331 mg, 2.40 mmol). The resulting product was purified by column chromatography (DCM:MOH = 40:1) to give a white solid, A-25 (245 mg, 59%). Mp: 216-219 °C. 1 HNMR (400MHz, CDCl3) δ: 10.71 (s, 1H), 9.06 (s, 1H), 8.15 (s, 1H), 7.88-7.86 (m, 1H), 7.35-7.28 (m, 2H), 7.22-7.20 (m, 2H) , 6.52 (ddd, J=3.1, 2.0, 0.9Hz, 1H), 3.72 (d, J=1.0Hz, 2H), 3.16 (s, 2H), 2.68 (d, J=4.8Hz, 4H), 2.60 (s, 4H), 2.29 (s, 3H).

[0220]

[0221] N-(1H-benzo[d]imidazol-2-yl)-2-chloroacetamide (5a26): Following the synthesis of 5a1 using 2-aminobenzimidazole (500 mg, 3.76 mmol), triethylamine (417 mg, 4.13 mmol), and chloroacetyl chloride (466 mg, 4.13 mmol) from DCM, the intermediate 5a26 (632 mg, 80%) was purified by column chromatography (n-hexane / EtOAc = 2:1) to give a white solid intermediate 5a26. 1 HNMR (400MHz, DMSO-d6) δ: 7.44 (d, J=2.7Hz, 1H), 7.17 (dd, J=5.8, 3.2Hz, 1H), 7.12 ( d, J=2.8Hz, 1H), 6.96 (dd, J=5.8, 3.1Hz, 1H), 6.90 (s, 1H), 4.37 (s, 2H), 4.16 (s, 1H).

[0222]

[0223] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(1H-benzo[d]imidazol-2-yl)acetamide (A-26): Compound A-1 was synthesized using intermediates 5a26 (210 mg, 1.00 mmol) in acetonitrile, intermediate 3b (425 mg, 1.20 mmol), and K2CO3 (331 mg, 2.40 mmol). The resulting product was purified by column chromatography (DCM:MOH = 20:1) to give a white solid, A-26 (104 mg, 25%). Mp: 233-236 °C. 1 HNMR (400MHz, DMSO-d6) δ: 12.06 (s, 1H), 11.93 (s, 1H), 11.06 (s, 1H), 7.43 (s, 2H), 7.26 (s, 1H) , 7.08 (dd, J=6.1, 3.1Hz, 2H), 3.64 (s, 2H), 3.28 (s, 2H), 2.59 (s, 4H), 2.45 (s, 4H), 2.11 (s, 3H).

[0224]

[0225] N-(benzo[d]thiazol-2-yl)-2-chloroacetamide (5a27): Following the synthesis of 5a1 using 2-aminobenzimidazole (500 mg, 3.33 mmol), triethylamine (370 mg, 3.66 mmol), and chloroacetyl chloride (413 mg, 3.66 mmol) from DCM, the intermediate 5a27 (477 mg, 63%) was purified by column chromatography (n-hexane / EtOAc = 5:1) to give a white solid intermediate 5a27. 1 HNMR (400MHz, CDCl3) δ: 9.76 (s, 1H), 7.87-7.79 (m, 2H), 7.48 (ddd, J=8.2, 7.2, 1.3Hz, 1H), 7.36 (ddd, J=8.2, 7.2, 1.2Hz, 1H), 4.32 (s, 2H).

[0226]

[0227] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(benzo[d]thiazol-2-yl)acetamide (A-27): Compound A-1 was synthesized using intermediates 5a27 (227 mg, 1.00 mmol) in acetonitrile, intermediate 3b (425 mg, 1.20 mmol), and K2CO3 (331 mg, 2.40 mmol). The resulting product was purified by column chromatography (DCM:MOH = 40:1) to give a white solid, A-27 (129 mg, 30%). Mp: 248-249 °C. 1 HNMR (400MHz, DMSO-d6) δ: 11.94 (s, 1H), 7.97 (dd, J=7.9, 1.1Hz, 1H), 7.74 (dd, J=8.1, 0.9Hz, 1H), 7.43 (td, J=7.7 , 1H), 7.30 (td, J=7.7, 1.2Hz, 1H), 7.26 (s, 1H), 3.63 (s, 2H), 3.29 (s, 2H), 2.56 (s, 4H), 2.44 (s, 4H), 2.11 (s, 3H).

[0228]

[0229] 2-Chloro-N-(6-methoxybenzo[d]thiazol-2-yl)acetamide (5a28): Following the synthesis of 5a1 using 2-amino-6-methoxybenzothiazole (500 mg, 2.77 mmol), triethylamine (308 mg, 3.05 mmol), and chloroacetyl chloride (344 mg, 3.05 mmol) from DCM, the product was purified by column chromatography (n-hexane / EtOAc = 5:1) to give a white solid intermediate 5a28 (425 mg, 60%). 1 HNMR (400MHz, CDCl3) δ: 9.66 (s, 1H), 7.71 (d, J=8.9Hz, 1H), 7.30 (d, J=2.6Hz, 1H), 7.07 (dd, J=8.9, 2.6Hz, 1H), 4.30 (s, 2H), 3.88 (s, 3H).

[0230]

[0231] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(6-methoxybenzo[d]thiazol-2-yl)acetamide (A-28): Compound A-1 was synthesized using intermediates 5a28 (256 mg, 1.00 mmol) in acetonitrile, intermediate 3b (425 mg, 1.20 mmol), and K2CO3 (331 mg, 2.40 mmol). The resulting product was purified by column chromatography (DCM:MOH = 20:1) to give a white solid, A-28 (333 mg, 72%). Mp: 241-244 °C. 1 HNMR (400MHz, DMSO-d6) δ: 11.93 (s, 1H), 7.62 (d, J=8.8Hz, 1H), 7.56 (d, J=2.6Hz, 1H), 7.26 (s, 1H), 7.02 (dd, J=8 .8, 2.6Hz, 1H), 3.80 (s, 3H), 3.63 (d, J=1.0Hz, 2H), 3.27 (s, 2H), 2.55 (d, J=5.6Hz, 4H), 2.44 (s, 4H), 2.11 (s, 3H).

[0232]

[0233] 2-Chloro-N-(6-ethoxybenzo[d]thiazol-2-yl)acetamide (5a29): Following the synthesis of 5a1 using 2-amino-6-ethoxybenzothiazole (500 mg, 2.57 mmol), triethylamine (288 mg, 2.83 mmol), and chloroacetyl chloride (319 mg, 2.83 mmol) from DCM, the product was purified by column chromatography (n-hexane / EtOAc = 1:1) to give a white solid intermediate 5a29 (660 mg, 96%).

[0234] 1 HNMR (400MHz, CDCl3) δ: 7.69 (dd, J=8.9, 0.4Hz, 1H), 7.29 (d, J=2.5Hz, 1H), 7.06 ( dd, J=8.9, 2.5Hz, 1H), 4.30 (s, 2H), 4.09 (q, J=7.0Hz, 2H), 1.45 (t, J=7.0Hz, 3H).

[0235]

[0236] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(6-ethoxybenzo[d]thiazol-2-yl)acetamide (A-29): Compound A-1 was synthesized using intermediates 5a29 (270 mg, 1.00 mmol) in acetonitrile, intermediate 3b (425 mg, 1.20 mmol), and K2CO3 (331 mg, 2.40 mmol). The resulting product was purified by column chromatography (DCM:MOH = 20:1) to give a white solid, A-29 (240 mg, 51%). Mp: 244-246 °C. 1HNMR (400MHz, DMSO-d6) δ: 11.94 (s, 1H), 7.61 (d, J=8.8Hz, 1H), 7.54 (d, J=2.6Hz, 1H), 7.26 (s, 1H), 7.01 (dd, J=8.8, 2.6Hz , 1H), 4.07 (q, J=7.0Hz, 2H), 3.63 (s, 2H), 3.30 (s, 2H), 2.58-2.52 (m, 4H), 2.44 (s, 4H), 2.11 (s, 3H), 1.35 (t, J=7.0Hz, 3H).

[0237]

[0238] 2-Chloro-N-(4-chlorobenzo[d]thiazol-2-yl)acetamide (5a30): Following the synthesis of 5a1 using 2-amino-4-chlorobenzothiazole (500 mg, 2.70 mmol), triethylamine (303 mg, 2.98 mmol), and chloroacetyl chloride (336 mg, 2.98 mmol) from DCM, the product was purified by column chromatography (n-hexane / EtOAc = 5:1) to give a white solid intermediate 5a30 (350 mg, 49%). 1 HNMR (400MHz, CDCl3) δ: 9.94 (s, 1H), 7.74 (dd, J=8.0, 1.1Hz, 1H), 7.50 (dd, J=7.8, 1.0Hz, 1H), 7.29 (t, J=7.9Hz, 1H), 4.33 (s, 2H).

[0239]

[0240] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(4-chlorobenzo[d]thiazol-2-yl)acetamide (A-30): Compound A-1 was synthesized using intermediates 5a30 (262 mg, 1.00 mmol) in acetonitrile, intermediate 3b (425 mg, 1.20 mmol), and K2CO3 (331 mg, 2.40 mmol). The resulting product was purified by column chromatography (DCM:MOH = 20:1) to give a white solid, A-30 (88 mg, 19%). Mp: 255-257 °C. 1 HNMR (400MHz, DMSO-d6) δ: 11.94 (s, 1H), 7.95 (dd, J=8.0, 1.1Hz, 1H), 7.52 (dd, J=7.8, 1.1Hz, 1H ), 7.30 (t, J=7.9Hz, 1H), 7.26 (s, 1H), 3.34 (s, 2H), 2.57-2.55 (m, 4H), 2.44 (s, 4H), 2.12 (s, 3H).

[0241]

[0242] 2-Chloro-N-methyl-N-phenylacetamide (6): At 0 °C, NaH (318 mg, 2.12 mmol) was slowly added to a solution of compound 5a1 (300 mg, 1.77 mmol) in DMF (20 mL), followed by the addition of iodomethane (51 mg, 2.12 mmol). The reaction mixture was stirred at room temperature for 1 hour. Extraction with EtOAc gave intermediate 6 (233 mg, 70%). 1 HNMR (400MHz, CDCl3) δ: 7.49-7.37 (m, 4H), 7.24 (dd, J=1.8, 1.1Hz, 1H), 3.85 (s, 2H), 3.32 (s, 3H).

[0243]

[0244] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-methyl-N-phenylacetamide (2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-methyl-N-phenylacetamide)(A-31): Compound A-1 was synthesized using intermediates 6a1 (183 mg, 1.00 mmol) and 3b (425 mg, 1.20 mmol) in acetonitrile and K2CO3 (331 mg, 2.40 mmol). The resulting product was purified by column chromatography (DCM:MOH = 30:1) to give a white solid, A-31 (105 mg, 31%). Mp: 208-210 °C. 1 HNMR (400MHz, CDCl3) δ: 12.25 (s, 1H), 7.41 (dd, J=8.3, 6.6Hz, 2H), 7.34 (t, J=7.2Hz, 1H), 7.20 (d, J=1.6H z, 1H), 7.18 (d, J=0.9Hz, 2H), 3.63 (s, 2H), 3.26 (s, 3H), 2.91 (s, 2H), 2.47 (d, J=13.9Hz, 8H), 2.30 (s, 3H).

[0245]

[0246] 2-(4-((2-acetamidothiazol-5-yl)methyl)-3-methylpiperazin-1-yl)-N-phenylacetamide (A-32): Compound A-1 was synthesized using intermediates 5a1 (255 mg, 1.51 mmol) and 3c (460 mg, 1.81 mmol) from acetonitrile and K2CO3 (250 mg, 1.81 mmol). The resulting product was purified by column chromatography (DCM:MOH = 30:1) to give a white solid, A-32 (173 mg, 30%). Mp: 174-176 °C. 1HNMR (400MHz, CDCl3) δ: 10.91 (s, 1H), 9.06 (s, 1H), 7.56-7.54 (m, 2H), 7.35-7. 31 (m, 2H), 7.22 (s, 1H), 7.13-7.08 (m, 1H), 4.04 (d, J=14.3Hz, 1H), 3.70 (d, J=14 .5Hz, 1H), 3.10 (d, J=2.8Hz, 2H), 2.84-2.81 (m, 1H), 2.75-2.72 (m, 2H), 2.62 (s , 1H), 2.54-2.40 (m, 2H), 2.31 (s, 3H), 2.26-2.25 (m, 1H), 1.19 (d, J=6.2Hz, 3H).

[0247]

[0248] 2-(4-((2-acetamidothiazol-5-yl)methyl)-3-methylpiperazin-1-yl)-N-(4-fluorophenyl)acetamide (A-33): Compound A-1 was synthesized using intermediates 5a11 (200 mg, 1.06 mmol) and 3c (323 mg, 1.27 mmol) from acetonitrile, followed by purification by column chromatography (DCM:MOH = 50:1) to give a pale yellow solid, compound A-33 (130 mg, 30%). Mp: 102-105 °C. 1 HNMR (400MHz, CDCl3) δ: 11.15 (s, 1H), 9.04 (s, 1H), 7.53-7.49 (m, 2H), 7.22 (s, 1H), 7. 04-7.00 (m, 2H), 4.04 (d, J = 14.6Hz, 1H), 3.72 (d, J = 14.6Hz, 1H), 3.10 (d, J = 2.7Hz, 2H), 2.82 (dd, J=11.1, 3.1Hz, 1H), 2.73 (d, J=7.3Hz, 2H), 2.65-2.60 (m, 1H), 2.51 (t, J=10. 1Hz, 1H), 2.46-2.40 (m, 1H), 2.31 (s, 3H), 2.26 (d, J=9.6Hz, 1H), 1.19 (d, J=6.2Hz, 3H).

