1H-pyrrole-2-amide derivative and application thereof

Abstract

The invention discloses a 1H-pyrrole-2-amide derivative and an application thereof, and belongs to the field of chemical medicines. The 1H-pyrrole-2-amide derivative is shown in the description. In order to obtain a specific inhibitor for reader protein YTHDC1 of RNA modified by m6A of AML, the invention provides the 1H-pyrrole-2-amide derivative as shown in the formula I, and the 1H-pyrrole-2-amide derivative has high inhibitory activity on YTHDC1; in-vitro experiments prove that proliferation of acute myelogenous leukemia cells can be effectively inhibited, the cycle of the acute myelogenous leukemia cells is remarkably retarded in a G0 / G1 phase, and differentiation and apoptosis of the acute myelogenous leukemia cells are induced; according to the compound of the 1H-pyrrole-2-amide derivative and the salt or the pharmaceutical composition of the compound, a new choice is provided for development of anti-tumor drugs targeting YTHDC1 in the field, and the compound and the salt or the pharmaceutical composition have a good application prospect.

Description

1H-pyrrole-2-amide derivatives and uses thereof Technical Field

[0001] The present invention relates to 1H-pyrrole-2-amide derivatives and uses thereof, and belongs to the field of chemical medicine. Background Art

[0002] N6-methyladenosine (N6-methyladenosine, m 6 A) modification is the most common chemical modification in eukaryotic mRNA. 6 A methylation modification mainly regulates the stability, transcription, processing, translation and splicing of precursor RNA. 6 A modification is a dynamic and reversible process. The "writer" methyltransferase METTL 3-14 is responsible for transferring methyl groups to RNA, the "eraser" demethylase FTO and ALKBH5 are responsible for removing the methyl modifications on the transferred RNA, and the "reader" YTH domain family (YTHDF1-3, YTHDC1-2) specifically recognizes m6A methylation modifications. More and more research results show that RNA m 6 A modification has a great influence on the production and metabolism of RNA and is closely related to the pathogenesis of many diseases, such as tumors, neurological diseases, viral infections and immune system related diseases. 6 The biological functions and mechanisms of action of several key proteins dynamically modified by A have not yet been elucidated, and there is a particular lack of reports on highly active and selective small molecule inhibitors.

[0003] YTHDC1 (also known as YT521-B) was originally discovered as an RNA splicing-related protein because it contains a splicing factor-rich glutamic acid / arginine carboxyl domain. The YTH domain in YTHDC1 specifically recognizes m 6 A modification, and preferentially recognizes the G(m6A)C sequence through the hydrophobic aromatic cage pocket formed by its W377, W428, L430 and L439. 6 A-modified pre-RNA recruits the splicing factors serine and arginine rich splicing factor 3 (SRSF3) and serine and arginine rich splicing factor 10 (SRSF10) to bind to nuclear speckles, thereby promoting exon splicing inclusions and mRNA export from the nucleus to the cytoplasm. YTHDC1 is the only one in the YTH domain family that can directly bind to nuclear mRNA.6 A modified RNA "reader", and in m 6 YTHDC1 plays a crucial role in the dynamic modification of A. Recent research indicates that YTHDC1 is closely associated with the development and progression of numerous diseases, including acute myeloid leukemia, liver cancer, pancreatic cancer, breast cancer, glioma, and hepatitis B. YTHDC1 is considered a potential therapeutic target for these diseases and has recently attracted significant attention from major pharmaceutical companies and drug development institutions. However, to date, no specific small molecule inhibitors targeting YTHDC1 have been reported, either domestically or internationally.

[0004] Therefore, the development of highly active and specific YTHDC1 small molecule inhibitors not only provides new means for the treatment of various related diseases such as tumors and hepatitis B, but also helps to explore the regulatory mechanism of YTHDC1 and its role in physiological and pathological processes.

[0005] Summary of the Invention

[0006] The present invention has discovered a 1H-pyrrole-2-amide derivative, which has high inhibitory activity against YTHDC1 and provides a new means for treating various YTHDC1-related diseases such as tumors and hepatitis B.

