YTHDC2 inhibitor as well as preparation method and application thereof

Abstract

The invention belongs to the field of chemical synthesis, and particularly relates to a YTHDC2 inhibitor and a preparation method and application thereof. A series of compounds capable of effectively inhibiting the activity of YTHDC2 are successfully found by preparing a series of compounds and screening the compounds. The compounds show a remarkable inhibition effect at low concentration, can be used as inhibitors, provide an important basis for subsequent drug development and related research, and have a broad application prospect in preparation of drugs for treating diseases related to YTHDC2 overexpression, research of functions and action mechanisms of YTHDC2 in organisms and specific effects of YTHDC2 in occurrence and development of diseases, and the application of YTHDC2 in preparation of drugs for treating diseases related to YTHDC2 overexpression in preparation of drugs for treating diseases related to YTHDC2 overexpression in preparation of drugs for treating diseases related to YTHDC2 overexpression. Good prospects are realized.

Description

Technical Field

[0001] The present invention belongs to the field of chemical synthesis, and specifically relates to a YTHDC2 inhibitor and its preparation method and use Background Art

[0002] YTHDC2 is a protein containing a YT521-B homology domain (YTH) and belongs to the YTH family. YTH family members can recognize and bind to m 6 YTHDC2 modifies RNA, thereby regulating gene expression after transcription. YTHDC2 has multiple RNA binding domains, including a highly conserved YTH domain and multiple helicase domains. 6 YTHDC2 is a protein that plays an important role in a variety of physiological and pathological processes, including cancer, neurological diseases, cardiovascular diseases, and metabolic diseases. Recent studies have revealed the potential mechanisms of action of YTHDC2 in these diseases, providing a theoretical basis for the development of new diagnostic and therapeutic strategies.

[0003] Studies have shown that elevated YTHDC2 expression is closely associated with a variety of diseases, including prostate cancer, rheumatoid arthritis, hepatitis C, and temporal lobe epilepsy with hippocampal sclerosis. YTHDC2 holds promise as a target for both diagnosis and treatment. While YTHDC2 demonstrates promising therapeutic potential in a variety of diseases, its specific mechanisms of action and regulatory networks in these conditions require further investigation. Furthermore, the development of inhibitors or modulators specific for YTHDC2 remains a significant challenge.

[0004] Therefore, developing a YTHDC2 inhibitor for use as a research tool for YTHDC2 or YTHDC2-related drug development is a challenge facing this field. Summary of the Invention

[0005] In view of the shortcomings of the prior art, the present invention provides a YTHDC2 inhibitor and a preparation method thereof, which aims to inhibit YTHDC2 with high activity and be used as a research tool or drug for YTHDC2.

[0006] The present invention provides a compound represented by Formula I or Formula II, or an optical isomer thereof, or a tautomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a hydrate thereof, or a solvate thereof, or a crystalline form thereof:

[0007]

[0008] in,

[0009] Ring A is selected from C6-C 10 Aryl, 8-20 membered fused heterocycloalkyl, 9-20 membered fused heteroaryl, C8-C20 Fused ring aromatic group, C7-C 20 Condensed cycloalkyl,

[0010] wherein ring F is selected from C6-C 10 Aryl, 6-10 membered heteroaryl, ring G is selected from C6-C 10 Aryl, 6-10 membered heteroaryl, R4 is selected from heteroatoms, p is selected from 0, 1, 2, q is selected from 1, 2, k is selected from 0, 1, 2, Indicates no chemical bond or double bond. When p is selected from 2, independently selected from no chemical bond or double bond;

[0011] Ring E is selected from C6-C 10 Aryl, 6-10 membered heteroaryl;

[0012] R1 is selected from halogen, hydroxy, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Alkoxy, substituted or unsubstituted C2-C 10 Ester group, substituted or unsubstituted C1-C 10 Carboxyl, substituted or unsubstituted C1-C 10 Sulfonamide, substituted or unsubstituted C7-C 11 Aralkyloxy, substituted or unsubstituted C7-C 11 Aroyl, substituted or unsubstituted C6-C 10 Aryloxy, substituted or unsubstituted C6-C 10 Aryl, wherein the substituent is selected from halogen, hydroxyl, C1-C 10 alkyl;

[0013] R2 is selected from halogen, hydroxy, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Alkoxy, substituted or unsubstituted C2-C 10 Ester group, substituted or unsubstituted C1-C 10 Carboxyl, wherein the substituent is selected from halogen, hydroxyl, C1-C 10 alkyl;

[0014] R3 is selected from hydrogen, C1-C 10 Alkyl, C6-C 10 Aryl, halogen, hydroxyl;

[0015] n is selected from 0, 1, 2, 3, 4, 5, 6;

[0016] m is selected from 0, 1, 2, 3, 4, and 5.