[0249]

[0250] 2-(4-((2-acetamidothiazol-5-yl)methyl)-3-methylpiperazin-1-yl)-N-(4-chlorophenyl)acetamide (A-34): Following the synthesis of compound A-1 using intermediates 5a12 (200 mg, 0.98 mmol) and 3c (295 mg, 1.16 mmol) from acetonitrile, and K2CO3 (163 mg, 1.16 mmol), the compound was purified by column chromatography (DCM:MOH = 50:1) to give a white solid compound A-34 (120 mg, 30%). Mp: 184-187 °C. 1 HNMR (400MHz, CDCl3) δ: 12.51 (d, J=11.3Hz, 1H), 9.09 (s, 1H), 7.54-7.48 (m, 2H), 7. 30-7.26 (m, 2H), 7.23 (s, 1H), 4.05 (d, J = 14.5Hz, 1H), 3.72 (d, J = 14.6Hz, 1H), 3.11 (d , J=2.9Hz, 2H), 2.84 (dt, J=11.6, 2.9Hz, 1H), 2.73 (dt, J=10.2, 4.3Hz, 2H), 2.66-2. 60 (m, 1H), 2.54-2.41 (m, 2H), 2.34 (s, 3H), 2.30-2.24 (m, 1H), 1.19 (d, J=6.1Hz, 3H).

[0251]

[0252] 2-(4-((2-acetamidothiazol-5-yl)methyl)-3-methylpiperazin-1-yl)-N-cyclohexylacetamide (A-35): Following the synthesis of compound A-1 using intermediates 5a20 (200 mg, 1.14 mmol) and 3c (348 mg, 1.37 mmol) from acetonitrile, and K2CO3 (169 mg, 1.37 mmol), the compound was purified by column chromatography (DCM:MOH = 50:1) to give a white solid compound A-35 (120 mg, 27%). Mp: 184-187 °C. 1HNMR (400MHz, CDCl3) δ: 12.34 (s, 1H), 7.21 (s, 1H), 7.00 (d, J = 8.7Hz, 1H), 4.01 (d, J = 14.5Hz, 1H), 3.78 (dtd, J = 14.1, 10.0, 8.4, 4.2Hz, 1H), 3.69 (d, J=14.6Hz, 1H), 3.49-3.48 (m, 1H), 3.01-2.88 (m, 2H), 2.82-2.74 (m, 1H), 2.63 (dd, J=1 0.1, 3.2Hz, 2H), 2.57 (d, J=9.3Hz, 1H), 2.43-2.35 (m, 2H), 2.32 (s, 3H), 2.21-2.12 (m, 2H), 1.87 (dt, J=13.0, 4.2Hz, 2 H), 1.69 (d, J=15.1Hz, 2H), 1.60 (dt, J=13.0, 3.8Hz, 1H), 1.41-1.31 (m, 2H), 1.22-1.17 (m, 2H), 1.15 (d, J=6.1Hz, 3H).

[0253] Scheme 3. Synthesis of intermediate 4a31

[0254]

[0255] Reagents and conditions: (i) K2CO3, DMSO, 80℃, 6h; (ii) acetyl chloride, TEA, DCM, rt, 1h.

[0256]

[0257] 1-(4-nitrophenyl)piperazine (8a31): 4-bromo-1-nitrobenzene (3.00 g, 14.58 mmol) was added to a gusxirdor of piperazine (1.92 g, 22.28 mmol) in DMSO (80 mL) and K₂CO₃ (3.08 g, 22.28 mmol). The reaction mixture was stirred at 80 °C for 8 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc to give a yellow solid intermediate 8a31 (1.94 g, 65%). 1 HNMR (400MHz, CDCl3) δ: 8.15-8.11 (m, 2H), 6.85-6.82 (m, 2H), 3.44 (t, J=5.1Hz, 4H), 3.07 (s, 4H).

[0258]

[0259] 1-(4-(4-nitrophenyl)piperazin-1-yl)ethan-1-one (-(4-(4-nitrophenyl)piperazin-1-yl)ethan-1-one)(7a31): At 0 °C, acetyl chloride (418 mg, 5.31 mmol) in DCM (50 mL) was added dropwise to a solution of intermediate 8a31 (1.00 g, 4.83 mmol) and trimethylamine (541 mg, 5.31 mmol). The reaction mixture was stirred at room temperature for 1 hour. DCM was evaporated under vacuum, and the resulting residue was purified by column chromatography (DCM:MeOH = 30:1) to give intermediate 7a31 (1.16 g, 96%) as a yellow solid. 1 HNMR (500MHz, CDCl3) δ: 8.20-8.13 (m, 2H), 6.88-6.80 (m, 2H), 3.82 (t, J=5.4Hz, 2H), 3.68 (t, J=5.2Hz, 2H), 3.47 (dt, J=21.4, 5.6Hz, 4H), 2.17 (s, 3H).

[0260]

[0261] 1-(4-(4-aminophenyl)piperazin-1-yl)ethan-1-one (4a31): Intermediate 7a31 (1.16 g, 4.64 mg) was added to a 10% (98 mg, 0.93 mmol) solution of carbon-supported palladium in anhydrous MeOH (50 mL). The reaction mixture was stirred overnight under hydrogen atmosphere at room temperature. The reaction mixture was filtered through diatomaceous earth, the residue was washed with EtOH, and the filtrate was evaporated under vacuum to give intermediate 4a31 (1.13 g, 99%) as a white solid. 1 HNMR (400MHz, CDCl3) δ: 6.84-6.79 (m, 2H), 6.70-6.63 (m, 2H), 3.78-3.72 (m, 2H), 3.63-3.58 (m, 2H), 3.00 (dt, J=12.8, 5.2Hz, 4H), 2.13 (s, 3H).

[0262]

[0263] N-(4-(4-acetylpiperazin-1-yl)phenyl)-2-chloroacetamide (5a31): 5a1 was synthesized using intermediate 4a31 (1.13 mg, 5.16 mmol) from DCM, triethylamine (579 mg, 5.68 mmol), and chloroacetyl chloride (641 mg, 5.68 mmol). The resulting product was purified by column chromatography (DCM / MeOH = 30:1) to give a green solid intermediate 5a31 (1.13 mg, 74%). 1 HNMR (400MHz, CDCl3) δ: 8.14 (s, 1H), 7.49-7.41 (m, 2H), 6.93 (d, J=8.6Hz, 2H), 4.19 (s, 2H) ), 3.78 (t, J=5.2Hz, 2H), 3.63 (t, J=5.2Hz, 2H), 3.15 (dt, J=13.9, 5.3Hz, 4H), 2.14 (s, 3H).

[0264]

[0265] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(4-(4-acetylpiperazin-1-yl)phenyl)acetamide (A-36): Compound A-1 was synthesized using intermediates 5a31 (295 mg, 1.00 mmol) and 3b (425 mg, 1.20 mmol) from acetonitrile, and K2CO3 (165 mg, 1.20 mmol). The resulting product was purified by column chromatography (DCM:MOH = 30:1) to give a white solid, A-36 (51 mg, 10%). Mp: 180-182 °C. 1 HNMR (500MHz, CDCl3) δ: 11.77 (s, 1H), 8.97 (s, 1H), 7.48-7.46 (m, 2H), 7.23 (s, 1H), 6.91 (d, J=8.5Hz, 2H), 3.78 (t, J=5.2Hz, 2H), 3.72 (s, 2H), 3.63 (t, J=5.0Hz, 2H), 3.15-3.09 (m, 6H), 2.66 (s, 4H), 2.59 (s, 4H), 2.18 (s, 6H).

[0266]

[0267] 2-(4-((2-acetamidothiazol-5-yl)methyl)-3-methylpiperazin-1-yl)-N-(4-(4-acetylpiperazin-1-yl)phenyl)acetamide (A-37): Compound A-1 was synthesized using intermediates 5a31 (295 mg, 1.00 mmol) and 3c (305 mg, 1.20 mmol) from acetonitrile, and K2CO3 (165 mg, 1.20 mmol). The resulting product was purified by column chromatography (DCM:MOH = 20:1) to give a pale yellow solid, A-37 (204 mg, 40%). Mp: 232–232 °C. 1 HNMR (500MHz, CDCl3) δ: 12.28 (s, 1H), 8.91 (s, 1H), 7.43 (d, J = 8.5Hz, 2H), 6.86 (d, J = 8.5Hz, 2 H), 4.01 (d, J=14.5Hz, 1H), 3.73 (t, J=5.1Hz, 2H), 3.68 (d, J=14.5Hz, 1H), 3.59 (t, J=5.1Hz, 2H ), 3.16-3.01(m, 6H), 2.81-2.76(m, 1H), 2.69(d, J=10.0Hz, 2H), 2.48-2.43(m, 1H), 2.39(t, J =10.2Hz, 1H), 2.29 (s, 3H), 2.23 (dd, J = 20.4, 10.5Hz, 2H), 2.11 (s, 3H), 1.15 (d, J = 6.2Hz, 3H).

[0268]

[0269] N-(4-benzylphenyl)-2-chloroacetamide (5a32): Following the synthesis of 5a1 using 4-aminodiphenylmethane (300 mg, 1.64 mmol), triethylamine (184 mg, 1.80 mmol), and chloroacetyl chloride (203 mg, 1.80 mmol) from DCM, the intermediate 5a32 (1.13 mg, 74%) was purified by column chromatography (n-hexane / EtOAc = 5:1) to give a purple solid intermediate 5a32. 1HNMR (400MHz, CDCl3) δ: 8.25 (s, 1H), 7.49-7.44 (m, 2H), 7.31-7.27 (m, 2H), 7.23-7.14 (m, 5H), 4.19 (s, 2H), 3.96 (s, 2H).

[0270]

[0271] 2-(4-((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)-N-(4-benzylphenyl)acetamide (A-38): Compound A-1 was synthesized using the same method as compound 5a32 (414 mg, 1.60 mmol) from acetonitrile, intermediate 3b (676 mg, 1.91 mmol), and K₂CO₃ (264 mg, 1.91 mmol). The resulting product was purified by column chromatography (DCM:MOH = 40:1) to give a pale yellow solid, A-38 (70 mg, 15%). Mp: 132-134 °C. 1 HNMR (400MHz, CDCl3) δ: 11.10 (s, 1H), 9.02 (s, 1H), 7.49-7.45 (m, 2H), 7.27 (d, J = 1.4Hz, 1H), 7.25 (d, J = 0.7Hz, 1H), 7.21 (d, J = 1.0Hz , 1H), 7.21-7.18(m, 1H), 7.18-7.14(m, 4H), 3.95(s, 2H), 3.71(d, J=1.0Hz, 2H), 3.13(s, 2H), 2.64(s, 4H), 2.57(s, 4H), 2.30(s, 3H).

[0272]

[0273] 2-(4-((2-acetamidothiazol-5-yl)methyl)-3-methylpiperazin-1-yl)-N-(4-benzylphenyl)acetamide (A-39): Following the synthesis of compound A-1 using intermediates 5a32 (400 mg, 1.54 mmol) and 3c (468 mg, 1.84 mmol) from acetonitrile, and K₂CO₃ (255 mg, 1.84 mmol), the compound was purified by column chromatography (DCM:MOH = 30:1) to give a pale yellow solid, compound A-39 (157 mg, 33%). Mp: 193-195 °C. 1 HNMR (400MHz, CDCl3) δ: 11.96 (s, 1H), 9.00 (s, 1H), 7.48 7.44 (m, 2H), 7.27 (d, J = 1.4Hz, 1H), 7.25 (q, J = 1.4Hz, 1H), 7.21 (d, J = 0.9Hz, 1H), 7.21 7.18(m,1H),7.17 7.13 (m, 4H), 4.04 (d, J = 14.6Hz, 1H), 3.94 (s, 2H), 3.69 (d, J = 14.5Hz, 1H), 3.09 ( d, J=2.7Hz, 2H), 2.842.78 (m, 1H), 2.72 (dd, J=9.8, 2.8Hz, 2H), 2.61 (s, 1H), 2.52 2.38 (m, 2H), 2.32 (s, 3H), 2.29 2.23 (m, 1H), 1.18 (d, J=6.2Hz, 3H).

[0274] Scheme 4. Synthesis of intermediate 4a33

[0275]

[0276] Reagents and conditions: (i) LiAlH4, THF, 0℃-rt, 1.5h.

[0277]

[0278] [1,1'-Biphenyl]-4-ylmethylamine (4a33): Lithium aluminum hydride (424 mg, 11.16 mmol) was added portionwise to a solution of 4-cyanobiphenyl (500 mg, 2.79 mmol) in THF (30 mL) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h. Extraction with DCM gave a white solid intermediate 4a33 (450 mg, 88%). 1 HNMR (400MHz, CDCl3) δ: 7.58 (ddt, J=7.6, 6.3, 1.7Hz, 4H), 7.45-7.32 (m, 5H), 3.92 (s, 2H).