[0007] The present invention provides a compound represented by formula I or a hydrate thereof, or a pharmaceutically acceptable salt thereof, the structure of which is shown below:

[0008] wherein Ring A is selected from a 6- to 10-membered aromatic ring and a 5- to 10-membered heteroaromatic ring;

[0009] In ring A, the 5- to 10-membered heteroaromatic ring contains 1 to 3 heteroatoms selected from N, S, and O;

[0010] R 1 is selected from H, halogen, cyano, halogen-substituted or unsubstituted C1-C8 alkyl, halogen-substituted or unsubstituted C1-C8 alkoxy, halogen-substituted or unsubstituted C2-C8 alkanoyl, halogen-substituted or unsubstituted C2-C8 alkoxycarbonyl, halogen-substituted or unsubstituted 3-8-membered cycloalkyl, substituted or unsubstituted 6-10-membered aryl, substituted or unsubstituted 5-10-membered heteroaryl;

[0011] R 1 wherein the 5- to 10-membered heteroaryl group contains 1 to 3 heteroatoms selected from N, S, and O;

[0012] R 1 wherein the substituents of the substituted or unsubstituted 6- to 10-membered aryl group or the substituted or unsubstituted 5- to 10-membered heteroaryl group are selected from cyano, halogen-substituted or unsubstituted C1- to C6-alkyl, -NR 13 R14 at least one of;

[0013] R 13 ~R 14 are independently selected from H, halogen-substituted or unsubstituted C1-C4 alkyl, or R 13 、R 14 with -NR 13 R 14 The N in the group is connected to form a halogen-substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, wherein the 3- to 8-membered heterocycloalkyl group contains 0 to 2 heteroatoms in addition to the aforementioned N, and the heteroatoms are selected from N, S, and O;

[0014] Ring B is selected from

[0015] R 2 ~R 6 Independently selected from H, halogen, halogen-substituted or unsubstituted C1-C8 alkyl, halogen-substituted or unsubstituted C1-C8 alkoxy;

[0016] R 7 ~R 9 、R 11 Independently selected from H, halogen, halogen-substituted or unsubstituted C1-C6 alkyl;

[0017] R 10 、R 12 Independently selected from substituted or unsubstituted 6- to 10-membered aryl groups, and substituted or unsubstituted 5- to 10-membered heteroaryl groups;

[0018] R 10 、R 12 wherein the 5- to 10-membered heteroaryl group contains 1 to 3 heteroatoms selected from N, S, and O;

[0019] R 10 、R 12 wherein the substituents of the substituted 6-10 membered aryl and substituted 5-10 membered heteroaryl are selected from cyano, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, -NR 15 R 16 、-SO2R 17 ;

[0020] R 10 、R 12 wherein the substituents of the substituted C1-C6 alkyl and substituted C1-C6 alkoxy are selected from hydroxyl and halogen;

[0021] R 15 、R 16 、R 17Independently selected from H, halogen-substituted or unsubstituted C1-C4 alkyl;

[0022] X is selected from a bond, -CH(R 18 )(CH2) n -; n is an integer selected from 0 to 3;

[0023] R 18 Selected from H, C1-C4 alkyl;

[0024] Y is selected from -NH- (the left end is connected to benzene, the right end is connected to pyrrole);

[0025] R 19 、R 20 independently selected from H, hydroxy, cyano, halogen, halogen-substituted or unsubstituted C1-C4 alkyl;

[0026] Z and W are independently selected from N, CR 21 ;

[0027] R 21 Selected from H, halogen.

[0028] In some embodiments of the present invention, ring A is selected from a 6-10 membered aromatic ring and a 5-6 membered heteroaromatic ring; in ring A, the 5-6 membered heteroaromatic ring contains 1-2 heteroatoms, and the heteroatoms are selected from N, S, and O.

[0029] In some preferred embodiments of the present invention, ring A is selected from a benzene ring and a pyridine ring.