[0017] Preferably, ring A is selected from C6 aryl, 9-15 membered fused heterocycloalkyl, 9-13 membered fused heteroaryl, C 10 Fused ring aryl, C9 fused ring alkyl, wherein the heteroatoms in the fused heterocycloalkyl group and the fused heteroaryl group are independently selected from oxygen and nitrogen, the number of heteroatoms is 1 or 2, ring F is selected from C6 aryl, ring G is selected from C6 aryl, R4 is selected from oxygen, nitrogen, and sulfur, q is selected from 1, and k is selected from 0 and 1;

[0018] Ring E is selected from C6 aryl, 6-membered heteroaryl;

[0019] R1 is selected from fluorine, chlorine, bromine, hydroxyl, C1-C4 alkyl, C1-C2 alkoxy, C2-C3 ester, C1 carboxyl, C1 sulfonamide, C7 aralkyloxy, C7 aroyl, C6-aryloxy, C6 aryl;

[0020] R2 is selected from fluorine, chlorine, bromine, hydroxyl, substituted or unsubstituted C1 alkyl, C1 alkoxy, C2 ester, C1 carboxyl, wherein the substituent is selected from fluorine;

[0021] R3 is selected from hydrogen, C1 alkyl, C6 aryl;

[0022] n is selected from 0, 1, 2;

[0023] m is selected from 1, 2, 3, and 4.

[0024] Preferably, the structural formula of the compound is as shown in Formula I;

[0025] Ring A is selected from C6 aryl, 9-14 membered fused heterocycloalkyl, 9-13 membered fused heteroaryl, C9 fused cycloalkyl,

[0026] R4 is selected from oxygen and nitrogen;

[0027] Ring E is selected from C6 aryl;

[0028] R1 is selected from fluorine, chlorine, bromine, hydroxyl, C1 alkyl, C1-C2 alkoxy, C2-C3 ester, C1 carboxyl, C1 sulfonamide, C7 aralkyloxy, C7 aroyl, C6-aryloxy, C6 aryl;

[0029] R2 is selected from fluorine, chlorine, bromine, hydroxyl, substituted C1 alkyl, C2 ester, C1 carboxyl, wherein the substituent is selected from fluorine.

[0030] Preferably, ring A is selected from C6 aryl, 9-membered fused heteroaryl, wherein the number of heteroatoms in the fused heteroaryl group is 1, and k is selected from 0;

[0031] R1 is selected from fluorine, chlorine, bromine, hydroxyl, C1 alkyl, C1 alkoxy, C2 ester, C7 aralkyloxy; R2 is selected from fluorine, chlorine, bromine, hydroxyl;

[0032] R3 is selected from hydrogen, C1 alkyl.

[0033] Preferably, the compound represented by formula I is selected from one of the compounds represented by the following structural formulas:

[0034]

[0035]

[0036]

[0037]

[0038]

[0039] The present invention provides a method for preparing any of the above-mentioned compounds, or optical isomers, tautomers, deuterated compounds, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or crystalline forms thereof, comprising the following steps:

[0040]

[0041] Reactant 1 reacts with reactant 2 to obtain.

[0042] Preferably, the reaction is carried out in the presence of an organic base and a condensation activator;

[0043] And / or, the reaction temperature is 20-30°C.

[0044] Preferably, the organic base is selected from at least one of N-methylimidazole, 4-dimethylaminopyridine, N,N-diisopropylethylamine, and triethylamine, and the condensation activator is selected from at least one of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate, 1-propyl phosphoric anhydride, 1-butyl phosphoric anhydride, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

[0045] And / or, the molar ratio of reactant 1 to reactant 2 is 0.54-0.84:0.45-0.7;

[0046] And / or, the molar ratio of the reactant 1 to the organic base and the condensation activator is 0.54-0.84:

[0047] 1.57-2.44:0.58-0.91;

[0048] And / or, the reaction is performed by mixing reactant 1 and reactant 2 with an organic base, reacting for 5-10 minutes, adding a condensation activator, and then reacting for another 3-6 hours.