[0279]

[0280] N-([1,1'-biphenyl]-4-ylmethyl)-2-chloroacetamide (5a33): The synthesis of 5a1 was performed using intermediate 4a33 (300 mg, 1.64 mmol) from DCM, triethylamine (184 mg, 1.80 mmol), and chloroacetyl chloride (203 mg, 1.80 mmol). The intermediate was purified by column chromatography (n-hexane / EtOAc = 1:1) to give a white solid intermediate 5a33 (472 mg, 100%). 1 HNMR (400MHz, CDCl3) δ: 8.25 (s, 1H), 7.49-7.44 (m, 2H), 7.31-7.27 (m, 2H), 7.23-7.14 (m, 5H), 4.19 (s, 2H), 3.96 (s, 2H). 1 HNMR (400MHz, CDCl3) δ: 7.62-7.56 (m, 4H), 7.48-7.42 (m, 2H), 7.41-7.32 (m, 3H), 6.92 (s, 1H), 4.55 (d, J = 5.9Hz, 2H), 4.14 (s, 2H).

[0281]

[0282] N-([1,1'-biphenyl]-4-ylmethyl)-2-(4-(((2-acetamidothiazol-5-yl)methyl)piperazin-1-yl)acetamide (A-40): Following the synthesis of compound A-1 using intermediates 5a33 (290 mg, 1.12 mmol), 3b (475 mg, 1.34 mmol), and K₂CO₃ (171 mg, 1.34 mmol) in acetonitrile, the compound was purified by column chromatography (DCM:MOH = 30:1) to give a pale yellow solid, compound A-40 (32 mg, 6%). Mp: 167-170 °C. 1 HNMR (500MHz, CDCl3) δ: 10.38 (s, 1H), 7.59 (dd, J=8.0, 6.4Hz, 4H), 7.45 (t, J=7.5Hz, 2H), 7.35 (d, J=7.9Hz , 3H), 7.19 (s, 1H), 4.53 (d, J=6.0Hz, 2H), 3.68 (s, 2H), 3.10 (s, 2H), 2.59 (s, 4H), 2.51 (s, 4H), 2.28 (s, 3H).

[0283]

[0284] N-([1,1'-biphenyl]-4-ylmethyl)-2-(4-(((2-acetamidothiazol-5-yl)methyl)-3-methylpiperazin-1-yl)acetamide (A-41): Compound A-1 was synthesized using intermediates 5a33 (290 mg, 1.12 mmol) and 3c (340 mg, 1.34 mmol) in acetonitrile and K2CO3 (171 mg, 1.34 mmol). The resulting product was purified by column chromatography (DCM:MOH = 40:1) to give a pale yellow solid, A-41 (37 mg, 7%). Mp: 215-216 °C. 1HNMR (500MHz, CDCl3) δ: 9.86 (s, 1H), 7.58 (t, J=8.9Hz, 4H), 7.44 (d, J=7.6Hz , 2H), 7.35 (dd, J=11.4, 7.6Hz, 3H), 7.18 (s, 1H), 4.52 (d, J=5.1Hz, 2H), 3.99 (d, J=14.5Hz, 1H), 3.69 (d, J=14.6Hz, 1H), 3.06 (s, 2H), 2.71 (dd, J=45.1, 11 .9Hz, 4H), 2.39 (dt, J=37.8, 10.5Hz, 3H), 2.26 (s, 3H), 1.11 (d, J=6.2Hz, 3H).

[0285] Example 2

[0286] Synthesis of compounds with chemical formula 3

[0287] The compound of chemical formula 3 below was prepared by the following process.

[0288]

[0289] Scheme 5. Synthesis of B-1 to B-12

[0290]

[0291] Reagents and conditions: (i) K2CO3, di-tert-butyl dicarbonate, H2O:THF (1:1), 0℃-rt, overnight; (ii) amine compounds, EDCI, DMAP, DCM, 0℃-rt, overnight; (iii) TFA, DCM, rt, overnight; (iv) paraformaldehyde, AcOH, 100℃, 4h

[0292]

[0293] 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (b1): At 0 °C, di-tert-butyl dicarbonate (845 mg, 3.87 mmol) in 8 mL of THF was added dropwise to a suspension of 4-piperidine carboxylicacid (500 mg, 3.87 mmol) and K₂CO₃ (1.07 g, 7.74 mmol) in water (8 mL). The reaction mixture was stirred overnight at room temperature. THF was removed under vacuum, and the aqueous layer was washed with DCM and acidified with 1 N HCl (pH = 4). Filtration gave a white solid intermediate b1 (770 mg, 87%). 1HNMR (400MHz, CDCl3): δ: 4.02 (d, J=13.1Hz, 2H), 2.86 (t, J=12.5Hz, 2H), 2.4 9 (tt, J=10.9, 3.9Hz, 1H), 1.65 (dtd, J=13.4, 11.2, 4.2Hz, 2H), 1.46 (s, 9H).

[0294]

[0295] 4-(phenylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (b2a): At room temperature, one part of intermediate b1 and one part of EDCI (326 mg, 1.70 mmol) were added to a solution of aniline (122 mg, 1.31 mmol), DMAP (208 mg, 1.70 mmol), and DCM (30 mL). The reaction mixture was stirred overnight at room temperature. The reaction was quenched with TH2O and extracted with DCM. The DCM layer was washed with brine, dried over NaSO4, filtered under vacuum, and concentrated. The solution was purified by rapid column chromatography (DCM:MeOH = 98:2) to give intermediate b2a (374 mg, 94%) as a white solid. 1 HNMR (400MHz, CDCl3): δ: 7.51 (d, J=7.9Hz, 2H), 7.32 (dd, J=8.5, 7.4Hz, 2H), 7.18 (s, 1H), 7.11 (t, J=7.4Hz, 1H), 4. 19 (bs, 2H), 2.79 (t, J=12.6Hz, 2H), 2.38 (tt, J=11.5, 3.8Hz, 1H), 1.75 (dtd, J=13.3, 11.8, 4.4Hz, 2H), 1.47 (s, 9H).

[0296]

[0297] N-phenylpiperidine-4-carboxamide (b3a): At room temperature, TFA (1.39 g, 12.16 mmol) was added to a solution of intermediate b2a (370 mg, 1.22 mmol) in DCM (30 mL). The reaction mixture was stirred overnight at room temperature. DCM was evaporated under vacuum, and the resulting residue was reacted with NaHCO3 in DCM. After filtration, a white solid intermediate b3b (232 mg, 94%) was given. 1HNMR (400MHz, DMSO-d6): δ: 10.02 (s, 1H), 7.59 (d, J=7.9Hz, 2H), 7.32-7.27 (m, 3H), 7.05 (t, J=7.3Hz, 1H), 2.93 (td, J=12.6, 3.2Hz, 3H), 2.63 (tt, J=11.1, 3.9Hz, 1H), 2.00-1.91 (m, 3H), 1.80 (dtd, J=14.8, 11.9, 4.0Hz, 3H).

[0298]

[0299] 1-((2-acetamidothiazol-5-yl)methyl)-N-phenylpiperidine-4-carboxamide (B-1): Paraformaldehyde (338 mg, 11.26 mmol) was added to a solution of 2-acetamidothiazol (240 mg, 1.69 mmol) and intermediate b3a (230 mg, 1.13 mmol) in acetic acid (20 mL) with stirring at 100 °C. The reaction mixture was stirred at 100 °C for 4 hours. Acetic acid was evaporated under vacuum. The final residue was purified by rapid column chromatography (DCM:MeOH = 20:1) to give compound B-1 (180 mg, 45%) as a white solid. Mp: 172-174 °C. 1 HNMR (400MHz, DMSO-d6): δ: 11.94 (s, 1H), 9.82 (s, 1H), 7.64-7.51 (m, 2H), 7.32-7.20 (m, 3H), 7.05-6.96 (m, 1H), 3.63 (s, 2H) ), 2.90 (dt, J=11.8, 3.3Hz, 2H), 2.30 (tt, J=11.4, 3.7Hz, 1H), 2.12 (s, 3H), 1.97 (td, J=11.7, 2.6Hz, 2H), 1.81-1.57 (m, 4H).

[0300]

[0301] 4-((4-chlorophenyl)carbamoyl)piperidine-1-carboxylate (tert-butyl 4-((4-chlorophenyl)carbamoyl)piperidine-1-carboxylate)(b2b): After the synthesis of intermediate b2a using intermediate b1 (500 mg, 2.18 mmol) from DCM, 4-chloroaniline (278 mg, 2.18 mmol), EDCI (502 mg, 2.62 mmol) and DMAP (320 mg, 2.62 mmol), the intermediate b2b was purified by rapid column chromatography (n-hexane:EtOAc = 5:1) to give a white solid intermediate b2b (645 mg, 87%). 1 HNMR (400MHz, CDCl3) δ: 7.51-7.43 (m, 2H), 7.30-7.27 (m, 2H), 7.18 (s, 1H), 4.18 (bs, 2H), 2.79 (t, J=12.8Hz, 2H), 2.37 (tt, J=11.5, 3.8Hz, 1H), 1.90 (d, J=12.4Hz, 2H), 1.74 (dtd, J=13.3, 11.8, 4.4Hz, 2H), 1.47 (s, 9H).

[0302]

[0303] N-(4-chlorophenyl)piperidine-4-carboxamide and 2,2,2-trifluoroacetaldehyde (1:1) (b3b): At room temperature, TFA (2.09 g, 18.30 mmol) was added to a solution of intermediate b2b (620 mg, 1.83 mmol) in DCM (30 mL). The reaction mixture was stirred overnight at room temperature. DCM was evaporated under vacuum. The resulting residue was washed with MeOH (2 mL) and filtered to give a white solid intermediate b3b (610 mg, 99%). 1 HNMR (400MHz, DMSO-d6): δ: 10.18 (s, 1H), 8.53 (d, J=111.5Hz, 1H), 7.66-7.59 (m, 2H), 7. 40-7.30 (m, 2H), 2.93 (t, J=12.4Hz, 2H), 2.63 (tt, J=11.0, 3.7Hz, 1H), 2.01-1.72 (m, 4H).

[0304]

[0305] 1-((2-acetamidothiazol-5-yl)methyl)-N-(4-chlorophenyl)piperidine-4-carboxamide (B-2): Following the synthesis of compound b-1 using 2-acetamidothiazol in acetic acid (127 mg, 0.89 mmol), intermediate b2b (200 mg, 0.60 mmol), and paraformaldehyde (89 mg, 2.98 mmol), the compound was purified by rapid column chromatography (n-hexane:EtOAc = 2:1) to give a white solid compound B-2 (194 mg, 83%). Mp: 258-260 °C. 1 HNMR (400MHz, DMSO-d6): δ: 11.93 (s, 1H), 9.97 (s, 1H), 7.66-7.57 (m, 2H), 7.38-7.28 (m, 2H), 7.25 (s, 1H), 3.62 (s, 2H), 2.95-2.84 (m , 2H), 2.29 (ddt, J=11.5, 8.0, 3.9Hz, 1H), 2.12 (s, 3H), 1.97 (td, J=11.7, 2.8Hz, 2H), 1.80-1.72 (m, 2H), 1.63 (qd, J=12.2, 3.8Hz, 2H).

[0306]

[0307] 4-((4-isopropylphenyl)carbamoyl)piperidine-1-carboxylate (tert-butyl 4-((4-isopropylphenyl)carbamoyl)piperidine-1-carboxylate)(b2c): After synthesizing intermediate b2a using intermediate b1 (500 mg, 2.18 mmol) from DCM, 4-isopropylaniline (295 mg, 2.18 mmol), EDCI (502 mg, 2.62 mmol), and DMAP (320 mg, 2.62 mmol), the intermediate b2c was purified by rapid column chromatography (n-hexane:EtOAc = 10:1) to give a white solid intermediate b2c (708 mg, 94%). 1HNMR (400MHz, CDCl3): δ: 7.44-7.40 (m, 2H), 7.19-7.15 (m, 2H), 4.18 (s, 2H), 2.93-2.73 (m, 3H), 2.3 6 (tt, J=11.5, 3.8Hz, 1H), 1.74 (dtd, J=13.3, 11.8, 4.4Hz, 2H), 1.47 (s, 9H), 1.22 (d, J=7.0Hz, 6H).

[0308]

[0309] N-(4-isopropylphenyl)piperidine-4-carboxamide and 2,2,2-trifluoroacetaldehyde (1:1) (b3c): After synthesizing intermediate b3c using intermediate b2c (650 mg, 1.88 mmol) from DCM and TFA (2.14 g, 18.80 mmol), a white solid intermediate b3c (570 mg, 89%) was obtained. 1 HNMR (400MHz, DMSO-d6): δ: 9.95 (s, 1H), 8.54 (d, J=110.6Hz, 1H), 7.54-7.42 (m, 2H), 7.22-7.11 (m, 2H), 3.33 (d, J=2.0Hz, 2H), 2.98-2.79 (m, 3H), 2.62 (tt, J=11.1, 3.8Hz, 1H), 2.01-1.73 (m, 4H), 1.17 (d, J=6.9Hz, 6H).

[0310]

[0311] 1-((2-acetamidothiazol-5-yl)methyl)-N-(4-isopropylphenyl)piperidine-4-carboxamide (B-3): Following the synthesis of compound b-1 using acetic acid (20 mL) containing 2-acetamidothiazol (124 mg, 0.87 mmol), intermediate b3c (200 mg, 0.58 mmol), and paraformaldehyde (87 mg, 2.91 mmol), the compound was purified by rapid column chromatography (DCM:MeOH = 20:1) to give a white solid compound B-3 (20 mg, 9%). Mp: 257-258 °C. 1HNMR (400MHz, DMSO-d6) δ: 11.93 (s, 1H), 9.73 (s, 1H), 7.53-7.45 (m, 2H), 7.25 (s, 1H), 7.17-7.10 (m, 2H), 3.62 (s, 2H), 2.93-2.77 (m, 3H), 2.12 (s, 3H), 2.01-1.92 (m, 2H), 1.77-1.57 (m, 5H), 1.16 (d, J=6.9Hz, 6H).

