Heterocyclic compound containing oxygen and its use

Abstract

A heterocyclic compound containing oxygen and the use of the compound are disclosed. The present disclosure provides a heterocyclic compound containing oxygen represented by formula I, a pharmaceutically acceptable salt of the compound, a deuterated derivative of the compound, a solvate of the compound, a solvate of a pharmaceutically acceptable salt of the compound, or a crystalline form of the compound, and the heterocyclic compound containing oxygen is expected to selectively inhibit the activation of Smad3.

Description

Cross - reference to related applications

[0001] This application claims priority based on U.S. Provisional Patent Application No. 63 / 370,516, filed on August 5, 2022, and the disclosure of U.S. Provisional Patent Application No. 63 / 370,516 is hereby incorporated by reference in its entirety into this application. The field of the present disclosure

[0002] The present disclosure relates to oxygen - containing heterocyclic compounds and the use of such compounds. The background of the present disclosure

[0003] Fibrosis is characterized by the overproduction and accumulation of extracellular matrix proteins, leading to progressive loss of tissue function and ultimately organ dysfunction. Chronic kidney disease usually involves interstitial fibrosis of the kidney, regardless of the initial injury. Treatment strategies for chronic kidney disease require not only the removal of causative factors such as hyperglycemia, hypertension, and HIV infection to halt the decline in kidney function, but also anti - fibrosis therapies to restore the normal structure and function of the kidney. In addition to kidney fibrosis, many other organ - specific fibrotic disorders, such as liver, heart, and lung fibrosis, are known.

[0004] Kidney fibrosis is considered the final common pathway that progressive chronic kidney disease leads to, regardless of the original etiology of the disease. Although much has been discovered about the molecular mechanisms underlying kidney fibrogenesis, the application of this knowledge to clinical practice has been less than successful. It has been demonstrated that HIPK2 is a multifunctional activator of the TGF - β / Smad3 pathway, the NF - κB pathway, and the p53 pathway, and that systemic knockout of HIPK2 in mice reduces kidney fibrosis in vivo. U.S. Patent No. 10,669,266 discloses small molecule HIPK2 inhibitors that specifically block the TGF - β / Smad3 pathway and reduce kidney fibrosis without causing systemic side effects. However, the compounds disclosed in U.S. Patent No. 10,669,266 still have problems with solubility and efficacy.

[0005] Transforming growth factor β1 (TGF-β1) has been confirmed to be the most important fibrotic factor related to kidney diseases. TGF-β1 binds to the type II TGF-β receptor, enabling dimerization of the receptor with the type I TGF-β receptor and resulting in phosphorylation of Smad2 and Smad3. Phosphorylated Smad3 translocates into the nucleus, binds to the Smad binding element of the promoter, and activates the transcription of target genes including fibrosis-promoting genes such as collagen I, fibronectin, and alpha smooth muscle actin (α-SMA). It is known that Smad3 is highly activated in fibrotic kidneys and that renal fibrosis is reduced in animal models of kidney diseases by knockout of Smad3. Therefore, blockade of the TGF-β1 / Smad3 pathway provides a treatment strategy for renal fibrosis. The content of the present disclosure

[0006] The technical problem to be solved in the present disclosure is that in the prior art, there is a lack of effective drugs that can serve as Smad3 activation inhibitors for clinical treatment. Therefore, the present disclosure provides an oxygen-containing heterocyclic compound that can selectively inhibit the activation of Smad3 and its use.

[0007] The present disclosure solves the above technical problems through the following technical solutions.

[0008] The present disclosure provides an oxygen-containing heterocyclic compound represented by formula I, a pharmaceutically acceptable salt of the compound, a deuterated derivative of the compound, a solvate of the compound, a solvate of the pharmaceutically acceptable salt of the compound, or a crystalline form of the compound:

Chemical formula

Chemical formula

[0009] In certain embodiments, the oxygen-containing heterocyclic compound represented by Formula I has the structure of Formula II:

Chemical formula

Chemical formula

[0010] In certain embodiments, the oxygen-containing heterocyclic compound represented by Formula I is represented by Formula III: [ka] having the structure In the above formula, Ar and [ka] is defined as in Formula I; [ka] teeth [ka] represents a mixture of; R 3 and R 4 is a deuterium-substituted C 1‐6 It is alkyl.

[0011] In one embodiment, Formula III has the following structure: [ka] having; In the above formula, [ka] , Ar and [ka] It is defined in the same way as formula III.

[0012] In certain embodiments, in formula II or III', Ar is C 1‐1 substituted with one or more R 6‐20 aryl, or "5- to 12-membered heteroaryl containing 1 to 4 heteroatoms selected from O, S, and N" substituted with one or more R 1‐2 ; R 1‐1 and R 1‐2 are independently selected from halogen and C 1‐6 alkyl;

Chemical formula

Chemical formula

Chemical formula

[0013] In certain embodiments, in formula II, Ar is C 1‐1 substituted with one or more R 6‐20 aryl, or "5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S, and N" substituted with one or more R 1‐2 ; R 1‐1 and R 1‐2 are independently selected from halogen and C 1‐6 alkyl;

Chemical formula

Chemical formula

[0014] In certain embodiments, in Formula II or III’, Ar is a C 1‐1 substituted with one or more R 6‐20 aryl; R 1‐1 is halogen; [Chem.] is a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, and N; [Chem.] is; [Chem.] represents; n is 2.

[0015] In certain embodiments, n is 1, 2, or 3.

[0016] In certain embodiments, Ar is a C 1‐1 substituted with one or more R 6‐20 aryl, or a “5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S, and N” substituted with one or more R 1‐2 .

[0017] In certain embodiments, R 1‐1 and R 1‐2 are independently selected from halogen and C 1‐6 alkyl;

[0018] In certain embodiments, [Chem.] is a 5-membered heteroaryl containing 3 heteroatoms selected from O and N. In certain embodiments, R 3 and R 4 together with the atom to which R 3 and R 4 are attached form a 3- to 8-membered cyclic ring.

[0019] In certain embodiments, when Ar is C 6‐20 aryl, or C 1‐1 aryl substituted with one or more R 6‐20 the C 6‐20 aryl, and C 1‐1 aryl substituted with one or more R 6‐20 the C 6‐20 aryl in aryl is C 6‐10 aryl; C 6‐10 aryl is phenyl or naphthyl;

[0020] In certain embodiments, when Ar is a "5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S, and N", or a "5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S, and N" substituted with one or more R 1‐2 the "5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S, and N", and the "5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S, and N" substituted with one or more R 1‐2 in the "5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S, and N" is a "5-membered heteroaryl containing 2 heteroatoms selected from N", such as pyrazolyl

Chemical formula

[0021] In certain embodiments,

Chemical formula

Chemical formula

Chemical formula

[0022] In certain embodiments, when R 1‐1 and R 1‐2 are independently selected from halogen, the halogen is -F, -Cl, -Br or -I.

[0023] In certain embodiments, when R 1‐1 and R 1‐2 are independently selected from C 1‐6 alkyl, the C 1‐6 alkyl is C 1‐4 alkyl, that is, it may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, or it may be methyl.