[0030] In some most preferred embodiments of the present invention, ring A is selected from

[0031] In some embodiments of the present invention, R 1 R is selected from H, halogen, cyano, halogen-substituted or unsubstituted C1-C6 alkyl, halogen-substituted or unsubstituted C1-C6 alkoxy, halogen-substituted or unsubstituted C2-C6 alkanoyl, halogen-substituted or unsubstituted C2-C6 alkoxycarbonyl, halogen-substituted or unsubstituted 3-6-membered cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6-membered heteroaryl; 1 In the embodiment, the 5- to 6-membered heteroaryl group contains 1 to 2 heteroatoms, and the heteroatoms are selected from N, S, and O.

[0032] In some preferred embodiments of the present invention, R 1R is selected from H, halogen, cyano, halogen-substituted or unsubstituted C1-C4 alkyl, halogen-substituted or unsubstituted C1-C4 alkoxy, halogen-substituted or unsubstituted C2-C4 alkanoyl, halogen-substituted or unsubstituted C2-C5 alkoxycarbonyl, halogen-substituted or unsubstituted 3-6-membered cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6-membered heteroaryl; 1 In the embodiment, the 5- to 6-membered heteroaryl group contains 1 to 2 heteroatoms, and the heteroatoms are selected from N, S, and O.

[0033] In some further preferred embodiments of the present invention, R 1 R is selected from H, F, Cl, Br, cyano, fluorine-substituted or unsubstituted C1-C4 alkyl, fluorine-substituted or unsubstituted C1-C4 alkoxy, fluorine-substituted or unsubstituted C2-C4 alkanoyl, fluorine-substituted or unsubstituted C2-C5 alkoxycarbonyl, fluorine-substituted or unsubstituted 3-6-membered cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6-membered heteroaryl; 1 In the embodiment, the 5- to 6-membered heteroaryl group contains 1 to 2 heteroatoms, and the heteroatoms are selected from N, S, and O.

[0034] In some further preferred embodiments of the present invention, R 1 R is selected from H, F, Cl, Br, cyano, fluorine-substituted or unsubstituted C1-C4 alkyl, fluorine-substituted or unsubstituted C1-C4 alkoxy, fluorine-substituted or unsubstituted C2-C4 alkanoyl, fluorine-substituted or unsubstituted C2-C5 alkoxycarbonyl, fluorine-substituted or unsubstituted 3-6-membered cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6-membered heteroaryl; 1 wherein the 5- to 6-membered heteroaryl group is selected from pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, and pyrazolyl.

[0035] In some most preferred embodiments of the present invention, R 1 R is selected from H, F, Cl, Br, methyl, trifluoromethyl, methoxy, trifluoromethoxy, acetyl, ethoxycarbonyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; 1 wherein the 5- to 6-membered heteroaryl group is selected from

[0036] In some embodiments of the present invention, R 1 wherein the substituents of the substituted or unsubstituted aryl group or the substituted or unsubstituted heteroaryl group are selected from cyano group, halogen substituted or unsubstituted C1-C4 alkyl group, -NR 13 R 14 At least one of R 13 ~R 14are independently selected from halogen-substituted or unsubstituted C1-C4 alkyl, or R 13 、R 14 with -NR 13 R 14 The N in the group is connected to form a halogen-substituted or unsubstituted 3- to 6-membered heterocycloalkyl group, wherein the 3- to 6-membered heterocycloalkyl group contains 0 to 1 heteroatom in addition to the aforementioned N, and the heteroatom is selected from N, S, and O.

[0037] In some preferred embodiments of the present invention, R 1 wherein the substituents of the substituted or unsubstituted aryl group or the substituted or unsubstituted heteroaryl group are selected from cyano group, fluorine-substituted or unsubstituted C1-C4 alkyl group, -NR 13 R 14 At least one of R 13 ~R 14 are independently selected from fluorine-substituted or unsubstituted C1-C4 alkyl, or R 13 、R 14 with -NR 13 R 14 The N in the group is connected to form a fluorine-substituted or unsubstituted 3- to 6-membered heterocycloalkyl group, wherein the 3- to 6-membered heterocycloalkyl group contains 0 to 1 heteroatom in addition to the aforementioned N, and the heteroatom is selected from S and O.