[0312]

[0313] 4-(pyrazin-2-ylcarbamoyl)piperidine-1-carboxylate (tert-butyl4-(pyrazin-2-ylcarbamoyl)piperidine-1-carboxylate) (b2d): After the synthesis of intermediate b2a using intermediate b1 (500 mg, 2.18 mmol) from DCM, 2-aminopyrazine (207 mg, 2.18 mmol), EDCI (502 mg, 2.62 mmol), and DMAP (320 mg, 2.62 mmol), the intermediate b2d was purified by rapid column chromatography (n-hexane:EtOAc = 5:1) to give a white solid intermediate b2d (627 mg, 94%). 1 HNMR (400MHz, CDCl3) δ: 9.59 (d, J=1.6Hz, 1H), 8.65 (s, 1H), 8.37 (d, J=2.6Hz, 1H), 8.19 (dd, J=2.7, 1.6Hz, 1H), 4.19 (s, 2 H), 2.83 (t, J=12.7Hz, 2H), 2.52 (tt, J=11.4, 3.8Hz, 1H), 1.91 (s, 2H), 1.76 (dtd, J=13.4, 11.8, 4.4Hz, 3H), 1.47 (s, 9H).

[0314]

[0315] N-(pyrazin-2-yl)piperidine-4-carboxamide and 2,2,2-trifluoroacetaldehyde (1:1) (b3d): The intermediate b3d (530 mg, 89%) was obtained by using intermediate b2d (600 mg, 1.96 mmol) from DCM and TFA (2.23 g, 19.58 mmol). 1HNMR (400MHz, DMSO-d6): δ: 10.88 (s, 1H), 9.32 (d, J=1.5Hz, 1H), 8.71-8.58 (m, 1H), 8.41 (dd, J=2.6, 1.5Hz, 1H) , 8.37 (d, J=2.6Hz, 1H), 3.34 (s, 2H), 2.98-2.78 (m, 3H), 2.05-1.94 (m, 2H), 1.81 (qd, J=14.4, 13.1, 4.1Hz, 2H).

[0316]

[0317] 1-((2-acetamidothiazol-5-yl)methyl)-N-(pyrazin-2-yl)piperidine-4-carboxamide (B-4): Following the synthesis of compound b-1 using acetic acid (20 mL) containing 2-acetamidothiazol (141 mg, 0.99 mmol), intermediate b3d (200 mg, 0.66 mmol), and paraformaldehyde (99 mg, 3.30 mmol), the compound was purified by rapid column chromatography (DCM:MeOH = 20:1) to give a white solid compound B-4 (108 mg, 45%). Mp: 178-180 °C. 1 HNMR (400MHz, DMSO-d6): δ: 11.94 (s, 1H), 10.70 (s, 1H), 9.32 (d, J = 1.5Hz, 1H), 8.38 (dd, J = 2.6, 1.6Hz, 1H), 8.34 (d, J = 2.6Hz, 1H), 7.26 (s, 1H), 3.64 (s, 2H), 2.92-2.86 (m, 2H), 2.12 (s, 3H), 2.02-1.93 (m, 3H), 1.79 (d, J=11.8Hz, 2H), 1.62 (qd, J=12.1, 3.7Hz, 2H).

[0318]

[0319] 4-(cyclohexylcarbamoyl)piperidine-1-carboxylate (tert-butyl 4-(cyclohexylcarbamoyl)piperidine-1-carboxylate) (b2e): After synthesizing intermediate b2a using intermediate b1 (500 mg, 2.18 mmol) from DCM, cyclohexylamine (216 mg, 2.18 mmol), EDCI (502 mg, 2.62 mmol), and DMAP (320 mg, 2.62 mmol), the intermediate b2e was purified by rapid column chromatography (n-hexane:EtOAc = 1:1) to give a white solid intermediate b2e (619 mg, 91%). 1 HNMR (400MHz, CDCl3): δ: 5.27 (d, J=8.1Hz, 1H), 3.76 (dddd, J=14.7, 10.7, 8.0, 3.9Hz, 1H), 2.73 (t, J=12.8Hz, 2H), 2.16 (t t, J=11.6, 3.8Hz, 1H), 1.79 (dd, J=13.1, 3.5Hz, 2H), 1.73-1.60 (m, 4H), 1.45 (s, 9H), 1.42-1.30 (m, 2H), 1.22-1.03 (m, 3H).

[0320]

[0321] N-cyclohexylpiperidine-4-carboxamide and 2,2,2-trifluoroacetaldehyde (1:1) (b3e): The intermediate b3e (540 mg, 92%) was obtained by using intermediate b2e (590 mg, 1.90 mmol) from DCM and TFA (2.16 g, 19.00 mmol). 1 HNMR (400MHz, DMSO-d6): δ: 8.44 (d, J=75.4Hz, 1H), 7.80 (d, J=7.9Hz, 1H), 3.28 (dt, J=12.9, 3.7Hz, 3 H), 2.86 (td, J=12.5, 3.3Hz, 2H), 2.37 (tt, J=11.0, 3.9Hz, 1H), 1.85-1.50 (m, 9H), 1.30-1.07 (m, 5H).

[0322]

[0323] 1-((2-acetamidothiazol-5-yl)methyl)-N-cyclohexylpiperidine-4-carboxamide (B-5): Following the synthesis of compound b-1 using acetic acid (20 mL) containing 2-acetamidothiazol (139 mg, 0.98 mmol), intermediate b3e (200 mg, 0.65 mmol), and paraformaldehyde (98 mg, 3.25 mmol), the compound was purified by rapid column chromatography (DCM:MeOH = 40:1) to give a white solid compound B-5 (80 mg, 34%). Mp: 231-232 °C. 1 HNMR (400MHz, DMSO-d6): δ: 11.93 (s, 1H), 7.60 (d, J=7.9Hz, 1H), 7.24 (s, 1H), 2.83 (d, J=11.2Hz, 2H) , 2.12 (s, 3H), 1.96-1.87 (m, 3H), 1.66 (td, J=9.2, 4.0Hz, 4H), 1.60-1.51 (m, 5H), 1.27-1.06 (m, 7H).

[0324]

[0325] 4-(quinolin-6-ylcarbamoyl)piperidine-1-carboxylate (tert-butyl 4-(quinolin-6-ylcarbamoyl)piperidine-1-carboxylate) (b2f): After synthesizing intermediate b2a using intermediate b1 (500 mg, 2.18 mmol) from DCM, 6-aminoquinoline (314 mg, 2.18 mmol), EDCI (502 mg, 2.62 mmol), and DMAP (320 mg, 2.62 mmol), the intermediate b2f (665 mg, 86%) was purified by rapid column chromatography (DCM:MeOH = 20:1) to obtain a white solid intermediate b2f (665 mg, 86%). 1HNMR (400MHz, CDCl3): δ: 8.84 (dd, J=4.2, 1.7Hz, 1H), 8.40 (d, J=2.4Hz, 1H), 8.168.01 (m, 2H), 7.53 (dd, J=9.0, 2.4Hz, 1H), 7.44 (s, 1H), 7.39 (d d, J=8.3, 4.2Hz, 1H), 4.21 (s, 2H), 2.83 (t, J=12.7Hz, 2H), 2.46 (tt, J=1 1.4, 3.8Hz, 1H), 1.95 (d, J=12.1Hz, 2H), 1.871.73 (m, 2H), 1.48 (s, 9H).

[0326]

[0327] N-(quinolin-6-yl)piperidine-4-carboxamide and 2,2,2-trifluoroacetaldehyde (1:1) (b3f): The intermediate b3f was synthesized using intermediate b2f (640 mg, 1.80 mmol) from DCM and TFA (2.05 g, 18.00 mmol) to give a yellow solid compound b3f (620 mg, 98%). 1 HNMR (400MHz, DMSO-d6): δ: 10.58 (s, 1H), 8.95 (dd, J=4.6, 1.6Hz, 1H), 8.77 (d, J=11.3Hz, 1H), 8.62 (dd, J=8.5, 1.5Hz, 1H), 8.55 (d, J=2.3Hz, 1H), 8.51-8.42 (m, 1H), 8.09 (d, J=9.1 Hz, 1H), 7.94 (dd, J=9.1, 2.3Hz, 1H), 7.71 (dd, J=8.4, 4.6Hz, 1H), 3.39 (dt, J=13.2, 3.4Hz , 2H), 2.98 (dtd, J=12.7, 9.9, 2.6Hz, 2H), 2.75 (tt, J=11.1, 3.8Hz, 1H), 2.12-1.75 (m, 4H).

[0328]

[0329] 1-((2-acetamidothiazol-5-yl)methyl)-N-(quinolin-6-yl)piperidine-4-carboxamide (B-6): Following the synthesis of compound b-1 using acetic acid (20 mL) containing 2-acetamidothiazol (121 mg, 0.85 mmol), intermediate b3f (200 mg, 0.57 mmol), and paraformaldehyde (85 mg, 2.84 mmol), the compound was purified by rapid column chromatography (DCM:MeOH = 20:1) to give a white solid compound B-6 (215 mg, 93%). Mp: 234-236 °C. 1 HNMR (400MHz, DMSO-d6): δ: 12.21 (s, 1H), 10.39 (s, 1H), 8.76 (d, J=3.8Hz, 1H ), 8.34 (d, J = 2.3Hz, 1H), 8.25 (d, J = 8.0Hz, 1H), 7.95 (d, J = 9.1Hz, 1H), 7.78 ( dd, J=9.2, 2.4Hz, 1H), 7.54-7.44 (m, 2H), 4.31 (s, 2H), 3.32 (d, J=11.2Hz, 2H ), 2.82-2.57 (m, 3H), 2.15 (s, 3H), 2.05-1.95 (m, 2H), 1.88 (d, J=11.4Hz, 2H).

[0330]

[0331] 4-(benzylcarbamoyl)piperidine-1-carboxylate (tert-butyl 4-(benzylcarbamoyl)piperidine-1-carboxylate) (b2g): After synthesizing intermediate b2a using intermediate b1 (500 mg, 2.18 mmol) from DCM, benzylamine (234 mg, 2.18 mmol), EDCI (502 mg, 2.62 mmol), and DMAP (320 mg, 2.62 mmol), the intermediate b2a was purified by rapid column chromatography (DCM:MeOH = 40:1) to obtain a white solid intermediate b2g (690 mg, 99%). 1HNMR (400MHz, CDCl3): δ: 7.37-7.24 (m, 5H), 5.74 (s, 1H), 4.45 (d, J=5.6Hz, 2H), 4.12 (bs, J=7.2Hz, 1H), 2.74 (s, 2H), 2.26 (tt, J=11.6, 3.8Hz, 1H), 1.88-1.78 (m, 2H), 1.72-1.63 (m, 2H), 1.45 (s, 9H).

[0332]

[0333] N-benzylpiperidine-4-carboxamide and 2,2,2-trifluoro-1l3-ethan-1-one (1:1) (b3g): Intermediate b3b was synthesized using intermediate b2g (650 mg, 2.04 mmol) from DCM and TFA (2.33 g, 20.41 mmol) to give a yellow solid intermediate b3g (640 mg, quantitative yield). 1 HNMR (400MHz, DMSO-d6) δ: 8.67-8.26 (m, 3H), 7.39-7.16 (m, 5H), 4.27 (d, J=5.9Hz, 2H), 3.30 (dt , J=12.7, 3.3Hz, 2H), 2.90 (dtd, J=12.6, 9.8, 2.8Hz, 2H), 2.50-2.42 (m, 1H), 1.93-1.68 (m, 4H).

[0334]

[0335] 1-((2-acetamidothiazol-5-yl)methyl)-N-benzylpiperidine-4-carboxamide (B-7): Following the synthesis of compound b-1 using acetic acid (20 mL) containing 2-acetamidothiazol (135 mg, 0.95 mmol), intermediate b3 g (200 mg, 0.63 mmol), and paraformaldehyde (95 mg, 3.17 mmol), the compound was purified by rapid column chromatography (DCM:MeOH = 50:1) to give a white solid compound B-7 (100 mg, 42%). Mp: 176-178 °C. 1HNMR (400MHz, DMSO-d6): δ: 11.95 (s, 1H), 8.27 (t, J=6.0Hz, 1H), 7.34-7.18 (m, 5H), 4.25 (d, J= 5.9Hz, 2H), 3.60 (s, 2H), 2.85 (d, J=11.2Hz, 2H), 2.11 (s, 4H), 1.93 (m, 2H), 1.71-1.51 (m, 4H).

[0336]

[0337] 4-((4-methoxybenzyl)carbamoyl)piperidine-1-carboxylate (tert-butyl 4-((4-methoxybenzyl)carbamoyl)piperidine-1-carboxylate)(b2h): After synthesizing intermediate b2a using intermediate b1 (300 mg, 1.32 mmol) from DCM, 4-methoxybenzylamine (179 mg, 1.31 mmol), EDCI (301 mg, 1.57 mmol), and DMAP (192 mg, 1.57 mmol), the intermediate b2h was purified by rapid column chromatography (DCM:MeOH = 20:1) to obtain a white solid intermediate b2h (346 mg, 76%). 1 HNMR (400MHz, CDCl3): δ: 7.21-7.15 (m, 2H), 6.89-6.83 (m, 2H), 5.70 (s, 1H), 4.37 (d, J=5.5Hz, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.80 (s, 3H), 2.73 (s, 2H), 2.24 (tt, J=11.6, 3.7Hz, 1H), 1.65 (dtd, J=13.3, 11.9, 4.5Hz, 2H), 1.45 (s, 9H).