[0024] In certain embodiments, when R 3 and R 4 together with the atoms to which they are attached to R 3 and R 4 form C 3‐8 cycloalkyl, the C 3‐8 cycloalkyl is C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C7 cycloalkyl, or C8 cycloalkyl.

[0025] In certain embodiments, when R 3 and R 4 are C 1‐6 alkyl substituted with deuterium, the C 1‐6 alkyl is C 1‐4It may be alkyl, i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, or it may be methyl.

[0026] In certain embodiments, R 3 and R 4 are C 1‐6 alkyl substituted with deuterium. When it is C 1‐6 alkyl substituted with deuterium, it is -CD3.

[0027] In certain embodiments, Ar is

Chemical formula

[0028] In certain embodiments,

Chemical formula

Chemical formula

[0029] In certain embodiments,

Chemical formula

Chemical formula

Chemical formula

[0030] In certain embodiments,

Chemical formula

Chemical formula

[0031] In certain embodiments, [Chemical Formula] is [Chemical Formula] is as follows.

[0032] In certain embodiments, the oxygen-containing heterocyclic compound of Formula I has the following structure: [Chemical Formula] and can have any one of the following:

[0033] The present disclosure further provides a pharmaceutical composition comprising Substance A and a pharmaceutically acceptable additive, wherein Substance A is a therapeutically effective amount of an oxygen-containing heterocyclic compound of Formula I as described above, a pharmaceutically acceptable salt of the compound, a deuterated derivative of the compound, a solvate of the compound, a solvate of a pharmaceutically acceptable salt of the compound, or a crystalline form of the compound.

[0034] In the present disclosure, the pharmaceutical composition can be in a form suitable for oral administration and in the form of a sterile aqueous injection solution, which can be prepared according to any known method for preparing pharmaceutical compositions in the art.

[0035] The present disclosure further provides a method for inhibiting the interaction between homeodomain interacting protein kinase 2 and Smad3, the method comprising binding HIPK2 to Substance A, wherein Substance A is a therapeutically effective amount of an oxygen-containing heterocyclic compound of Formula I as described above, a pharmaceutically acceptable salt of the compound, a deuterated derivative of the compound, a solvate of the compound, a solvate of a pharmaceutically acceptable salt of the compound, or a crystalline form of the compound.

[0036] The present disclosure further provides a method for inhibiting the activation of Smad3, the method comprising contacting Smad3 with Substance A, wherein Substance A is a therapeutically effective amount of a heterocyclic compound containing oxygen of Formula I as described above, a pharmaceutically acceptable salt of the compound, a deuterated derivative of the compound, a solvate of the compound, a solvate of the pharmaceutically acceptable salt of the compound, or a crystalline form of the compound.

[0037] The present disclosure further provides a method for treating fibrosis, comprising administering Substance A to a subject suffering from fibrosis, wherein Substance A is a therapeutically effective amount of a heterocyclic compound containing oxygen of Formula I as described above, a pharmaceutically acceptable salt of the compound, a deuterated derivative of the compound, a solvate of the compound, a solvate of the pharmaceutically acceptable salt of the compound, or a crystalline form of the compound, and the fibrosis is renal fibrosis, cardiac fibrosis, hepatic fibrosis, or pulmonary fibrosis.

[0038] The term "pharmaceutically acceptable salt" refers to salts of the compounds disclosed herein, prepared using relatively safe and pharmaceutically acceptable acids or bases. When the compounds disclosed herein contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compounds disclosed herein contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. Pharmaceutically acceptable acids include inorganic acids, such as, but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, and sulfuric acid. Pharmaceutically acceptable acids include organic acids, such as, but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acidic citric acid, oleic acid, tannic acid, pantothenic acid, bitartaric acid, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthoic acid)), and amino acids (e.g., glutamic acid and arginine).

[0039] When the compounds disclosed in this specification contain both a relatively acidic functional group and a relatively basic functional group, they can be converted into either a base addition salt or an acid addition salt. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, (U.S.), 1977, Vol. 66, p.1-19, or P. Heinrich Stahl and Camille G. Wermuth, eds., "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", (Germany), Wiley-VCH, 2002.

[0040] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0041] The term "alkyl" refers to a straight or branched chain alkyl group having the specified number of carbon atoms. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0042] The terms "cycloalkyl" and "carbocyclic ring" refer to a saturated cyclic group consisting only of carbon atoms having the specified number of carbon atoms (e.g., C3-C6), which is a monocyclic ring, a bridged ring or a spiro ring. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0043] The term "heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5 to 12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and specified heteroatom species (one or more of N, O, and S), which is monocyclic or polycyclic and has (in accordance with Hückel's rule) at least one aromatic ring. Heteroaryl is linked to other fragments in the molecule by an aromatic or non-aromatic ring. Examples of heteroaryl include, but are not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, and indolyl.

[0044] The terms "heterocyclyl", "heterocycle", or "heterocycloalkyl" refer to a cyclic group having a specified number of ring atoms (e.g., 3 to 8 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and specified heteroatom species (one or more of N, O, and S), which is monocyclic, bridged cyclic, or spirocyclic and each ring is saturated. Examples of heterocycloalkyl include, but are not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuryl, morpholinyl, piperidinyl, etc.

[0045] The term "hydroxyl" refers to the -OH group.

[0046] The term "cyano" refers to the -CN group.

[0047] [Experimental Section] <Example 1: Synthetic Route of Compound 1> [Chemical Formula]

[0048] ≪Synthesis of Compound 1-j≫ A mixture containing 4-chlorobenzonitrile (11 g, 79.96 mmol) in EtOH (150 mL) was added with hydroxylamine (21.13 g, 319.85 mmol). The mixture was stirred at 90 °C for 2 hours. After the raw materials were consumed (confirmed by LCMS), the mixture was concentrated in vacuo and the product was dried by lyophilization to obtain Compound 1-j (13 g, crude).

[0049] ≪Synthesis of Compound 1-i≫ To a round-bottom flask (100 mL) containing Compound 1-j (700 mg, 4.10 mmol), 1,1-carbonyldiimidazole (CDI, 642.14 mg, 4.46 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU, 1.23 g, 4.87 mmol) were added. Subsequently, 1,4-dioxane (10 mL) was continuously added and the reaction mixture was stirred at 100 °C for 3 hours. After cooling to ambient temperature, the mixture was diluted with water, adjusted to pH ~2 using 3M HCl dissolved in H2O, and extracted with ethyl acetate (30 mL * 2). The combined organic phases were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by silica column (EA:PE = 0~15%) to obtain Compound 1-i (400 mg, yield 50%).

[0050] ≪Synthesis of Compound 1-h≫ To a mixture of Compound 1-i (1.0 g, 5.09 mmol) and POCl3 (16.45 g, 105.90 mmol, 10 mL), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU, 1.53 g, 10.05 mmol, 1.5 mL) was added at 0 °C. The mixture was stirred at 100 °C for 12 hours. The mixture was poured into ice water and the pH was adjusted to 9 by adding saturated NaHCO3. The mixture was extracted with ethyl acetate (30 mL * 3). The combined organic phases were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by silica column (EA:PE = 0~10%) to obtain Compound 1-h (455 mg, yield 42%).