[0049] The present invention provides use of any of the above compounds, or optical isomers, tautomers, deuterated compounds, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or crystalline forms thereof, in the preparation of YTHDC2 inhibitors.

[0050] Preferably, the YTHDC2 inhibitor is used to treat YTHDC2 overexpression-related diseases, including prostate cancer, rheumatoid arthritis, hepatitis C, and temporal lobe epilepsy with hippocampal sclerosis.

[0051] The compounds and derivatives provided herein can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0052] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

[0053] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0054] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C 1～4 "Alkyl" refers to an alkyl group containing 1 to 4 carbon atoms.

[0055] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. For example, C1-C6 alkyl refers to an alkyl group having 1 to 6 member atoms, such as 1 to 4 member atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. Alkyl groups may optionally be substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. Alkyl groups can also be part of other groups, such as C1-C6 alkoxy.

[0056] "Halogen" is fluorine, chlorine, bromine or iodine.

[0057] "Alkoxy" refers to an alkyl group attached to the site of attachment through an oxygen atom, for example, C2 alkoxy refers to -OCH2CH3.

[0058] "Aralkyloxy" refers to a group in which an aromatic ring is attached to a site of attachment via an alkoxy group, wherein the aromatic ring is attached to an oxygen atom via a methylene group, for example, a C7 aralkyloxy group is

[0059] "Aryloxy" refers to a group in which an aromatic ring is attached via an oxygen atom to a site of attachment, e.g. It is a C6 aryloxy group.

[0060] The "heteroatom" refers to a nitrogen atom, an oxygen atom, and a sulfur atom.

[0061] "Ester group" means a group comprising at least one and a saturated alkane chain with a specified number of carbon atoms, e.g. It is a C2 ester group.

[0062] "Carboxyl" refers to a saturated alkane chain containing at least one carboxyl group and having the specified number of carbon atoms, for example, -CH2COOH is a C2 carboxyl group.

[0063] "Sulfonamide" means a and a saturated alkane chain with a specified number of specified atoms, e.g. It is C1 sulfonamide.

[0064] "Aryl" refers to an aromatic ring containing the specified number of member atoms and having a single ring, for example, a benzene ring is a C6 aryl group.

[0065] "Aroyl" refers to a group having the specified number of member atoms with the aryl group attached to the point of attachment through a carbonyl group, e.g. It is a C7 aromatic acyl group.

[0066] "Condensed ring" refers to a cyclic compound composed of at least two rings sharing adjacent carbon atoms, and the rings may be aromatic unsaturated rings, saturated rings, or non-aromatic unsaturated rings.

[0067] The "fused heterocycloalkyl group" refers to a fused ring consisting of a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom.

[0068] "Fused heteroaryl" refers to a fused ring containing at least one heteroatom and having aromatic character.

[0069] "Fused ring aryl" refers to a fused ring having the specified number of member atoms and having aromatic character.

[0070] "Fused cycloalkyl" refers to a fused ring containing the specified number of member atoms and containing at least one saturated ring or non-aromatic unsaturated ring.

[0071] "Heteroaryl" refers to an aromatic ring containing at least one heteroatom and having a single ring.

[0072] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form and physiologically compatible with the receptor.

[0073] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts of the above-mentioned compounds or their stereoisomers, formed with inorganic and / or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final isolation and purification of the compound. They can also be obtained by mixing the above-mentioned compound, or its stereoisomer, with a certain amount of acid or base appropriately (e.g., equivalent amounts). These salts may form a precipitate in the solution and be collected by filtration, or be recovered after evaporation of the solvent, or be obtained by freeze-drying after reaction in an aqueous medium. The salts described in the present invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluorides, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates or trifluoroacetates of the compound.

[0074] The present invention provides a YTHDC2 inhibitor, its preparation method, and use. By preparing and screening a series of compounds, the present invention successfully discovered a series of compounds that effectively inhibit YTHDC2 activity. These compounds exhibit significant inhibitory effects at low concentrations, providing an important foundation for subsequent drug development and related research. They have great potential for the preparation of drugs to treat diseases associated with YTHDC2 overexpression and for studying the functions and mechanisms of action of YTHDC2 in vivo, as well as its specific role in disease development.

[0075] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0076] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. DETAILED DESCRIPTION

[0077] In the following examples and experimental examples, reagents and materials not otherwise specified are commercially available.

