Oxadiazolyl dihydropyrano[2,3-b]pyridine HIPK2 inhibitors for the treatment of renal fibrosis

Abstract

Disclosed are compounds that are selective inhibitors of Smad3 activation. The compounds are (3-aryl-1,2,4-oxadiazol-5-yl)-3,4-dihydro-2H-pyrano[2,3-b]pyridines of structure (I), where Ar is aryl or heteroaryl. The disclosed compounds are useful for the treatment of fibrotic diseases, particularly renal fibrosis, and similar diseases associated with dysregulation of the HIPK2 / Smad3 signaling pathway.

Description

Detailed description of the invention

[0001] [Cross-reference of related applications] This application claims priority to U.S. Provisional Patent Application No. 63 / 147,859, filed on 10 February 2021, the entire disclosure of U.S. Provisional Patent Application No. 63 / 147,859 is incorporated herein by reference.

[0002] [Technical Field of Inventions] This invention relates to an oxadiazolyldihydropyrano[2,3-b]pyridine inhibitor of homeodomain interacting protein kinase 2 (HIPK2). The disclosed compounds are useful in the treatment of fibrotic diseases, particularly renal fibrosis.

[0003] [background] Fibrosis is characterized by the overproduction and accumulation of extracellular matrix proteins, leading to progressive tissue loss and ultimately organ failure. Chronic kidney disease, unrelated to an initial injury, usually involves interstitial fibrosis of the kidneys. Treatment strategies for chronic kidney disease require not only the elimination of etiologies such as hyperglycemia, hypertension, and HIV infection to halt the decline in kidney function, but also antifibrotic therapy to restore normal kidney structure and function. In addition to renal fibrosis, many other organ-specific fibrotic disorders are known, such as hepatic, cardiac, and pulmonary fibrosis.

[0004] Renal fibrosis is considered the ultimate fate of progressive chronic kidney disease, regardless of its underlying etiology. While much has been discovered about the molecular mechanisms underlying renal fibrosis, the clinical application of this knowledge remains unsuccessful. It has been demonstrated that HIPK2 is a multifunctional activator of the TGF-β / Smad3, NF-κB, and p53 pathways, and that systemic knockout of HIPK2 in mice reduced renal fibrosis in vivo. U.S. Patent No. 10,669,266 discloses a small molecule HIPK2 inhibitor that specifically blocks the TGF-β / Smad3 pathway to alleviate renal fibrosis without causing systemic side effects. However, the compounds disclosed in U.S. Patent No. 10,669,266 still have issues with solubility and potency.

[0005] Transforming growth factor β1 (TGF-β1) has been identified as the most important pro-fibrotic factor in kidney disease. TGF-β1 binds to the type II TGF-β receptor, enabling dimerization with the type I TGF-β receptor and resulting in phosphorylation of Smad2 and Smad3. Phosphorylated Smad3 translocates to the nucleus and binds to the Smad-binding element of the promoter, activating the transcription of target genes, including pro-fibrotic genes such as collagen I, fibronectin, and alpha-smooth muscle actin (α-SMA). Smad3 is known to be highly activated in fibrotic kidneys, and knockout of Smad3 reduces renal fibrosis in animal models of kidney disease. Therefore, blocking the TGF-β1 / Smad3 pathway offers a therapeutic strategy for renal fibrosis.

[0006] [Overview of the prefecture] It was found that certain compounds listed below selectively inhibit the activation of Smad3. In one embodiment, the present invention relates to general formula I [ka] (In the formula, Ar is (a) Phenyl substituted at the meta and / or para positions with one or more substituents independently selected from hydrogen, -(C1-C8)hydrocarbyl, OH, -O(C1-C8)hydrocarbyl, halogen, nitro, amino, (C1-C3)alkylamino, (C1-C3)dialkylamino, (C1-C3)acylamino, (C1-C3)alkylsulfonyl, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, 5-membered or 6-membered heterocyclyl, and -B(OH)2; or (b) Five-membered heteroaryl molecules substituted with one substituent selected from hydrogen, -(C1-C3)alkyl, OH, -O(C1-C3)alkyl, halogen, amino, (C1-C3)alkylamino, (C1-C3)dialkylamino, (C1-C3)haloalkyl, and (C1-C3)haloalkoxy. and; R 4 This is selected from hydrogen, hydroxy, (C1-C3)alkyl, (C1-C3)alkoxy, amino, (C1-C3)alkylamino, and (C1-C3)dialkylamino; R 5 This is selected from hydrogen, hydroxy, (C1-C3)alkyl, (C1-C3)alkoxy, amino, (C1-C3)alkylamino, and (C1-C3)dialkylamino; R 6 is selected from hydrogen and (C1-C6) hydrocarbyl; and R 7 These are selected from hydrogen and (C1-C3) alkyl groups; However, R 4 , R 5 , R 6 , and R 7 (Not all of it is hydrogen.) This relates to compounds represented by [the specified formula / method].

[0007] In another embodiment, the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound represented by formula I.

[0008] In another aspect, the present invention relates to a method for inhibiting the interaction between homeodomain-interacting protein kinase 2 (HIPK2) and Smad3. The method comprises contacting HIPK2 with a compound represented by formula I. In another aspect, the present invention relates to a method for inhibiting the activation of Smad3. The method comprises contacting Smad3 with a compound represented by formula I. In another aspect, the present invention relates to a method for treating a fibrotic disease, comprising administering a compound represented by formula I.

[0009] Detailed Description of the Invention In one aspect, the present invention relates to a compound having general formula I as described above: Chemical formula .

[0010] In some embodiments of formula I, Ar is phenyl. In some embodiments, the phenyl may be substituted at the para position with a substituent selected from bromo, chloro, fluoro, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, oxetanyl, and -B(OH)2. In addition to the substituent at the para position, the phenyl may be further substituted with other substituents.

[0011] In some embodiments, Ar is 5-membered heteroaryl. In some embodiments, the 5-membered heteroaryl is selected from oxazole, thiophene, pyrazole, and thiazole, and may be unsubstituted or substituted with a substituent selected from -(C1-C3) hydrocarbyl, bromo, chloro, fluoro, fluoromethyl, difluoromethyl, and trifluoromethyl. In some embodiments, Ar is thiazol-2-yl substituted at the 3-position or 4-position with chloro or methyl.

[0012] In some embodiments of formula I, R 4 is selected from hydrogen, hydroxy, and amino. In some embodiments, R 5R is selected from hydrogen, hydroxyl, and amino. In some embodiments, R 6 and R 7 R is independently selected from hydrogen and methyl. In certain embodiments, Ar is chlorophenyl, and R 4 is hydrogen, R 5 is hydroxyl and R 6 and R 7 In all cases, methyl is present. In another specific embodiment, Ar is chlorophenyl, and R 4 R is hydroxyl, 5 is hydrogen, and R 6 and R 7 All of them are methyl.

[0013] For convenience and clarity, certain terms used in this specification, examples, and claims are hereby defined. Substituent R n The term is generally defined when it is introduced, and that definition is retained throughout the specification and in all independent claims.

[0014] Unless otherwise specified, alkyl (or alkylene) is intended to include linear or branched saturated hydrocarbon structures and combinations thereof. "Alkyl" refers to an alkyl group having 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, and t-butyl.

[0015] Cycloalkyl groups are a type of hydrocarbon that contain cyclic hydrocarbon groups with 3 to 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, and norbornyl.

[0016] Hydrocarbons or hydrocarbils include alkyl, cycloalkyl, polycycloalkyl, alkenyl, alkynyl, aryl, and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, adamantyl, camphoryl, and naphthylethyl. Hydrocarbons or hydrocarbils refer to any substituents consisting only of hydrogen and carbon as elemental components. Aliphatic hydrocarbons or aliphatic hydrocarbils are non-aromatic hydrocarbons or hydrocarbils; they may be saturated or unsaturated, cyclic, linear, or branched. Examples of aliphatic hydrocarbons or aliphatic hydrocarbils include isopropyl, 2-butenyl, 2-butynyl, cyclopentyl, and norbornyl. Aromatic hydrocarbons or aromatic hydrocarbils include benzene (phenyl), naphthalene (naphthyl), and anthracene.

[0017] Oxaalkyl groups refer to alkyl residues in which one or more carbon atoms (and the hydrogen atoms bonded to those carbon atoms) are replaced by oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, methoxypropoxy, and 3,6,9-trioxadecyl. The term oxaalkyl is intended to be understood in this field as it is understood [see paragraph 196 of “Naming and Indexing of Chemical Substances for Chemical Abstracts” published by the American Chemical Society, but without the constraints of paragraph 127(a)], that is, the term refers to compounds in which oxygen is bonded to its adjacent atom by a single bond (forming an ether bond); it does not refer to double-bonded oxygen as seen in carbonyl groups. Alkoxy groups are a subgroup of oxaalkyl groups and include groups with linear or branched structures. Examples include methoxy, ethoxy, propoxy, and isopropoxy. Lower alkoxy groups refer to groups containing 1 to 4 carbon atoms.

[0018] In some embodiments, one, two, or three hydrogen atoms are replaced by the designated group. In the case of alkyl and cycloalkyl groups, it is possible to replace four or more hydrogen atoms with fluorine; in fact, it is conceivable that all replaceable hydrogen atoms may be replaced with fluorine. Such compounds (e.g., perfluoroalkyl groups) fall into the categories of "halohydrocarbons" and "haloalkyl groups." The term "halogen" refers to fluorine, chlorine, bromine, or iodine atoms.

[0019] Unless otherwise specified, acyl refers to formyl and groups with 1, 2, 3, 4, 5, 6, 7, and 8 carbon atoms, which are saturated, unsaturated, aromatic, and combinations thereof, in linear, branched, and cyclic structures, and are bonded to the parent structure by a carbonyl functional group. Examples include acetyl, benzoyl, propionyl, and isobutyryl. Lower acyls refer to groups containing 1 to 4 carbon atoms. A double-bonded oxygen atom is called "oxo" when it is referred to as a substituent itself.

[0020] As used herein and as will be understood by those skilled in the art, when we say “compound,” we intend to include salts of that compound unless it is clearly stated that it is further limited. For example, when we say “compound represented by formula I” as shown above, we mean salts of (3-aryl-1,2,4-oxadiazole-5-yl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine: [ka] (wherein X is a counterion, preferably a pharmaceutically acceptable anion) the compound will include. In certain embodiments, the term “compound represented by formula I” refers to the compound or a pharmaceutically acceptable salt thereof.

[0021] The term "pharmaceutically acceptable salt" refers to a salt whose counterion is derived from a pharmaceutically acceptable, non-toxic acid or base. Suitable pharmaceutically acceptable acids for salts of the compounds of the present invention include, for example, acetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid (besylic acid), benzoic acid, boric acid, lacic acid, camphoric acid, camphorsulfonic acid, carbonic acid, citric acid, ethanedisulfonic acid, ethanesulfonic acid, ethylenediaminetetraacetic acid, formic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, and hydroiodic acid. Examples include hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucinic acid, naphthylenesulfonic acid, nitric acid, oleic acid, pamoic acid, pantothenic acid, phosphoric acid, pivalic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid, teoclatic acid, and p-toluenesulfonic acid. Suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include, but are not limited to, metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts made from lysine, arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium cations and carboxylate, sulfonate, and phosphonate anions bonded to alkyl groups having 1 to 20 carbon atoms.

[0022] "A therapeutically effective dose" means an amount sufficient to achieve treatment when administered to a person for the purpose of treating a disorder or condition.

[0023] It will be recognized that the compounds of the present invention can exist in a form labeled with radioisotopes, that is, the compounds may contain one or more atoms with atomic masses or mass numbers different from those commonly found in nature. Alternatively, multiple molecules of a single structure may contain at least one atom present in an isotopic abundance different from that found in nature. The radioisotopes of hydrogen, carbon, phosphorus, fluorine, chlorine, and iodine, respectively 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 35 S, 18 F, 36 Cl, 125 I, 124 I and 131 I is an example. Compounds containing those radioactive isotopes and / or other radioactive isotopes of other atoms are within the scope of the present invention. Tritium, i.e. 3 H and carbon-14, that is 14 Radioactive isotopes of 1C are particularly preferred due to their ease of preparation and detectability. 11 C, 13 N, 15 O, 124 I and 18 Compounds containing F are well-suited for positron emission tomography. The compounds represented by formula I of the present invention, labeled with radioisotopes, can generally be prepared by methods well known to those skilled in the art. Conveniently, such radioisotope-labeled compounds can be prepared by performing the procedures disclosed in the examples and schemes, using readily available radioisotope-labeled reagents in place of unlabeled reagents.

[0024] Those skilled in the art will readily recognize that the compounds described herein, when appropriately labeled as described above, can be used to identify (i.e., label) HIPK2. It is possible to locate HIPK2 in tissues, cells, and organelles using methods well known to those skilled in the art.

[0025] While compounds represented by formula I may be administered as chemical substances in their pure form, it is preferable to provide the compounds as pharmaceutical compositions. In a further embodiment, the present invention provides a pharmaceutical composition comprising a compound represented by formula I together with one or more pharmaceutically acceptable carriers of the compound and optionally one or more other therapeutic components. The carriers must be "acceptable" in the sense that they are miscible with other components of the formulation and are not harmful to the recipient of the formulation.

[0026] Preparations may include those suitable for oral, parenteral (subcutaneous, intradermal, intramuscular, intravenous, and intra-articular, etc.), rectal, and topical (transdermal, oral, sublingual, and intraocular, etc.) administration. Compounds are preferably administered orally or by injection (intravenous or subcutaneous). The precise amount of compound administered to the patient is the responsibility of the attending physician. However, the dose used will vary depending on many factors, such as the patient's age and sex, the disease being treated, and its severity. Similarly, the route of administration may change depending on the condition and its severity. Preparations may be provided in unit dosage forms for convenience and may be prepared by any method well known in the field of pharmacy. Generally, preparations are prepared by homogeneously and thoroughly combining the active ingredient with a liquid carrier, a fine powder solid carrier, or both, and then, if necessary, shaping the product to the desired preparation.

[0027] The formulations of the present invention, suitable for oral administration, can be provided as individual constituent units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as powders or granules; as solutions or suspensions contained in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil emulsions. The active ingredient may also be provided as pills, licks, or pastes.

[0028] In addition to the components specifically described above, it should be understood that the formulations of the present invention may contain other active ingredients conventionally used in the art, depending on the type of formulation in question; for example, formulations intended for oral administration may contain fragrances.

[0029] As used herein, “treatment,” “treating,” “palliating,” and “ameliorating” are interchangeable. These terms refer to methods for achieving therapeutic benefit in the form of eradication or reduction of the underlying disease being treated. Furthermore, therapeutic benefit is achieved by eradication or reduction of one or more physiological symptoms associated with the underlying disease, such that improvement is observed in the patient even if the patient still suffers from the underlying disease. The composition may be administered to patients who are at risk of developing a particular disease, or who complain of one or more physiological symptoms of the disease, even if the disease has not been diagnosed.

[0030] The terminology related to "protecting," "deprotecting," and "protected" functional groups is used in this application. Such terminology is well understood by those skilled in the art and is used in the context of reaction steps involving a series of reagents. In that context, a protecting group refers to a group used to mask a functional group in a reaction step where the reaction would otherwise occur but is undesirable. The protecting group prevents the reaction in that step, but can then be removed to expose the original functional group. Removal, or "deprotection," is performed after one or more reactions that would be hindered by the functionality have been completed. Thus, when a series of reagents are specified, as in the reaction steps described herein, those skilled in the art can easily imagine which group would be suitable as a "protecting group." Suitable groups for this purpose are discussed in standard textbooks in the field of chemistry, e.g., TW Greene, “Protective Groups in Organic Synthesis”, [John Wiley and Sons, New York, 1991], which is incorporated herein by reference.

[0031] A comprehensive list of abbreviations used by organic chemists is published in the first issue of each volume of the Journal of Organic Chemistry. This list, typically presented in a table titled "Standard List of Abbreviations," is incorporated herein by reference.

[0032] In general, the compounds of the present invention can be prepared using readily available starting materials, reagents, and conventional synthesis procedures by methods illustrated in the general reaction schemes described below, or by modifications thereof. Modifications of these reactions, known in themselves but not mentioned herein, may also be utilized. Starting materials may be commercially available or synthesized as described in the examples, or they may be obtained by methods well known to those skilled in the art.

[0033] Specific examples of the compound of the present invention prepared by the above scheme, and the test results of the compound in the luciferase screening described later, are shown in Table 1.