[0051] ≪Synthesis of Compound 1-g≫ A mixture containing diethyl cyanomethylphosphonate (51.43 g, 290.35 mmol), triethylamine (TEA, 26.65 g, 263.95 mmol), and lithium bromide (25.21 g, 290.35 mmol) in tetrahydrofuran (THF, 700 mL) was stirred at 25 °C for 2 hours. Then, cyclobutanone (18.5 g, 263.95 mmol) was added to the mixture, and some solids were separated and removed. Subsequently, the mixture was stirred at 25 °C for 12 hours. TLC (EA (ethyl acetate):PE (petroleum ether) = 1:20, KMnO4) indicated that the raw materials were consumed and new spots were detected. The reaction mixture was diluted with water (500 ml) and extracted with ethyl acetate (500 mL * 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by column (EA:PE = 0 - 5%, detected at 220 nm) to obtain compound 1-g (10.6 g, yield 43%).

[0052] ≪Synthesis of Compound 1-f≫ To a solution of compound 1-g (10.6 g, 113.82 mmol) in dichloromethane (DCM, 200 mL), 1.0 mol / L DIBAL-H in hexane (113.8 mL, 113.8 mmol) was slowly added at -78 °C under N2. After the addition, the reaction mixture was allowed to warm to 0 °C. Then, the reaction mixture was stirred at 0 °C for 2.5 hours under N2. TLC (EA:PE = 1:10, 254 nm) indicated that the raw materials were consumed. The reaction mixture was slowly poured into a 1M H2SO4 solution (200 mL) at 0 °C and stirred for 30 minutes. Then, the organic layer was separated, and the aqueous phase was extracted with DCM (200 mL * 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated at 25 °C in vacuo, and purified by silica column (DCM:PE = 0 - 20%) to obtain compound 1-f (3.1 g, yield 28%).

[0053] ≪Synthesis of Compound 1-e≫ To a solution of Compound 1-f (3.1 g, 32.25 mmol) and 3,5-dibromo-2-methoxypyridine (8.61 g, 32.25 mmol) in THF (100 mL), a 2.5 M n-BuLi solution in hexane (13.0 mL, 32.25 mmol) was slowly added at -78 °C under N2. Then, the reaction mixture was stirred at this condition for 2.5 h. After the raw materials were consumed (confirmed by LCMS), the reaction was quenched with saturated NH4Cl (200 mL), and the mixture was extracted with ethyl acetate (200 mL * 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by silica column (EA:PE = 0~26%) to obtain Compound 1-e (3 g, yield 33%).

[0054] ≪Synthesis of Compound 1-d≫ To a mixture of Compound 1-e (400 mg, 1.41 mmol) in glacial acetic acid (12 mL), 33% HBr / AcOH (0.8 mL, 4.94 mmol) was added. Then, the reaction was stirred at 80 °C for 3 h. After the raw materials were consumed (confirmed by LCMS), the reaction mixture was directly concentrated to remove the solvent, and then saturated sodium carbonate (100 mL) was added to the residue. The mixture was extracted with ethyl acetate (60 ml * 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by silica column (EA:PE = 0~50%) to obtain Compound 1-d (110 mg, yield 31%).

[0055] ≪Synthesis of Compound 1-c≫ 4,4,4’,4’,5,5,5’,5’-Octamethyl-2,2’-bi(1,3,2-dioxaborolane) (151 mg, 0.59 mmol), compound 1-d (100 mg, 0.40 mmol) and potassium acetate (117 mg, 1.2 mmol) were included in a mixture of 1,4-dioxane (3 mL), and Pd(dppf)Cl2 (28 mg, 0.04 mmol) was added thereto. After the addition, the reaction mixture was bubbled with N2 for 3 minutes and stirred at 85 °C for 3 hours. After the raw materials were consumed (confirmed by LCMS), the reaction mixture was concentrated and purified by silica column (EA:PE = 0~20%) to obtain compound 1-c (110 mg, yield 93%).

[0056] ≪Synthesis of Compound 1-b≫ Compound 1-h (79 mg, 0.37 mmol), compound 1-c (110 mg, 0.37 mmol) and sodium carbonate (120 mg, 1.11 mmol) were included in a mixture of 1,4-dioxane (4 mL) and H2O (1 mL), and Pd(dppf)Cl2 (27 mg, 0.037 mmol) was added thereto. After the addition, the reaction mixture was bubbled with N2 for 3 minutes and then stirred at 95 °C for 3 hours. After the raw materials were consumed (confirmed by LCMS), the reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL * 2). The organic layers were combined, washed with brine, dehydrated with anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by column (EA:PE = 0~30%) to obtain compound 1-b (51 mg, yield 39%).

[0057] ≪Synthesis of Compound 1-a≫ To a flask, compound 1-b (51 mg, 0.15 mmol), (S,S)-[N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine] manganese(III) chloride (Jacobsen catalyst (S,S)) (16 mg, 0.025 mmol), and Na2HPO4 solution (2.56 mg, 0.021 mmol) and DCM (2 mL) contained in H2O (0.4 mL) were added respectively. The reaction mixture was cooled to 0 °C, and a solution of sodium hypochlorite (42 mg, 0.57 mmol) contained in H2O (1.03 mL) was gradually added to the mixture under this condition. Then, the reaction was stirred at 25 °C for 12 hours. After the raw materials were consumed (confirmed by LCMS), the reaction was diluted with water (10 mL) and extracted with DCM (20 mL * 2). The combined organic layers were washed with brine, dehydrated with anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by silica column (EA:PE = 0~30%) to obtain compound 1-a (51 mg, yield 96%).

[0058] ≪Synthesis of Compound 1≫ Sodium borohydride (10.5 mg, 0.28 mmol) was added to a solution of compound 1-a (51 mg, 0.14 mmol) in THF (1.5 mL) under N2. Then, the reaction mixture was stirred at 50 °C for 12 hours under N2. After the raw materials were consumed (confirmed by LCMS), the reaction was quenched with saturated NH4Cl (10 mL) and extracted with ethyl acetate (20 mL * 2). The combined organic layers were washed with brine, dehydrated with anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by silica column (EA:PE = 0~40%) to obtain compound 1 (13.3 mg, yield 26%). MS (found): 370.0 [M+H] + ; 11H NMR (400 MHz, CDCl3): δ 8.95 (d, J = 2.2 Hz, 1H), 8.22 - 8.18 (m, 1H), 8.12 - 8.06 (m, 2H), 7.51 - 7.46 (m, 2H), 4.30 - 4.19 (m, 1H), 3.19 (dd, J = 17.0, 4.0 Hz, 1H), 2.98 (dd, J = 17.1, 3.8 Hz, 1H), 2.54 - 2.48 (m, 2H), 2.48 - 2.40 (m, 1H), 2.13 - 2.03 (m, 2H), 1.82 - 1.73 (m, 1H).

[0059] <Example 2: Synthetic Route of Compound 2>

Chemical Structure

[0060] ≪Synthesis of Compound 2-a≫ To a mixture of 1-e (98 mg, 0.28 mmol), (R,R)-[N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine] manganese(III) chloride (Jacobsen catalyst (R,R)) (31.7 mg, 0.05 mmol), and Na2HPO4 (5.07 mg, 0.042 mmol) in H2O (0.4 mL) and DCM (4 mL) cooled to 0 °C was added a solution of sodium hypochlorite (83.8 mg, 1.12 mmol) in H2O (2.04 mL). The reaction mixture was stirred at 25 °C for 12 hours. After the raw materials were consumed (confirmed by LCMS), the reaction was diluted with water (20 mL) and extracted with DCM (30 mL * 2). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by silica column (EA:PE = 0 - 30%) to obtain Compound 2-a (65 mg, yield 63%).