[0078] The structure of the compound was determined by H NMR spectroscopy ( 1 H NMR) and electrospray ionization mass spectrometry (ESI-MS).

[0079] Example 1 Compound 1-87

[0080] 1. Preparation method

[0081] 1. Compound 1 (2-(5-chloro-2-fluorophenyl)-N-(5-chloro-2-hydroxyphenyl)acetamide)

[0082] Compound 1 was prepared by the following method:

[0083]

[0084] 4-Chloro-2-aminophenol (100 mg, 0.70 mmol) and 5-chloro-2-fluorophenylacetic acid (158 mg, 0.84 mmol) were dissolved in acetonitrile (5 ml), and N-methylimidazole (200 mg, 2.44 mmol) was added. After reacting at room temperature for 10 minutes, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (254 mg, 0.91 mmol) was added and the reaction was continued at room temperature for 6 hours. After TLC detection, the mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution and sodium chloride solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound 1 was obtained by column chromatography, 126 mg, a white solid, with a yield of 69%, MS (ESI) m / z: 314.0 [M+H] + .

[0085] 2. Compound 2-87

[0086] The preparation was carried out according to the preparation method 1 of this example, except that 5-chloro-2-fluorophenylacetic acid and 4-chloro-2-aminophenol were adaptively adjusted according to the structure of compound 2-87 in Table 1; the molar concentration of each reactant remained unchanged.

[0087] 2. Structure and Characterization of Compounds

[0088] The structures and characterization results of compounds 1-87 of this example are shown in Table 1.

[0089] Example 2 Compounds 88-93

[0090] 1. Preparation method

[0091] 1. Compound 88 (5-chloro-2-hydroxy-3-(2-(11-oxo-6,11-dihydrodibenzo[b,e]oxo-2-yl)acetamido)benzoic acid)

[0092] Compound 88 was prepared by the following method:

[0093]

[0094] (1) Step a: Preparation of Intermediate 1 (5-chloro-2-hydroxy-3-(2-(11-oxo-6,11-dihydrodibenzo[b,e]oxo-2-yl)acetamido)benzoic acid methyl ester)

[0095] Intermediate 1 was obtained by referring to the synthetic method of method 1 in Example 1. The yield was 76% and the MS (ESI) m / z was 452.9 [M+H]. + .

[0096] (2) Step b: Intermediate 1 (100 mg, 0.22 mmol) was dissolved in methanol (4 mL), and 2 M sodium hydroxide solution (1 mL) was added. The reaction mixture was then heated to 50°C for 6 h. After TLC analysis, the resulting mixture was concentrated to obtain a crude product. The residue was diluted with water, and 2 M hydrochloric acid solution was added to adjust the pH to approximately 4. The precipitate was filtered, ground, and dried to obtain compound 88 as a white solid, 85 mg, in a yield of 88%. MS (ESI) m / z: 438.1 [M+H] + .

[0097] 1 H NMR (400MHz, DMSO-d6) δ9.79(s,1H),8.29(d,J=2.7Hz,1H),8.10(d,J=2.4Hz,1H),7.80–7.77(m,1H),7. 68–7.64(m,1H),7.59–7.53(m,3H),7.50–7.47(m,1H),7.08(d,J=8.3Hz,1H),5.29(s,2H),3.86(s,2H).

[0098] 2. Compounds 89-93

[0099] The preparation was carried out according to the steps of Preparation Method 1 of this Example, except that isoxacic acid and methyl 3-amino-5-chloro-2-hydroxybenzoate were adjusted according to the structures of compounds 89-93 in Table 1. The molar concentration of each reactant remained unchanged.

[0100] 2. Structure and Characterization of Compounds

[0101] The structures and characterization results of compounds 88-93 of this example are shown in Table 1.

[0102] Example 3 Compounds 94-99

[0103] 1. Preparation method

[0104] 1. Compound 99 (N-(5-bromo-3-chloro-2-hydroxyphenyl)-2-(11-oxo-6,11-dihydrodibenzo[b,e]oxo-2-yl)propionamide)

[0105] Compound 99 was prepared by the following method:

[0106]

[0107] (1) Step a: Preparation of Intermediate 1 (Methyl 2-(4-hydroxyphenyl)propionate)

[0108] The raw material (4-hydroxyphenyl)-2-propionic acid (5 g, 30.09 mmol) was dissolved in methanol (25 mL). In an ice bath, thionyl chloride (8.95 g, 75.22 mmol) was slowly added dropwise, and the reaction was continued at room temperature for 2 h. TLC was performed. After completion of the reaction, ice water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated sodium bicarbonate solution and sodium chloride solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain Intermediate 1, 4.55 g, as a white solid. The yield was 84%. MS (ESI) m / z: 181.1 [M+H] + .