[0038] In some further preferred embodiments of the present invention, R 1 wherein the substituents of the substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl are selected from cyano, methyl, trifluoromethyl, -NR 13 R 14 At least one of R 13 ~R 14 are independently selected from methyl, trifluoromethyl, or R 13 、R 14 with -NR 13 R 14 The N in the group is connected to form a fluorine-substituted or unsubstituted 3- to 6-membered heterocycloalkyl group, wherein the 3- to 6-membered heterocycloalkyl group is selected from

[0039] In some most preferred embodiments of the present invention, R 1 wherein the substituents of the substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl are selected from cyano, methyl, trifluoromethyl,

[0040] In some embodiments of the present invention, the structural unit Selected from:

[0041] In some embodiments of the present invention, R 2 ~R 6 Independently selected from H, halogen, halogen-substituted or unsubstituted C1-C6 alkyl, halogen-substituted or unsubstituted C1-C6 alkoxy.

[0042] In some preferred embodiments of the present invention, R 2 ~R 6 Independently selected from H, halogen, halogen-substituted or unsubstituted C1-C4 alkyl, halogen-substituted or unsubstituted C1-C4 alkoxy.

[0043] In some further preferred embodiments of the present invention, R 2 ~R 6 Independently selected from H, F, Cl, Br, fluorine-substituted or unsubstituted C1-C4 alkyl, fluorine-substituted or unsubstituted C1-C4 alkoxy.

[0044] In some further preferred embodiments of the present invention, R 2 ~R 6 are independently selected from H, F, Cl, Br, fluorine-substituted or unsubstituted C1-C4 alkyl, fluorine-substituted or unsubstituted C1-C4 alkoxy, and R 2 and R 6 The only difference is H.

[0045] In some most preferred embodiments of the present invention, R 2 is selected from H, F, Cl, Br, methyl, trifluoromethyl, ethyl, tert-butyl, methoxy, trifluoromethoxy, ethoxy, R 3 Selected from H, F, Cl, Br, R 4 is selected from H, F, Cl, Br, methyl, trifluoromethyl, R 5 Selected from H, F, Cl, Br, R 6 is selected from H, F, Cl, Br, methyl, trifluoromethyl, ethyl, tert-butyl, methoxy, trifluoromethoxy, ethoxy, and R 2 and R 6 The only difference is H.

[0046] In some embodiments of the present invention, the structural unit Selected from:

[0047] In some embodiments of the present invention, Y is selected from -NH-;R 19 、R 20 Independently selected from H, hydroxy, cyano, F, F-substituted or unsubstituted C1-C4 alkyl.

[0048] In some preferred embodiments of the present invention, Y is selected from -NH-;R 19 、R 20 Independently selected from H, hydroxy, cyano, F, methyl, trifluoromethyl.

[0049] In some most preferred embodiments of the present invention, Y is selected from -NH-.

[0050] In some embodiments of the present invention, R 7 ~R 9 、R 11 Independently selected from H, halogen, halogen-substituted or unsubstituted C1-C4 alkyl.

[0051] In some preferred embodiments of the present invention, R 7 ~R 9 、R 11 Independently selected from H, F, F-substituted or unsubstituted C1-C4 alkyl.

[0052] In some most preferred embodiments of the present invention, R 7 ~R 9 、R 11 Independently selected from H, F, methyl, trifluoromethyl.

[0053] In some embodiments of the present invention, R 10 、R 12 R is independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; 10 、R 12 In the embodiment, the 5- to 6-membered heteroaryl group contains 1 to 2 heteroatoms, and the heteroatoms are selected from N, S, and O.

[0054] In some preferred embodiments of the present invention, R 10 、R 12 R is independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; 10 、R 12 wherein the 5- to 6-membered heteroaryl group is selected from pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, and pyrazolyl.

[0055] In some most preferred embodiments of the present invention, R 10 、R 12 R is independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; 10 、R 12 wherein the 5- to 6-membered heteroaryl group is selected from

[0056] In some embodiments of the present invention, R 10 、R 12 wherein the substituents of the substituted aryl and substituted heteroaryl are selected from cyano, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, -NR 15 R 16 、-SO2R 17 ; R 10 、R 12 wherein the substituents of the substituted C1-C4 alkyl and substituted C1-C4 alkoxy are selected from hydroxyl and halogen; R 15 、R 16 、R 17 Independently selected from H, halogen-substituted or unsubstituted C1-C4 alkyl.