[0061] ≪Synthesis of Compound 2≫ A solution of compound 2-a (65 mg, 0.18 mmol) in THF (2 mL) was added with sodium borohydride (13 mg, 0.35 mmol) under N2. Subsequently, the reaction mixture was stirred at 50 °C for 12 h under N2. After the raw materials were consumed (confirmed by LCMS), the reaction was quenched with saturated NH4Cl (10 mL), and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by silica column (EA:PE = 0~40%) to obtain compound 2 (9.01 mg, yield 14%). MS (found): 370.0 [M+H] + ; 1 H NMR (400 MHz, CDCl3): δ 8.96 (d, J = 2.3Hz, 1H), 8.23 - 8.19 (m, 1H), 8.12 - 8.07 (m, 2H), 7.51 - 7.45 (m, 2H), 4.26 (dd, J = 9.6Hz, 4.0 Hz, 1H), 3.19 (dd, J = 17.0Hz, 4.1Hz, 1H), 3.00 - 2.94 (m, 1H), 2.55 - 2.47 (m, 2H), 2.43 (dd, J = 12.3, 8.6Hz, 1H), 2.13 - 2.03 (m, 2H), 1.80 - 1.72 (m, 1H).

[0062] <Example 3: Synthetic Route of Compound 3>

Chemical Structure

[0063] ≪Synthesis of Compound 3-g≫ A mixture containing diethyl cyanomethylphosphonate (81.12 g, 457.94 mmol), TEA (46.29 g, 456.96 mmol), and lithium bromide (39.42 g, 458.33 mmol) in THF (400 mL) was stirred at 25 °C for 2 h. Then, cyclopentanone (35 g, 416.07 mmol) was added to the mixture, and some solids were separated and removed. Subsequently, the mixture was stirred at 25 °C for 12 h. TLC (EA:PE = 1:20, KMnO4) indicated that the raw materials were consumed and new spots were detected. The reaction mixture was diluted with water (300 ml) and extracted with ethyl acetate (500 mL * 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by silica column (EA:PE = 0 - 5%, detected at 220 nm) to obtain compound 3-g (33 g, yield 74%). 1 1H NMR (400 MHz, CDCl3): δ 5.23 - 5.14 (m, 1H), 2.66 - 2.48 (m, 2H), 2.47 - 2.37 (m, 2H), 1.80 - 1.67 (m, 4H).

[0064] ≪Synthesis of Compound 3-f≫ To a solution of compound 3-g (33 g, 307.95 mmol) in DCM (300 mL), 1.0 mol / L DIBAL-H in hexane (616.9 mL, 616.9 mmol) was slowly added at -78 °C under N2. After the addition, the reaction mixture was left to warm to 0 °C and stirred at 0 °C under N2 for 2.5 h. TLC (EA:PE = 1:8, 254 nm) indicated that the raw materials were consumed. The reaction mixture was slowly poured into a 0 °C 1M H2SO4 solution (600 mL) and stirred for 30 min. Then, the organic layer was separated, and the aqueous phase was extracted with DCM (300 mL * 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated at 25 °C in vacuo, and purified by silica column (DCM:PE = 0 - 20%) to obtain compound 3-f (13 g, yield 38%). 11H NMR (400 MHz, CDCl3): δ 9.77 (d, J = 8.0 Hz, 1H), 6.02 - 5.87 (m, 1H), 2.73 (t, J = 7.3 Hz, 2H), 2.47 (t, J = 7.2 Hz, 2H), 1.82 - 1.72 (m, 2H), 1.66 (dd, J = 13.8, 6.8 Hz, 2H).

[0065] ≪Synthesis of Compound 3-e≫ To a solution of 5-bromo-3-iodo-2-methoxypyridine (5 g, 15.93 mmol) in THF (50 mL), i-PrMgBr (2.8 M in 2-MeTHF, 6.3 mL, 17.64 mmol) was gradually added at 0 °C under N2. The reaction mixture was stirred at 0 °C for 1 h. Then, compound 3-f (2.11 g, 19.15 mmol) was added to the reaction mixture. Then the reaction mixture was stirred under these conditions for 1 h. After the raw materials were consumed (confirmed by LCMS), the reaction was quenched with saturated NH4Cl (200 mL), and the mixture was extracted with ethyl acetate (200 mL × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo, and purified by silica column (EA:PE = 0~25%) to obtain compound 3-e (1.1 g, yield 23%). 1 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 5.44 (dd, J = 5.4, 3.5 Hz, 2H), 3.97 (s, 3H), 2.53 - 2.39 (m, 2H), 2.31 (d, J = 8.4 Hz, 3H), 1.77 - 1.65 (m, 3H).

[0066] ≪Synthesis of Compound 3-d≫ A mixture containing compound 3-e (1.1 g, 3.69 mmol) in glacial acetic acid (20 mL) was added with 33% HBr / AcOH (2.1 mL, 12.92 mmol). Subsequently, the reaction mixture was stirred at 80 °C for 3 hours. After the raw materials were consumed (confirmed by LCMS), the reaction mixture was directly concentrated to remove the solvent. Saturated sodium carbonate (200 mL) was added to the resulting residue, and the mixture was extracted with ethyl acetate (50 ml * 2). The combined organic layers were washed with brine, dehydrated with anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by silica column (EA:PE = 0~10%) to obtain compound 3-d (84 mg, yield 8.5%). 1 H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 2.4 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 6.25 (d, J = 9.8 Hz, 1H), 5.73 (d, J = 9.8 Hz, 1H), 2.26 - 2.14 (m, 2H), 2.05 - 1.97 (m, 2H), 1.70 (t, J = 4.7 Hz, 4H).

[0067] ≪Synthesis of Compound 3-c≫ To a mixture containing 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (149 mg, 0.59 mmol), compound 3-d (103 mg, 0.39 mmol) and potassium acetate (116 mg, 1.2 mmol) in 1,4-dioxane (5 mL) was added Pd(dppf)Cl2 (29 mg, 0.04 mmol). After the addition, the reaction mixture was bubbled with N2 for 3 minutes. The reaction mixture was stirred at 85 °C for 3 hours. After the raw materials were consumed (confirmed by LCMS), the reaction mixture was concentrated and purified by silica column (EA:PE = 0~15%) to obtain compound 3-c (150 mg, crude).

[0068] ≪Synthesis of Compound 3-b≫ A mixture of compound 1-h (125 mg, 0.58 mmol), compound 3-c (150 mg, crude), and sodium carbonate (132 mg, 0.96 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was added with Pd(dppf)Cl2 (18 mg, 0.024 mmol) under N2. After the addition, the reaction mixture was bubbled with N2 for 3 minutes. The reaction mixture was stirred at 100 °C for 3 hours. After the raw materials were consumed (confirmed by LCMS), the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by silica column (EA:PE = 0 - 30%) to obtain compound 3-b (72 mg, yield 51%).