[0109] (2) Step b: Preparation of Intermediate 2 (methyl 2-((4-(1-methoxy-1-oxopropan-2-yl)phenoxy)methyl)benzoate)

[0110] Intermediate 1 (3.93 g, 21.83 mmol) was dissolved in N,N-dimethylformamide (25 mL), and potassium carbonate (6.03 g, 43.65 mmol) and methyl 2-bromomethylbenzoate (5 g, 21.83 mmol) were added. The mixture was reacted at 80°C for 12 h. After TLC analysis, water was added and the mixture was stirred thoroughly until a white solid precipitated. The white solid was filtered and then dried at 50°C to obtain Intermediate 2, 5.31 g, as a white solid, in a 74% yield. MS (ESI) m / z: 329.1 [M+H] + .

[0111] (3) Step c: Preparation of Intermediate 3 (2-((4-(1-carboxyethyl)phenoxy)methyl)benzoic acid)

[0112] Intermediate 2 (5 g, 15.23 mmol) was dissolved in methanol (30 mL), and 2 M sodium hydroxide solution (30 mL) was added. The reaction mixture was then heated to 50°C for 6 h. After cooling to room temperature, the mixture was concentrated and the pH was adjusted to approximately 4 by adding 2 M hydrochloric acid solution to obtain a solid precipitate. The white solid was filtered, filtered, and dried to obtain Intermediate 3 as a white solid, 4.16 g, in a 91% yield. MS (ESI) m / z: 301.1 [M+H]+ .

[0113] (4) Step d: Preparation of Intermediate 4 (2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)propionic acid)

[0114] Intermediate 3 (1 g, 3.33 mmol) was dissolved in dichloromethane (10 mL), and thionyl chloride (1.19 g, 10 mmol) was added and stirred at 40 ° C for 2 h. After the mixture was concentrated, it was dissolved in dichloromethane (10 mL), and aluminum chloride (0.67 g, 4.99 mmol) was added and reacted at room temperature for 3 h. After the reaction was completed, the mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give a crude product. Intermediate 4 was obtained by column chromatography as a white solid, 461 mg, with a yield of 49%, MS (ESI) m / z: 283.1 [M+H] + .

[0115] (5) Step e: Synthesis of Compound 99 (N-(5-bromo-3-chloro-2-hydroxyphenyl)-2-(11-oxo-6,11-dihydrodibenzo[b,e]oxo-2-yl)propionamide)

[0116] 2-Amino-4-bromo-6-chlorophenol (100 mg, 0.45 mmol) and intermediate 4 (152 mg, 0.54 mmol) were dissolved in acetonitrile (5 ml), and N-methylimidazole (129 mg, 1.57 mmol) was added. After reacting at room temperature for 10 minutes, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (164 mg, 0.58 mmol) was added and the reaction was continued at room temperature for 6 hours. After TLC detection, the mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution and sodium chloride solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound 99 was obtained by column chromatography, 138 mg, as a white solid, with a yield of 63%. MS (ESI) m / z: 486.0 [M+H] + .

[0117] 2. Compounds 94-98

[0118] The preparation was carried out according to step be of Preparation Method 1 of this Example, except that methyl 2-bromomethylbenzoate was adapted according to the structures of compounds 94-97 in Table 1 to produce compounds 94-97; and methyl 2-(4-hydroxyphenyl)propionate was adapted according to the structure of compound 98 in Table 1 to produce compound 98. The molar concentrations of the reactants remained unchanged.

[0119] 2. Structure and Characterization of Compounds

[0120] The structures and characterization data of compounds 94-99 are shown in Table 1.