[0338]

[0339] N-(4-methoxybenzyl)piperidine-4-carboxamide and 2,2,2-trifluoroacetaldehyde (1:1) (b3h): Intermediate b3h was synthesized using intermediate b2h (310 mg, 0.89 mmol) from DCM and TFA (1.01 g, 8.89 mmol) to give a yellow solid intermediate b3h (320 mg, quantitative yield). 1HNMR (400MHz, DMSO-d6): δ: 8.60 (s, 1H), 8.39 (t, J=5.9Hz, 1H), 8.31 (s, 1H), 7.18-7.12 (m, 2H), 6.92-6.83 (m, 2H), 4.19 (d, J=5 .8Hz, 2H), 3.72 (s, 5H), 3.29 (d, J=12.5Hz, 2H), 2.88 (td, J=12.5, 9.7Hz, 2H), 2.44 (dt, J=11.0, 3.9Hz, 1H), 1.91-1.65 (m, 4H).

[0340]

[0341] 1-((2-acetamidothiazol-5-yl)methyl)-N-(4-methoxybenzyl)piperidine-4-carboxamide (B-8): Following the synthesis of compound b-1 using acetic acid (20 mL) containing 2-acetamidothiazol (148 mg, 1.04 mmol), intermediate b3h (240 mg, 0.69 mmol), and paraformaldehyde (104 mg, 3.47 mmol), the compound was purified by rapid column chromatography (DCM:MeOH = 50:1) to give a white solid compound B-8 (90 mg, 32%). Mp: 215-217 °C. 1 HNMR (400MHz, CDCl3): δ: 11.42 (s, 1H), 7.24-7.12 (m, 3H), 6.88-6.79 (m, 2H), 6.60 (s, 1H), 4.34 (d, J=5.6Hz, 2H), 3.79 (s, 3H), 3.66 (s, 2H), 2.95 (d, J=11.2Hz, 2H), 2.21 (s, 3H), 2.02 (d, J=8.2Hz, 2H).

[0342] Synthesis of schemes 6.4i to 4j

[0343]

[0344] Reagents and conditions: (i) MeMgBr, THF, -10℃-rt, 3h or NaBH4, MeOH, 0℃-rt, 1h; (ii) TFA, NaN3, DCM, 0℃-rt, 6h; (iii) PPh3, THF, 0℃-rt, 1day.

[0345]

[0346] 1-(benzo[d][1,3]dioxol-5-yl)ethan-1-ol (176A) (2i): MeMgBr (3.57 g, 29.94 mmol) was added dropwise to a solution of 1,3-benzodioxole-5-carboxaldehyde (3.00 g, 19.98 mmol) in anhydrous THF (100 mL) at -10 °C, and the reaction mixture was stirred at room temperature for 3 hours. The reaction was then quenched with saturated NH4Cl solution and extracted with EtOAc. The EtOAc layer was washed with saturated brine, dried over Na2SO4, filtered, and concentrated under vacuum. Purification by rapid column chromatography (n-hexane:EtOAc = 10:1) gave a white solid, compound 176A (3.24 g, 98%). 1 HNMR (400MHz, CDCl3): δ: 6.89 (d, J=1.6Hz, 1H), 6.84-6.74 (m, 2H), 5.94 (s, 2H), 4.81 (q, J=6.4Hz, 1H), 1.92 (s, 1H).

[0347]

[0348] 5-(1-azidoethyl)benzo[d][1,3]dioxole (3i): TFA (2.06 g, 18.05 mmol) and NaN3 (313 mg, 4.81 mmol) were added to a stirred solution of intermediate 2i (200 mg, 1.20 mmol) in DCM (30 mL) at 0 °C. The reaction mixture was stirred at room temperature for 6 hours. The reaction was then extracted with saturated NaHCO3 solution and DCM. The DCM layer was washed with saturated brine, dried with Na2SO4, filtered, and concentrated under vacuum to give a slurry (200 mg, 87%). 1 HNMR (400MHz, CDCl3): δ: 6.84-6.82 (m, 1H), 6.78 (t, J=0.9Hz, 2H), 5.97 (s, 2H), 4.53 (q, J=6.8Hz, 1H), 1.48 (d, J=6.8Hz, 3H).

[0349]

[0350] 1-(benzo[d][1,3]m-dioxole-5-yl)ethane-1-amine (5-(1-azidoethyl)benzo[d][1,3]dioxole)(4i): PPh3 (521 mg, 1.99 mmol) was added to a stirred solution of intermediate 3i (190 mg, 0.99 mmol) in THF (40 mL) at 0 °C, and the mixture was stirred for 30 min, followed by the addition of H2O. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was then diluted with H2O and extracted with EtOAc. The EtOAc layer was washed with saturated brine, dried over Na2SO4, filtered, and concentrated under vacuum. Purification by rapid column chromatography (DCM:MeOH = 20:1) yielded a white solid intermediate 4i (199 mg, 99%). 1 HNMR (400MHz, CDCl3): δ: 6.90 (d, J=1.8Hz, 1H), 6.82 (dd, J=8.0, 1.8Hz, 1H), 6.75 (d, J=8.0Hz, 1H), 5.93 (s, 2H), 4.18 (q, J=6.8Hz, 1H), 1.50 (s, 3H).

[0351]

[0352] 4-((1-(benzo[d][1,3]m-dioxol-5-yl)ethyl)carbamoyl)piperidine-1-carboxylate (tert-butyl 4-((1-(benzo[d][1,3]dioxol-5-yl)ethyl)carbamoyl)piperidine-1-carboxylate)(b2i): After the synthesis of intermediate b2a using intermediate b1 (250 mg, 1.09 mmol), intermediate 4i (180 mg, 1.09 mmol), EDCI (251 mg, 1.31 mmol), and DMAP (160 mg, 1.31 mmol) from DCM, the intermediate b2i was purified by rapid column chromatography (n-hexane:EtOAc = 10:1) to obtain a white solid intermediate b2i (110 mg, 27%). 1 HNMR (400MHz, CDCl3): δ: 6.80-6.73 (m, 3H), 5.94 (s, 2H), 5.59 (d, J=7.7Hz, 1H), 5.03 (p, J=7.0Hz, 1H), 4.1 3 (s, 2H), 2.73 (t, J=12.8Hz, 2H), 2.20 (tt, J=11.6, 3.8Hz, 1H), 1.66-1.57 (m, 4H), 1.44 (d, J=5.9Hz, 12H).

[0353]

[0354] N-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperidine-4-carboxamide) compound and 2,2,2-trifluoroacetaldehyde (1:1) (b3i): After the synthesis of intermediate b3b using intermediate b2i (100 mg, 0.27 mmol) from DCM and TFA (303 mg, 2.66 mmol), a yellow solid compound b3i (99 mg, 98%) was obtained. 1 HNMR (400MHz, DMSO-d6): δ: 8.52 (s, 1H), 8.28 (d, J=8.0Hz, 2H), 6.89-6.70 (m, 3H), 5.97 (s, 2H), 4.81 (p, J=7 .1Hz, 1H), 3.28 (s, 2H), 2.87 (s, 2H), 2.44 (tt, J=11.0, 3.8Hz, 1H), 1.87-1.58 (m, 4H), 1.29 (d, J=7.0Hz, 3H).

[0355]

[0356] 1-((2-acetamidothiazol-5-yl)methyl)-N-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperidine-4-carboxamide (B-9): Following the synthesis of compound b-1 using 2-acetamidothiazol (57 mg, 0.40 mmol) in acetic acid (20 mL), intermediate b3i (100 mg, 0.27 mmol), and paraformaldehyde (40 mg, 1.34 mmol), the compound was purified by rapid column chromatography (DCM:MeOH = 20:1) to give a white solid compound B-9 (52 mg, 45%). Mp: 211-213 °C. 1HNMR (400MHz, DMSO-d6): δ: 11.93 (s, 1H), 8.07 (d, J=8.2Hz, 1H), 7.23 (s, 1H), 6.88-6.68 (m, 3H), 5.96 (s, 2H), 4.81 (p, J =7.0Hz, 1H), 3.59 (s, 2H), 2.88-2.79 (m, 2H), 2.11 (s, 3H), 1.95-1.87 (m, 3H), 1.68-1.45 (m, 4H), 1.27 (d, J = 7.0Hz, 3H).

[0357]

[0358] 1-Phenylethan-1-ol (2j): NaBH4 (315 mg, 8.32 mmol) was added to a solution of acetophenone (1.00 g, 8.32 mmol) in MeOH (50 mL) at 0 °C. The reaction mixture was stirred for 1 hour at room temperature. MeOH was evaporated under vacuum, the residue was washed with H2O and extracted with EtOAc, the EtOAc layer was washed with saturated brine, dried with Na2SO4, filtered, and concentrated to give a slurry intermediate 2j (989 mg, 97%). 1 HNMR (400MHz, CDCl3): δ: 7.40-7.26 (m, 5H), 4.89 (q, J=6.5Hz, 1H), 1.89 (s, 1H), 1.49 (d, J=6.5Hz, 3H).

[0359]

[0360] (1-Azidoethyl)benzene (3j): Intermediate 3j was synthesized using intermediate 2j (900 mg, 7.37 mmol) in DCM (50 mL), TFA (12.60 g, 110.52 mmol) and NaN3 (1.92 g, 29.47 mmol). The intermediate was then purified by rapid column chromatography (DCM:MeOH = 20:1) to give a white solid intermediate 3j (1.00 g, 92%). 1 HNMR (400MHz, CDCl3): δ: 7.41-7.34 (m, 4H), 7.34-7.29 (m, 1H), 4.61 (q, J=6.8Hz, 1H), 1.53 (d, J=6.9Hz, 3H).

[0361]

[0362] 1-Phenylethan-1-amine (4j): After the synthesis of intermediate 4i using intermediate 3j (1.00 g, 6.79 mmol) from THF and PPh3 (3.56 g, 13.59 mmol), the intermediate was purified by rapid column chromatography (DCM:MeOH = 20:1) to give a white solid intermediate 4j (382 mg, 38%). 1 HNMR (400MHz, CDCl3): δ: 7.39-7.31 (m, 4H), 7.20-7.11 (m, 1H), 4.19 (q, J=6.7Hz, 1H), 1.48 (d, J=6.7Hz, 3H).

[0363]

[0364] 4-((1-phenylethyl)carbamoyl)piperidine-1-carboxylate (tert-butyl 4-((1-phenylethyl)carbamoyl)piperidine-1-carboxylate)(b2j): After synthesizing intermediate b2a using intermediate b1 (1.44 g, 6.27 mmol), intermediate 4j (760 mg, 6.27 mmol), EDCI (1.44 g, 7.53 mmol), and DMAP (919 mg, 7.53 mmol) from DCM, the intermediate b2j (157 mg, 7%) was purified by rapid column chromatography (n-hexane:EtOAc = 10:1) to give a white solid intermediate b2j (157 mg, 7%). 1 HNMR (400MHz, CDCl3): δ: 7.38-7.27 (m, 5H), 5.65 (d, J=7.8Hz, 1H), 5.13 (p, J=7.1Hz, 1H), 4.13 (s, 2H ), 2.73 (s, 2H), 2.21 (tt, J=11.6, 3.8Hz, 1H), 1.71-1.61 (m, 2H), 1.49 (d, J=6.8Hz, 3H), 1.45 (s, 9H).

[0365]

[0366] N-(1-phenylethyl)piperidine-4-carboxamide and 2,2,2-trifluoroacetaldehyde (1:1) (b3j): The intermediate b3j was synthesized using intermediate b2j (150 mg, 0.45 mmol) from DCM and TFA (514 mg, 4.51 mmol) to give a white solid b3j (150 mg, quantitative yield).1 HNMR (400MHz, DMSO-d6): δ: 8.58-8.19 (m, 3H), 7.35-7.17 (m, 5H), 4.89 (p, J=7.1Hz, 1H), 3.28 (s, 3H), 2. 87 (ddd, J=9.6, 6.4, 3.2Hz, 2H), 2.45 (dt, J=10.9, 3.9Hz, 1H), 1.89-1.60 (m, 4H), 1.34 (d, J=7.0Hz, 3H).

[0367]

[0368] 1-((2-acetamidothiazol-5-yl)methyl)-N-(1-phenylethyl)piperidine-4-carboxamide (B-10): Following the synthesis of compound b-1 using 2-acetamidothiazol (97 mg, 0.68 mmol), b3j (150 mg, 0.46 mmol), and paraformaldehyde (68 mg, 2.28 mmol) in acetic acid (20 mL), the compound was purified by rapid column chromatography (DCM:MeOH = 30:1) to give a white solid compound B-10 (112 mg, 64%). Mp: 178-179 °C. 1 HNMR (400MHz, DMSO-d6): δ: 11.93 (s, 1H), 8.17 (d, J=8.1Hz, 1H), 7.33-7.17 (m, 6H), 4.88 (p, J=7.1Hz, 1H), 3. 62-3.55 (m, 2H), 2.89-2.80 (m, 2H), 2.11 (s, 3H), 1.96-1.88 (m, 2H), 1.69-1.46 (m, 4H), 1.31 (d, J=7.0Hz, 3H).