[0069] ≪Synthesis of Compound 3-a≫ A solution of compound 3-b (72 mg, 0.20 mmol), (S,S)-[N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine]manganese(III) chloride (Jacobsen catalyst (S,S)) (19 mg, 0.03 mmol), and Na2HPO4 (4.3 mg, 0.03 mmol) in H2O (0.5 mL) and a mixture of DCM (5 mL) cooled to 0 °C was gradually added with a solution of sodium hypochlorite (60 mg, 0.8 mmol) in H2O (1 mL). Then, the reaction mixture was stirred at 25 °C for 12 hours. After the raw materials were consumed (confirmed by LCMS), the reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by silica column (EA:PE = 0 - 30%) to obtain compound 3-a (42 mg, yield 56%).

[0070] ≪Synthesis of Compound 3≫ A mixture containing compound 3-a (42 mg, 0.11 mmol) in THF (3 mL) was added with sodium borohydride (13 mg, 0.33 mmol) under N2. Then the reaction mixture was stirred at 50 °C for 12 h under N2. After the raw materials were consumed (confirmed by LCMS), the reaction was quenched with saturated NH4Cl (10 mL), and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by preparative HPLC to obtain compound 3 (3.01 mg, yield 7.1%). MS (found) 384.1 [M+1] + ; 1 H NMR (400 MHz, CDCl3): δ 8.90 (s, 1H), 8.14 (d, J = 51.1 Hz, 3H), 7.47 (s, 2H), 4.02 (s, 1H), 3.16 (d, J = 15.3 Hz, 1H), 2.98 (d, J = 15.4 Hz, 1H), 2.29 (s, 1H), 2.05 (d, J = 38.5 Hz, 4H), 1.77 (s, 3H).

[0071] <Example 4: Synthetic route of compound 4>

Chemical formula

[0072] ≪Synthesis of compound 4-f≫ To a mixture containing 4-chloro-3-fluorobenzonitrile (311 mg, 2 mmol) in EtOH (10 mL) was added 50% aqueous NH2OH solution (528 mg, 8 mmol). The mixture was stirred at 90 °C for 1 h. Then LCMS indicated that the desired product was formed. The mixture was concentrated in vacuo to obtain compound 4-f (350 mg, yield 93%).

[0073] ≪Synthesis of compound 4-e≫ 1-d (7.7 g, 30.54 mmol), Zn(CN)2 (14.3 g, 112.16 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (S-Phos, 2.5 g, 6.11 mmol), and Pd2(dba)3 (5.6 g, 6.11 mmol) were included in DMF (200 mL), and the mixture was heated at 100 °C for 1 hour in a microwave reactor. Saturated aqueous NH4Cl solution (50 mL) was added, and the mixture was partitioned between water (100 mL) and DCM (100 mL), and the layers were separated. The organic layer was washed with brine (20 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with 0 - 25% EtOAc / hexane to obtain compound 4-e (4.3 g, yield 71%).

[0074] ≪Synthesis of Compound 4-d≫ To a solution of compound 4-e (3 g, 15.13 mmol) in MeOH (80 mL), concentrated H2SO4 (20 mL) at 0 °C was gradually added. After the addition, the reaction mixture was stirred at 80 °C for 24 hours. The solution was cooled to room temperature and concentrated under reduced pressure. Then DCM (100 mL) and NaOH (2 M) were added to adjust the pH to 7 - 8, and the layers were separated. The aqueous layer was treated with DCM (50 mL), the organic phases were combined, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with 0 - 25% EtOAc / hexane to obtain compound 4-d (2.4 g, yield 69%).

[0075] ≪Synthesis of Compound 4-c≫ A solution containing Compound 4-d (1.5 g, 6.49 mmol), (S,S)-[N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine] manganese(III) chloride (Jacobsen catalyst (S,S)) (0.72 g, 1.13 mmol), and Na2HPO4 (0.12 g, 0.85 mmol) in H2O (18 mL), and a mixture of DCM (80 mL) cooled to 0 °C were added dropwise with a solution of sodium hypochlorite (1.93 g, 25.96 mmol) in H2O (46 mL). Then, the reaction mixture was stirred at rt (25 °C) for 12 hours. After the starting materials were consumed (confirmed by LCMS), the reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by silica column (EA:PE = 0 - 30%) to obtain Compound 4-c (850 mg, yield 53%).

[0076] ≪Synthesis of Compound 4-b≫ To a mixture containing Compound 4-c (850 mg, 3.44 mmol) in MeOH (20 mL), 10% Pd / C (250 mg) containing water was added. The mixture was purged with H2 twice. Then, the mixture was stirred at rt (25 °C) for 12 hours. The mixture was filtered, and the filter cake was washed with MeOH (50 mL × 2). The filtrate was concentrated in vacuo to obtain the crude compound (830 mg), which was dissolved in MeOH (35 mL) and purified by supercritical fluid chromatography (SFC). The eluent was concentrated in vacuo, and the residue was dried to obtain Compound 4-b (430 mg, yield 50%).

[0077] ≪Synthesis of Compound 4-a≫ To a mixture of compound 4-b (430 mg, 1.73 mmol) and H2O (8 mL) in MeOH (20 mL) was added sodium hydroxide (138 mg, 3.46 mmol). The mixture was stirred at 25 °C for 12 h. The solution was concentrated under reduced pressure and diluted with H2O (8 mL). The pH of the mixture was adjusted to 6 with HCl (2 M). The mixture was dried by lyophilization. 600 mg of compound 4-a was obtained. Some NaCl remained. This product was used in the next step reaction without purification.

[0078] ≪Synthesis of Compound 4≫ To a mixture of compound 4-a (100 mg, 0.43 mmol) in DMF (2 mL) was added CDI (139 mg, 0.86 mmol). The mixture was stirred at 25 °C for 1 h. Then 4-f (121 mg, 0.64 mmol) was added to the above mixture and the mixture was stirred at 120 °C for 12 h. The mixture was purified by preparative HPLC to give compound 4 (21.07 mg, yield 13%). MS (found) 388.1 [M+1] + ; 1 H NMR (400 MHz, CDCl3): δ 8.87 (d, J = 1.9 Hz, 1H), 8.13 (s, 1H), 7.92 - 7.79 (m, 2H), 7.53 - 7.44 (m, 1H), 4.19 (t, J= 3.9 Hz, 1H), 3.12 (dd, J = 17.0, 3.9 Hz, 1H), 2.96-2.89 (m, 1H), 2.45 (dd, J= 10.5, 6.6 Hz, 2H), 2.41-2.33 (m, 1H), 2.07-1.93 (m, 2H), 1.78-1.65 (m,1H).

[0079] <Example 5: Synthetic Route of Compound 5>

Chemical Structure

[0080] ≪Synthesis of Compound 5-a≫ A mixture of 4-methylbenzonitrile (500 mg, 4.27 mmol) in EtOH (10 mL) was added with 50% aqueous NH₂OH solution (1.13 g, 17.08 mmol). The mixture was stirred at 90 °C for 1 hour. Then, LCMS indicated that the desired product was formed. The mixture was concentrated in vacuo to obtain compound 5-a (520 mg, 81% yield).