[0034] [Table 1] TIFF0007927001000005.tif184158 TIFF0007927001000006.tif172158 TIFF0007927001000007.tif185158 TIFF0007927001000008.tif170158 TIFF0007927001000009.tif174158 Typical synthesis methods are described below.

[0035] [Experiment Section] <General Information>: All evaporation was performed under vacuum using a rotary evaporator. Analytical samples were dried under vacuum (1–5 mmHg) at room temperature (rt). Thin-layer chromatography (TLC) was performed on silica gel plates, and spots were visualized with UV light (214 and 254 nm). Purification by column chromatography and flash chromatography was performed using silica gel (200–300 mesh). Solvent systems are shown as volume ratio mixtures. All NMR spectra were recorded using a Bruker 400 (400 MHz) spectrometer. 1The chemical shift of H is reported as a δ value in ppm using a deuterated solvent as an internal standard. The data is reported as follows: chemical shift, multiplicity (s=single line, d=double line, t=triple line, q=quadruple line, br=broad line, m=multiple line), coupling constant (Hz), and integral value. LCMS spectra were obtained using electrospray ionization with an Agilent 1200 series 6110 or 6120 mass spectrometer, and unless otherwise indicated, the general LCMS conditions were as follows: Waters XBridge® C18 column (50 mm × 4.6 mm × 3.5 μm), flow rate: 2.0 ml / min, column temperature: 40 °C. <Example 1>: Synthesis of ethyl 2,2-dimethyl-2H-pyrano[2,3-b]pyridine-6-carboxylate (0097-1).

[0036] [ka] A solution of 0095-3 (2g, 8.4 mmol), Pd(OAc)2 (190 mg, 0.84 mmol), dppf (932 mg, 1.68 mmol), and TEA (3.4 g, 33.6 mmol) in EtOH / DMF (1 / 1 (v / v), 20 mL) was stirred at 100°C for 40 hours under a CO atmosphere (3 MPa). After the starting materials were consumed (confirmed by LC-MS), the solution was concentrated under vacuum and purified by column (PE:EA = 15:1) to obtain product 0097-1 (1 g, yield 51%) as a white solid.

[0037] Synthesis of ethyl 4-bromo-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-6-carboxylate (0097-2).

[0038] [ka] NBS (1.6 g, 9 mmol) was added to a stirred solution of compound 0097-1 (700 mg, 3 mmol) in DMSO / H2O (10 ml). The mixture was stirred at room temperature for 5 hours. After the starting material was consumed (confirmed by LC-MS), the reaction solution was extracted with ethyl acetate, the organic phase was combined and dehydrated with anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by column chromatography (PE:EA = 3:1) to obtain 0097-2 (750 mg, yield 76%) as a white solid.

[0039] Synthesis of ethyl 2,2-dimethyl-2,7b-dihydro-1aH-oxyreno[2',3':4,5]pyrano[2,3-b]pyridine-6-carboxylate (0097-3).

[0040] [ka] A solution of 0097-2 (750 mg, 2.28 mmol) and KOH (255 mg, 4.56 mmol) in THF (10 mL) was stirred at room temperature for 5 hours. After the starting material was consumed (confirmed by LC-MS), the solution was concentrated under vacuum and purified by column (PE:EA = 3:1) to obtain product 0097-3 (500 mg, yield 88%) as a white solid. Synthesis of ethyl 3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-6-carboxylate (0097-4).

[0041] [ka] Pd / C (30 mg, 10% (w / w)) was added to a stirred solution of compound 0097-3 (300 mg, 1.2 mmol) in MeOH (10 mL). The mixture was stirred at room temperature under an H2 atmosphere (1.0 atm) for 5 hours. After the starting material was consumed (confirmed by LC-MS), the reaction mixture was filtered, washed with MeOH, and the filtrate was concentrated under vacuum. The filtrate was purified by column chromatography (PE:EA = 2:1) to obtain product 0097-4 (280 mg, yield 93%) as a colorless oil. Synthesis of 3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-6-carboxylate (0097-5).

[0042] [ka] A mixture of 0097-4 (280 mg, 1.12 mmol) and KOH (314 mg, 5.6 mmol) in MeOH / H2O (1 / 4, 10 mL) was stirred overnight at room temperature. The reaction mixture was then neutralized with 1 M HCl until the pH reached 6.0. The resulting mixture was concentrated under vacuum and purified by preparative HPLC to obtain product 0097-5 (200 mg, 80% yield) as a white solid.

[0043] Synthesis of 6-(3-(4-bromophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0097-01).

[0044] [ka] Compound 0097-5 (150 mg, 0.67 mmol), 4-bromo-N'-hydroxybenzimidoamide (160 mg, 0.81 mmol), and HBTU (384 mg, 1.01 mmol) were mixed in DMF (5 ml) and DIEA (173 mg, 1.34 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the starting materials were consumed (confirmed by LC-MS), the reaction solution was extracted with ethyl acetate, the organic phases were combined and dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum. DBU (204 mg, 1.34 mmol) and NBS (240 mg, 1.34 mmol) were added to the crude product in ethyl acetate (5 mL). The mixed solution was stirred at room temperature for 30 minutes. After the starting material was consumed (confirmed by LC-MS), the reaction mixture was concentrated under vacuum and purified by preparative HPLC to obtain the desired product SMS21032-0097-01 (30 mg, yield 11%) as a white solid.

[0045] Agilent LC-MS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 0.7 minutes. Purity: 100%, Rt = 2.197 mins; MS (calculated): 402.24; MS (measured): 402.2 [M+H] + .

[0046] Agilent HPLC 1200, column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity: 99.59%, Rt = 10.582 mins.

[0047] 1 H NMR (400 MHz, CDCl3) δ 8.94 (s, 1 H), 8.23 ​​(s, 1 H), 8.01 (d, J = 8.4 Hz, 2 H), 7.64 (d, J = 8.8 Hz, 2 H), 3.97 (t, J = 5.2 Hz, 1 H), 3.17-3.23 (m, 1 H), 2.94-2.99 (m, 1 H), 1.51 (s, 3 H), 1.46 (s, 3 H).

[0048] <Example 2>: Synthesis of ethyl 4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-6-carboxylate (0098-2). [ka] Compound 0097-3 (330 mg, 1.33 mmol) was stirred in EtOH (10 ml), to which NH4OH (12 mL) was added. The mixture was stirred at 80°C for 8 hours. After the starting material was consumed (confirmed by LC-MS), the reaction solution was concentrated under vacuum to obtain crude product 0098-2 (350 mg, yield 98.9%) as a yellow solid.

[0049] Synthesis of ethyl 4-(tert-butoxycarbonylamino)-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-6-carboxylate (0098-3).

[0050] [ka] Boc2O (432 mg, 1.98 mmol) was added to a stirred solution of compound 0098-2 (350 mg, 1.32 mmol) and TEA (267 mg, 2.64 mmol) in DCM (10 ml). The mixture was stirred overnight at room temperature. After the starting materials were consumed (confirmed by LC-MS), the reaction solution was concentrated under vacuum and purified by column chromatography (PE:EA = 3:1) to obtain product 0098-3 (170 mg, yield 35.2%) as a colorless oil.

[0051] Synthesis of 4-(tert-butoxycarbonylamino)-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-6-carboxylate (0098-4).

[0052] [ka] A solution of 0098-3 (170 mg, 0.46 mmol) and KOH (130 mg, 2.3 mmol) in MeOH / H2O (4 / 1, 5 mL) was stirred overnight at room temperature. After the starting materials were consumed (confirmed by LC-MS), the reaction mixture was neutralized with 1 M HCl until the pH reached 6. The solution was concentrated under vacuum and purified by preparative HPLC to obtain product 0098-4 (120 mg, 77% yield) as a white solid.

[0053] Synthesis of tert-butyl-6-(3-(4-bromophenyl)-1,2,4-oxadiazole-5-yl)-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-4-ylcarbamate (0098-5).

[0054] [ka] To a stirred solution of compound 0098-4 (120 mg, 0.36 mmol) in DMF (10 ml), CDI (121 mg, 0.72 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then 4-bromo-N'-hydroxybenzimidoamide (154 mg, 0.72 mmol) was added. The mixture was stirred at 120°C for 3 hours. After the starting material was consumed (confirmed by LC-MS), the reaction mixture was concentrated under vacuum and purified by column chromatography (DCM:MeOH = 50:1) to obtain product 0098-5 (150 mg, yield 80.6%) as a white solid.

[0055] Synthesis of 4-amino-6-(3-(4-bromophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0098-01).

[0056] [ka] A solution of compound 0098-5 (100 mg, 0.2 mmol) in HCl / dioxane (4 M, 5 ml) was stirred at room temperature for 2 hours. After the starting material was consumed (confirmed by LC-MS), the reaction solution was concentrated under vacuum and purified by preparative HPLC to obtain the desired product SMS21032-0098-01 (21 mg, yield 25.3%) as a white solid.

[0057] Agilent LC-MS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 0.7 minutes. Purity: 96.20%, Rt = 2.061 min; MS (calculated): 417.26; MS (measured): 417.2 [M+H] + .

[0058] Agilent HPLC 1200, column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity: 98.49%, Rt = 9.810 min.

[0059] 1 H NMR (400 MHz, CDCl3) δ 8.98 (d, J = 2.0 Hz, 1 H), 8.55-8.56 (m, 1 H), 8.02-8.04 (m, 2 H), 7.64-7.66 (m, 2 H), 3.79 (d, J = 10 Hz, 1 H), 3.43 (d, J= 10 Hz, 1 H), 3.02 (br., 1 H), 1.64 (s, 3 H), 1.35 (s, 3 H)

[0060] <Examples 3 and 4>: Synthesis of ethyl(S)-6-(3-(4-bromophenyl)-1,2,4-oxadiazole-5-yl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine (SMS21032-0130) and ethyl(R)-6-(3-(4-bromophenyl)-1,2,4-oxadiazole-5-yl)-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine (SMS21032-0131)

[0061] [ka] ≪SMS21032-0130≫: Agilent LC-MS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 0.7 minutes. Purity is 99.3%. Rt = 2.496 mins; MS (calculated): 371.0; MS (measured): 371.8 [M+H] + .

[0062] Agilent HPLC 1200, column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity is 98.0%. Rt = 11.975 minutes.

[0063] 1HNMR (400 MHz, CDCl3) δ 8.93 (d, J = 2.0 Hz, 1 H), 8.18 (d, J = 2.0 Hz, 1 H), 8.04 (d, J = 8.8 Hz, 2 H), 7.66 (d, J = 8.8 Hz, 2 H), 4.53-4.44 (m, 1 H), 3.03-2.88 (m, 2 H), 2.17-2.09 (m, 1 H), 1.87-1.75 (m, 1 H), 1.54 (d, J = 6.4 Hz, 3 H).

[0064] ≪SMS21032-0131≫: Agilent LC-MS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 0.7 minutes. Purity is 99.4%. Rt = 2.491 mins; MS (calculated): 371.0; MS (measured): 372.2 [M+H] + .

[0065] Agilent HPLC 1200, column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity is 97.0%. Rt = 11.972 mins.

[0066] 1HNMR (400 MHz, CDCl3) δ 8.93 (d, J = 2.0 Hz, 1 H), 8.17 (d, J = 2.0 Hz, 1 H), 8.03 (d, J = 8.4 Hz, 2 H), 7.65 (d, J = 8.4 Hz, 2 H), 4.52-4.43 (m, 1 H), 3.02-2.87 (m, 2 H), 2.16-2.08 (m, 1 H), 1.87-1.75 (m, 1 H), 1.53 (d, J = 6.0 Hz, 3 H).

[0067] <Example 5>: Synthesis of 6-(3-(4-bromophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-4-ol (SMS21032-0143) [ka] To a solution of SMS21032-0142 (40 mg, 0.1 mmol) in MeOH (1 mL) / THF (2 mL), NaBH4 (4 mg, 0.1 mmol) was added at 5°C, and the mixture was then stirred at 5°C for 1 hour. The mixture was concentrated to obtain an oily substance, which was purified by preparative HPLC to obtain SMS21032-0143 (8 mg, yield: 20%) as a white solid.

[0068] LC-MS (Agilent LCMS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 0.7 minutes). Purity 100%, Rt = 2.245 mins; MS (calculated value): 401.0; MS (measured value): 402.2 [M+H] + .

[0069] Agilent HPLC 1200, Column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.0mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity 99.3%, Rt = 10.808 mins; MS (calculated): 401.0; MS (measured): 402.2 [M+H] + .

[0070] 1 H NMR (400 MHz, CDCl3) δ 9.01 (d, J = 2.4 Hz, 1 H), 8.63 (d, J = 1.6 Hz, 1 H), 8.04 (d, J = 8.4 Hz, 2 H), 7.66 (d, J = 8.8 Hz, 2 H), 4.98-5.06 (m, 1 H), 2.33 (dd, J = 13.6, 6.0 Hz, 1 H), 2.10 (d, J = 7.6 Hz, 1 H), 1.96 (dd, J = 13.4, 10.2 Hz, 1 H), 1.60 (s, 3 H), 1.44 (s, 3 H).

[0071] <Example 6>: Synthesis of (R)-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-6-carboxylate (0097-5a). [ka] A solution of 0097-4a (180 mg, 0.72 mmol) and NaOH (144 mg, 3.6 mmol) in MeOH / H2O (1 / 4, 10 mL) was stirred at room temperature for 5 hours. After the starting material was consumed (confirmed by LC-MS), the reaction mixture was neutralized with 1 M HCl until the pH reached 6. The solution was concentrated under vacuum and purified by preparative HPLC to obtain product 0097-5a (130 mg, yield 81%) as a white solid.

[0072] Synthesis of (R)-6-(3-(4-bromophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0151-01).

[0073] [ka] Compound 0097-5a (70 mg, 0.32 mmol), 4-bromobenzimidoamide (77 mg, 0.39 mmol), and HBTU (183 mg, 0.48 mmol) were mixed in DMF (5 ml) and DIEA (83 mg, 0.64 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the starting materials were consumed (confirmed by LC-MS), the reaction solution was extracted with ethyl acetate, the organic phases were combined and dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum. DBU (98 mg, 0.64 mmol) and NBS (114 mg, 0.64 mmol) were added to the crude product in ethyl acetate (5 mL). The mixed solution was stirred at room temperature for 30 minutes. After the starting material was consumed (confirmed by LC-MS), the reaction mixture was concentrated under vacuum and purified by preparative HPLC to obtain the desired product SMS21032-0151-01 (27 mg, yield 21%) as a white solid.

[0074] Agilent LC-MS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 0.7 minutes. Purity: 96.88%, Rt = 2.212 mins; MS (calculated): 402.24; MS (measured): 401.8 [M+H] + .

[0075] Agilent HPLC 1200, column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity: 96.03%, Rt = 10.749 mins.

[0076] 1 H NMR (400 MHz, CDCl3) δ 8.94 (d, J = 2.0 Hz, 1 H), 8.26 (d, J = 1.2 Hz, 1 H), 7.99 (d, J = 8.4 Hz, 2 H), 7.63 (d, J = 8.4 Hz, 2 H), 3.98 (t, J = 4.8 Hz, 1 H), 3.17-3.23 (m, 1 H), 2.97-3.03 (m, 1 H), 1.52 (s, 3 H), 1.46 (s, 3 H).

[0077] <Example 7>: Synthesis of (S)-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-6-carboxylate (0097-5b). [ka] A solution of 0097-4b (190 mg, 0.76 mmol) and NaOH (152 mg, 3.8 mmol) in MeOH / H2O (1 / 4, 10 mL) was stirred overnight at room temperature. After the starting material was consumed (confirmed by LC-MS), the reaction mixture was neutralized with 1 M HCl until the pH reached 6. The solution was concentrated under vacuum and purified by preparative HPLC to obtain product 0097-5b (140 mg, yield 82.3%) as a white solid.

[0078] Synthesis of (S)-6-(3-(4-bromophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0152-01).

[0079] [ka] Compound 0097-5b (70 mg, 0.32 mmol), 4-bromobenzimidoamide (77 mg, 0.39 mmol), and HBTU (183 mg, 0.48 mmol) were mixed in DMF (5 ml) and DIEA (83 mg, 0.64 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the starting materials were consumed (confirmed by LC-MS), the reaction solution was extracted with ethyl acetate, the organic phases were combined and dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum. DBU (98 mg, 0.64 mmol) and NBS (114 mg, 0.64 mmol) were added to the crude product in ethyl acetate (5 mL). The mixed solution was stirred at room temperature for 30 minutes. After the starting material was consumed (confirmed by LC-MS), the reaction mixture was concentrated under vacuum and purified by preparative HPLC to obtain the desired product SMS21032-0152-01 (25 mg, yield 19.5%) as a white solid.