[0369]

[0370] Following the synthesis of intermediate 2j from 1-(p-tolyl)ethane-1-ol (1-(p-tolyl)ethan-1-ol)(2k): 4-methylacetophenone (2.00 g, 14.91 mmol) in MeOH (50 mL) and NaBH4 (564 mg, 14.91 mmol), a slurry 2k (1.60 g, 79%) was obtained. 1HNMR (400MHz, CDCl3): δ: 7.27 (d, J=6.1Hz, 2H), 7.19-7.11 (m, 2H), 4.86 (q, J=6.5Hz, 1H), 2.34 (s, 3H), 1.48 (d, J=6.4Hz, 3H).

[0371]

[0372] 1-(1-azidoethyl)-4-methylbenzene (3k): Following the synthesis of intermediate 3i using intermediate 2k (1.00 g, 7.34 mmol), TFA (8.73 g, 73.42 mmol), and NaN3 (1.91 g, 29.37 mmol) from DCM (80 mL), a paste-like 3k (1.15 g, 97%) was obtained. 1 HNMR (400MHz, CDCl3): δ: 7.24-7.16 (m, 4H), 4.58 (q, J=6.8Hz, 1H), 2.35 (s, 3H), 1.51 (d, J=6.8Hz, 3H).

[0373]

[0374] 1-(p-Tolyl)ethane-1-amine (1-(p-tolyl)ethan-1-amine)(4k): After the synthesis of intermediate 4i using 3k (1.10 g, 6.82 mmol) in THF and PPh3 (3.56 g, 13.65 mmol), the intermediate was obtained by rapid column chromatography (DCM: MeOH = 20:

[0375] 1) Purification yielded a white solid 4k (911 mg, 99%). 1 HNMR (400MHz, CDCl3): δ: 7.30-7.22 (m, 2H), 7.18-7.10 (m, 2H), 6.02 (s, 2H), 4.14 (q, J=6.7Hz, 1H), 2.33 (s, 3H), 1.47 (d, J=6.7Hz, 3H).

[0376]

[0377] 4-((1-(p-tolyl)ethyl)carbamoyl)piperidine-1-carboxylate (tert-butyl 4-((1-(p-tolyl)ethyl)carbamoyl)piperidine-1-carboxylate (b2k): After the synthesis of intermediate b2a using intermediate b1 (1.42 g, 6.21 mmol), 4k (840 mg, 6.21 mmol), EDCI (1.43 g, 7.46 mmol), and DMAP (911 mg, 7.46 mmol) from DCM, the intermediate b2k was purified by rapid column chromatography (n-hexane:EtOAc = 10:1) to give a white solid b2k (360 mg, 17%). 1 HNMR (400MHz, CDCl3): δ: 7.21-7.11 (m, 4H), 5.60 (d, J=7.9Hz, 1H), 5.09 (p, J=7.0Hz, 1H), 2.72 (s, 2H), 2.33 (s, 3H), 2.19 (tt, J=11.6, 3.8Hz, 1H), 1.69-1.59 (m, 2H), 1.46 (d, J=11.4Hz, 12H).

[0378]

[0379] N-(1-(p-tolyl)ethyl)piperidine-4-carboxamide and 2,2,2-trifluoroacetaldehyde (1:1) (b3k): The synthesis of b3k was carried out using b2k (340 mg, 0.98 mmol) and TFA (1.12 mg, 9.81 mmol) from DCM, yielding a white solid b3k (150 mg, quantitative yield). 1 HNMR (400MHz, DMSO-d6): δ: 8.31 (d, J=8.0Hz, 1H), 7.21-7.05 (m, 4H), 4.85 (p, J=7.1Hz, 1H), 3.29-3.20 (m, 3H), 2.86 (t dd, J=12.4, 6.7, 3.2Hz, 2H), 2.45 (ddd, J=11.1, 7.2, 3.9Hz, 1H), 2.26 (s, 3H), 1.91-1.57 (m, 4H), 1.31 (d, J=7.0Hz, 3H).

[0380]

[0381] 1-((2-acetamidothiazol-5-yl)methyl)-N-(1-(p-tolyl)ethyl)piperidine-4-carboxamide (B-11): Compound B-1 was synthesized using 2-acetamidothiazol (124 mg, 0.87 mmol), b3k (200 mg, 0.58 mmol), and paraformaldehyde (87 mg, 2.91 mmol) in acetic acid (20 mL). The resulting product was purified by rapid column chromatography (DCM:MeOH = 40:1) to give an oily compound B-11 (60 mg, 3%). 1 HNMR (400MHz, DMSO-d6): δ: 11.93 (s, 1H), 8.12 (d, J=8.1Hz, 1H), 7.23 (s, 1H), 7.17-7.07 (m, 4H), 4.84 (p, J=7. 1Hz, 1H), 3.59 (s, 2H), 2.25 (s, 3H), 2.11 (s, 4H), 1.97-1.86 (m, 2H), 1.67-1.44 (m, 4H), 1.29 (d, J=7.0Hz, 3H).

[0382]

[0383] 1-(naphthalen-2-yl)ethan-1-ol (2l): After the synthesis of intermediate 2j using 2'-acetonaphthone (2.00 g, 11.75 mmol) in MeOH (50 mL) and NaBH4 (445 mg, 11.75 mmol), a white solid 2l (2.00 g, 99%) was obtained. 1 HNMR (400MHz, CDCl3): δ7.83 (ddd, J=7.4, 4.9, 2.9Hz, 4H), 7.56-7.40 (m, 3H), 5.08 (q, J=6.4Hz, 1H), 1.59 (d, J=6.5Hz, 3H).

[0384]

[0385] 2-(1-azidoethyl)naphthalene (3l): After synthesizing intermediate 3i using 2l (2.00 mg, 11.51 mmol), TFA (13.24 g, 116.12 mmol), and NaN3 (3.02 g, 46.45 mmol) in DCM (80 mL), the intermediate was purified by rapid column chromatography (DCM:MeOH = 50:1) to obtain slurry 3l (1.86 g, 81%). 1 HNMR (400MHz, CDCl3): δ: 7.93-7.73 (m, 4H), 7.54-7.41 (m, 3H), 4.79 (q, J=6.8Hz, 1H), 1.61 (d, J=6.8Hz, 3H).

[0386]

[0387] 1-(naphthalen-2-yl)ethan-1-amine (4l): After the synthesis of intermediate 4i using 3l (2.79 g, 14.14 mmol) in THF and PPh3 (7.42 g, 28.29 mmol), the intermediate was purified by rapid column chromatography (DCM:MeOH = 40:1) to give 4l (1.21 mg, 50%) as a white solid. 1 HNMR (400MHz, CDCl3): δ7.82-7.73 (m, 4H), 7.52-7.41 (m, 3H), 5.99 (s, 2H), 4.34 (q, J=6.7Hz, 1H), 1.56 (s, 3H).

[0388]

[0389] 4-((1-(naphthalen-2-yl)ethyl)carbamoyl)piperidine-1-carboxylate (tert-butyl 4-((1-(naphthalen-2-yl)ethyl)carbamoyl)piperidine-1-carboxylate (b2l): After synthesizing intermediate b2a using intermediates b1 (3.21 g, 14.02 mmol), 4l (2.40 g, 14.02 mmol), EDCI (3.22 g, 16.82 mmol), and DMAP (2.05 g, 16.82 mmol) from DCM, the intermediate was purified by rapid column chromatography (n-hexane:EtOAc = 10:1) to give a white solid b2l (140 mg, 3%). 1HNMR (400MHz, CDCl3): δ: 7.85-7.70 (m, 4H), 7.52-7.37 (m, 3H), 5.73 (d, J=8.0Hz, 1H), 5.30 (p, J=7.1Hz, 1H), 4.13 (s, 2H), 2 .24 (tt, J=11.6, 3.7Hz, 1H), 1.82 (t, J=12.9Hz, 2H), 1.66 (qd, J=13.0, 12.6, 4.4Hz, 2H), 1.59 (d, J=4.5Hz, 3H), 1.45 (s, 9H).

[0390]

[0391] N-(1-(naphthalen-2-yl)ethyl)piperidine-4-carboxamide and 2,2,2-trifluoroacetaldehyde (1:1) (b3l): The intermediate b3l (130 mg, 94%) was obtained by using 180D (140 mg, 0.37 mmol) in DCM and TFA (417 mg, 3.66 mmol). 1 HNMR (500MHz, DMSO-d6): δ: 8.58 (s, 1H), 8.51 (d, J=7.9Hz, 1H), 8.29 (s, 1H), 7.86 (dt, J=7.3, 2.8Hz, 3H), 7.75 (s, 1H), 7.53-7.41 (m, 3 H), 5.04 (p, J=7.2Hz, 1H), 3.28 (t, J=14.9Hz, 2H), 2.94-2.82 (m, 2H), 1.85 (d, J=11.5Hz, 2H), 1.78-1.59 (m, 3H), 1.43 (d, J=7.1Hz, 3H).

[0392]

[0393] 1-((2-acetamidothiazol-5-yl)methyl)-N-(1-(naphthalen-2-yl)ethyl)piperidine-4-carboxamide (B-12): Compound B-1 was synthesized using 2-acetamidothiazol (73 mg, 0.51 mmol), b3l (130 mg, 0.34 mmol), and paraformaldehyde (51 mg, 1.71 mmol) in acetic acid (20 mL). The resulting compound was purified by rapid column chromatography (DCM:MeOH = 50:1) to give a white solid compound B-12 (75 mg, 50%). 1 HNMR (400MHz, CDCl3) δ: 11.28 (s, 1H), 7.85-7.71 (m, 4H), 7.51-7.38 (m, 3H), 7.20 (s, 1H), 5. 79 (s, 1H), 5.35-5.24 (m, 1H), 3.70 (s, 2H), 3.00 (s, 2H), 2.28 (s, 3H), 1.58 (d, J=6.9Hz, 3H).

[0394] Option 7. Synthesis of SB-13 to B-19

[0395]

[0396] Reagents and conditions: (i) Paraformaldehyde, AcOH, 100℃, 4h; (ii) Anhydrous lithium hydroxide, THF:H2O (1:1), rt, 1d; (iii) Amines, EDCI, HOBt, DIPEA, DMF, 0℃-rt, overnight or amines, EDCI, HOBt, DMF, 0℃-rt, overnight.

[0397]

[0398] 1-((2-acetamidothiazol-5-yl)methyl)piperidine-4-carboxylate (b4a): Paraformaldehyde (382 mg, 12.72 mmol) was added to a solution of 2-acetamidothiazol (542 mg, 3.80 mmol) and ethyl 4-piperidinecarboxylate (400 mg, 2.54 mmol) in acetic acid (20 mL) with stirring at 100 °C. The reaction mixture was stirred at 100 °C for 1 hour. Acetic acid was evaporated under vacuum. The final residue was purified by column chromatography (DCM:MeOH = 20:1) to give a white solid b4a (750 mg, 95%). 1 HNMR (400MHz, CDCl3): δ: 12.06 (s, 1H), 7.18 (s, 1H), 4.13 (q, J=7.1Hz, 2H), 3.66 (d, J=1.0Hz, 2H), 2.88 (dt, J=11.7, 3.8Hz, 2H ), 2.31 (s, 3H), 2.34-2.20 (m, 1H), 2.15-2.04 (m, 2H), 1.89 (dd, J=13.4, 3.7Hz, 2H), 1.84-1.70 (m, 2H), 1.25 (t, J=7.1Hz, 3H).

[0399]

[0400] 1-((2-acetamidothiazol-5-yl)methyl)piperidine-4-carboxylate (b5a): Lithium hydroxide (34 mg, 1.42 mmol) was added to a solution of intermediate b4a in THF:H2O (1:1) at room temperature. The reaction mixture was stirred at 50 °C for 4 hours. The reaction mixture was diluted with EtOAc, the aqueous layer was separated, and the crude b5a was obtained by vacuum evaporation without further purification. 1 HNMR (400MHz, DMSO-d6): δ: 7.13 (s, 1H), 2.73 (dt, J=11.2, 3.7Hz, 2H), 2.06 (s, 3H ), 1.88 (td, J=11.4, 2.7Hz, 2H), 1.79-1.64 (m, 3H), 1.46 (qd, J=11.8, 3.7Hz, 2H).

[0401]

[0402] 1-((2-acetamidothiazol-5-yl)methyl)-N-(4-fluorophenyl)piperidine-4-carboxamide (B-14): At 0 °C, EDCI (280 mg, 1.46 mmol), HOBt (198 mg, 1.46 mmol), and DIPEA (393 mg, 3.04 mmol) were added to a solution of 4-fluoroaniline (135 mg, 1.22 mmol) and intermediate b5a (233 mg, 1.22 mmol) in DMF (30 mL). The reaction mixture was stirred overnight at room temperature. Ice water was added to the reaction mixture and it was extracted with EtOAc. The EtOAc layer was washed with saturated brine, dried over Na2SO4, filtered, and evaporated under vacuum. The compound COA-0159 (58 mg, 13%) was purified by rapid column chromatography (n-hexane:EtOAc = 3:1) to obtain a white solid compound. Mp: 254-256℃. 1 HNMR (400MHz, DMSO-d6): δ: 11.86 (bs, 1H), 9.89 (s, 1H), 7.64-7.56 (m, 2H), 7.25 (s, 1H), 7.16-7.07 (m, 2H), 3.64-3.61 (m, 2H), 2 .89 (d, J=11.1Hz, 2H), 2.34-2.23 (m, 1H), 2.12 (s, 3H), 2.01-1.93 (m, 2H), 1.75 (d, J=11.9Hz, 2H), 1.64 (tt, J=12.5, 6.2Hz, 2H).