[0081] ≪Synthesis of Compound 5≫ To a solution of compound 4-a (125 mg, 0.53 mmol) in DMF (3 mL) was added CDI (172 mg, 1.06 mmol). The mixture was stirred at 25 °C for 1 hour. Then compound 5-a (120 mg, 0.8 mmol) was added to the above mixture and stirred at 120 °C for 3 hours. LCMS showed that the desired product was generated. The mixture was extracted with EtOAc (80 mL * 3). The organic layer was concentrated in vacuo. The product was purified by preparative HPLC to obtain compound 5 (9.75 mg, 5.3% yield). MS (found) 350.1 [M+1] + ; 1 H NMR (400 MHz, CDCl₃): δ 8.91 (d, J = 1.8 Hz, 1H), 8.19 (s, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 4.24 (t, J = 3.8 Hz, 1H), 3.17 (dd, J = 17.0, 3.8 Hz, 1H), 2.97 (dd, J = 17.0, 3.7 Hz, 1H), 2.50 (t, J = 8.3 Hz, 2H), 2.42 (s, 3H), 2.13 - 2.02 (m, 2H), 1.82 - 1.70 (m, 2H).

[0082] <Example 6: Synthetic Route of Compound 6>

Chemical Structure

[0083] ≪Synthesis of Compound 6-a≫ A mixture of 1-methyl-1H-pyrazole-3-carbonitrile (100 mg, 0.93 mmol) in EtOH (5 mL) was added with 50% aqueous NH₂OH solution (246 mg, 3.72 mmol). The mixture was stirred at 90 °C for 1 h. Subsequently, LCMS indicated that the desired product was formed. The mixture was concentrated in vacuo to give compound 6-a (130 mg, 99% yield).

[0084] ≪Synthesis of Compound 6≫ To a mixture of compound 4-a (146 mg, 0.62 mmol) in DMF (3 mL) was added CDI (201 mg, 1.24 mmol). The mixture was stirred at 25 °C for 1 h. Then 6-a (140 mg, 0.93 mmol) was added to the above mixture and stirred at 120 °C for 3 h. LCMS indicated that the desired product was generated. The product was purified by preparative HPLC to give compound 6 (46.17 mg, 22% yield). MS (found) 340.1 [M+1] + ; 1 H NMR (400 MHz, CDCl₃): δ 8.98 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 1.0 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 6.87 (d, J = 2.3 Hz, 1H), 4.22 (t, J = 3.9 Hz, 1H), 4.02 (s, 3H), 3.14 (dd, J = 17.0, 4.0 Hz, 1H), 2.93 (dd, J = 17.1, 3.9 Hz, 1H), 2.57 - 2.31 (m, 3H), 2.03 (ddd, J = 14.6, 10.4, 5.8 Hz, 3H), 1.84 - 1.63 (m, 1H).

[0085] <Example 7: Synthetic Route of Compound 7>

Chemical Structure

[0086] ≪Synthesis of Compound 7-a≫ To a solution of compound 4-b (150 mg, 0.60 mmol) in EtOH (10 mL) was added hydrazine monohydrate (2 mL). The mixture was stirred at 90 °C for 12 h. The solvent was removed in vacuo, and the crude product was triturated with PE to give compound 7-a (140 mg, 93% yield).

[0087] <Synthesis of Compound 7> To a solution of compound 7-a (140 mg, 0.56 mmol) in DCM (20 mL) was added 4-chlorobenzaldehyde (79 mg, 0.56 mmol) and ceric ammonium nitrate (307 mg, 0.56 mmol). The mixture was stirred at 40° C. for 12 h. The mixture was purified by preparative HPLC to give compound 7 as a white solid (6.15 mg, 3% yield). MS (observed) 370.0 [M+1] + ; 1 H NMR (400 MHz, CDCl3): δ 8.75 (d, J= 2.2 Hz, 1H), 8.15 - 8.07 (m, 1H), 8.05 - 7.96 (m, 2H), 7.48 - 7.41 (m, 2H), 4.18 (t, J = 3.9 Hz, 1H), 3.11 (dd, J = 17.1, 4.0 Hz, 1H), 2.90 (dd, J = 17.2, 3.9 Hz, 1H), 2.44 (t, J = 8.5 Hz, 2H), 2.38 - 2.32 (m, 1H), 2.08 - 1.99 (m, 2H), 1.77 (d, J = 9.1 Hz, 1H).

[0088] <Example 8: Synthesis route of compound 8> [ka]

[0089] <Synthesis of compound 8-c> A mixture containing compound 4-e (120 mg, 0.61 mmol) in EtOH (5 mL) was added with an aqueous 50% NH₂OH solution (161 mg, 2.44 mmol). The mixture was stirred at 90 °C for 1 hour. Subsequently, LCMS indicated that the desired product was formed. The mixture was concentrated in vacuo to obtain compound 8-c (130 mg, 93% yield).

[0090] ≪Synthesis of Compound 8-b≫ To a mixture containing 4-chlorobenzoic acid (58 mg, 0.37 mmol) in DMF (3 mL) was added CDI (120 mg, 0.74 mmol). The mixture was stirred at 25 °C for 1 hour. Then compound 8-c (130 mg, 0.56 mmol) was added and the mixture was stirred at 120 °C for 3 hours. LCMS showed that the desired product was formed. After the raw materials were consumed (confirmed by LCMS), the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by silica column (EA:PE = 0 - 20%) to obtain compound 8-b (30 mg, 23% yield).

[0091] ≪Synthesis of Compound 8-a≫ To a mixture of compound 8-b (30 mg, 0.085 mmol), (S,S)-[N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine]manganese(III) chloride (Jacobsen catalyst) (S,S) (8.3 mg, 0.013 mmol), a solution of Na₂HPO₄ (1.7 mg, 0.012 mmol) in H₂O (0.2 mL), and DCM (2 mL) cooled to 0 °C was gradually added a solution of sodium hypochlorite (25 mg, 0.34 mmol) in H₂O (0.5 mL). Then, the reaction was stirred at 25 °C for 12 hours. After the raw materials were consumed (confirmed by LCMS), the reaction was diluted with water (10 mL) and extracted with DCM (20 mL × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by silica column (EA:PE = 0 - 30%) to obtain compound 8-a (27 mg, 86% yield).

[0092] ≪Synthesis of Compound 8≫ Sodium borohydride (5.76 mg, 0.152 mmol) was added to a mixture of compound 8-a (28 mg, 0.076 mmol) in THF (2 mL) under N2. Then the reaction mixture was stirred at 50 °C for 12 h under N2. After consumption of the starting material (confirmed by LCMS), the reaction was quenched with saturated NH4Cl (10 mL), and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by silica column (EA:PE = 0 - 40%) to give compound 8 (2.57 mg, yield 9.1%). MS (found): 370.0 [M+H] + ; 1 H NMR (400 MHz, CDCl3): δ 8.90 (d, J = 2.1 Hz, 1H), 8.20 - 8.11 (m, 3H), 7.54 (d, J = 8.6 Hz, 2H), 4.23 (t, J = 3.8 Hz, 1H), 3.18 (dd, J = 17.0, 4.1 Hz, 1H), 2.96 (dd, J = 17.1, 3.8 Hz, 1H), 2.49 (dd, J = 15.6, 6.9 Hz, 2H), 2.44 - 2.37 (m, 1H), 2.13 - 2.03 (m, 2H), 1.80 - 1.72 (m, 1H).