[0080] Agilent LC-MS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 0.7 minutes. Purity: 100%, Rt = 2.214 mins; MS (calculated): 402.24; MS (measured): 401.8 [M+H] + .

[0081] Agilent HPLC 1200, column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity: 99.30%, Rt = 10.750 min.

[0082] 1 H NMR (400 MHz, CDCl3) δ 8.93 (d, J = 1.6 Hz, 1 H), 8.24 (d, J = 0.8 Hz, 1 H), 8.00 (d, J = 8.4 Hz, 2 H), 7.63 (d, J = 8.4 Hz, 2 H), 3.97 (t, J = 4.8 Hz, 1 H), 3.17-3.23 (m, 1 H), 2.96-3.02 (m, 1 H), 1.51 (s, 3 H), 1.45 (s, 3 H).

[0083] <Example 8>: Synthesis of (3R,4S)-ethyl 3,4-dihydroxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-6-carboxylate (0164-2). [ka] A stirring solution of compound 0164-1 (120 mg, 0.48 mmol) in acetone was mixed with H2SO4 (1 M, 3 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized to pH=7 using NaHCO3. Dichloromethane was added to the reaction mixture to separate the organic phase. The aqueous layer was extracted with dichloromethane, and the organic layers were dehydrated together with Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA=2:1) ​​to obtain product 0164-2 (80 mg, yield 62.5%) as a yellow oil.

[0084] Synthesis of (3R,4S)-3,4-dihydroxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-6-carboxylate (0164-3).

[0085] [ka] A solution of 0164-2 (80 mg, 0.3 mmol) and NaOH (60 mg, 1.5 mmol) in MeOH / H2O (4 / 1, 5 mL) was stirred at room temperature for 5 hours. After the starting material was consumed (confirmed by LC-MS), the reaction mixture was neutralized with 1 M HCl until the pH reached 6. The solution was concentrated under vacuum and purified by preparative HPLC to obtain product 0164-3 (55 mg, yield 76.7%) as a white solid.

[0086] Synthesis of (3R,4S)-6-(3-(4-bromophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3,4-diol (SMS21032-0164-01).

[0087] [ka] Compound 0164-3 (55 mg, 0.23 mmol), 4-bromobenzimidoamide (56 mg, 0.28 mmol), and HBTU (133 mg, 0.35 mmol) were stirred in DMF (5 ml), to which DIEA (60 mg, 0.46 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the starting materials were consumed (confirmed by LC-MS), the reaction solution was extracted with ethyl acetate, the organic phases were combined and dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum. DBU (70 mg, 0.46 mmol) and NBS (82 mg, 0.34 mmol) were added to the crude product in ethyl acetate (5 mL). The mixed solution was stirred at room temperature for 30 minutes. After the starting material was consumed (confirmed by LC-MS), the reaction mixture was concentrated under vacuum and purified by preparative HPLC to obtain the desired product SMS21032-0164-01 (28 mg, yield 29.2%) as a white solid.

[0088] Agilent LC-MS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 0.7 minutes. Purity: 96.88%, Rt = 2.078 mins; MS (calculated): 418.24; MS (measured): 418.3 [M+H] + .

[0089] Agilent HPLC 1200, column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity: 99.50%, Rt = 9.860 min.

[0090] 1 H NMR (400 MHz, CDCl3) δ 9.03 (d, J = 2.0 Hz, 1 H), 8.65 (s, 1 H), 8.04 (d, J = 8.4 Hz, 2 H), 7.66 (d, J = 8.0 Hz, 2 H), 4.76 (d, J = 9.2 Hz, 1 H), 3.73 (d, J = 9.2 Hz, 1 H), 1.64 (s, 3 H), 1.38 (s, 3 H).

[0091] <Example 9>: Synthesis of (3S,4R)-ethyl 3,4-dihydroxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-6-carboxylate (0165-2). [ka] To a stirred solution of compound 0165-1 (130 mg, 0.52 mmol) in acetone, H2SO4 (1 M, 3 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized to pH=7 using NaHCO3. Dichloromethane was added to the reaction mixture to separate the organic phase. The aqueous layer was extracted with dichloromethane, and the organic layers were dehydrated together with Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (PE:EA=2:1) ​​to obtain product 0165-2 (90 mg, yield 64.7%) as a yellow oil.

[0092] Synthesis of (3S,4R)-3,4-dihydroxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-6-carboxylate (0165-3).

[0093] [ka] A solution of 0165-2 (90 mg, 0.34 mmol) and NaOH (68 mg, 1.7 mmol) in MeOH / H2O (4 / 1, 5 mL) was stirred at room temperature for 5 hours. After the starting materials were consumed (confirmed by LC-MS), the reaction mixture was neutralized with 1 M HCl until the pH reached 6. The solution was concentrated under vacuum and purified by preparative HPLC to obtain product 0165-3 (60 mg, yield 73.8%) as a white solid.

[0094] Synthesis of (3S,4R)-6-(3-(4-bromophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3,4-diol (SMS21032-0165-01).

[0095] [ka] Compound 0165-3 (60 mg, 0.25 mmol), 4-bromobenzimidoamide (60 mg, 0.3 mmol), and HBTU (143 mg, 0.38 mmol) were stirred in DMF (5 ml), to which DIEA (65 mg, 0.5 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the starting materials were consumed (confirmed by LC-MS), the reaction solution was extracted with ethyl acetate, the organic phases were combined and dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum. DBU (76 mg, 0.5 mmol) and NBS (89 mg, 0.5 mmol) were added to the crude product in ethyl acetate (5 mL). The mixed solution was stirred at room temperature for 30 minutes. After the starting materials were consumed (confirmed by LC-MS), the reaction mixture was concentrated under vacuum and purified by preparative HPLC to obtain the desired product SMS21032-0165-01 (27 mg, yield 26%) as a white solid.

[0096] Agilent LC-MS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 0.7 minutes. Purity: 97.44%, Rt = 2.076 mins; MS (calculated): 418.24; MS (measured): 418.2 [M+H] + .

[0097] Agilent HPLC 1200, column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed back to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity: 100%, Rt = 9.858 mins.

[0098] 1 H NMR (400 MHz, CDCl3) δ 9.03 (d, J = 2.0 Hz, 1 H), 8.63 (d, J = 1.2 Hz, 1 H), 8.04 (d, J = 8.4 Hz, 2 H), 7.66 (d, J = 8.8 Hz, 2 H), 4.75 (d, J = 9.2 Hz, 1 H), 3.73 (d, J = 8.8 Hz, 1 H), 1.64 (s, 3 H), 1.38 (s, 3 H).

[0099] <Examples 10 and 11>: Synthesis of (R)-6-(3-(4-bromophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-4-ol (SMS21032-0171) and (S)-6-(3-(4-bromophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-4-ol (SMS21032-0172)

[0100] Synthesis of 6-(3-(4-bromophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-2H-pyrano[2,3-b]pyridine-4(3H)-one (SMS21032-0142) Synthesis of 1-(5-bromo-2-methoxypyridine-3-yl)-3-methylbuta-2-en-1-one (142-1)

[0101] [ka] To a solution of 0095-3 (1 g, 3.67 mmol) in DCM (160 mL), MnO2 (6.71 g, 77.17 mmol) was added at room temperature, and the mixture was stirred at room temperature for 3 days. The mixture was filtered and concentrated to obtain an oily substance, which was purified in cc (EA:PE = 1:30) to obtain 142-1 (0.71 g, yield: 72%) as a yellow liquid. Synthesis of 6-bromo-2,2-dimethyl-2H-pyrano[2,3-b]pyridine-4(3H)-one(142-2)

[0102] [ka] To a solution of 142-1 (2.9 g, 10.74 mmol) in DCM (150 mL), BCl3 (55 mL) was added dropwise at -45°C. After the addition was complete, the mixture was stirred at room temperature for 16 hours. The reaction was then quenched with saturated NaHCO3, diluted with DCM (20 mL), washed with brine (50 mL), and dehydrated with Na2SO4. The mixture was filtered and concentrated to obtain an oily substance, which was purified by cc (EA:PE = 1:3) to obtain 142-2 (1.3 g, yield: 47%) as a yellow solid.

[0103] Synthesis of 6'-bromo-2',2'-dimethyl-2',3'-dihydrospiro[[1,3]dioxolane-2,4'-pyrano[2,3-b]pyridine](142-3)

[0104] [ka] To a solution of 142-2 (200 mg, 0.78 mmol) in toluene (10 mL), ethylene glycol (97 mg, 1.56 mmol) and TsOH (8 mg, 0.16 mmol) were added, and the mixture was refluxed for 16 hours. The mixture was washed with saturated NaHCO3 (20 mL) and dehydrated with Na2SO4. The mixture was filtered and concentrated to obtain a solid, and 142-3 (100 mg, yield: 43%) was obtained as a yellow solid.

[0105] Synthesis of methyl 2',2'-dimethyl-2',3'-dihydrospiro[[1,3]dioxolane-2,4'-pyrano[2,3-b]pyridine]-6'-carboxylate (142-4)

[0106] [ka] To a solution of 142-3 (400 mg, 1.33 mmol) in DMF (6 mL) / MeOH (6 mL), TEA (674 mg, 6.66 mmol), dppf (111 mg, 0.20 mmol), and Pd(OAc)2 (45 mg, 0.20 mmol) were added, and the mixture was then heated in CO (3 bar) at 100°C for 16 hours. The filtrate was filtered and concentrated, the residue was diluted with EA (50 mL), washed with brine (30 mL), and dehydrated with Na2SO4. The filtrate was filtered and concentrated to obtain an oily substance, which was purified in cc (EA:PE = 1:4) to obtain 142-4 (330 mg, yield: 89%) as a yellow oil.

[0107] Synthesis of 2',2'-dimethyl-2',3'-dihydrospiro[[1,3]dioxolane-2,4'-pyrano[2,3-b]pyridine]-6'-carboxylate (142-5)

[0108] [ka] A solution of 142-4 (110 mg, 0.4 mmol) in MeOH (2 mL) / THF (1 mL) was added to a solution of NaOH (40 mg, 0.99 mmol) in H2O (0.5 mL), and the mixture was then stirred at room temperature for 2 hours. The mixture was concentrated to obtain a solid, acidified to pH=5 with HCl (2 N), and then concentrated to obtain 142-5 as a crude solid.

[0109] Synthesis of 6'-(3-(4-bromophenyl)-1,2,4-oxadiazole-5-yl)-2',2'-dimethyl-2',3'-dihydrospiro[[1,3]dioxolan-2,4'-pyrano[2,3-b]pyridine](SMS21032-0169)

[0110] [ka] 142-5 (crude product), 4-bromo-N'-hydroxybenzamidine (105 mg, 0.50 mmol) was dissolved in dioxane (15 mL), to which DCC (131 mg, 0.64 mmol) was added at room temperature, and the mixture was refluxed for 4 hours. The mixture was concentrated to obtain an oily substance, and the residue was further purified by preparative HPLC to obtain SMS21032-0169 (10 mg, 2-step yield 5.6%) as a white solid.

[0111] LC-MS (Agilent LCMS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 0.7 minutes), Purity: 96.6%, Rt = 2.481 min; MS (calculated value): 399.0; MS (measured value): 400.2 [M+H] + .

[0112] Agilent HPLC 1200, Column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.0 mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity: 97.0%, Rt = 11.932 mins. MS (calculated): 399.0; MS (measured): 400.2 [M+H] + .

[0113] 1H NMR (400 MHz, CDCl3) δ 9.07 (d, J = 2.4 Hz, 1 H), 8.50 (d, J = 2.4 Hz, 1 H), 8.03-8.07 (m, 2 H), 7.63-7.68 (m, 2 H), 4.30-4.36 (m, 2 H), 4.12-4.20 (m, 2 H), 2.23 (s, 2 H), 1.56 (s, 6 H).

[0114] [ka] To a solution of SMS21032-0169 (crude product) in THF (3 mL), HCl (2N, 0.2 mL) was added, and the mixture was refluxed for 2 hours. The mixture was concentrated to obtain an oily substance, diluted with DCM (10 mL), washed with saturated NaHCO3, and dehydrated with Na2SO4. The mixture was filtered, and the filtrate was concentrated to obtain a solid. The crude product was washed with MeOH to obtain SMS21032-0142 (25 mg, yield: 16%) as a white solid.

[0115] LC-MS (Agilent LCMS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 0.7 minutes), Purity: 96.6%, Rt = 2.481 min; MS (calculated value): 399.0; MS (measured value): 400.2 [M+H] + .

[0116] Agilent HPLC 1200, Column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.0 mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity is 96.4%. Rt = 7.558 mins. Purity: 97.0%, Rt = 11.932 mins. MS (calculated): 399.0; MS (measured): 400.2 [M+H] + .

[0117] 1 H NMR (400 MHz, CDCl3) δ 9.28 (d, J = 2.4 Hz, 1 H), 8.96 (d, J = 2.4 Hz, 1 H), 8.04 (d, J = 8.4 Hz, 2 H), 7.65 (d, J = 8.4 Hz, 2 H), 2.87 (s, 2 H), 1.59 (s, 6 H).

[0118] Synthesis of 6-(3-(4-bromophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-4-ol (171-2)

[0119] [ka] NaBH4 (13.2 mg, 0.35 mmol) was added at 0°C to a solution of SMS21032-0142 (70 mg, 0.17 mmol) in MeOH / THF (2 mL / 2 mL), and the reaction mixture was then stirred at 5°C for a further 1 hour. After the reaction was complete (confirmed by LC-MS), water (10 mL) and dichloromethane (10 mL) were added to the solution to separate the organic phase. The aqueous phase was extracted with dichloromethane (2 × 10 mL), the combined organic solutions were washed with water, then with brine, dehydrated with anhydrous Na2SO4, concentrated, and purified by preparative HPLC to obtain 171-2 (30 mg, yield: 43%) as a white solid.

[0120] Synthesis of (R)-6-(3-(4-bromophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-4-ol (SMS21032-0171) and (S)-6-(3-(4-bromophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-4-ol (SMS21032-0172)

[0121] [ka] SMS21032-0171 and SMS21032-0172 were separated by chiral HPLC using a CHIRALCEL® OX-10 column (30 × 250 mm, 10 μm) with MeOH as the mobile phase. SMS21032-0171 (10 mg) was the first eluted compound, and SMS21032-0172 (10 mg) was the second eluted compound.

[0122] ≪SMS21032-0171≫ LC-MS (Agilent LCMS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 0.7 minutes). Purity 100%, Rt = 2.200 mins; MS (calculated value): 401.0; MS (measured value): 402.0 [M+H] + .

[0123] Agilent HPLC 1200, Column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.0 mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed back to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity 100%, Rt = 10.607 mins; MS (calculated): 401.0; MS (measured): 402.2 [M+H] + .

[0124] 1 H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 2.4 Hz, 1 H), 8.55 (d, J = 1.2 Hz, 1 H), 7.95 (d, J = 8.4 Hz, 2 H), 7.57 (d, J = 8.4 Hz, 2 H), 4.90-4.99 (m, 1 H), 2.33-2.48 (m, 1 H), 2.25 (dd, J = 13.6, 6.0 Hz, 1 H), 1.86-1.92 (m, 1 H), 1.52 (s, 3 H), 1.36 (s, 3 H).

[0125] ≪SMS21032-0172≫ LC-MS (Agilent LCMS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 0.7 minutes). Purity 100%, Rt = 2.206 mins; MS (calculated value): 401.0; MS (measured value): 402.0 [M+H] + .

[0126] Agilent HPLC 1200, Column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.0 mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed back to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity 100%, Rt = 10.599 mins; MS (calculated): 401.0; MS (measured): 402.2 [M+H] + .

[0127] 1 H NMR (400 MHz, CDCl3) δ 9.00 (d, J = 2.0 Hz, 1 H), 8.62 (d, J = 1.2 Hz, 1 H), 8.02 (d, J = 8.4 Hz, 2 H), 7.65 (d, J = 8.4 Hz, 2 H), 4.97-5.07 (m, 1 H), 2.39-2.48 (m, 1 H), 2.32 (dd, J = 13.2, 6.0 Hz, 1 H), 1.93-1.99 (m, 1 H), 1.59 (s, 3 H), 1.44 (s, 3 H).