[0057] In some preferred embodiments of the present invention, R 10 、R 12 wherein the substituents of the substituted aryl and substituted heteroaryl are selected from cyano, F, Cl, Br, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, -NR 15 R 16 、-SO2R 17 ; R 10 、R 12 wherein the substituents of the substituted C1-C4 alkyl and substituted C1-C4 alkoxy are selected from hydroxyl, F; R 15 、R 16 、R 17 Independently selected from H, fluorine-substituted or unsubstituted C1-C4 alkyl.

[0058] In some most preferred embodiments of the present invention, R 10 、R 12 In the embodiment, the substituents of the substituted aryl and substituted heteroaryl are selected from cyano, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, hydroxymethyl, trifluoromethyl, methoxy, trifluoromethoxy, amino, -SO2CF3, and -SO2CH3.

[0059] In some embodiments of the present invention, X is selected from a bond, -CH(R 18 )(CH2) n -; n is an integer selected from 0 to 1; R 18 Selected from H, C1~C4 alkyl.

[0060] In some preferred embodiments of the present invention, X is selected from a bond, -CH(CH3)-, and -CH2-.

[0061] In some embodiments of the present invention, Z and W are independently selected from N, CR 21 ; R 21 Selected from H, F.

[0062] In some preferred embodiments of the present invention, Z is selected from N, CH, CF, and W is selected from N.

[0063] In some embodiments of the present invention, Selected from:

[0064] In some embodiments of the present invention, Selected from:

[0065] In some embodiments of the present invention, Selected from:

[0066] The present invention also provides some specific compounds represented by formula I, characterized in that: the structural formula is as follows:

[0067] Based on the above-mentioned compound of formula I, the present invention also provides some compounds, wherein the structural unit Selected from:

[0068] Based on the above-mentioned compound of formula I, the present invention also provides some compounds, among which: Selected from:

[0069] Based on the above-mentioned compound of formula I, the present invention also provides some specific compounds, the structural formulas of these compounds are as follows:

[0070] Based on the above-mentioned compound of formula I, the present invention also provides some specific compounds, the structural formulas of these compounds are as follows:

[0071] Based on the above compounds of formula I, the present invention further provides some compounds, wherein the structural unit Selected from:

[0072] Based on the above compounds of formula I, the present invention further provides some compounds, wherein the structural unit Selected from:

[0073] Based on the above compounds of formula I, the present invention further provides some compounds, among which: Selected from:

[0074] Based on the above-mentioned compound of formula I, the present invention further provides some specific compounds, the structural formulas of these compounds are as follows:

[0075] Based on the above-mentioned compound of formula I, the present invention further provides some specific compounds, the structural formulas of these compounds are as follows:

[0076] The present invention also provides a pharmaceutical composition, which is composed of the above-mentioned compound and its hydrate and pharmaceutically acceptable salt as active ingredients, and pharmaceutically acceptable auxiliary ingredients.

[0077] The present invention also provides uses of the above-mentioned compound, its hydrate, pharmaceutically acceptable salt, and pharmaceutical composition in the preparation of YTHDC1 small molecule inhibitors.

[0078] The present invention also provides uses of the above-mentioned compound, its hydrate, pharmaceutically acceptable salt, and the above-mentioned pharmaceutical composition in the preparation of drugs for treating and / or preventing YTHDC1-related diseases.

[0079] In some preferred embodiments of the present invention, the YTHDC1-related disease includes acute myeloid leukemia, T-cell lymphoma, liver cancer, pancreatic cancer, breast cancer, glioma or hepatitis B.

[0080] Some more preferred embodiments of the present invention include acute myeloid leukemia and T-cell lymphoma.

[0081] Definition of terms: 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.

[0082] The term "alkyl" refers to a group of straight or branched saturated hydrocarbon groups. Examples of C1-C8 alkyl groups include, but are not limited to, methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6).