[0403]

[0404] 1-((2-acetamidothiazol-5-yl)methyl)-N-(p-tolyl)piperidine-4-carboxamide (B-15): Following the synthesis of compound B-14 using p-toluidine (74 mg, 0.69 mmol), b5a (200 mg, 0.69 mmol), EDCI (159 mg, 0.83 mmol), HOBt (113 mg, 0.83 mmol), and DIPEA (223 mg, 1.73 mmol) in DMF (30 mL), the compound was purified by rapid column chromatography (DCM:MeOH = 40:1) to give a white solid compound B-15 (28 mg, 11%). Mp: 262-264 °C. 1 HNMR (400MHz, DMSO-d6): δ: 11.93 (s, 1H), 9.72 (s, 1H), 7.49-7.44 (m, 2H), 7.25 (s, 1H), 7.10-7.05 (m, 2H), 3.62 (s, 2 H), 2.89 (dd, J=7.7, 3.9Hz, 2H), 2.34-2.26 (m, 1H), 2.23 (s, 3H), 2.12 (s, 3H), 2.02-1.90 (m, 2H), 1.77-1.58 (m, 4H).

[0405]

[0406] 1-(benzo[d][1,3]m-dioxol-5-yl)ethyl 1-((2-acetamidothiazol-5-yl)methyl)piperidine-4-carboxylate (B-13): Compound B-14 was synthesized using intermediates b5a (400 mg, 1.38 mmol), 2i (230 mg, 1.38 mmol), EDCI (318 mg, 1.66 mmol), and HOBt (225 mg, 1.66 mmol) from DMF. The resulting compound was purified by rapid column chromatography (DCM:MeOH = 50:1) to give a white solid, B-13 (50 mg, 8%). Mp: 215-217 °C. 1HNMR (400MHz, DMSO-d6): δ: 11.93 (s, 1H), 7.23 (s, 1H), 6.93-6.79 (m, 3H), 6.00 (d, J =5.5Hz, 2H), 5.72 (dt, J = 13.1, 6.7Hz, 1H), 3.59 (s, 2H), 2.77 (dd, J = 10.2, 5.2Hz, 2H) , 2.30 (ddt, J=10.7, 7.7, 3.8Hz, 1H), 2.11 (s, 3H), 2.02 (dt, J=11.5, 3.1Hz, 2H), 1.7 8 (dd, J=11.6, 7.2Hz, 2H), 1.54 (tdd, J=13.2, 8.7, 3.4Hz, 2H), 1.41 (d, J=6.5Hz, 3H).

[0407]

[0408] 1-((2-acetamidothiazol-5-yl)methyl)piperidine-3-carboxylate (ethyl 1-((2-acetamidothiazol-5-yl)methyl)piperidine-3-carboxylate)(b4b): After synthesizing intermediate b4a using acetic acid (50 mL) containing 2-acetamidothiazol (1.15 g, 8.11 mmol), ethyl piperidine (850 mg, 5.41 mmol), and paraformaldehyde (811 mg, 27.03 mmol), the intermediate b4b (1.01 mg, 60%) was purified by rapid column chromatography (DCM:MeOH = 30:1) to obtain a white solid intermediate b4b (1.01 mg, 60%). 1 HNMR (400MHz, CDCl3): δ: 7.13 (s, 1H), 4.12 (q, J=7.2, 2H), 3.67 (t, J=1.0Hz, 2H), 2.97 (d, J=10.1Hz, 1H), 2.77 (d, J=1 1.1Hz, 1H), 2.57 (tt, J=10.4, 3.8Hz, 1H), 2.27 (s, 3H), 2.23 (t, J=10.4Hz, 1H), 2.09-2.04 (m, 1H), 1.98-1.88 (m, 1H),

[0409] 1.72 (dt, J=13.0, 3.7Hz, 1H), 1.43 (qd, J=11.7, 3.9Hz, 1H), 1.23 (t, J=7.1Hz, 3H).

[0410]

[0411] 1-((2-acetamidothiazol-5-yl)methyl)piperidine-3-carboxylate (b5b): The crude compound b5b was obtained by synthesizing intermediate b5a using b4b (200 mg, 0.64 mmol) in THF:H2O (1:1) and lithium hydroxide (34 mg, 1.41 mmol) without further purification. 1 HNMR (400MHz, DMSO-d6): δ: 7.03 (s, 1H), 2.93 (dd, J=11.2, 3.7Hz, 1H), 2.71 (d, J=10.6Hz, 1H), 1.98 (s, 4H), 1.8 6-1.70 (m, 3H), 1.55 (dt, J=13.2, 3.5Hz, 1H), 1.36 (tdt, J=12.7, 8.1, 4.0Hz, 1H), 1.11 (qd, J=12.6, 3.9Hz, 1H).

[0412]

[0413] 1-((2-acetamidothiazol-5-yl)methyl)-N-phenylpiperidine-3-carboxamide (B-16): Following the synthesis of compound B-14 using intermediate b5b (230 mg, 0.80 mmol) from DMF, aniline (74 mg, 0.80 mmol), EDCI (183 mg, 0.95 mmol), and HOBt (129 mg, 0.95 mmol), the compound was purified by rapid column chromatography (DCM:MeOH = 20:1) to give a white solid compound B-16 (35 mg, 12%). Mp: 257-259 °C. 1 HNMR (400MHz, DMSO-d6): δ: 11.96 (s, 1H), 9.93 (s, 1H), 7.61-7.51 (m, 2H), 7.32-7.21 (m, 3H), 7.06-6.95 (m, 1H), 3.65 (s, 2H), 2.95-2.86 (m, 1H) , 2.79 (d, J=11.2Hz, 1H), 2.62-2.53 (m, 1H), 2.11 (s, 4H), 1.95 (t, J=10. 3Hz, 1H), 1.82 (d, J=12.3Hz, 1H), 1.71-1.63 (m, 1H), 1.53-1.32 (m, 2H).

[0414]

[0415] 1-((2-acetamidothiazol-5-yl)methyl)-N-(4-fluorophenyl)piperidine-3-carboxamide (B-17): Following the synthesis of compound B-14 using intermediate b5b (200 mg, 0.69 mmol) from DMF, 4-fluoroaniline (77 mg, 0.69 mmol), EDCI (159 mg, 0.83 mmol), and HOBt (113 mg, 0.83 mmol), the compound was purified by rapid column chromatography (DCM:MeOH = 20:1) to give a pink solid compound B-17 (40 mg, 15%). Mp: 127-129 °C. 1 HNMR (400MHz, DMSO-d6): δ: 11.96 (s, 1H), 9.99 (s, 1H), 7.64-7.53 (m, 2H), 7.26 (s, 1H), 7.17-7.05 (m, 2H), 3.65 (s, 2H), 2.95-2.86 (m, 1 H), 2.79 (d, J=11.2Hz, 1H), 2.53 (s, 1H), 2.11 (s, 4H), 2.02-1.90 (m, 1H), 1.81 (d, J=11.8Hz, 1H), 1.73-1.64 (m, 1H), 1.52-1.33 (m, 2H).

[0416]

[0417] 1-((2-acetamidothiazol-5-yl)methyl)-N-(4-isopropylphenyl)piperidine-3-carboxamide (B-18): Following the synthesis of compound B-14 using intermediate b5b (200 mg, 0.69 mmol) from DMF, 4-isopropylaniline (93 mg, 0.69 mmol), EDCI (159 mg, 0.83 mmol), and HOBt (113 mg, 0.83 mmol), the compound was purified by rapid column chromatography (DCM:MeOH = 20:1) to give a white solid compound B-18 (80 mg, 29%). Mp: 234-236 °C. 1HNMR (400MHz, DMSO-d6): δ: 11.96 (s, 1H), 9.85 (s, 1H), 7.52-7.41 (m, 2H), 7.26 (s, 1H), 7.17-7.09 (m, 2H), 3.65 (s, 2H), 2.93-2.75 (m, 3H), 2 .59-2.52 (m, 1H), 2.11 (s, 4H), 1.99-1.91 (m, 1H), 1.80 (d, J = 11.7Hz, 1H), 1.67 (d, J = 12.5Hz, 1H), 1.52-1.35 (m, 2H), 1.16 (d, J = 6.9Hz, 6H).

[0418]

[0419] 1-((2-acetamidothiazol-5-yl)methyl)-N-cyclohexylpiperidine-3-carboxamide (B-19): Following the synthesis of compound B-14 using intermediate b5b (200 mg, 0.69 mmol) from DMF, cyclohexyl amine (69 mg, 0.69 mmol), EDCI (159 mg, 0.83 mmol), and HOBt (113 mg, 0.83 mmol), the compound was purified by rapid column chromatography (DCM:MeOH = 20:1) to give a white solid compound B-19 (25 mg, 7%). Mp: 265-267 °C. 1 HNMR (400MHz, DMSO-d6) δ11.96 (s, 1H), 7.68 (d, J = 7.9Hz, 1H), 7.24 (s, 1H), 3.63-3.53 (m, 2H), 3.47 (s, 1H), 2.69 (d, J = 10.6Hz , 2H), 2.35-2.25(m, 1H), 2.11(s, 3H), 2.09-1.92(m, 2H), 1.64(dt, J=13.3, 3.5Hz, 5H), 1.44-1.29(m, 2H), 1.26-1.05(m, 5H).

[0420] Example 3

[0421] Synthesis of compounds with chemical formula 4

[0422] The compound of chemical formula 4 below was prepared by the following process.

[0423]

[0424] Scheme 8. Synthesis of C-1 to C-8

[0425]

[0426] C:

[0427]

[0428] Reagents and conditions: (i) Triethylphosphonoacetate, NaH, THF, 0℃-rt, overnight; (ii) TFA, DCM, rt, overnight; (iii) 2-acetylamthiazole, paraformaldehyde, AcOH, 100℃, 1h; (iv) Lithium hydroxide, THF:H2O (1:1), rt, 1d; (v) Amine compounds, EDCI, HOBt, DMF, 0℃-rt, overnight.

[0429]

[0430] 4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate (c-2): Triethyl phosphoroacetate (292 mg, 1.30 mmol) was added dropwise to a stirred solution of NaH (48 mg, 1.20 mmol) in 5 mL of THF at 0 °C. After stirring for 30 minutes at room temperature, 1-boc-4-piperidone (200 mg, 1.00 mmol) was added dropwise to 2 mL of THF. The reaction mixture was stirred overnight at room temperature, diluted with 5 mL of H2O, and extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with 5 mL of brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by rapid column chromatography (n-hexane:EtOAc = 10:1) to give compound 1 (200 mg, 74%) as a white solid. 1 HNMR (400MHz, CDCl3) δ: 5.71 (p, J=1.2Hz, 1H), 4.16 (q, J=7.1Hz, 2H), 3.49 (dt, J=11.4, 6 .0Hz, 4H), 2.97-2.89 (m, 2H), 2.28 (t, J=5.7Hz, 2H), 1.47 (s, 9H), 1.28 (t, J=7.2Hz, 3H).

[0431]

[0432] ethyl 2-(piperidin-4-ylidene)acetate and 2,2,2-trifluoroacetaldehyde (1:1) (c-3): TFA (974 mg, 8.54 mmol) was added to a stirred solution of compound c-2 (230 mg, 1.00 mmol) in DCM (30 mL) at room temperature, and the reaction mixture was stirred for 4 hours at room temperature. The DCM was then evaporated under vacuum to give compound c-2 as a white solid (quantitative yield). 1 HNMR (400MHz, DMSO-d6): δ: 8.89 (s, 2H), 5.85 (t, J=1.3Hz, 1H), 4.10 (q, J=7.1Hz, 2H), 3.05 (t, J=6.3Hz, 2H), 1.20 (t, J=7.1Hz, 3H).

[0433]

[0434] 2-(1-((2-acetamidothiazol-5-yl)methyl)piperidin-4-ylidene)acetate (c-4): At room temperature, paraformaldehyde was added to a stirred solution of compound c-3 (235 mg, 0.88 mmol) and 2-acetamidothiazol (188 mg, 1.32 mmol) in acetic acid (20 mL). The reaction mixture was stirred at 100 °C for 1 hour. Acetic acid was evaporated under vacuum. The final residue was purified by column chromatography (n-hexane:EtOAc = 2:1) to give a pale yellow solid compound c-3 (200 mg, 70%). 1 HNMR (400MHz, CDCl3) δ: 11.74 (s, 1H), 7.31 (s, 1H), 5.69 (s, 1H), 4.15 (q, J=7.1Hz, 2H), 3.92 (s, 2H), 3.09 (s, 3H), 2.76 (s, 3H), 2.45 (s, 2H), 2.31 (s, 3H), 1.27 (t, J=7.2Hz, 3H).

[0435]

[0436] 2-(1-((2-acetamidothiazol-5-yl)methyl)piperidin-4-ylidene)acetate (c-5): Anhydrous lithium hydroxide (5 ml, 8.66 mmol) was added to a stirred solution of compound c-4 (280 mg, 0.87 mmol) in THF:H₂O (1:1) at room temperature. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was diluted with EtOAc and the aqueous layer was separated. The water was evaporated under vacuum to give compound c-4. 1 HNMR (400MHz, DMSO-d6): δ: 5.50 (s, 1H), 3.57 (s, 2H), 2.87 (s, 2H), 2.38 (dt, J=18.7, 5.6Hz, 4H), 2.10 (t, J=5.5Hz, 2H), 2.05 (s, 3H).