[0121] Example 4 Compounds 100-101

[0122] 1. Preparation method

[0123] 1. Compound 100 was prepared by the following method:

[0124]

[0125] (1) Step a: Synthesis of Intermediate 1 (Methyl 2-(2-((4-(2-methoxy-2-oxoethyl)phenyl)amino)-2-oxoethyl)benzoate)

[0126] The raw materials methyl p-aminophenylacetate (4.25 g, 25.75 mmol) and 2-(2-methoxycarbonylphenyl)acetic acid (5 g, 25.75 mmol) were dissolved in tetrahydrofuran (30 ml), and then 4-dimethylaminopyridine (7.86 g, 64.37 mmol) and 1-butylphosphonic anhydride (27.83 g, 77.25 mmol) were added and reacted at room temperature for 3 hours. After the reaction was completed, it was concentrated and the mixture was diluted with dichloromethane, then washed with saturated sodium bicarbonate solution and sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Intermediate 1 was obtained by column chromatography, 6.5 g, a white solid, with a yield of 74%, MS (ESI) m / z: 342.0 [M+H] + .

[0127] (2) Step b: Synthesis of Intermediate 2 (2-(2-((4-(carboxymethyl)phenyl)amino)-2-oxoethyl)benzoic acid)

[0128] Intermediate 1 (5 g, 14.65 mmol) was dissolved in methanol (30 mL), and 2 M sodium hydroxide solution (30 mL) was added. The reaction mixture was then heated to 50°C for 6 h. After cooling to room temperature, the mixture was concentrated and the pH was adjusted to approximately 4 by adding 2 M hydrochloric acid solution to obtain a solid precipitate. The white solid was filtered, filtered, and dried to obtain Intermediate 2 as a white solid, 4.31 g, in a 94% yield. MS (ESI) m / z: 314.1 [M+H] + .

[0129] (3) Step c: Synthesis of Intermediate 3 (2-(6,12-dioxo-5,6,7,12-tetrahydrodibenzo[b,e]azepin-2-yl)acetic acid)

[0130] Intermediate 2 (1 g, 3.19 mmol) was dissolved in dichloromethane (10 mL), and thionyl chloride (1.14 g, 9.58 mmol) was added and stirred at 40 ° C for 2 h. After the mixture was concentrated, it was dissolved in dichloromethane (10 mL), and aluminum chloride (0.64 g, 4.79 mmol) was added and reacted at room temperature for 3 h. After the reaction was completed, the mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give a crude product. Intermediate 3 was obtained by column chromatography as a white solid, 509 mg, with a yield of 54%, MS (ESI) m / z: 296.1 [M+H] + .

[0131] (4) Step d: Synthesis of Compound 100 (N-(5-bromo-3-chloro-2-hydroxyphenyl)-2-(6,12-dioxo-5,6,7,12-tetrahydrodibenzo[b,e]azepin-2-yl)acetamide)

[0132] 2-Amino-4-bromo-6-chlorophenol (100 mg, 0.45 mmol) and intermediate 3 (159 mg, 0.54 mmol) were dissolved in acetonitrile (5 ml), and N-methylimidazole (129 mg, 1.57 mmol) was added. After reacting at room temperature for 10 minutes, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (164 mg, 0.58 mmol) was added and the reaction was continued at room temperature for 6 hours. After TLC detection, the mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution and sodium chloride solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound 100 was obtained by column chromatography, 166 mg, as a white solid, with a yield of 67%. MS (ESI) m / z: 499.0 [M+H] + .

[0133] 2. Compound 101

[0134] The preparation was carried out according to the steps of Preparation Method 1 of this Example, except that methyl p-aminophenylacetate was replaced by methyl p-carboxyphenylacetate, and 2-(2-methoxycarbonylphenyl)acetic acid was replaced by methyl 2-aminobenzoate; the molar concentration of each reactant remained unchanged.

[0135] 2. Structure and Characterization of Compounds

[0136] The structures and characterization results of compounds 100-101 are shown in Table 1.

[0137] Table 1 Structure and characterization data of the compounds in Examples 1-4

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154] Note: “—” means not tested.

[0155] The following experiments further illustrate the technical solution of the present invention. The following compounds 1-101 were prepared by the methods of Examples 1-4 above.