[0083] The term "C2-C8 alkanoyl" refers to a group in which a straight-chain or branched saturated hydrocarbon group is linked to an acyl group. Examples of C2-C8 alkanoyl groups include, but are not limited to, acetyl (C2), propionyl (C3), n-propionyl (C4), isopropionyl (C4), n-butyryl (C5), and tert-butyryl (C5). The term "C2-C8 alkoxycarbonyl" refers to a group in which a straight-chain or branched saturated hydrocarbon group is linked to an acyl group via an oxygen group. Examples of C2-C8 alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl (C2), ethoxycarbonyl (C3), n-propoxycarbonyl (C4), isopropoxycarbonyl (C4), n-butoxycarbonyl (C5), and tert-butoxycarbonyl (C5).

[0084] The term "cycloalkyl" refers to a saturated cyclic hydrocarbon group containing no heteroatoms, which may be a monocyclic structure or a polycyclic structure (such as a bridged ring structure or a spirocyclic structure), for example: cyclopropane (3-membered), cyclohexane (6-membered).

[0085] The term "aryl" refers to an all-carbon monocyclic or condensed ring group having a conjugated π electron system, such as phenyl, naphthyl, anthracenyl, phenanthrenyl, pyrenyl, etc. The term "heteroaryl" refers to a carbon atom in an aryl group replaced by a heteroatom selected from sulfur, oxygen and / or nitrogen, such as thiophene, furan, pyrrole, pyridine, quinoline, indole, etc.

[0086] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0087] 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.

[0088] The term "pharmaceutically acceptable salt" refers to organic salts and inorganic salts of the compounds of the present invention, preferably inorganic salts, salts formed by pharmaceutically acceptable non-toxic acids, including but not limited to inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, nitrates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, hydrochlorides, oleates, stearates, ascorbates, formates, borates, camphorates, methanesulfonates, ethanesulfonates, malates, and the like.

[0089] The pharmaceutically acceptable auxiliary ingredients of the present invention refer to substances contained in the dosage form in addition to the active ingredients, such as cyclodextrin, arginine or meglumine. The cyclodextrin is selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, (C 1-4 Alkyl)-α-cyclodextrin, (C 1-4 Alkyl)-β-cyclodextrin, (C 1-4 Alkyl)-γ-cyclodextrin, (hydroxy-C 1-4 Alkyl)-α-cyclodextrin, (hydroxy-C 1-4 Alkyl)-β-cyclodextrin, (hydroxy-C 1-4 Alkyl)-γ-cyclodextrin, (carboxyl-C 1-4 Alkyl)-α-cyclodextrin, (carboxyl-C 1-4 Alkyl)-β-cyclodextrin, (carboxyl-C 1-4 The auxiliary ingredients may also include medically acceptable carriers, adjuvants, or vehicles. Pharmaceutically acceptable pharmaceutical compositions may also include ion exchangers, alumina, aluminum stearate, and egg yolk gelatin; buffer substances include phosphates, glycine, arginine, and sorbic acid.

[0090] Beneficial Effects: The present invention has discovered a 1H-pyrrole-2-carboxamide derivative with high inhibitory activity against YTHDC1, providing a new approach for treating various YTHDC1-related diseases, including tumors and hepatitis B. In vitro experiments have demonstrated that this class of compounds can effectively inhibit the proliferation of acute myeloid leukemia cells, significantly arrest the cell cycle at the G0 / G1 phase, and induce differentiation and apoptosis in acute myeloid leukemia cells. BRIEF DESCRIPTION OF THE DRAWINGS

[0091] Figure 1 shows the results of in vitro cell experiments with compound 29; wherein, a shows the results of compound 29 inhibiting AML cell proliferation, b shows the results of compound 29 inducing AML cell cycle arrest, c shows the results of compound 29 inducing AML cell differentiation, and d shows the results of compound 29 inducing AML cell apoptosis. DETAILED DESCRIPTION

[0092] Below, the scheme of the present invention will be explained in conjunction with embodiment.It will be understood by those skilled in the art that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.In the embodiment, if specific technology or conditions are not indicated, the technology or conditions described in the literature in this area or the product instructions are used.The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be obtained by commercial purchase.