[0128] <Example 12>: Synthesis of (R)-6-(3-(4-chlorophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0173-01) [ka] CDI (72 mg, 0.44 mmol) was added to a stirred solution of compound 0097-5a (50 mg, 0.22 mmol) in DMF (5 ml). The mixture was stirred at room temperature for 30 minutes, and then 4-chloro-N'-hydroxybenzimidoamide (88 mg, 0.44 mmol) was added. The mixture was stirred at 120°C for 3 hours. After the starting material was consumed (confirmed by LC-MS), the reaction mixture was concentrated under vacuum and purified by preparative HPLC to obtain product SMS21032-0173-01 (14 mg, yield 17.8%) as a white solid.

[0129] Agilent LC-MS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 0.7 minutes. Purity: 98.55%, Rt = 2.191 min; MS (calculated): 357.79; MS (measured): 358.4 [M+H] + .

[0130] Agilent HPLC 1200, column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity: 99.77%, Rt = 10.470 min.

[0131] 1H NMR (400 MHz, CDCl3) δ 8.91 (d, J= 2.0 Hz, 1 H), 8.21 (d, J = 1.6 Hz, 1 H), 8.07 (d, J = 8.4 Hz, 2 H), 7.47 (d, J = 8.4 Hz, 2 H), 3.97 (t, J = 4.4 Hz, 1 H), 3.18-3.23 (m, 1 H), 2.93-2.99 (m, 1 H), 2.23 (s, 1 H), 1.52 (s, 3 H), 1.46 (s, 3 H).

[0132] <Example 13>: Synthesis of (S)-6-(3-(4-chlorophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0174-01)

[0133] [ka] CDI (88 mg, 0.54 mmol) was added to a stirred solution of compound 0097-5b (60 mg, 0.27 mmol) in DMF (5 ml). The mixture was stirred at room temperature for 30 minutes, and then 4-chloro-N'-hydroxybenzimidoamide (96 mg, 0.54 mmol) was added. The mixture was stirred at 120°C for 3 hours. After the starting material was consumed (confirmed by LC-MS), the reaction mixture was concentrated under vacuum and purified by preparative HPLC to obtain product SMS21032-0174-01 (21 mg, yield 21.8%) as a white solid.

[0134] Agilent LC-MS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 0.7 minutes. Purity: 98.47%, Rt = 2.191 mins; MS (calculated): 357.79; MS (measured): 358.3 [M+H] + .

[0135] Agilent HPLC 1200, column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity: 99.79%, Rt = 10.470 min.

[0136] 1 H NMR (400 MHz, CDCl3) δ 8.95 (d, J = 1.6 Hz, 1 H), 8.22 (s, 1 H), 8.09 (d, J = 8.4 Hz, 2 H), 7.49 (d, J = 8.4 Hz, 2 H), 3.97 (t, J = 5.2 Hz, 1 H), 3.18-3.23 (m, 1 H), 2.93-2.99 (m, 1 H), 1.97 (br, 1 H), 1.51 (s, 3 H), 1.46 (s, 3 H.).

[0137] <Example 14>: Synthesis of (R)-2,2-dimethyl-6-(3-(thiazole-2-yl)-1,2,4-oxadiazole-5-yl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0182-01).

[0138] [ka] CDI (59 mg, 0.36 mmol) was added to a stirred solution of compound 0097-5a (40 mg, 0.18 mmol) in DMF (5 ml). The mixture was stirred at room temperature for 30 minutes, and then 154-2 (52 mg, 0.36 mmol) was added. The mixture was stirred at 130°C for 16 hours. After the starting material was consumed (confirmed by LC-MS), the reaction mixture was concentrated under vacuum and purified by preparative HPLC to obtain product SMS21032-0182-01 (7.2 mg, yield 12%) as a white solid.

[0139] Agilent LC-MS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 0.7 minutes. Purity: 98.63%, Rt = 1.598 min; MS (calculated): 330.36; MS (measured): 331.3 [M+H] + .

[0140] Agilent HPLC 1200, column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity: 96.44%, Rt = 7.244 min.

[0141] 1 H NMR (400 MHz, CDCl3) δ 9.03 (d, J = 2.4 Hz, 1 H), 8.31-8.32 (m, 1 H), 8.10 (d, J = 3.2 Hz, 1 H), 7.62 (d, J = 3.2 Hz, 1 H), 3.97 (t, J = 5.2 Hz, 1 H), 3.17-3.23 (m, 1 H), 2.93-2.98 (m, 1 H), 1.51 (s, 3 H), 1.47 (s, 3 H). <Example 15>: Synthesis of 5-bromo-N'-hydroxythiophene-2-carboximamide [ka] Compound 0123-1 (200 mg, 1.07 mmol) and hydroxylamine hydrochloride (150 mg, 2.14 mmol) were stirred in EtOH (10 ml), to which TEA (325 mg, 3.21 mmol) was added. The mixture was refluxed for 1 hour. After the starting materials were consumed (confirmed by LC-MS), the reaction solution was concentrated under vacuum. The residue was extracted with ethyl acetate, the organic phases were combined and dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain product 0123-2 (200 mg, yield 85%) as a white solid.

[0142] <Example 16>: Synthesis of (S)-2,2-dimethyl-6-(3-(thiazole-2-yl)-1,2,4-oxadiazole-5-yl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0183-01). [ka] CDI (59 mg, 0.36 mmol) was added to a stirred solution of compound 0097-5b (40 mg, 0.18 mmol) in DMF (5 ml). The mixture was stirred at room temperature for 30 minutes, and then N'-hydroxythiazole-2-carboximidoamide (52 mg, 0.36 mmol) was added. The mixture was stirred at 130°C for 16 hours. After the starting material was consumed (confirmed by LC-MS), the reaction mixture was concentrated under vacuum and purified by preparative HPLC to obtain product SMS21032-0183-01 (22 mg, yield 37%) as a white solid.

[0143] Agilent LC-MS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 0.7 minutes. Purity: 99.02%, Rt = 1.597 mins; MS (calculated): 330.36; MS (measured): 331.4 [M+H] + .

[0144] Agilent HPLC 1200, column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity: 94.10%, Rt = 7.258 min.

[0145] 1 H NMR (400 MHz, CDCl3) δ 9.03 (d, J = 2.4 Hz, 1 H), 8.30-8.31 (m, 1 H), 8.10 (d, J = 3.2 Hz, 1 H), 7.62 (d, J = 3.2 Hz, 1 H), 3.97 (t, J = 5.2 Hz, 1 H), 3.17-3.23 (m, 1 H), 2.92-2.98 (m, 1 H), 1.50 (s, 3 H), 1.47 (s, 3 H)

[0146] <Example 17>: Synthesis of (R)-2,2-dimethyl-6-(3-(1-methyl-1H-pyrazole-3-yl)-1,2,4-oxadiazole-5-yl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0184-01). [ka] CDI (59 mg, 0.36 mmol) was added to a stirred solution of compound 0097-5a (40 mg, 0.18 mmol) in DMF (5 ml). The mixture was stirred at room temperature for 30 minutes, and then 158-2 (51 mg, 0.36 mmol) was added. The mixture was stirred at 120°C for 3 hours. After the starting material was consumed (confirmed by LC-MS), the reaction mixture was concentrated under vacuum and purified by preparative HPLC to obtain product SMS21032-0184-01 (16 mg, yield 27%) as a white solid.

[0147] Agilent LC-MS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 0.7 minutes. Purity: 97.38%, Rt = 1.492 mins; MS (calculated): 327.34; MS (measured): 328.3 [M+H] + .

[0148] Agilent HPLC 1200, column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed back to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity: 100%, Rt = 6.715 min.

[0149] 1 H NMR (400 MHz, CDCl3) δ 9.03 (d, J = 2.4 Hz, 1 H), 8.31-8.32 (m, 1 H), 7.49 (d, J = 2.0 Hz, 1 H), 6.90 (d, J = 2.4 Hz, 1 H), 4.05 (s, 3 H), 3.96 (t, J = 5.2 Hz, 1 H), 3.15-3.21 (m, 1 H), 2.90-2.96 (m, 1 H), 1.49 (s, 3 H), 1.46 (s, 3 H).

[0150] <Example 18>: Synthesis of (S)-2,2-dimethyl-6-(3-(1-methyl-1H-pyrazole-3-yl)-1,2,4-oxadiazole-5-yl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0185-01). [ka] CDI (59 mg, 0.36 mmol) was added to a stirred solution of compound 0097-5b (40 mg, 0.18 mmol) in DMF (5 ml). The mixture was stirred at room temperature for 30 minutes, and then 158-2 (51 mg, 0.36 mmol) was added. The mixture was stirred at 120°C for 3 hours. After the starting material was consumed (confirmed by LC-MS), the reaction mixture was concentrated under vacuum and purified by preparative HPLC to obtain product SMS21032-0185-01 (11 mg, yield 18.6%) as a white solid.

[0151] Agilent LC-MS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 0.7 minutes. Purity: 97.12%, Rt = 1.492 mins; MS (calculated): 327.34; MS (measured): 328.4 [M+H] + .

[0152] Agilent HPLC 1200, column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed back to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity: 100%, Rt = 6.701 min.

[0153] 1 H NMR (400 MHz, CDCl3) δ 9.03 (d, J = 2.4 Hz, 1 H), 8.30-8.31 (m, 1 H), 7.49 (d, J = 2.4 Hz, 1 H), 6.90 (d, J = 2.4 Hz, 1 H), 4.05 (s, 3 H), 3.93-3.98 (m, 1 H), 3.15-3.21 (m, 1 H), 2.90-2.96 (m, 1 H), 1.90 (d, J = 6.0 Hz, 1 H), 1.49 (s, 3 H), 1.46 (s, 3 H).

[0154] <Example 19>: Synthesis of (S)-6-(3-(4-chlorophenyl)-1,2,4-oxadiazole-5-yl)-3-methoxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine (SMS21032-0187-01). [ka] NaH (13 mg, 0.51 mmol) was gradually added to a stirred solution of compound SMS21032-0174 (60 mg, 0.17 mmol) and CH3I (121 mg, 0.85 mmol) in THF. The mixture was stirred at room temperature for 2 hours. After the starting materials were consumed (confirmed by LC-MS), water was added, the reaction solution was extracted with ethyl acetate, the organic phases were combined and dehydrated with anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by preparative HPLC to obtain product SMS21032-0187-01 (37 mg, yield 59%) as a white solid.

[0155] Agilent LC-MS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 0.7 minutes. Purity: 100%, Rt = 2.461 mins; MS (calculated): 371.82; MS (measured): 372.2 [M+H] + .

[0156] Agilent HPLC 1200, column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity: 100%, Rt = 11.848 mins.

[0157] 1H NMR (400 MHz, CDCl3) δ 8.97 (d, J = 2.4 Hz, 1 H), 8.23-8.24 (m, 1 H), 8.09-8.11 (m, 2 H), 7.48-7.51 (m, 2 H), 3.47 (s, 3 H), 3.44-3.45 (m, 1 H), 3.14-3.19 (m, 1 H), 2.93-2.99 (m, 1 H), 1.49 (s, 3 H), 1.45 (s, 3 H).

[0158] <Example 20>: Synthesis of (S)-6-(3-(4-fluorophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0190)

[0159] [ka] CDI (174.39 mg, 1.08 mmol) was added to a solution of 0097-5b (120 mg, 0.54 mmol) in DMF (5 mL). The resulting solution was stirred at rt for 30 minutes, and then (Z)-4-fluoro-N'-hydroxybenzimidoamide (124.29 mg, 0.81 mmol) was added to the mixture. This mixture was heated at 120°C for 3 hours. After the starting material was consumed, the mixture was filtered and concentrated. The residue was purified by preparative HPLC to obtain SMS21032-0190 (43 mg, yield 23.41%) as a white solid.

[0160] Agilent LC-MS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, then under these conditions for 0.7 minutes; Purity: 99.10%, Rt = 2.041 minutes; MS (measured value): 342.3 [M+H] + .

[0161] Agilent HPLC 1200, Column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.0mL / min; Mobile phase: Changed from 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, under these conditions for 5 minutes. Purity: 99.14%, Rt = 9.643 minutes.

[0162] 1 H NMR (400 MHz, CDCl3) δ 8.95 (d, J = 2.4 Hz, 1 H), 8.21-8.22 (m, 1 H), 8.13-8.17 (m, 2 H), 7.17-7.22 (m, 2 H), 3.97 (s, 1 H), 3.18-3.23 (m, 1 H), 2.93-2.99 (m, 1 H), 2.08 (s, 1 H), 1.51 (s, 3 H), 1.46 (s, 3 H).

[0163] <Example 21>: Synthesis of N'-hydroxy-4-methylbenzimidoamide (0191-2). [ka] Compound 0191-1 (500 mg, 4.27 mmol) and hydroxylamine hydrochloride (594 mg, 8.54 mmol) were stirred in EtOH (10 ml), to which TEA (1.3 g, 12.81 mmol) was added. The mixture was refluxed for 1 hour. After the starting materials were consumed (confirmed by LC-MS), the reaction solution was concentrated under vacuum. The residue was extracted with ethyl acetate, the organic phase was combined and dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain product 0191-2 (510 mg, yield 79.7%) as a pale yellow liquid.

[0164] Synthesis of (S)-2,2-dimethyl-6-(3-p-tolyl-1,2,4-oxadiazole-5-yl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0191-01).

[0165] [ka] CDI (75 mg, 0.46 mmol) was added to a stirred solution of compound 0097-5b (50 mg, 0.23 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 30 minutes, and then 0191-2 (69 mg, 0.46 mmol) was added. The mixture was stirred at 120 °C for 3 hours. After the starting material was consumed (confirmed by LC-MS), the reaction mixture was concentrated under vacuum and purified by preparative HPLC to obtain product SMS21032-0191-01 (45 mg, yield 58%) as a white solid.

[0166] Agilent LC-MS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 0.7 minutes. Purity: 100%, Rt = 2.155 mins; MS (calculated): 337.37; MS (measured): 338.1 [M+H]+ .

[0167] Agilent HPLC 1200, column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity: 99.74%, Rt = 10.194 min.

[0168] 1 H NMR (400 MHz, CDCl3) δ 8.95 (d, J = 2.0 Hz, 1 H), 8.21-8.22 (m, 1 H), 8.02 (d, J = 8.0 Hz, 2 H), 7.30 (d, J = 8.0 Hz, 2 H), 3.95 (t, J = 5.2 Hz, 1 H), 3.16-3.22 (m, 1 H), 2.92-2.98 (m, 1 H), 2.43 (s, 3 H), 1.49 (s, 3 H), 1.45 (s, 3 H).

[0169] <Example 22>: Synthesis of (Z)-3,4-dichloro-N'-hydroxybenzimidoamide (0192-2). [ka] To a solution of 0192-1 (1 g, 5.81 mmol) in ethanol (15 ml), NH2OH-HCl (808 mg, 11.63 mmol) and TEA (3.2 mL) were added. The mixture was heated and refluxed for 3 hours. After the starting material was consumed (confirmed by LC-MS), the solvent was removed, water (100 mL) was added, and then the mixture was extracted with dichloromethane. The organic phases were combined and dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 0192-2 (600 mg, yield: 50%) as a white solid.

[0170] Synthesis of (S)‐6‐(3‐(3,4‐dichlorophenyl)‐1,2,4‐oxadiazol‐5‐yl)‐2,2‐dimethyl‐3,4‐dihydro‐2H‐pyrano[2,3‐b]pyridin‐3‐ol (SMS21032‐0192‐01).

[0171]

Chemical Structure

[0172] Agilent LCMS 1200‐6120, column: Waters X‐Bridge C18 (50 mm*4.6 mm*3.5 μm); column temperature: 40°C; flow rate: 2.0 mL / min; mobile phase: changed from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] over 1.6 minutes, then maintained under this condition for 1.4 minutes, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] over 0.1 minutes, and maintained under this condition for 0.7 minutes. Purity: 99.18%, Rt=2.359 min; MS (calculated): 391.1; MS (found): 392.2 [M+H] + .

[0173] Agilent HPLC 1200, column: Waters X-Bridge C18 (150 mm*4.6 mm*3.5 μm); column temperature: 40°C; flow rate: 1.0 mL / min; mobile phase: gradient elution from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] over 10 minutes, then holding under this condition for 5 minutes, finally changing back to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minute, and holding under this condition for 5 minutes. Purity: 99.38%, Rt=11.393 min.