[0156] Experimental Example 1: Test of the Inhibitory Level of YTHDC2 Enzyme Activity by the Compounds of the Present Invention

[0157] 1. Experimental Methods

[0158] Fluorescence polarization experiments were performed in a pH 7.5 buffer containing 20 mM HEPES and 180 mM NaCl. GST-tagged protein (650 nM) was incubated with 7 nM probe (FAM-m6A-mRNA). The FAM-m6A-mRNA sequence is: UUCUUCUGUGG-(m6A)-CUGUG (SEQ ID NO. 1), with a FAM group modified at the 5' end. "m6A" indicates methylation at the 6th nitrogen atom of the adenosine (A) in the RNA molecule. Experiments were performed in 384-well black plates, and fluorescence polarization (FP) readings were performed using a CLARIOstar PLUS plate reader. To determine the effects of compounds of the present invention on YTHDC2 enzyme activity, compounds 1-122 of the present invention were incubated with the protein for 30 minutes, followed by addition of the substrate to the assay system and further incubation for 2 hours. Data were fitted using GraphPad Prism software.

[0159] 2. Experimental Results

[0160] The experimental results are shown in Table 2. From the data in the table, it can be seen that the effects of different compounds of the present invention on the YTHDC2 enzyme activity are different, and the differences are large. In particular, IC 50 The compounds with a concentration of less than 30 μM include compounds 1, 3-6, 8-10, 13-15, 17, 18, 20-24, 26-32, 34, 36-60, 62-64, 67, 68, 70, 71, 73-75, 77, 78, 82-85, and 88-101. This indicates that the above compounds have a strong inhibitory effect on the enzyme activity of YTHDC2.

[0161] Among them, IC 50 Compounds with activity levels <1 μM include compounds 31, 40-43, 45, 53, 54, 56, 57, 59, 68, 74, 75, 77, 78, and 94-100. This indicates that these compounds have a very strong inhibitory ability against YTHDC2; in particular, the IC 50 The value is the smallest, which is 0.137μM.

[0162] Table 2 Inhibition level of compounds on YTHDC2 enzyme activity

[0163]

[0164]

[0165] These results demonstrate that the compounds have potent inhibitory effects on YTHDC2 enzymatic activity and could be used as YTHDC2 inhibitors. They are promising for treating diseases associated with YTHDC2 overexpression or as research tools to help researchers gain a deeper understanding of YTHDC2's function in cells or animals and its mechanisms of action in disease.

[0166] As demonstrated in the above examples and experimental examples, the present invention successfully discovered a series of compounds capable of effectively inhibiting YTHDC2 activity through the preparation and screening of a series of compounds. These compounds exhibit significant inhibitory effects at low concentrations, providing an important foundation for subsequent drug development and related research. They hold great promise for the development of drugs to treat diseases associated with YTHDC2 overexpression and for studying the in vivo functions and mechanisms of action of YTHDC2, as well as its specific role in disease development.

Claims

1. A compound represented by Formula I or Formula II, or an optical isomer thereof, or a tautomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a hydrate thereof, or a solvate thereof, or a crystalline form thereof: in, Ring A is selected from C6-C 10 Aryl, 8-20 membered fused heterocycloalkyl, 9-20 membered fused heteroaryl, C8-C 20 Fused ring aromatic group, C7-C 20 Condensed cycloalkyl, wherein ring F is selected from C6-C 10 Aryl, 6-10 membered heteroaryl, ring G is selected from C6-C 10 Aryl, 6-10 membered heteroaryl, R4 is selected from heteroatoms, p is selected from 0, 1, 2, q is selected from 1, 2, k is selected from 0, 1, 2, == represents no chemical bond or double bond, when p is selected from 2, == is independently selected from no chemical bond or double bond; Ring E is selected from C6-C 10 Aryl, 6-10 membered heteroaryl; R1 is selected from halogen, hydroxy, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Alkoxy, substituted or unsubstituted C2-C 10 Ester group, substituted or unsubstituted C1-C 10 Carboxyl, substituted or unsubstituted C1-C 10 Sulfonamide, substituted or unsubstituted C7-C 11 Aralkyloxy, substituted or unsubstituted C7-C 11 Aroyl, substituted or unsubstituted C6-C 10 Aryloxy, substituted or unsubstituted C6-C 10 Aryl, wherein the substituent is selected from halogen, hydroxyl, C1-C 10 alkyl; R2 is selected from halogen, hydroxy, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Alkoxy, substituted or unsubstituted C2-C 10 Ester group, substituted or unsubstituted C1-C 10 Carboxyl, wherein the substituent is selected from halogen, hydroxyl, C1-C 10 alkyl; R3 is selected from hydrogen, C1-C 10 Alkyl, C6-C 10 Aryl, halogen, hydroxyl; n is selected from 0, 1, 2, 3, 4, 5, 6; m is selected from 0, 1, 2, 3, 4, and 5.