[0093] Example 1

[0094] The preparation operating conditions shown in Example 1 above include: i. aluminum chloride, ultra-dry dichloromethane, 0°C to room temperature, 16 hours; ii. sodium hydroxide, ethanol:water, 80°C, 1.5 hours; iii. 1-propylphosphoric anhydride, 4-dimethylaminopyridine, ultra-dry tetrahydrofuran, room temperature, 12 hours, 79%.

[0095] Intermediate 3: Preparation of ethyl 4-(2-bromo-6-fluorophenyl)-1H-pyrrole-2-carboxylate

[0096] 2-Bromo-6-fluorobenzoyl chloride (3.27 mL, 24 mmol) was added to ethyl 1h-pyrrole-2-carboxylate (1.5 g, 12 mmol), and an AlCl₃ suspension (4 g, 30 mmol) was added in DCM (1 mL / mmol AlCl₃) at 0°C. After the mixture reached room temperature, it was stirred for 16 hours. The reaction was quenched with 1M aqueous HCl (20 mL) at 0°C. The product was extracted with dichloromethane (3 × 100 mL), washed with saturated NaHCO₃ solution (2 × 100 mL), washed with saturated sodium chloride solution (100 mL), dried over Na₂SO₄, and concentrated in vacuo to obtain a white solid, Compound 3. 1 H NMR(400MHz,DMSO-d6)δ12.90(s,1H),7.59(d,J=8.3Hz,1H)7.52(s,1H),7.50(dd,J=6.3,8.3Hz,1 H),7.39-7.43(m,1H),7.00(s,1H),4.21(q,J=6.9Hz,2H),1.25(t,J=7.0Hz,3H).MS(ESI,positive ion)m / z:325.9[M+H] + .

[0097] Intermediate 4: Preparation of 4-(2-bromo-6-fluorophenyl)-1H-pyrrole-2-carboxylic acid

[0098] Add 2N aqueous NaOH (10.0 mL, 20.0 mmol) to a solution of ethyl 4-(2-bromo-6-fluorobenzoyl)-1H-pyrrole-2-carboxylate (Intermediate 3, 1.00 g, 3.08 mmol) in ethanol (5.0 mL). Stir at 80°C for 1.5 h and evaporate under reduced pressure. Dilute the residue with water and acidify with aqueous hydrochloric acid (3N). The aqueous mixture is extracted with ethyl acetate (2 x 50 mL), and the organic phase is washed with saturated brine (50 mL), dried over sodium sulfate, and filtered. The solvent is removed under vacuum and the product is used in the next step without further purification.

[0099] Compound 1: Preparation of 4-(2-bromo-6-fluorophenyl)-nitrogen-(pyridin-3-yl)-1H-pyrrole-2-carboxamide

[0100] A solution of 4-(2-bromo-6-fluorobenzoyl)-1H-pyrrole-2-carboxylic acid (Intermediate 4, 0.50 g, 1.70 mmol), pyridin-3-amine (0.16 g, 1.70 mmol), 4-dimethylaminopyridine (0.42 g, 3.40 mmol), and 1-propylphosphonic anhydride (50 wt.% in ethyl acetate, 1.00 mL) in ultra-dry tetrahydrofuran (30 mL) was stirred at room temperature for 12 hours. The mixture was then quenched with water and evaporated under reduced pressure. The residue was purified by chromatography (petroleum ether / ethyl acetate = 1:6) to afford a white solid, Compound 1, in a 79% yield. 1 H NMR(400MHz,DMSO-d6)δ12.71(s,1H),10.25(s,1H),8.90(s,1H),8.31(s,1H),8.14(d ,J=6.8Hz,1H),7.62(d,J=7.9Hz,1H),7.56–7.42(m,3H),7.39(dt,J=8.3,4.0Hz,1H). 13 C NMR (101MHz, DMSO) δ185.35,159.19,144.88,142.12,135.98,132.69,132.61,130.54,130.31,129.86,129.3 6,129.33,128.63,127.48,125.43,124.04,119.58,119.52,115.95,115.74,112.13.HRMS(m / z):calculated for C 17 H 11 BrFN3O2 + [M+H] + 388.0019;found,388.0092.