[0174] 1 H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 2.4 Hz, 1 H), 8.33 (d, J = 2.0 Hz, 1 H), 8.26 (d, J = 2.0 Hz, 1 H), 8.06 (dd, J = 8.4 Hz, 2.0 Hz, 1 H), 7.90 (d, J = 8.4 Hz, 1 H), 5.40 (d, J = 4.8 Hz, 1 H), 3.76-3.80 (m, 1 H), 3.13 (dd, J = 16.8 Hz, 4.8 Hz, 1 H), 2.83 (dd, J = 17.2 Hz, 6.0 Hz, 1 H), 1.34 (s, 6 H).

[0175] <Example 23>: Synthesis of (S)-6-(3-(5-chlorothiazol-2-yl)-1,2,4-oxadiazol-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-3-ol (SMS21032-0193)

Chemical formula

[0176] [ka] To a solution of 193-1 (1 g, 6.36 mmol) in THF (20 mL), n-BuLi (3.1 mL, 2.5 M hexane solution) was added dropwise at -78°C. After the addition was complete, the mixture was stirred at -78°C for 30 minutes, then CCl4 (3.1 mL) was added dropwise over 5 minutes, and the mixture was stirred at 0°C for 2 hours. The mixture was quenched with water (20 mL), extracted with EA (35 mL x 2), and the EA phase was dehydrated with Na2SO4. The filtrate was filtered and concentrated to obtain an oily substance, which was purified with CC (EA:PE = 1:4) to obtain 193-2 (0.9 g, yield: 75%) as a yellow liquid.

[0177] [ka] To a solution of 193-2 (0.91 g, 4.75 mmol) in THF (10 mL), HCl (2 N, 5 mL) was added, and the mixture was refluxed for 8 hours. EA (40 mL) was added, and the mixture was washed with water (30 mL) and saturated NaHCO3 (40 mL x 2), and dehydrated with Na2SO4. The mixture was filtered, and the filtrate was concentrated to obtain an oily substance, which was purified by CC (EA:PE = 1:10) to obtain 193-3 (0.35 g, yield: 50%) as a yellow liquid.

[0178] [ka] To a solution of 193-3 (350 mg, 2.37 mmol) in EtOH (10 mL), hydroxylamine hydrochloride (247 mg, 3.56 mmol) and pyridine (1.88 g, 23.72 mmol) were added at room temperature, and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated to obtain an oily substance, diluted with EA (20 mL), washed with brine (15 mL), and dehydrated with Na2SO4. The filtrate was filtered and concentrated to obtain 193-4 (371 mg, yield: 96%) as a brown solid.

[0179] [ka] To a solution of 193-4 (340 mg, 2.09 mmol) in THF (3 mL), CDI (452 ​​mg, 3.14 mmol) was added at room temperature, and the mixture was stirred at room temperature for 5 hours. The mixture was diluted with EA (40 mL), washed with brine (20 mL), and dehydrated with Na2SO4. The mixture was filtered, and the filtrate was concentrated to obtain 193-5 (250 mg, yield: 83%) as a yellow oil.

[0180] [ka] To a solution of 193-5 (250 mg, 1.73 mmol) in EtOH (15 mL), hydroxylamine hydrochloride (144 mg, 2.07 mmol) and TEA (700 mg, 6.92 mmol, 964.02 μL) were added, and the mixture was refluxed for 2 hours. The mixture was concentrated to obtain a solid, diluted with EA (80 mL), washed with water (10 mL), and dehydrated with Na2SO4. The filtrate was filtered and concentrated to obtain 193-6 (235 mg, yield: 77%) as a brown solid.

[0181] [ka] To a solution of 0097-5b (60 mg, 269 umol) in DMF (3 mL) was added HATU (112 mg, 296 umol) at room temperature, followed by 193-6 (53 mg, 296 umol) and DIPEA (52 mg, 403 umol), and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (20 mL), extracted with EA (20 mL), and the EA phase was washed with brine (20 mL) and dried over Na2SO4. Filtration and concentration gave 193-7 (70 mg, yield: 68%) as a yellow oil.

[0182]

Chemical Formula

[0183] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50 mm * 4.6 mm * 3.5 μm); column temperature: 40°C; flow rate: 2.0 mL / min; mobile phase: changed from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] over 1.6 minutes, then held under this condition for 1.4 minutes, finally changed back to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] over 0.1 minute and held under this condition for 0.7 minute), purity: 100%, Rt = 1.866 min; MS (calculated): 364.0; MS (observed): 365.0 [M+H] + .

[0184] Agilent HPLC 1200, Column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.0 mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed back to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity: 100%, Rt = 8.528 mins. MS (calculated): 364.0; MS (measured): 365.2 [M+H] + .

[0185] 1 H NMR (400 MHz, CDCl3) δ 9.00 (d, J = 2.4 Hz, 1H), 8.26-8.29 (m, 1H), 7.88 (s, 1H), 3.94-3.99 (m, 1H), 3.19 (dd, J= 16.8, 4.8 Hz, 1H), 2.95 (dd, J = 17.0, 5.8 Hz, 1H), 1.92 (d, J = 6.0 Hz, 1H), 1.50 (s, 3H), 1.47 (s, 3H).

[0186] <Example 24>: Synthesis of (S)-2,2-dimethyl-6-(3-(5-methylthiazole-2-yl)-1,2,4-oxadiazole-5-yl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0194) [ka] To a solution of 5-methylthiazole (500 mg, 5.0 mmol) in THF (5 mL), n-BuLi (2 mL) was added dropwise at -78°C. The mixture was then stirred at -78°C for 10 minutes, DMF (553 mg, 7.6 mmol) was added, and the mixture was stirred at -78°C for 10 minutes. The mixture was then warmed to room temperature and stirred for 2 hours. The mixture was quenched with saturated NH4Cl and extracted with EA (30 mL). The EA phase was dehydrated with Na2SO4. The mixture was filtered, and the filtrate was concentrated to obtain an oily substance. Purification by CC (EA:PE = 1:8) yielded 194-1 (32 mg, yield: 50%) as a yellow oil.

[0187] [ka] To a solution of 194-1 (50 mg, 393 umol) in EtOH (1 mL), pyridine (0.2 mL) and hydroxylamine hydrochloride (55 mg, 786 umol) were added at room temperature, and the mixture was stirred at room temperature for 16 hours. The solution was diluted with water (10 mL), extracted with EA (15 mL x 2), and the EA phase was dehydrated with Na2SO4. The solution was filtered, and the filtrate was concentrated to obtain 194-2 (51 mg, yield: 91%) as a white solid.

[0188] [ka] To a solution of 194-2 (50 mg, 352 umol) in DCM (3 mL), CDI (68 mg, 422 umol) was added, and the mixture was stirred at room temperature for 16 hours. The solution was diluted with water (10 mL), extracted with DCM (20 mL), and dehydrated with Na2SO4. The solution was filtered and concentrated to obtain 194-3 (30 mg, yield: 69%) as a yellow liquid.

[0189] [ka] To a solution of 194-3 (40 mg, 322 umol) in EtOH (5 mL), hydroxylamine hydrochloride (45 mg, 644 umol) and TEA (33 mg, 322 umol) were added, and the mixture was refluxed for 2 hours. The mixture was concentrated to obtain a solid, diluted with EA (10 mL), then filtered, and the solid was washed with EA. The filtrate was concentrated to obtain 194-4 (25 mg, yield: 49%) as a white solid.

[0190] [ka] To a solution of 0097-5b (60 mg, 269 umol) in DMF (1 mL), HATU (112 mg, 296 umol) was added at room temperature, followed by the addition of 194-4 (47 mg, 296 umol) and DIPEA (52 mg, 403 umol). The mixture was stirred at room temperature for 16 hours. The solution was diluted with water (10 mL), extracted with EA (20 mL), the EA phase was washed with brine (20 mL), and dehydrated with Na2SO4. The solution was filtered and concentrated to obtain 194-5 (80 mg, yield: 82%) as a yellow oily substance.

[0191] [ka] A solution of 194-5 (80 mg, 221 umol) in DMF (2 mL) was heated at 125°C for 8 hours. The solution was diluted with water (10 mL), extracted with EA (20 mL), the EA phase was washed with brine (20 mL), and dehydrated with Na2SO4. The solution was filtered and concentrated to obtain an oily substance, which was purified by preparative HPLC to obtain SMS21032-0194 (10 mg, yield: 13%) as a white solid.

[0192] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 μm); column temperature: 40°C; flow rate: 2.0 mL / min; mobile phase: linear gradient from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] over 1.6 min, hold at this condition for 1.4 min, then change back to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] over 0.1 min, hold at this condition for 0.7 min), purity: 100%, Rt=1.705 min; MS (calculated): 344.1; MS (found): 345.1 [M+H] + .

[0193] Agilent HPLC 1200, column: Waters X-Bridge C18 (150 mm*4.6 mm*3.5 μm); column temperature: 40°C; flow rate: 1.0 mL / min; mobile phase: linear gradient from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] over 10 min, hold at this condition for 5 min, then change back to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] over 0.1 min, hold at this condition for 5 min. Purity: 100%, Rt=7.587 min. MS (calculated): 344.1; MS (found): 345.2 [M+H] + .

[0194] 1 H NMR (400 MHz, CDCl3) δ 9.01 (d, J = 2.4 Hz, 1H), 8.28-8.30 (m, 1H), 7.74 (d, J = 1.2 Hz, 1H), 3.93-3.99 (m, 1H), 3.19 (dd, J = 17.2, 4.8 Hz, 1H), 2.94 (dd, J = 17.0, 5.8 Hz, 1H), 2.60 (d, J = 1.2 Hz, 3H), 1.95 (d, J = 6.0 Hz, 1H), 1.50 (s, 3H), 1.46 (s, 3H).

[0195] <Example 25>: Synthesis of (R)-6-(3-(5-chlorothiazol-2-yl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0197)

[0196] [ka] 0097-5a (50 mg, 224 umol) was added to DMF (3 mL) with EDC (56 mg, 291 umol) and DMAP (3 mg, 22 umol) at room temperature, then 193-6 (44 mg, 246 umol) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (20 mL), extracted with EA (20 mL), the EA phase was washed with brine (20 mL), and dehydrated with Na2SO4. The mixture was filtered and concentrated to obtain 197-1 (55 mg, yield: 64%) as a yellow oil.

[0197] [ka] A solution of 197-1 (55 mg, 144 umol) in DMF (2 mL) was heated at 125°C for 6 hours. The solution was diluted with water (10 mL), extracted with EA (20 mL), the EA phase was washed with brine (20 mL), and dehydrated with Na2SO4. The solution was filtered and concentrated to obtain an oily substance, which was purified by preparative HPLC to obtain SMS21032-0197 (10 mg, yield: 19%) as a yellow solid.

[0198] LC-MS (Agilent LCMS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 0.7 minutes), Purity: 100%, Rt = 1.909 min; MS (calculated value): 364.0; MS (measured value): 365.1 [M+H]+ .

[0199] Agilent HPLC 1200, Column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.0 mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed back to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity: 100%, Rt = 8.516 mins. MS (calculated): 364.0; MS (measured): 365.2 [M+H] + .

[0200] 1 H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 2.0 Hz, 1H), 8.19-8.22 (m, 1H), 7.81 (s, 1H), 3.87-3.92 (m, 1H), 3.12 (dd, J= 17.0, 4.6 Hz, 1H), 2.88 (dd, J = 17.2, 6.0 Hz, 1H), 1.90 (d, J = 6.0 Hz, 1H), 1.43 (s, 3H), 1.40 (s, 3H).

[0201] <Example 26>: Synthesis of (R)-2,2-dimethyl-6-(3-(5-methylthiazole-2-yl)-1,2,4-oxadiazole-5-yl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0198) [ka] To a solution of 0097-5a (50 mg, 224 umol) in DMF (5 mL), CDI (44 mg, 269 umol) was added, followed by 194-4 (35 mg, 224 umol), and the mixture was heated at 120°C for 3 hours. The mixture was diluted with water (10 mL), extracted with EA (20 mL), the EA phase was washed with brine (20 mL), and dehydrated with Na2SO4. The mixture was filtered and concentrated to obtain an oily substance, which was purified by preparative HPLC to obtain SMS21032-0198 (7 mg, yield: 9%) as a white solid.

[0202] Agilent LC-MS1200-6110, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.05 minutes, and under these conditions for 0.7 minutes. Purity: 99.6%, Rt = 1.583 mins; MS (calculated): 344.1; MS (measured): 345.3 [M+H] + .

[0203] Agilent HPLC 1200, Column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.0 mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed back to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity: 100%, Rt = 7.548 mins. MS (calculated): 344.1; MS (measured): 345.2 [M+H] + .

[0204] 1H NMR (400 MHz, CDCl3) δ 9.01 (d, J = 2.4 Hz, 1H), 8.28-8.31 (m, 1H), 7.74 (d, J = 1.2 Hz, 1H), 3.94-3.99 (m, 1H), 3.19 (dd, J = 17.2, 4.8 Hz, 1H), 2.94 (dd, J = 17.0, 5.8 Hz, 1H), 2.60 (d, J = 0.8 Hz, 3H), 1.92 (d, J = 6.0 Hz, 1H), 1.50 (s, 3H), 1.46 (s, 3H).

[0205] <Example 27>: Synthesis of (R)-6-(3-(4-chlorothiazol-2-yl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0199) [ka] To a solution of 4-chlorothiazole (1.0 g, 8.36 mmol) in THF (15 mL), n-BuLi (4 mL) was added dropwise at -78°C. The mixture was then stirred at -78°C for 10 minutes, DMF (673 mg, 9.20 mmol) was added, and the mixture was stirred at -78°C for 10 minutes. The mixture was then warmed to room temperature and stirred for 2 hours. The mixture was quenched with water (20 mL), extracted with EA (35 mL x 2), and the EA phase was dehydrated with Na2SO4. The mixture was filtered, and the filtrate was concentrated to obtain an oily substance. Purification by CC (EA:PE = 1:10) yielded 199-1 (371 mg, yield: 30%) as a white solid.

[0206] [ka] To a solution of 199-1 (370 mg, 2.51 mmol) in EtOH (10 mL), hydroxylamine hydrochloride (261 mg, 3.76 mmol) and pyridine (1.98 g, 25.07 mmol) were added at room temperature, and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated to obtain an oily substance, diluted with EA (50 mL), washed with brine (25 mL), and dehydrated with Na2SO4. The mixture was filtered, and the filtrate was concentrated to obtain 199-2 (270 mg, yield: 66%) as a white solid.

[0207] [ka] To a solution of 199-2 (240 mg, 1.48 mmol) in THF (10 mL), CDI (359 mg, 2.21 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with EA (35 mL), washed with brine (20 mL), and dehydrated with Na2SO4. The solution was filtered, and the filtrate was concentrated to obtain 199-3 (200 mg, yield: 94%) as a yellow liquid.

[0208] [ka] To a solution of 199-3 (200 mg, 1.38 mmol) in EtOH (10 mL), hydroxylamine hydrochloride (115 mg, 1.66 mmol) and TEA (560 mg, 5.53 mmol) were added, and the mixture was refluxed for 2 hours. The mixture was concentrated to obtain a solid, diluted with EA (80 mL), washed with water (10 mL), and the EA phase was dehydrated with Na2SO4. The mixture was filtered, and the filtrate was concentrated to obtain 199-4 (210 mg, yield: 85%) as a yellow solid.

[0209] [ka] To a solution of 0097-5a (60 mg, 269 umol) in DMF (1 mL), EDC (62 mg, 323 umol) and DMAP (3 mg, 27 umol) were added at room temperature. The mixture was stirred at room temperature for 15 minutes, then 199-4 (46 mg, 296 umol) was added, and the mixture was stirred at room temperature for 16 hours. The solution was diluted with water (10 mL), extracted with EA (20 mL), the EA phase was washed with brine (20 mL), and dehydrated with Na2SO4. The solution was filtered and concentrated to obtain 199-5 (65 mg, yield: 67%) as a yellow oil.

[0210] [ka] A solution of 199-5 (65 mg, 179 umol) in DMF (3 mL) was heated at 125°C for 6 hours. The solution was diluted with water (10 mL), extracted with EA (20 mL), the EA phase was washed with brine (20 mL), and dehydrated with Na2SO4. The solution was filtered and concentrated to obtain an oily substance, which was purified by preparative HPLC to obtain SMS21032-0199 (10 mg, yield: 16%) as a white solid.

[0211] LC-MS (Agilent LCMS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 0.7 minutes), Purity: 100%, Rt = 1.826 min; MS (calculated value): 364.0; MS (measured value): 365.0 [M+H] + .