2. The compound according to claim 1, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystalline form, characterized in that: Ring A is selected from C6 aryl, 9-15 membered fused heterocycloalkyl, 9-13 membered fused heteroaryl, C 10 Fused ring aryl, C9 fused ring alkyl, wherein the heteroatoms in the fused heterocycloalkyl group and the fused heteroaryl group are independently selected from oxygen and nitrogen, the number of heteroatoms is 1 or 2, ring F is selected from C6 aryl, ring G is selected from C6 aryl, R4 is selected from oxygen, nitrogen, and sulfur, q is selected from 1, and k is selected from 0 and 1; Ring E is selected from C6 aryl, 6-membered heteroaryl; R1 is selected from fluorine, chlorine, bromine, hydroxyl, C1-C4 alkyl, C1-C2 alkoxy, C2-C3 ester, C1 carboxyl, C1 sulfonamide, C7 aralkyloxy, C7 aroyl, C6-aryloxy, C6 aryl; R2 is selected from fluorine, chlorine, bromine, hydroxyl, substituted or unsubstituted C1 alkyl, C1 alkoxy, C2 ester, C1 carboxyl, wherein the substituent is selected from fluorine; R3 is selected from hydrogen, C1 alkyl, C6 aryl; n is selected from 0, 1, 2; m is selected from 1, 2, 3, and 4.

3. The compound according to claim 2, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystalline form, characterized in that: The structural formula of the compound is shown in Formula I; Ring A is selected from C6 aryl, 9-14 membered fused heterocycloalkyl, 9-13 membered fused heteroaryl, C9 fused cycloalkyl, R4 is selected from oxygen and nitrogen; Ring E is selected from C6 aryl; R1 is selected from fluorine, chlorine, bromine, hydroxyl, C1 alkyl, C1-C2 alkoxy, C2-C3 ester, C1 carboxyl, C1 sulfonamide, C7 aralkyloxy, C7 aroyl, C6-aryloxy, C6 aryl; R2 is selected from fluorine, chlorine, bromine, hydroxyl, substituted C1 alkyl, C2 ester, C1 carboxyl, wherein the substituent is selected from fluorine.

4. The compound according to claim 3, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystalline form, characterized in that: Ring A is selected from C6 aryl, 9-membered fused heteroaryl, wherein the number of heteroatoms in the fused heteroaryl group is 1, and k is selected from 0; R1 is selected from fluorine, chlorine, bromine, hydroxyl, C1 alkyl, C1 alkoxy, C2 ester, C7 aralkyloxy; R2 is selected from fluorine, chlorine, bromine, and hydroxy; R3 is selected from hydrogen, C1 alkyl.

5. The compound according to claim 1, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystalline form, characterized in that: The compound represented by formula I is selected from one of the compounds represented by the following structural formulas:

6. A method for preparing the compound according to any one of claims 1 to 5, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystalline form, characterized in that: The steps include: Reactant 1 reacts with reactant 2 to obtain.

7. The preparation method according to claim 6, characterized in that: The reaction is carried out under the conditions of an organic base and a condensation activator; And / or, the reaction temperature is 20-30°C.

8. The preparation method according to claim 7, characterized in that: The organic base is selected from at least one of N-methylimidazole, 4-dimethylaminopyridine, N,N-diisopropylethylamine, and triethylamine; the condensation activator is selected from at least one of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate, 1-propyl phosphoric anhydride, 1-butyl phosphoric anhydride, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; And / or, the molar ratio of reactant 1 to reactant 2 is 0.54-0.84:0.45-0.7; and / or, the molar ratio of the reactant 1 to the organic base and the condensation activator is 0.54-0.84:1.57-2.44:0.58-0.91; And / or, the reaction is performed by mixing reactant 1 and reactant 2 with an organic base, reacting for 5-10 minutes, adding a condensation activator, and then reacting for another 3-6 hours.

9. Use of the compound according to any one of claims 1 to 5, or its optical isomer, or its tautomer, or its deuterated compound, or its pharmaceutically acceptable salt, or its prodrug, or its hydrate, or its solvate, or its crystalline form in the preparation of a YTHDC2 inhibitor.

10. The use according to claim 9, characterized in that: The YTHDC2 inhibitor is used to treat YTHDC2 overexpression-related diseases, including prostate cancer, rheumatoid arthritis, hepatitis C, and temporal lobe epilepsy with hippocampal sclerosis.

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