[0093] <Example 9: Synthetic Route of Compound 9>

Chemical Structure

[0094] ≪Synthesis of Compound 9-f-1≫ A mixture of 5-bromo-2-chloronicotinaldehyde (1.00 g, 4.54 mmol), methyl (triphenylphosphoranylidene) acetate (1.82 g, 5.44 mmol) and THF (20 mL) was stirred at 80 °C for 2 h under N2. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was purified by flash chromatography (PE / EA = 2:1) to give compound 9-f-1 (190 mg, yield 15%) as a white solid and compound 9-f-2 (877 mg, yield 70%) as a white solid. Compound 9-f-1: LC-MS (ESI): m / z = 275.9 [M+1] + ; Compound 9-f-2: MS (found): 275.9 [M+1] + .

[0095] ≪Synthesis of Compound 9-e-1≫ A solution of compound 9-f-1 (190 mg, 0.69 mmol) in THF (10 mL) cooled to 0 °C was gradually added with a CD3MgI solution (2.06 mL, 2.06 mmol, 1 M) in ethyl ether under N2. After the addition, the mixture was stirred at 0 °C for 2 h. The reaction was quenched with saturated NH4Cl (30 mL), and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by flash chromatography (PE / EA = 2:1) to give compound 9-e-1 (120 mg, yield 62%) as a white solid. MS (found): 281.9 [M+H] + .

[0096] ≪Synthesis of Compound 9-d≫ To a solution of compound 9-e-1 (10 mg, 0.035 mmol) in N,N-dimethylacetamide (2 mL) at room temperature, cesium carbonate (23 mg, 0.071 mmol) was added. The mixture was stirred at 80 °C overnight. The reaction mixture was cooled to room temperature and H2O (10 mL) was added. The mixture was extracted with ethyl acetate (25 mL × 2), the organic phases were combined, washed with saturated NH4Cl (50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (PE / EA = 2:1) to afford compound 9-d (6 mg, 69%) as a white solid. MS (found): 246.0 [M+H] + .

[0097] ≪Synthesis of Compound 9≫ According to Example 1, compound 9 was obtained using compound 9-d instead of compound 1-d. MS (found): 364.1 [M+H] + .

[0098] Other examples not specifically described above were prepared in the same manner.

[0099] For the data in Table 1, the Bight-Glo (trademark) luciferase assay system manufactured by Promega was used together with the SBE reporter·HEK293 cell line for the TGF / SMAD signaling pathway manufactured by BPSbioscience. On the first day, SBE reporter·HEK293 cells were seeded at a cell density of 25,000 cells per well in 100 μL of growth medium without geneticin (registered trademark) in a white and clear-bottom 96-well microplate. The plate was incubated at 37 °C in a CO2 incubator for 24 hours. The wells were supplemented with 60 μL of assay medium and treated with the test compound by adding 5 μL of the compound included in the medium. The concentration of the test compound included in the medium was adjusted so that a solution of the desired molar concentration was provided in 5 μL. After 4 hours, TGFβ was added to a concentration of 10 ng / mL. The plate was incubated at 37 °C in a CO2 incubator overnight (18 hours). One hour before the assay, all the medium was replaced. The luciferase assay was performed using the ONE-Step (trademark) luciferase assay system by adding 100 μL of the ONE-Step (trademark) luciferase reagent per well, rocking at room temperature for approximately 15 - 30 minutes, and measuring the luminescence using a luminometer. This signal was normalized to the inhibition rate (%) with TGF-untreated cells set as 100% inhibition, and the data was processed using Graphpad Prism.

[0100] The test results of the luciferase screening are shown in Table 1. The symbol "***" indicates IC 50 <100 nM, "**" indicates IC 50 ≧100 nM but <10 μM, and "*" indicates IC 50 ≧10 μM.

[0101]

Table 1

[0102] Although exemplary embodiments have been described for illustrative purposes, the foregoing description and examples should not be regarded as limitations on the scope of the invention. Accordingly, 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. Formula I: 【Chemical 1】 (In the above formula: Ar is C ６‐２０ aryl, C substituted with one or more R １‐１ ; aryl, "5- to 12-membered heteroaryl containing 1 to 4 heteroatoms selected from O, S, and N", or "5- to 12-membered heteroaryl containing 1 to 4 heteroatoms selected from O, S, and N" substituted with one or more R ６‐２０ ; and R is １‐２ ; provided that Ar is not phenyl when R is hydrogen R １‐１ and R １‐２ are each independently selected from halogen, hydroxyl and C １‐６ alkyl; [Chemical Formula 2] is a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from O, S, and N; R １ and R ２ are each independently selected from hydrogen, deuterium, hydroxyl, C １‐６ alkyl, amino, and -OC １‐６ alkyl; R ３ and R ４ is C alkyl substituted with deuterium, or R １‐６ and R ３ and R ４ is R ３ and R ４ together with the atom to which they are attached, form C ３‐８ cycloalkyl, C cycloalkyl substituted with R １‐３ 4- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from O, S and N, C cycloalkyl substituted with R ３‐８ form "4- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from O, S and N" substituted with R; and １‐４ ​ R １‐３ and R １‐４ are each independently selected from halogen, deuterium, hydroxyl and C １‐６ alkyl). a heterocyclic compound containing oxygen represented by, a pharmaceutically acceptable salt of the compound, a deuterated derivative of the compound, a solvate of the compound, a solvate of the pharmaceutically acceptable salt of the compound, or a crystalline form of the compound.

2. The heterocyclic compound containing oxygen represented by Formula I is of Formula II: 【Chemical Formula 3】 (In the above formula: 【Chemical 4】 represents 【Chemical Formula 5】 a mixture of; n is 1, 2, 3, 4, or 5; and Ar and 【Chemical Formula 6】 are defined as in Formula I) The heterocyclic compound containing oxygen represented by Formula I according to Claim 1, which has the structure of, a pharmaceutically acceptable salt of the compound, a deuterated derivative of the compound, a solvate of the compound, a solvate of the pharmaceutically acceptable salt of the compound, or a crystalline form of the compound.

3. Ar is C substituted by one or more Rs １‐１ aryl, or "5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N" substituted by one or more Rs ６‐２０ wherein; １‐２ ​ R １‐１ and R １‐２ are each independently selected from halogen and C １‐６ alkyl; 【Chemical Formula 7】 is a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from O, S, and N; 【Chemical 8】 is 【Chemical Formula 9】 represents; and n is 2 or 3, The heterocyclic compound containing oxygen represented by Formula II according to Claim 2, a pharmaceutically acceptable salt of the compound, a deuterated derivative of the compound, a solvate of the compound, a solvate of the pharmaceutically acceptable salt of the compound, or a crystalline form of the compound.

4. The heterocyclic compound containing oxygen represented by Formula I is of Formula III: 【Chemical Formula 10】 (In the above formula: Ar and 【Chemical Formula 11】 are defined as in Formula I; 【Chemical 12】 is 【Chemical 13】 a mixture of; and R ３ and R ４ is C substituted with deuterium １‐６ alkyl) having the structure of, the heterocyclic compound containing oxygen represented by Formula I according to Claim 1, a pharmaceutically acceptable salt of the compound, a deuterated derivative of the compound, a solvate of the compound, a solvate of the pharmaceutically acceptable salt of the compound, or a crystalline form of the compound.