[0212] Agilent HPLC 1200, Column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.0 mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed back to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity: 100%, Rt = 8.140 mins. MS (calculated): 364.0; MS (measured): 365.2 [M+H] + .

[0213] 1 H NMR (400 MHz, CDCl3) δ 8.93 (d, J = 2.4 Hz, 1H), 8.20-8.23 (m, 1H), 7.31 (s, 1H), 3.86-3.93 (m, 1H), 3.13 (dd, J= 17.0, 4.6 Hz, 1H), 2.88 (dd, J = 17.0, 5.8 Hz, 1H), 1.89 (d, J = 6.0 Hz, 1H), 1.44 (s, 3H), 1.40 (s, 3H).

[0214] <Example 28>: Synthesis of (S,E)-4-chloro-N'-(3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-6-carbonyloxy)thiazole-2-carboximidoamide (200-1) [ka] To a solution of 0097-5b (60 mg, 269 umol) in DMF (1 mL), EDC (62 mg, 323 umol) and DMAP (3 mg, 27 umol) were added at room temperature. The mixture was stirred at room temperature for 15 minutes, then 199-4 (46 mg, 296 umol) was added, and the mixture was stirred at room temperature for 16 hours. The solution was diluted with water (10 mL), extracted with EA (20 mL), the EA phase was washed with brine (20 mL), and dehydrated with Na2SO4. The solution was filtered and concentrated to obtain 200-1 (60 mg, yield: 62%) as a yellow oil.

[0215] Synthesis of (S)-6-(3-(4-chlorothiazol-2-yl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0200)

[0216] [ka] A solution of 199-5 (60 mg, 165 umol) in DMF (3 mL) was heated at 125°C for 6 hours. The solution was diluted with water (10 mL), extracted with EA (20 mL), the EA phase was washed with brine (20 mL), and dehydrated with Na2SO4. The solution was filtered and concentrated to obtain an oily substance, which was purified by preparative HPLC to obtain SMS21032-0200 (9 mg, yield: 16%) as a white solid.

[0217] LC-MS (Agilent LCMS1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 0.7 minutes), Purity: 100%, Rt = 1.833 min; MS (calculated value): 364.0; MS (measured value): 365.0 [M+H] + .

[0218] Agilent HPLC 1200, Column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.0 mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed back to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, and under these conditions for 5 minutes. Purity: 100%, Rt = 8.135 mins. MS (calculated): 364.0; MS (measured): 365.2 [M+H] + .

[0219] 1 H NMR (400 MHz, CDCl3) δ 9.00 (d, J = 2.0 Hz, 1H), 8.27-8.30 (m, 1H), 7.38 (s, 1H), 3.94-3.99 (m, 1H), 3.20 (dd, J= 17.0, 4.6 Hz, 1H), 2.95 (dd, J = 17.0, 5.8 Hz, 1H), 1.91 (d, J = 5.6 Hz, 1H), 1.50 (s, 3H), 1.47 (s, 3H).

[0220] <Example 29>: Synthesis of 1-ethyl-1H-pyrazole-3-carbonitrile (201-1) [ka] To a stirred solution of 201-0 (1.0 g, 10.74 mmol) in DMF (10 mL), iodoethane (2.01 g, 12.89 mmol) and Cs2CO3 (6.99 g, 21.48 mmol) were added. The mixture was stirred at rt for 3 hours. After the reaction was complete, the mixture was quenched with water and then extracted with EA (30 mL x 3). The organic layer was separated, dehydrated with Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / SiO5 = 1 / 1) to obtain 201-1 (1.1 g, yield 84.62%) as a white solid. Synthesis of (Z)-1-ethyl-N'-hydroxy-1H-pyrazole-3-carboximidoamide (201-2)

[0221] [ka] To a solution of 201-1 (1.1 g, 9.08 mmol) in EtOH (10 mL), NH2OH·HCl (946.45 mg, 13.62 mmol) and TEA (2.76 g, 27.24 mmol) were added. The resulting reaction mixture was stirred at 80°C for 2 hours. Water (30 mL) was then added, the aqueous phase was extracted with ethyl acetate (40 mL x 3), the organic phase was combined and washed with water (50 mL x 3), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 201-2 (1.3 g, yield 92.92%) as a white solid.

[0222] Synthesis of (R)-6-(3-(1-ethyl-1H-pyrazole-3-yl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0201)

[0223] [ka] To a solution of 0097-5a (50 mg, 223.98 umol) in DMF (5 mL), CDI (72.63 mg, 447.96 umol) and 201-2 (51.80 mg, 335.97 umol) were added. The resulting solution was stirred at rt for 30 minutes, and then the mixture was heated at 120°C for 3 hours. After the starting materials were consumed, the mixture was filtered off. The filtrate was purified by preparative HPLC to obtain SMS21032-0201 (20.5 mg, yield 26.81%) as a white solid.

[0224] Agilent LC-MS 1200-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 100% [CH3CN] in 1.6 minutes, then under these conditions for 1.4 minutes, and finally changed to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, then under these conditions for 0.7 minutes; Purity: 99.62%, Rt = 1.660 minutes; MS (measured value): 342.3 [M+H] + .

[0225] Agilent HPLC 1200, Column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.0mL / min; Mobile phase: Changed from 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 10 minutes, then under these conditions for 5 minutes, and finally changed back to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, under these conditions for 5 minutes, purity: 100%, Rt = 7.583 minutes.

[0226] 1 H NMR (400 MHz, CDCl3) δ 9.01 (d, J = 2.4 Hz, 1 H),8.29-8.30 (m, 1 H), 7.51 (d, J = 2.4 Hz, 1 H), 6.89 (d, J = 2.0 Hz, 1 H), 4.32 (q, J = 7.2 Hz, 2 H), 3.94 (t, J = 5.6 Hz, 1 H), 3.17 (dd, J = 11.6 Hz, J = 5.2 Hz, 1 H ), 2.92 (dd, J = 16.8 Hz, J = 6.0 Hz, 1 H), 2.00 (br, 1 H), 1.54 (t, J = 7.2 Hz, 3 H), 1.47 (d, J = 12.8 Hz, 6 H).

[0227] <Example 30>: Synthesis of (S)-6-(3-(3-chlorophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0211-01) [ka] Na2CO3 (847.59 mg, 8.00 mmol) was added to a mixture of 3-chlorobenzonitrile (500.0 mg, 3.63 mmol, 438.60 μL) and NH2OH·HCl (1.00 g, 14.54 mmol) in EtOH (10 mL) and H2O (5 mL). The mixture was stirred at 90°C for 1 hour. LC-MS showed that NBK0071-2-R1 was completely consumed. The purity on LC-MS was ~87%. The mixture was filtered and the filtrate was concentrated under vacuum. 3-chloro-N'-hydroxy-benzamidine (1.65 g, 3.63 mmol, yield 99.79%, purity 37.5%) was obtained as a pale yellow solid. Some salts remained in this solid. The product was used in the next reaction without purification.

[0228] [ka] CDI (77.38 mg, 537.57 umol) was added to a mixture of (3S)-3-hydroxy-2,2-dimethyl-3,4-dihydropyrano[2,3-b]pyridine-6-carboxylate (60.0 mg, 268.79 umol) in DMF (3 mL). The mixture was stirred at 20°C for 1 hour. Then, 3-chloro-N'-hydroxy-benzamidine (244.56 mg, 537.57 umol) was added to the mixture. The temperature was raised to 120°C and stirred at this temperature for 3 hours. LC-MS (NBK0071-6-P1-1) showed that the desired product had been formed. The mixture was combined with NBK0071-4. The mixture was filtered and purified by preparative HPLC. (3S)-6-[3-(3-chlorophenyl)-1,2,4-oxadiazole-5-yl]-2,2-dimethyl-3,4-dihydropyrano[2,3-b]pyridine-3-ol (38 mg, 106.21 umol, purity 100%) was obtained as a pale yellow solid. Yield: 29.6%.

[0229] Agilent LCMS21500-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.5mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 95% [CH3CN] in 2 minutes, then under these conditions for 4 minutes, and finally changed back to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 2 minutes, then under these conditions for 2 minutes; Purity: 96.35%, Rt = 1.942 mins; MS (measured value): 357.8 [M+H] + .

[0230] Agilent HPLC 1260-03, column: Agilent Eclipse C18 Plus 4.6X100mm 3.5um; column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 14 minutes, then under these conditions for 8 minutes, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, under these conditions for 6 minutes; purity: 99.85%, Rt = 10.279 minutes.

[0231] 1 H NMR (400 MHz, CDCl3) δ 8.95 (d, J = 2.3 Hz, 1H), 8.26 - 8.19 (m, 1H), 8.15 (t, J = 1.7 Hz, 1H), 8.04 (dt, J = 7.5, 1.3 Hz, 1H), 7.53 - 7.40 (m, 2H), 3.97 (dd, J = 10.9, 5.8 Hz, 1H), 3.21 (dd, J = 17.0, 4.8 Hz, 1H), 2.96 (dd, J = 17.0, 5.7 Hz, 1H), 2.01 (d, J = 6.2 Hz, 1H), 1.51 (s, 3H), 1.46 (s, 3H).ESI-MS (M+H+): 357.8

[0232] <Example 31>: Synthesis of (R)-6-(3-(3-chlorophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0212-01) [ka] (3R)-3-hydroxy-2,2-dimethyl-3,4-dihydropyrano[2,3-b]pyridine-6-carboxylate (80 mg, 358.38 umol) and then CDI (103.18 mg, 716.77 umol) were dissolved in DMF (1.5 mL). The mixture was stirred at 25°C for 1 hour. Then, 3-chloro-N'-hydroxy-benzamidine (326.07 mg, 716.77 umol) was added. The mixture was stirred at 120°C for 3 hours. The reaction product was then tested by LC-MS. The results showed that the starting materials had reacted completely. The mixture was then filtered. The crude product was purified by preparative HPLC. (3R)-6-[3-(3-chlorophenyl)-1,2,4-oxadiazole-5-yl]-2,2-dimethyl-3,4-dihydropyrano[2,3-b]pyridine-3-ol (50 mg, 139.75 umol, yield 38.99%) was obtained.

[0233] Agilent LCMS21500-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.5mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 95% [CH3CN] in 2 minutes, then under these conditions for 4 minutes, and finally changed back to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 2 minutes, then under these conditions for 2 minutes; Purity: 98.42%, Rt = 1.970 mins; MS (measured value): 357.8 [M+H] + .

[0234] Agilent HPLC 1260-03, column: Agilent Eclipse C18 Plus 4.6X100mm 3.5um; column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 14 minutes, then under these conditions for 8 minutes, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, under these conditions for 6 minutes; purity: 99.85%, Rt = 10.279 minutes.

[0235] 1 H NMR (400 MHz, CDCl3) δ 8.94 (d, J = 2.3 Hz, 1H), 8.25 - 8.20 (m, 1H), 8.15 (t, J = 1.7 Hz, 1H), 8.03 (dt, J = 7.6, 1.3 Hz, 1H), 7.54 - 7.47 (m, 1H), 7.44 (t, J = 7.8 Hz, 1H), 3.96 (q, J = 5.2 Hz, 1H), 3.21 (dd, J = 17.0, 4.8 Hz, 1H), 2.96 (dd, J = 17.0, 5.7 Hz, 1H), 2.14 (d, J = 5.8 Hz, 1H), 1.51 (s, 3H), 1.46 (s, 3H).

[0236] <Example 32>: Synthesis of (Z)-N'-hydroxyxazole-2-carboximamide (0213-1) [ka] NH2OH (561.28 mg, 8.50 mmol, purity 50%) was added to a mixture of oxazole-2-carbonitrile (0.2 g, 2.13 mmol) in EtOH (5 mL). The mixture was stirred in a sealed tube at 90°C for 1 hour. LC-MS (NBK0071-52-P1-1) showed that the desired product was produced and the purity was 100%. The mixture was concentrated under vacuum. N'-hydroxyxazole-2-carboxamidine (260 mg, 2.05 mmol, yield 96.22%, purity 100%) was obtained as a white solid.

[0237] Synthesis of (S)-2,2-dimethyl-6-(3-(oxazol-2-yl)-1,2,4-oxadiazole-5-yl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0213-01)

[0238] [ka] Di(imidazole-1-yl)methanone (87.17 mg, 537.57 umol) was added to a mixture of (3S)-3-hydroxy-2,2-dimethyl-3,4-dihydropyrano[2,3-b]pyridine-6-carboxylate (60 mg, 268.79 umol) in DMF (3 mL). The mixture was stirred at 25°C for 1 hour. Then, N'-hydroxyxazole-2-carboxamidine (47.83 mg, 376.30 umol) was added to the mixture and stirred at 120°C for 3 hours. LC-MS showed that the desired product was formed. The product was purified by preparative HPLC (base). (3S)-2,2-dimethyl-6-(3-oxazol-2-yl-1,2,4-oxadiazole-5-yl)-3,4-dihydropyrano[2,3-b]pyridine-3-ol (35 mg, 106.91 umol, purity 96%) was obtained as a white solid. Yield: 41.4%.

[0239] Agilent LCMS290520-6120, Column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.5mL / min; Mobile phase: 95% [Water + 0.05] % From FA and 5% [CH3CN] to 0% [Water + 0.05% FA] and 95% [CH3CN] for 2 minutes, then under these conditions for 4 minutes, and finally to 95% [Water + 0.05% % The solution was changed to FA and 5% [CH3CN] over 2 minutes, and under these conditions, the purity was 100%, Rt = 1.901 minutes; MS (measured value): 314.9 [M+H]. + .

[0240] Agilent HPLC 1260-03, Column: Agilent Eclipse C18 Plus 4.6X100mm 3.5um; Column temperature: 40℃; Flow rate: 1.0 mL / min; Mobile phase: Changed from 95% [water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10mM NH4HCO3] and 100% [CH3CN] in 14 minutes, then under these conditions for 8 minutes, and finally changed to 95% [water + 10mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, under these conditions for 6 minutes; Purity: 96.35%, Rt = 8.279 min

[0241] 1 H NMR (400 MHz, CDCl3) δ 9.02 (d, J = 2.1 Hz, 1H), 8.30 (d, J = 1.1 Hz, 1H), 7.91 (s, 1H), 7.45 (s, 1H), 3.97 (s, 1H), 3.19 (dd, J = 17.0, 4.7 Hz, 1H), 2.94 (dd, J = 17.0, 5.8 Hz, 1H), 2.01 (s, 1H), 1.50 (s, 3H), 1.47 (s, 3H).

[0242] <Example 33>: Synthesis of (R)-2,2-dimethyl-6-(3-(pyrimidine-5-yl)-1,2,4-oxadiazole-5-yl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (0214) [ka] (R)-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-6-carboxylate (80 mg, 446.39 umol) and CDI (128.52 mg, 892.78 umol) were dissolved in DMF (2 mL). The mixture was stirred at 25°C for 1 hour. N'-hydroxyoxazole-2-carboxamidine (113.47 mg, 892.78 umol) was added. The mixture was stirred at 120°C for 3 hours. The reaction product was then tested by LC-MS. The results showed that the starting materials had reacted completely to form the target compound.

[0243] (3R)-2,2-dimethyl-6-(3-oxazol-2-yl-1,2,4-oxadiazole-5-yl)-3,4-dihydropyrano[2,3-b]pyridine-3-ol (35 mg, 111.36 umol, yield 24.95%) was purified by preparative HPLC.

[0244] Agilent LCMS21500-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.5mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 95% [CH3CN] in 2 minutes, then under these conditions for 4 minutes, and finally changed back to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 2 minutes, then under these conditions for 2 minutes; Purity: 98.85%, Rt = 1.804 mins; MS (measured value): 314.9 [M+H] + .

[0245] Agilent HPLC 1260-03, column: Agilent Eclipse C18 Plus 4.6X100mm 3.5um; column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 14 minutes, then under these conditions for 8 minutes, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, under these conditions for 6 minutes; purity: 98.58%, Rt = 8.283 minutes.

[0246] H-NMR analysis: 1 H NMR (400 MHz, DMSO) δ 8.82 (d, J = 2.4 Hz, 1H), 8.50 (d, J = 0.7 Hz, 1H), 8.35 - 8.31 (m, 1H), 7.64 (d, J = 0.7 Hz, 1H), 5.38 (d, J = 4.1 Hz, 1H), 3.78 (dd, J = 9.5, 4.8 Hz, 1H), 3.13 (dd, J = 17.2, 4.6 Hz, 1H), 2.83 (dd, J = 17.2, 6.1 Hz, 1H), 1.34 (s, 6H).