[0437]

[0438] 2-(1-((2-acetamidothiazol-5-yl)methyl)piperidin-4-ylidene)-N-phenylacetamide (C-1): Compound B-14 was synthesized using intermediate c-5 (324 mg, 1.07 mmol) from DMF, aniline (200 mg, 2.15 mmol), EDCI (494 mg, 2.58 mmol), and HOBt (350 mg, 2.58 mmol). The resulting compound was purified by rapid column chromatography (DCM:MeOH = 50:1) to give a white solid, C-1 (24 mg, 6%). Mp: 184-185 °C. 1 HNMR (400MHz, CDCl3) δ: 12.07 (s, 1H), 7.56-7.49 (m, 2H), 7.32 (td, J=7.8, 5.5Hz, 2H), 7.24-7.06 (m, 3H), 5.69 (s, 1 H), 3.74 (d, J=32.0Hz, 2H), 3.10 (s, 1H), 3.06 (d, J=5.7Hz, 1H), 2.68-2.54 (m, 4H), 2.36-2.31 (m, 4H), 2.23 (s, 1H).

[0439]

[0440] 2-(1-((2-acetamidothiazol-5-yl)methyl)piperidin-4-ylidene)-N-(4-fluorophenyl)acetamide (C-2): Compound B-14 was synthesized using intermediate c-5 (542 mg, 1.80 mmol) from DMF, 4-fluoroaniline (200 mg, 1.80 mmol), EDCI (414 mg, 2.16 mmol), and HOBt (293 mg, 2.16 mmol). The resulting compound was purified by rapid column chromatography (DCM:MeOH = 20:1) to give a white solid compound C-2 (50 mg, 4%). Mp: 189-191 °C. 1 HNMR (400MHz, DMSO-d6): δ: 11.97 (s, 1H), 9.97 (s, 1H), 7.70-7.52 (m, 2H), 7.26 (d, J=0.9Hz, 1H), 7.12 (ddt, J=8.9, 6.8, 1.8Hz, 2H) , 5.82 (s, 1H), 3.74-3.58 (m, 2H), 2.95 (dd, J=14.6, 9.1Hz, 3H), 2.45 (t, J=5.7Hz, 2H), 2.27 (t, J=5.6Hz, 2H), 2.11 (d, J=3.0Hz, 4H).

[0441]

[0442] 2-(1-((2-acetamidothiazol-5-yl)methyl)piperidin-4-ylidene)-N-(4-chlorophenyl)acetamide (C-3): Compound B-14 was synthesized using intermediate c-5 (472 mg, 1.57 mmol) from DMF, 4-chloroaniline (200 mg, 1.57 mmol), EDCI (361 mg, 1.88 mmol), and HOBt (255 mg, 1.88 mmol). The resulting compound was purified by rapid column chromatography (DCM:MeOH = 20:1) to give a white solid, C-3 (32 mg, 5%). Mp: 225-228 °C. 1HNMR (500MHz, DMSO-d6): δ: 11.97 (s, 1H), 10.07 (d, J=20.5Hz, 1H), 7.65-7.57 (m, 2H), 7.36-7.30 (m, 2H), 7.25 (s, 1H ), 5.82 (s, 1H), 3.66 (d, J=5.9Hz, 2H), 3.02-2.85 (m, 4H), 2.27 (d, J=5.9Hz, 1H), 2.45 (s, 1H), 2.10 (t, J=7.1Hz, 5H).

[0443]

[0444] 2-(1-((2-acetamidothiazol-5-yl)methyl)piperidin-4-ylidene)-N-(4-isopropylphenyl)acetamide (C-4): Compound B-14 was synthesized using intermediate c-5 (446 mg, 1.48 mmol) from DMF, 4-isopropylaniline (200 mg, 1.48 mmol), EDCI (340 mg, 1.78 mmol), and HOBt (241 mg, 1.78 mmol). The resulting compound was purified by rapid column chromatography (DCM:MeOH = 20:1) to give a white solid, C-4 (20 mg, 3%). Mp: 232-236 °C. 1 HNMR (500MHz, DMSO-d6) δ: 11.93 (s, 1H), 9.81 (d, J=16.0Hz, 1H), 7.49 (dd, J=15.3, 8.2Hz, 2H), 7.25 (s, 1H), 7.19-7.08 (m, 2H), 5.82 (s, 1H), 3.66 (d, J=6.8Hz, 2H), 2.93 (d, J=23.7Hz, 3H), 2.82 (p, J=6.9Hz, 1H), 2.45 (t, J=5.7Hz, 2H), 2.25 (s, 2H), 2.11 (d, J=4.1Hz, 4H), 1.16 (d, J=6.9Hz, 6H).

[0445]

[0446] 2-(1-((2-acetamidothiazol-5-yl)methyl)piperidin-4-ylidene)-N-(4-methoxyphenyl)acetamide (C-5): Compound B-14 was synthesized using intermediate c-5 (489 mg, 1.62 mmol) from DMF, 4-methoxyaniline (200 mg, 1.62 mmol), EDCI (374 mg, 1.95 mmol), and HOBt (264 mg, 1.95 mmol). The resulting compound was purified by rapid column chromatography (DCM:MeOH = 20:1) to give a white solid, C-5 (80 mg, 12%). Mp: 212-214 °C. 1 HNMR (500MHz, DMSO-d6): δ: 11.96 (s, 1H), 9.76 (s, 1H), 7.51 (d, J=8.8Hz, 2H), 7.25 (s, 1H), 6.85 (d, J=8.8Hz, 2H), 5.79 (s, 1H), 3.70 ( d, J=1.3Hz, 3H), 3.65 (s, 2H), 3.16 (d, J=4.6Hz, 1H), 2.95 (d, J=7.4Hz, 3H), 2.44 (t, J=5.7Hz, 2H), 2.24 (t, J=5.4Hz, 2H), 2.11 (s, 3H).

[0447]

[0448] 2-(1-((2-acetamidothiazol-5-yl)methyl)piperidin-4-ylidene)-N-(3,4-dimethoxyphenyl)acetamide (C-6): Compound B-14 was synthesized using intermediate c-5 (393 mg, 1.31 mmol) from DMF, 3,4-dimethoxylaniline (200 mg, 1.31 mmol), EDCI (300 mg, 1.57 mmol), and HOBt (213 mg, 1.57 mmol). The resulting compound was purified by rapid column chromatography (DCM:MeOH = 20:1) to give C-6 (20 mg, 4%) as a white solid. Mp: 214–219 °C. 1HNMR (500MHz, DMSO-d6): δ: 11.97 (s, 1H), 9.77 (s, 1H), 7.37 (d, J=2.3Hz, 1H), 7.25 (s, 1H), 7.07 (dd, J=8.8, 2.3Hz, 1H), 6.85 (d, J=8 .7Hz, 1H), 5.79 (s, 1H), 3.70 (d, J=3.8Hz, 6H), 3.65 (s, 2H), 2.96 (s, 3H), 2.43 (d, J=6.2Hz, 2H), 2.25 (s, 2H), 2.10 (d, J=3.8Hz, 4H).

[0449]

[0450] 2-(1-((2-acetamidothiazol-5-yl)methyl)piperidin-4-ylidene)-N-(4-methoxybenzyl)acetamide (C-7): Compound B-14 was synthesized using intermediate c-5 (439 mg, 1.46 mmol) from DMF, 4-methoxybenzylamine (200 mg, 1.46 mmol), EDCI (335 mg, 1.75 mmol), and HOBt (237 mg, 1.75 mmol). The resulting compound was purified by rapid column chromatography (DCM:MeOH = 20:1) to give a white solid, C-7 (44 mg, 7%). Mp: 222-224 °C. 1 HNMR (500MHz, DMSO-d6): δ: 11.97 (s, 1H), 8.27 (t, J=6.0Hz, 1H), 7.24 (s, 1H), 7.15 (d, J=8.5Hz, 2H), 6.86 (d, J=8.5Hz, 2H), 5.65 (s , 1H), 4.18 (d, J=5.9Hz, 2H), 3.71 (s, 3H), 3.63 (s, 2H), 2.92 (s, 2H), 2.42 (dt, J=21.4, 5.8Hz, 4H), 2.21-2.15 (m, 2H), 2.11 (s, 3H).

[0451]

[0452] 2-(1-((2-acetamidothiazol-5-yl)methyl)piperidin-4-ylidene)-N-cyclohexylacetamide (C-8): Compound B-14 was synthesized using intermediate c-5 (451 mg, 1.50 mmol) from DMF, cyclohexylamine (148 mg, 1.50 mmol), EDCI (345 mg, 1.80 mmol), and HOBt (244 mg, 1.80 mmol). The resulting compound was purified by rapid column chromatography (DCM:MeOH = 20:1) to give a white solid, C-8 (25 mg, 4%). Mp: 222-224 °C. 1 HNMR (500MHz, DMSO-d6): δ: 11.96 (s, 1H), 7.68 (d, J=7.9Hz, 1H), 7.24 (s, 1 H), 5.59 (s, 1H), 3.62 (s, 2H), 3.52 (d, J = 9.7Hz, 1H), 2.89 (s, 2H), 2.41 (dt , J=26.1, 5.7Hz, 4H), 2.15 (t, J=5.7Hz, 2H), 2.10 (s, 3H), 1.68 (t, J=17.3H z, 4H), 1.53 (d, J=12.7Hz, 1H), 1.23 (q, J=12.5Hz, 2H), 1.15-1.05 (m, 3H).

[0453] Example 4

[0454] Enzyme activity analysis

[0455] Human OGA (recombinant hOGA protein, Advanced Protein Technologies Corp., Korea) enzyme reaction was carried out using 2 mM of 4-methylum belliferyl N-acetyl-β-D-glucosaminide (69585; Sigma) dissolved in DMSO as a substrate in a reaction solution containing 25 mM Tris / HCl and 0.1 mg / ml bovine serum albumin (pH 7.5). The amount of human OGA enzyme used in the reaction was 8 ng / well. Different amounts of the compounds from Examples 1 to 3 were added to the enzyme before starting the reaction. After reacting for 20 minutes at 37°C in 384-well plates, the substrate was added to initiate the reaction. The increase in fluorescence was measured using a SAFIRE (Tecan, Switzerland) fluorometer, and detected at excitation and emission wavelengths set to 360 nm and 460 nm, respectively. The detected enzyme activities are shown in Table 1 below.

[0456] Table 1

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464] *ND: Not determined

[0465] Furthermore, the inhibitory effects of compounds A-34S and A-34R, the enantiomers of the aforementioned compound A-34, on human OGA enzyme at different concentrations are as follows: Figure 1 As shown in Table 2, the IC50 concentration values ​​are as follows.

[0466] Table 2

[0467]

[0468] ND: Not determined

[0469] As can be confirmed by Table 2 above, among the two enantiomers of compound A-34, the (S) configuration of A-34 has a significantly better inhibitory effect on human OGA enzyme activity.

[0470] The compound name of A-34S:

[0471] (S)-2-(4-((2-acetamidothiazol-5-yl)methyl)-3-methylpiperazin-1-yl)-N-(4-chlorophenyl)acetamide)

[0472] The compound name of A-34R:

[0473] (R)-2-(4-((2-acetamidothiazol-5-yl)methyl)-3-methylpiperazin-1-yl)-N-(4-chlorophenyl)acetamide)

[0474] The present invention has been described above with reference to preferred embodiments. Those skilled in the art will understand that modifications can be made to the invention without departing from its essential characteristics. Therefore, the disclosed embodiments should be considered from an illustrative rather than restrictive viewpoint. Thus, the scope of the invention is defined by the scope of the claims that include the foregoing description, and it should be interpreted that distinctions within the equivalent scope are also included in the invention.

[0475] Industrial availability

[0476] This invention relates to a novel compound having O-GlcNAcase inhibitory activity, which can be used as a pharmaceutical composition for treating diseases caused by hyperphosphorylation of tau protein.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The above compounds include compounds represented by the following chemical formulas 2 to 4. Chemical formula 2: Where X is N; Chemical formula 3: Where X is O; Chemical formula 4: In the above chemical formula, R1, R2, and R3 are each independently hydrogen or C1 to C5 alkyl groups. n is an integer from 0 to 3; In the above chemical formula 2, A is selected from the following substituents: A： In the above chemical formula 3, B is selected from the following substituents: B： In the above chemical formula 4, C is selected from the following substituents: C： 2. A compound, characterized in that, The compounds are compounds A-1 to A-41 as follows:

3. A compound, characterized in that, The compounds are compounds B-1 to B-19 as follows:

4. The compound according to claim 1, characterized in that, The compounds of chemical formula 4 above include compounds C-1 to C-8:

5. The compound according to claim 2, characterized in that, The aforementioned compound A-34 is an enantiomer of the (S) configuration, represented by compound A-34S according to the following chemical formula 5. Chemical formula 5:

6. A pharmaceutical composition for treating or preventing diseases caused by hyperphosphorylation of tau protein, characterized in that, It contains the compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient.

7. The pharmaceutical composition according to claim 6 for treating or preventing diseases caused by hyperphosphorylation of tau protein, characterized in that, The above-mentioned diseases were selected from a group consisting of stroke, memory loss, dementia, Parkinson's disease, Alzheimer's disease, Pick's disease, Kreutzfeldt-Jacob disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, progressive supranuclear palsy, corticobasal degeneration, and Lou Gehrig's disease.

8. The pharmaceutical composition according to claim 7 for treating or preventing diseases caused by hyperphosphorylation of tau protein, characterized in that, The above-mentioned disease is selected from frontotemporal dementia.

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