5. Formula III has the following structure: 【Chemical 14】 (In the above formula: 【Chemical Formula 15】 , Ar and 【Chemical 16】 are defined as in Formula III) The heterocyclic compound containing oxygen represented by Formula III according to Claim 4, having the structure of, a pharmaceutically acceptable salt of the compound, a deuterated derivative of the compound, a solvate of the compound, a solvate of the pharmaceutically acceptable salt of the compound, or a crystalline form of the compound.

6. Ar is C substituted by one or more Rs １‐１ aryl, or "5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N" substituted by one or more Rs ６‐２０ wherein the substitution is as defined in １‐１ and ６‐２０ ; １‐２ and is as defined in １‐２ . R １‐１ and R １‐２ are each independently selected from halogen and C １‐６ alkyl; 【Chemical 17】 is a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from O, S, and N; 【Chemical 18】 is 【Chemical 19】 represents; and n is 2 or 3, The heterocyclic compound containing oxygen represented by formula II according to claim 2, a pharmaceutically acceptable salt of the compound, a deuterated derivative of the compound, a solvate of the compound, a solvate of a pharmaceutically acceptable salt of the compound, or a crystalline form of the compound.

7. Ar is C ６‐２０ aryl, or C substituted with one or more Rs １‐１ When it is aryl substituted with one or more Rs ６‐２０ aryl, and C substituted with one or more Rs ６‐２０ aryl, and C substituted with one or more Rs １‐１ When it is aryl substituted with one or more Rs ６‐２０ C in the aryl substituted with one or more Rs ６‐２０ The aryl is C ６‐１０ aryl; C ６‐１０ The aryl is phenyl or naphthyl; and / or, Ar is "a 5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S, and N", or a "5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S, and N" substituted with one or more R １‐２ when it is "a 5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S, and N", or a "5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S, and N" substituted with one or more R １‐２ the "5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S, and N" among the "5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S, and N" and the "5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S, and N" substituted with one or more R is a "5-membered heteroaryl containing 2 heteroatoms selected from N"; and / or 【Chemical 20】 when it is a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from O and N 【Chemical 21】 is a 5-membered heteroaryl containing 3 heteroatoms independently selected from O and N; and / or, R １‐１ and R １‐２ when R and R are each independently selected from halogen, the halogen is -F, -Cl, -Br or -I; and / or, R １‐１ and R １‐２ is independently C １‐６ alkyl, when selected, C １‐６ alkyl is C １‐４ alkyl, i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, or may be methyl: and / or, R ３ and R ４ where R ３及 and R ４ together with the atoms to which they are attached to C ３‐８ forms a cycloalkyl, the cycloalkyl C ３‐８ is cycloalkyl C ３ cycloalkyl C ４ cycloalkyl C ５ cycloalkyl C ６ cycloalkyl C ７ cycloalkyl, or C ８ [[ID= and / or, R ３ and R ４ when C １‐６ alkyl is replaced by deuterium, C １‐６ alkyl is C １‐４ alkyl, i.e., it may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, or it may be methyl; and / or, R ３ and R ４ when the C １‐６ alkyl substituted with deuterium is C １‐６ alkyl substituted with deuterium is -CD ３ is The heterocyclic compound containing oxygen represented by formula I according to claim 1, a pharmaceutically acceptable salt of the compound, a deuterated derivative of the compound, a solvate of the compound, a solvate of a pharmaceutically acceptable salt of the compound, or a crystalline form of the compound.

8. Ar is 【Chemical 22】 ; and / or 【Chemical 23】 is 【Chemical 24】 ; and / or 【Chemical 25】 is 【Chemical 26】 ; The heterocyclic compound containing oxygen represented by formula I according to claim 1, a pharmaceutically acceptable salt of the compound, a deuterated derivative of the compound, a solvate of the compound, a solvate of a pharmaceutically acceptable salt of the compound, or a crystalline form of the compound.

9. 【Fig. 27】 is 【Chemical formula 28】 ; The heterocyclic compound containing oxygen represented by formula I according to claim 1, a pharmaceutically acceptable salt of the compound, a deuterated derivative of the compound, a solvate of the compound, a solvate of a pharmaceutically acceptable salt of the compound, or a crystalline form of the compound.

10. R １ is hydrogen; R ２ is selected from hydrogen, deuterium, and hydroxyl; R ３ and R ４ is C １‐６ alkyl substituted with deuterium, or R ３ and R ４ are such that R ３ and R ４ together with the atom to which they are attached form C ３‐６ cycloalkyl; 【Chemical 29】 is oxadiazolyl; and Ar is phenyl substituted with one or more Rs １‐１ and pyrazolyl substituted with one or more Rs １‐２ selected from The compound according to claim 1, a pharmaceutically acceptable salt of the compound, a deuterated derivative of the compound, a solvate of the compound, a solvate of a pharmaceutically acceptable salt of the compound, or a crystalline form of the compound.

11. The heterocyclic compound containing oxygen of formula I has the following structure: 【Chemical Formula 30】 having any one of The heterocyclic compound containing oxygen represented by formula I according to claim 1, a pharmaceutically acceptable salt of the compound, a deuterated derivative of the compound, a solvate of the compound, a solvate of a pharmaceutically acceptable salt of the compound, or a crystalline form of the compound.

12. A pharmaceutical composition comprising substance A and a pharmaceutically acceptable excipient, wherein substance A is a therapeutically effective amount of the heterocyclic compound containing oxygen represented by formula I according to claim 1, a pharmaceutically acceptable salt of the compound, a deuterated derivative of the compound, a solvate of the compound, a solvate of a pharmaceutically acceptable salt of the compound, or a crystalline form of the compound.

13. A method for inhibiting the interaction between homeodomain interacting protein kinase 2 and Smad3, said method comprising binding HIPK2 to substance A, wherein substance A is a therapeutically effective amount of a heterocyclic compound containing oxygen of formula I according to claim 1, a pharmaceutically acceptable salt of said compound, a deuterated derivative of said compound, a solvate of said compound, a solvate of a pharmaceutically acceptable salt of said compound, or a crystalline form of said compound.

14. A method for inhibiting the activation of Smad3, said method comprising contacting Smad3 with substance A, wherein substance A is a therapeutically effective amount of a heterocyclic compound containing oxygen of formula I according to claim 1, a pharmaceutically acceptable salt of said compound, a deuterated derivative of said compound, a solvate of said compound, a solvate of a pharmaceutically acceptable salt of said compound, or a crystalline form of said compound.

15. A method for treating fibrosis, comprising administering substance A to a subject suffering from fibrosis, wherein substance A is a therapeutically effective amount of a heterocyclic compound containing oxygen of formula I according to claim 1, a pharmaceutically acceptable salt of said compound, a deuterated derivative of said compound, a solvate of said compound, a solvate of a pharmaceutically acceptable salt of said compound, or a crystalline form of said compound, and the fibrosis is renal fibrosis, cardiac fibrosis, hepatic fibrosis, or pulmonary fibrosis.

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