[0247] <Example 34>: Synthesis of (Z)-4-chloro-3-fluoro-N'-hydroxybenzimidoamide (0215-1) [ka] 4-chloro-3-fluoro-benzonitrile (200 mg, 1.29 mmol) was dissolved in EtOH (5 mL), and then NH2OH (339.73 mg, 5.14 mmol, 50% purity) was added. The mixture was stirred at 90°C for 1 hour. The reaction was then tested by LC-MS. The results showed that the starting material had disappeared. The mixture was then filtered under vacuum. Crude product 4-chloro-3-fluoro-N'-hydroxy-benzamidine (230 mg, 1.16 mmol, 95% purity) was obtained. This product was used in the next step without purification.

[0248] Synthesis of (S)-6-(3-(4-chloro-3-fluorophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (0215-1)

[0249] [ka] (3S)-3-hydroxy-2,2-dimethyl-3,4-dihydropyrano[2,3-b]pyridine-6-carboxylate (60 mg, 268.79 umol) and CDI (38.69 mg, 268.79 umol) were dissolved in DMF (1.5 mL). The mixture was stirred at 25°C for 1 hour. Then 4-chloro-3-fluoro-N'-hydroxybenzamidine (60.83 mg, 322.54 umol) was added. The mixture was stirred at 120°C for 3 hours. The reaction was then tested by LC-MS. The results showed that the starting materials had reacted completely. The mixture was then filtered under vacuum. The crude product was purified by preparative HPLC. (3S)-6-[3-(4-chloro-3-fluorophenyl)-1,2,4-oxadiazole-5-yl]-2,2-dimethyl-3,4-dihydropyrano[2,3-b]pyridine-3-ol (25 mg, 66.53 umol, yield 24.75%) was obtained.

[0250] Agilent LCMS21500-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.5mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 95% [CH3CN] in 2 minutes, then under these conditions for 4 minutes, and finally changed back to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 2 minutes, under these conditions for 2 minutes; Purity: 100%, Rt = 2.839 mins; MS (measured value): 375.8 [M+H] + .

[0251] Agilent HPLC 1260-03, column: Agilent Eclipse C18 Plus 4.6X100mm 3.5um; column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 14 minutes, then under these conditions for 8 minutes, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, under these conditions for 6 minutes; purity: 97.68%, Rt = 10.378 mins.

[0252] 1 H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 2.3 Hz, 1H), 8.24 - 8.17 (m, 1H), 7.93 (dd, J = 9.5, 1.8 Hz, 1H), 7.91 - 7.87 (m, 1H), 7.56 - 7.51 (m, 1H), 3.97 (dd, J = 10.8, 5.6 Hz, 1H), 3.21 (dd, J = 17.0, 4.8 Hz, 1H), 2.96 (dd, J = 17.0, 5.7 Hz, 1H), 2.14 (d, J = 6.2 Hz, 1H), 1.51 (s, 3H), 1.46 (s, 3H).

[0253] <Example 35>: Synthesis of (Z)-4-chloro-3-fluoro-N'-hydroxybenzimidoamide (0216-1) [ka] 4-chloro-3-fluoro-benzonitrile (200 mg, 1.29 mmol) was dissolved in EtOH (5 mL). NH2OH (339.73 mg, 5.14 mmol, 50% purity) was added. The mixture was stirred at 90°C for 1 hour. The reaction was then tested by LC-MS. The results indicated that the starting materials had reacted completely. The mixture was then filtered to obtain the crude product 4-chloro-3-fluoro-N'-hydroxybenzamidine (230 mg, 1.16 mmol, 95% purity). This product was used in the next step without purification.

[0254] ( R Synthesis of )-6-(3-(4-chloro-3-fluorophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0216-01)

[0255] [ka] (3 R )-3-hydroxy-2,2-dimethyl-3,4-dihydropyrano[2,3-b]pyridine-6-carboxylate (60 mg, 268.79 umol) and CDI (38.69 mg, 268.79 umol) were dissolved in DMF (1.5 mL). The mixture was stirred at 25°C for 1 hour. Then 4-chloro-3-fluoro-N'-hydroxybenzamidine (60.83 mg, 322.54 umol) was added. The mixture was stirred at 120°C for 3 hours. The reaction was then tested by LC-MS. The results showed that the starting materials reacted completely. Next, the mixture was concentrated, and the crude product was purified by preparative HPLC to obtain (3S)-6-[3-(4-chloro-3-fluorophenyl)-1,2,4-oxadiazole-5-yl]-2,2-dimethyl-3,4-dihydropyrano[2,3-b]pyridine-3-ol (25 mg, 66.53 umol, yield 24.75%).

[0256] Agilent LCMS21500-6120, Column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.5mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 95% [CH3CN] in 2 minutes, then under these conditions for 4 minutes, and finally changed back to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 2 minutes, under these conditions for 2 minutes; Purity: 100%, Rt = 2.839 mins; MS (measured value): 375.8 [M+H] + .

[0257] Agilent HPLC 1260-03, column: Agilent Eclipse C18 Plus 4.6X100mm 3.5um; column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 14 minutes, then under these conditions for 8 minutes, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, under these conditions for 6 minutes; purity: 96.39%, Rt = 10.364 minutes.

[0258] 1 H NMR (400 MHz, CDCl3) δ8.92 (d, J=2.3 Hz, 1H), 8.24- 8.17 (m, 1H), 7.93 (dd, J=9.5, 1.8 Hz, 1H), 7.91-7.87 (m, 1H), 7.56-7.51 (m, 1H), 3.97 (dd, J=10.8, 5.6 Hz, 1H), 3.21 (dd, J=17.0, 4.8 Hz, 1H), 2.96 (dd, J=17.0, 5.7 Hz, 1H), 2.14 (d, J=6.2 Hz, 1H), 1.51 (s, 3H), 1.46 (s, 3H).

[0259] <Example 36>: Synthesis of (Z)-4-chloro-N'-hydroxy-3-methylbenzimidoamide (0217-1) [ka] NH2OH (348.62 mg, 5.28 mmol, 480.19 μL, purity 50%) was added to a mixture of 4-chloro-3-methyl-benzonitrile (200.0 mg, 1.32 mmol) in EtOH (5 mL). The mixture was stirred at 90°C for 1 hour. LC-MS showed that the desired product was formed and a single main peak was detected. The mixture was concentrated under vacuum. 4-chloro-N'-hydroxy-3-methyl-benzamidine (240.0 mg, 1.27 mmol, purity 98%) was obtained as a white solid.

[0260] Synthesis of (S)-6-(3-(3-chlorophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0217-01)

[0261] [ka] Di(imidazole-1-yl)methanone (58.11 mg, 358.38 mg) was added to a mixture of (3S)-3-hydroxy-2,2-dimethyl-3,4-dihydropyrano[2,3-b]pyridine-6-carboxylate (40.0 mg, 179.19 mg) in DMF (2 mL). The mixture was stirred at 25°C for 1 hour. Next, 4-chloro-N'-hydroxy-3-methyl-benzamidine (39.70 mg, 215.03 mg) was added to the mixture and stirred at 120°C for 3 hours. LC-MS (NBK0071-39-P1-1) showed that the desired product had been formed. The mixture was combined with NBK0071-034. The product was purified by preparative HPLC (base). The eluent was dehydrated by freeze-drying. (3S)-6-[3-(4-chloro-3-methylphenyl)-1,2,4-oxadiazole-5-yl]-2,2-dimethyl-3,4-dihydropyrano[2,3-b]pyridine-3-ol (34 mg, 90.53 umol, purity 99%) was obtained as a white solid. QC (NBK0071-39-P1-2) indicated that this was suitable for delivery. Yield: 38.3%.

[0262] Agilent LCMS200520-6120, Column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.5mL / min; Mobile phase: 95% [water + 0.05 % From FA and 5% [CH3CN] to 0% [Water + 0.05% FA] and 95% [CH3CN] for 2 minutes, then under these conditions for 4 minutes, and finally to 95% [Water + 0.05% % The mixture was changed to FA and 5% [CH3CN] over 2 minutes, and under these conditions, the purity was 100%, Rt = 2.803 minutes; MS (measured value): 372.8 [M+H]. + .

[0263] Agilent HPLC 1260-03, column: Agilent Eclipse C18 Plus 4.6X100mm 3.5um; column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 14 minutes, then under these conditions for 8 minutes, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, under these conditions for 6 minutes, purity: 98.54%, Rt = 10.702 mins.

[0264] 1 H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 2.3 Hz, 1H), 8.24 - 8.18 (m, 1H), 8.01 (d, J = 1.4 Hz, 1H), 7.90 (dd, J = 8.3, 1.9 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 3.96 (q, J = 5.3 Hz, 1H), 3.20 (dd, J = 17.0, 4.7 Hz, 1H), 2.96 (dd, J = 17.0, 5.7 Hz, 1H), 2.46 (s, 3H), 2.15 (d, J = 6.0 Hz, 1H), 1.51 (s, 3H), 1.46 (s, 3H). ESI(M+H) + =372.8.

[0265] <Example 37>: Synthesis of (R)-6-(3-(3-chlorophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0218-01) [ka] Di(imidazole-1-yl)methanone (87.17 mg, 537.57 mg) was added to a mixture of (3R)-3-hydroxy-2,2-dimethyl-3,4-dihydropyrano[2,3-b]pyridine-6-carboxylate (60.00 mg, 268.79 mg) in DMF (3 mL). The mixture was stirred at 25°C for 1 hour. Then, 4-chloro-N'-hydroxy-3-methyl-benzamidine (59.55 mg, 322.54 mg) was added to the mixture and stirred at 120°C for 3 hours. LCMS (NBK0071-40-P1-1) showed that the desired product was formed. The product was purified by preparative HPLC (base). The eluent was dehydrated by freeze-drying. (3R)-6-[3-(4-chloro-3-methylphenyl)-1,2,4-oxadiazole-5-yl]-2,2-dimethyl-3,4-dihydropyrano[2,3-b]pyridine-3-ol (33 mg, 87.87 umol, yield 32.69%, purity 99%) was obtained as a white solid. Yield: 32.69%.

[0266] Agilent LCMS200520-6120, Column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.5mL / min; Mobile phase: 95% [Water + 0.05] % From FA and 5% [CH3CN] to 0% [Water + 0.05% FA] and 95% [CH3CN] for 2 minutes, then under these conditions for 4 minutes, and finally to 95% [Water + 0.05% % The mixture was changed to FA and 5% [CH3CN] over 2 minutes, and under these conditions, the purity was 100%, Rt = 2.802 minutes; MS (measured value): 373.8 [M+H]. + .

[0267] Agilent HPLC 1260-03, column: Agilent Eclipse C18 Plus 4.6X100mm 3.5um; column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 14 minutes, then under these conditions for 8 minutes, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, under these conditions for 6 minutes; purity: 99.22%, Rt = 10.701 min.

[0268] 1 H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 0.9 Hz, 1H), 8.00 (s, 1H), 7.89 (dd, J = 8.3, 1.7 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 4.01 - 3.90 (m, 1H), 3.20 (dd, J = 17.0, 4.7 Hz, 1H), 2.96 (dd, J = 17.0, 5.6 Hz, 1H), 2.46 (s, 3H), 2.18 (d, J = 6.3 Hz, 1H), 1.51 (s, 3H), 1.46 (s, 3H). ESI (M+H) + =372.8.

[0269] <Example 38>: Synthesis of (R)-6-(3-(3-fluorophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0259) [ka] N,N'-carbonyldiimidazole (116.12 mg, 716.77 umol) was added to a mixture of (3R)-3-hydroxy-2,2-dimethyl-3,4-dihydropyrano[2,3-b]pyridine-6-carboxylate (80 mg, 358.38 umol) in DMF (3 mL). The mixture was stirred at 25°C for 1 hour. Then, 3-fluoro-N'-hydroxy-benzamidine (55.24 mg, 358.38 umol) was added to the mixture and stirred at 120°C for 4 hours. LC-MS (NBK0071-184-P1-1) showed that the desired product had been formed. The product was purified by preparative HPLC (bases). (3R)-6-[3-(3-fluorophenyl)-1,2,4-oxadiazole-5-yl]-2,2-dimethyl-3,4-dihydropyrano[2,3-b]pyridine-3-ol (23 mg, 67.38 umol) was obtained as a white solid.

[0270] Agilent LC-MS6120, Column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.5mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 95% [CH3CN] in 2 minutes, then under these conditions for 4 minutes, and finally changed back to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 2 minutes, then under these conditions for 2 minutes; Purity: 99.10%, Rt = 2.406 mins; MS (measured value): 341.9 [M+H] + .

[0271] Agilent HPLC 1260, column: Agilent Eclipse C18 Plus 4.6X100mm 3.5um; column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 14 minutes, then under these conditions for 8 minutes, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, under these conditions for 6 minutes; purity: 97.65%, Rt = 9.849 minutes.

[0272] 1 H NMR (400 MHz, CDCl3) δ 8.96 (d, J = 2.2 Hz, 1H), 8.25 - 8.20 (m, 1H), 7.98 - 7.92 (m, 1H), 7.85 (ddd, J = 9.5, 2.5, 1.5 Hz, 1H), 7.48 (td, J = 8.0, 5.7 Hz, 1H), 7.23 (tdd, J = 8.4, 2.6, 0.9 Hz, 1H), 3.97 (dd, J = 5.6, 4.9 Hz, 1H), 3.21 (dd, J = 17.0, 4.8 Hz, 1H), 2.96 (dd, J = 17.0, 5.7 Hz, 1H), 1.51 (s, 3H), 1.47 (s, 3H). 19 FNMR (376 MHz, CDCl3) δ -111.86 (s).

[0273] <Example 39>: Synthesis of (Z)-3,5-dichloro-N'-hydroxybenzimidoamide (0260-1) [ka] Hydroxylamine (768.09 mg, 11.63 mmol) was added to a mixture of 3,5-dichlorobenzonitrile (0.5 g, 2.91 mmol, 882.61 μL) in EtOH (10 mL). The mixture was stirred at 90°C for 2 hours. LC-MS (NBK0071-180-P1-1) showed that the desired product had been formed. The mixture was concentrated under vacuum, and the product was dehydrated by freeze-drying. 3,5-dichloro-N'-hydroxybenzamidine (590 mg, 2.88 mmol) was obtained as a white solid.

[0274] Synthesis of (S)-6-(3-(3,5-dichlorophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0260-01)

[0275] [ka] N,N'-carbonyldiimidazole (116.12 mg, 716.77 umol) was added to a mixture of (3S)-3-hydroxy-2,2-dimethyl-3,4-dihydropyrano[2,3-b]pyridine-6-carboxylate (80 mg, 358.38 umol) in DMF (3 mL). The mixture was stirred at 25°C for 1 hour. Then, 3,5-dichloro-N'-hydroxy-benzamidine (110.22 mg, 537.57 umol) was added to the mixture and stirred at 120°C for 4 hours. LC-MS (NBK0071-185-P1-1) showed that the desired product had been formed. The product was purified by preparative HPLC (bases). (3S)-6-[3-(3,5-dichlorophenyl)-1,2,4-oxadiazole-5-yl]-2,2-dimethyl-3,4-dihydropyrano[2,3-b]pyridine-3-ol (9 mg, 22.95 umol) was obtained as a white solid.

[0276] Agilent LC-MS6120, Column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.5mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 95% [CH3CN] in 2 minutes, then under these conditions for 4 minutes, and finally changed back to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 2 minutes, then under these conditions for 2 minutes; Purity: 98.79%, Rt = 2.874 mins; MS (measured value): 393.8M+H + .

[0277] Agilent HPLC 1260, column: Agilent Eclipse C18 Plus 4.6X100mm 3.5um; column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 14 minutes, then under these conditions for 8 minutes, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, under these conditions for 6 minutes; purity: 96.01%, Rt = 11.281 minutes.

[0278] 1 H NMR (400 MHz, CDCl3) δ 8.94 (d, J = 2.3 Hz, 1H), 8.24 - 8.19 (m, 1H), 8.05 (d, J = 1.9 Hz, 2H), 7.51 (t, J = 1.9 Hz, 1H), 3.97 (d, J = 5.1 Hz, 1H), 3.21 (dd, J = 17.0, 4.8 Hz, 1H), 2.96 (dd, J = 17.0, 5.7 Hz, 1H), 2.07 (d, J = 6.2 Hz, 1H), 1.51 (s, 3H), 1.46 (s, 3H).

[0279] <Example 40>: Synthesis of (R)-6-(3-(3,5-dichlorophenyl)-1,2,4-oxadiazole-5-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-3-ol (SMS21032-0261-01) [ka] N,N'-carbonyldiimidazole (116.12 mg, 716.77 umol) was added to a mixture of (3R)-3-hydroxy-2,2-dimethyl-3,4-dihydropyrano[2,3-b]pyridine-6-carboxylate (80 mg, 358.38 umol) in DMF (3 mL). The mixture was stirred at 25°C for 1 hour. Then, 3,5-dichloro-N'-hydroxy-benzamidine (110.22 mg, 537.57 umol) was added to the mixture and stirred at 120°C for 4 hours. LC-MS (NBK0071-186-P1-1) showed that the desired product had been formed. The product was purified by preparative HPLC (bases). (3R)-6-[3-(3,5-dichlorophenyl)-1,2,4-oxadiazole-5-yl]-2,2-dimethyl-3,4-dihydropyrano[2,3-b]pyridine-3-ol (32 mg, 81.58 umol) was obtained as a white solid. QC demonstrated that this was suitable for delivery.

[0280] Agilent LC-MS6120, Column: Waters X-Bridge C18 (150mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.5mL / min; Mobile phase: Changed from 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] to 0% [Water + 10mM NH4HCO3] and 95% [CH3CN] in 2 minutes, then under these conditions for 4 minutes, and finally changed back to 95% [Water + 10mM NH4HCO3] and 5% [CH3CN] in 2 minutes, then under these conditions for 2 minutes; Purity: 97.45%, Rt = 2.877 mins; MS (measured value): 393.8 [M+H] + .

[0281] Agilent HPLC 1260, column: Agilent Eclipse C18 Plus 4.6X100mm 3.5um; column temperature: 40℃; flow rate: 1.0 mL / min; mobile phase: changed from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 14 minutes, then under these conditions for 8 minutes, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 minutes, under these conditions for 6 minutes; purity: 96.92%, Rt = 11.233 minutes.

[0282] 1 H NMR (400 MHz, CDCl3) δ 8.89 (d, J = 2.3 Hz, 1H), 8.23 ​​- 8.18 (m, 1H), 8.02 (d, J = 1.9 Hz, 2H), 7.50 (t, J = 1.9 Hz, 1H), 3.97 (t, J = 5.0 Hz, 1H), 3.21 (dd, J = 17.0, 4.7 Hz, 1H), 2.97 (dd, J = 17.0, 5.5 Hz, 1H), 2.34 (s, 1H), 1.52 (s, 3H), 1.46 (s, 3H). Other embodiments not specifically described above were also prepared in the same manner.

[0283] Using a combination of systems biology and experimental techniques, the inventors have identified homeodomain-interacting protein kinase 2 (HIPK2) as a crucial regulator of numerous pro-fibrotic pathways, including the TGF-β1 / Smad3 pathway. HIPK2 modulates the pathway through physical association with Smad3, thereby regulating Smad3 activity. Knockdown of HIPK2 in human primary tubular cells suppresses TGF-β1-induced activation of the TGF-β1 / Smad3 pathway. In vivo, HIPK2 knockout inhibits TGF-β1 / Smad3 activity and renal fibrosis in both HIV1 transgenic mice (Tg26) and unilateral ureteral obstruction (UUO) mice. Therefore, inhibition of the TGF-β1 / Smad3 pathway by HIPK2 provides a method for anti-fibrotic therapy of renal diseases.

[0284] HIPK2 inhibitors have not been sufficiently developed and are not commercially available. Recently, Cozza et al. [PLoS One, 2014, Vol. 9, e89176] reported on a selective HIPK2 inhibitor that competes for ATP binding in the kinase domain. However, since HIPK2 modulates numerous signaling pathways, including p53 regulation, there is concern that broad inhibition of HIPK2 may not be beneficial in all cellular situations. Here, we describe a compound that can inhibit the TGF-β1 / Smad3 pathway by interfering with the HIPK2-Smad3 protein-protein interaction without significant inhibition of HIPK2 kinase activity or inhibition of p53 activation. In the tests described below, examples of the compound of the present invention inhibited the pro-fibrosis pathway in vitro in cultured human renal tubular epithelial cells (RTEC) and in vivo in renal fibrosis in murine animal models (Tg26 mice and UUO mice).

[0285] HEK293T (293T) cells (ATCC) are cultured at 37°C in a humidified environment of 5% CO2 in Dulbecco's modified Eagle medium (Invitrogen) containing 10% fetal bovine serum (FBS), 0.5% penicillin, and streptomycin. Human primary tubular cells (PromoCell GmbH, Heidenberg, Federal Republic of Germany) are cultured in Renal Epithelial Cell Growth Medium-2 (PromoCell GmbH) with additives according to the manufacturer's protocol. Human primary renal tubular epithelial cells of passage <5 are used in all studies. For HIV infection of hRTECs, VSV-G pseudotype viruses are generated using pNL4-3:ΔG / P-EGFP, a gag / pol deletion HIV-1 construct containing EGFP within a gag open reading frame, and pHR-IRES-EGFP, a control EGFP construct. Cells are infected with either an HIV pseudotype virus or a control virus for two days prior to treatment with the test compound.

[0286] 4×Smad-binding element-driven firefly luciferase (SBE4-Luc) plasmids and sea urchin luciferase reporter plasmids (pRLs) are commercially available. A HIPK2 variant lacking the active domain has already been reported by Jin et al. [Nat Med, Vol. 18, p. 580-588]. The His6-HIPK2 construct is generated by PCR amplification of the coding region using a plasmid containing the human HIPK2 gene (GeneCopoeia®) as a template.

[0287] 293T cells (~60% confluent) seeded in 12-well plates are co-transfected with SBE4-Luc plasmid (0.5 μg) and pRL plasmid (0.2 μg) using the PolyJet® transfection kit according to the manufacturer's instructions (SignaGen Laboratories, Maryland, USA). 48 hours after transfection, cells are treated for 16 hours with the specified concentrations of the test compound, either with or without 10 ng / ml of TGF-β1. Luciferase activity is measured using the Dual-Luciferase® reporter assay kit (Promega, #E1910). Data are expressed as the ratio of firefly luciferase activity to sea urchin luciferase activity. For HIPK2 dominant-negative experiments, 293T cells are cotransfected with either a pcDNA3.1 empty vector (0.5 μg) or a HIPK2 KD plasmid (0.5 μg) along with the SBE4-firefly luciferase plasmid and the pRL (sea urticaria luciferase) plasmid. Luciferase activity is measured 48 hours after transfection.

[0288] For the data in Table 1, the Bight-Glo® luciferase assay system from Promega was used with the TGF / SMAD signaling pathway SBE reporter HEK293 cell line from BPSbioscience. On day 1, SBE reporter HEK293 cells were seeded at a cell density of 25,000 cells per well in 100 μl of geneticin®-free growth medium in a 96-well microplate with a white, clear bottom. The plate was incubated in a CO2 incubator at 37°C for 24 hours. Each well was treated with the test compound by replenishing it with 60 μL of assay medium and adding 5 μL of the compound included in the medium. The concentration of the test compound in the medium was adjusted so that 5 μL of solution provided the desired molar concentration. For example, if the desired test concentration was 30 μM, 5 μL of 660 μM of the compound was added. After 4 hours, TGFβ was added to bring the concentration to 10 ng / mL. The plates were incubated overnight (18 hours) at 37°C in a CO2 incubator. All media were replaced one hour before the assay. The luciferase assay was performed using the ONE-Step® luciferase assay system by adding 100 μl of ONE-Step® luciferase reagent per well, shaking at room temperature for approximately 15–30 minutes, and measuring luminescence using a light meter. The signal was standardized to inhibition rate (%) with TGF-untreated cells representing 100% inhibition, and the data were processed using GraphpadPrism.

[0289] The activity of the compound of the present invention was confirmed in vivo. Two chronic kidney disease models were used: (1) Tg26 mice, a model of HIV-associated nephropathy, and (2) Col4a3 null mice, a model of Alport syndrome. Both CKD models are characterized by severe glomerulosclerosis and tubulointerstitial fibrosis, leading to renal failure and death at approximately 12-20 weeks of age.

[0290] Tg26 mice carrying an incomplete HIV-1 provirus lacking gag-pol, based on the FVB / N genetic background, were reported by Feng et al. [J Am Soc Nephrol 2009, Vol. 20, p. 2138-2146]. Six-week-old heterozygous Tg26 mice were used. Wild-type littermate mice were used as controls. The treatment group mice were orally administered 30, 60, or 90 mg / kg (body weight) per day with the test compound dissolved in 20% NMP, 60% PEG400, and 20% H2O. The control group mice were administered the same volume of vehicle. The mice were administered for a total of four weeks and euthanized at 10 weeks of age. Treatment of Tg26 mice with the compound of Example 13 for 4 weeks improved survival rates (64% survival in the vehicle group [number of mice n=25] compared to 100% survival in the group treated with Example 13 [number of mice n=20]; hazard ratio comparing vehicle and treatment with Example 13 = 7.2; p-value by log-rank Mantel-Cox test: 0.003); mean multiplier change in urinary albumin-creatinine ratio. A reduction of approximately 65% ​​was observed (mean magnification change from week 0 to week 4 was 1.057 in the vehicle group [number of mice n=9] compared to 0.352 in the group of Example 13 [number of mice n=8]; p-value = 0.0001 by Welch's t-test), and a reduction of approximately 43% in the area of ​​renal fibrosis (mean area was 4.492% in the vehicle group [number of mice n=9] compared to 2.540 in the group of Example 13 [number of mice n=8], p-value = 0.008). In another study, 5-6 week old Tg26 mice were treated for 4 weeks with Example 13 (90 mg / kg per day, PO) or vehicle: 38% (8 / 21 mice) in the control group died from renal failure during the experiment; the mortality rate in the HIPK2i-174 group was 0% (0 / 18 mice). When comparing the urinary albumin-creatinine ratio (UCAR) as a measure of glomerular function, the vehicle group showed a ~16% increase from baseline (magnification change: 1.16±0.47, n=15), while the HIPK2i-174 group showed a ~57% decrease (magnification change: 0.43±0.28, n=17, p=0.0001 by unpaired two-sided t-test with Welch's correction).[Due to significant mutual variability in baseline UACR in 5-6 week old Tg26 mice, the therapeutic effect was calculated based on the multiplier change relative to baseline for each mouse.] Comparison of renal fibrosis, evaluated by histological staining with picrosilius red, showed a reduction of approximately 37% in fibrosis in the group treated with Example 13 (2.8±1.2%, n=18, p=0.008) compared to the vehicle group (4.44±1.2%, n=16).

[0291] Three-week-old Col4a3-deficient mice were treated for six weeks with either Example 13 (60 mg / kg per day, PO) or a vehicle. The median survival time was 56 days in the vehicle group and extended to 68 days in the treatment group (a 21% increase). Comparison of urinary albumin-creatinine ratio (UCAR) showed a ~45% reduction in the treatment group after six weeks of treatment (73.9 ± 34.9 vs. 41.4 ± 14.2 mg / mg). Comparison of renal fibrosis, evaluated by histological staining with picrosilius red, showed a ~51% reduction in fibrosis in the treatment group (13.7 ± 6.3%, n=9, p=0.0001) compared to the vehicle group (28.3 ± 4.4%, n=8).

[0292] Considering the mechanism of action of the compounds of the present invention, those skilled in the art will recognize that the treatment of fibrotic diseases in organs other than the kidneys would be equally successful. The compounds of the present invention are currently being tested in models for the treatment of fibrosis of the lungs, heart, and liver.

[0293] While typical embodiments have been described for illustrative purposes, the foregoing description and examples should not be considered limitations to the scope of the invention. Therefore, those skilled in the art can conceive of various modifications, adaptations, and alternative forms without departing from the spirit and scope of the invention.

Claims

1. Equation I 【Chemistry 1】 (In the formula, Ar is, (a) hydrogen, -(C １ -C ８ ) hydrocarbyl, OH, -O(C １‐ C ８ ) hydrocarbyl, halogen, nitro, amino, (C １ -C ３ ) alkylamino, (C １ -C ３ ) dialkylamino, (C １ -C ３ ) acylamino, (C １ -C ３ ) alkylsulfonyl, (C １ -C ３ ) haloalkyl, (C １ -C ３ ) haloalkoxy, 5- or 6-membered heterocyclyl, and -B(OH) ２ phenyl substituted at the meta position and / or para position with one or more substituents independently selected from; or (b) Hydrogen, -(C １ -C ３ ) alkyl, OH, -O(C １ -C ３ ) alkyl, halogen, amino, (C １ -C ３ ) alkylamino, (C １ -C ３ ) Dialkylamino, (C １ -C ３ ) Haloalkyl, and (C １ -C ３ ) A five-membered heteroaryl substituted with one substituent selected from a haloalkoxy And; R ４ is hydrogen, hydroxyl, (C １ -C ３ ) alkyl, (C １ -C ３ ) Alkoxy, amino, (C １ -C ３ ) alkylamino, and (C １ -C ３ ) Selected from dialkylaminos; R ５ is hydrogen, hydroxyl, (C １ -C ３ ) alkyl, (C １ -C ３ ) Alkoxy, amino, (C １ -C ３ ) alkylamino, and (C １ -C ３ ) Selected from dialkylaminos; R ６ is hydrogen and (C １ -C ６ ) Selected from hydrocarbil; and R ７ is hydrogen and (C １ -C ３ ) Selected from alkyl; However, R ４ , R ５ , R ６ , and R ７ (Not all of it is hydrogen.) A compound represented by the formula.

2. The compound according to claim 1, wherein Ar is a phenyl compound substituted at the meta and / or para positions with one or more substituents independently selected from -(C1-C8)hydrocarbyl, OH, -O(C1-C8)hydrocarbyl, halogen, nitro, amino, (C1-C3)alkylamino, (C1-C3)dialkylamino, (C1-C3)acylamino, (C1-C3)alkylsulfonyl, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, 5-membered or 6-membered heterocyclyl, and -B(OH)2.

3. The compound according to claim 2, wherein phenyl is substituted at the para position with a substituent selected from bromo, chloro, fluoro, fluoromethyl, difluoromethyl, trifluoromethyl, and methyl.

4. The compound according to claim 1, wherein Ar is a five-membered heteroaryl substituted with one substituent selected from -(C1-C3)alkyl,OH,-O(C1-C3)alkyl,halogen,amino, (C1-C3)alkylamino, (C1-C3)dialkylamino, (C1-C3)haloalkyl, and (C1-C3)haloalkoxy.

5. The compound according to claim 4, wherein Ar is selected from thiophene, pyrazole, oxazole, and thiazole.

6. Ar is either unsubstituted or -(C １ -C ３ The compound according to claim 5, wherein it is substituted with a substituent selected from hydrocarbyl, bromo, chloro, fluoro, fluoromethyl, difluoromethyl, and trifluoromethyl.

7. R ４ The compound is selected from hydrogen, hydroxyl, and amino, according to any one of claims 1 to 6.

8. R ５ The compound is selected from hydrogen, hydroxy, methoxy, and amino, according to any one of claims 1 to 6.

9. R ６ and R ７ The compound according to any one of claims 1 to 6, which is independently selected from hydrogen and methyl.

10. R ６ and R ７ is methyl, R ４ and R ５ The compound according to claim 9, wherein one of the components is hydroxyl. 【Request Item 11】 【Chemistry 2】 A compound according to claim 1, selected from the following.

12. The compound according to claim 9, wherein Ar is thiazole-2-yl substituted with chloro or methyl at the 3rd or 4th position.

13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1 to 6 or 11.

14. An in vitro method for inhibiting the interaction between homeodomain-interacting protein kinase 2 (HIPK2) and Smad3, the method comprising contacting HIPK2 with a compound according to any one of claims 1 to 6 or 11.

15. An in vitro method for inhibiting the activation of Smad3, the method comprising contacting Smad3 with a compound according to any one of claims 1 to 6 or 11.

16. A pharmaceutical composition for use in the treatment of fibrotic diseases, comprising the compound described in any one of claims 1 to 6 or 11.

17. The pharmaceutical composition according to claim 16, wherein the disease is renal fibrosis.

18. The pharmaceutical composition according to claim 16, wherein the disease is cardiac fibrosis.

19. The pharmaceutical composition according to claim 16, wherein the disease is hepatic fibrosis.

20. The pharmaceutical composition according to claim 16, wherein the disease is pulmonary fibrosis.

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