[0101] Example 2

[0102] The preparation operating conditions shown in Example 2 above include: i. aluminum chloride, ultra-dry dichloromethane, 0°C to room temperature, 10 hours; ii. methyl fluorosulfonyldifluoroacetate, cuprous iodide, ultra-dry DMF, 80°C, 12 hours; iii. sodium hydroxide, ethanol:water, 15°C, 12 hours; iv. 1-propylphosphoric anhydride, 4-dimethylaminopyridine, ultra-dry tetrahydrofuran, room temperature, 12 hours, 85%.

[0103] Intermediate 7: Preparation of ethyl 4-(2-iodophenyl)-1H-pyrrole-2-carboxylate

[0104] 2-Iodobenzoyl chloride (5.77 g, 21.72 mmol) was added to anhydrous dichloromethane at 0°C, followed by ethyl 1H-pyrrole-2-carboxylate (1.50 g, 10.86 mmol) and 27.15 mmol of AlCl₃ to obtain a suspension. After the mixture reached room temperature, it was stirred for 10 hours. The reaction was quenched with 1M hydrochloric acid (20 mL) at 0°C. The reaction solution was extracted with dichloromethane (3 × 100 mL) and washed with saturated NaHCO₃ solution (2 × 100 mL) and saturated brine (100 mL). The organic phase was dried over Na₂SO₄ and concentrated in vacuo to obtain a white solid. This is Intermediate 7. 1 H NMR (400MHz, DMSO-d6) δ11.94(s,1H),8.05(d,J=1.5Hz,1H),7.98(d,J=7.5Hz,1H),7.7 1(dd,J=7.5,1.5Hz,1H),7.58(t,J=4.8Hz,1H),2.89(d,J=4.8Hz,3H).MS(ESI,positive ion)m / z:369.8[M+H] + .

[0105] Intermediate 8: Preparation of ethyl 4-(2-trifluoromethylphenyl)-1H-pyrrole-2-carboxylate

[0106] Cuprous iodide (0.2 mol) and ethyl 4-(2-iodobenzoyl)-1H-pyrrole-2-carboxylate (2.71 mmol) were added to a Schleck tube. Anhydrous DMF (20 mL) and methyl fluorosulfonyldifluoroacetate (1.56 g, 8.13 mmol) were added under argon. The reaction mixture was then gradually heated to 80°C and stirred for 12 hours. Water (40 mL) was then added, and the mixture was extracted with ethyl acetate (3 × 20 mL), dried over Na2SO4, and concentrated to afford the crude product. Purification by column chromatography afforded ethyl 4-(2-trifluoromethylphenyl)-1H-pyrrole-2-carboxylate (Intermediate 8). 1 H NMR(400MHz, DMSO-d6)δ12.77(s,1H),7.87(dd,J=7.6,1.4Hz,1H),7.81-7.71(m,2H),7.58(d,J=7.1Hz,1H), 7.39(d,J=1.7Hz,1H),6.97(d,J=1.7Hz,1H),4.26(q,J=7.1Hz,2H),1.28(t,J=7.1Hz,3H).MS(ESI,positive ion)m / z:311.9[M+H] + .

[0107] Intermediate 9: Preparation of 4-(2-trifluoromethylphenyl)-1H-pyrrole-2-carboxylic acid

[0108] To a solution of 4-(2-(trifluoromethyl)benzoyl)-1H-pyrrole-2-carboxylic acid (Intermediate 8) (200 mg) in ethanol (30 ml) was added 2M aqueous NaOH (20 ml). The reaction mixture was stirred at 75°C for 1.5 hours. After confirming the reaction by thin-layer chromatography, the ethanol was concentrated and the solution was acidified to a pH of approximately 3 with hydrochloric acid. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were concentrated. Intermediate 9 was used in the next reaction without further purification.

[0109] Compound 2: Preparation of N-(pyridin-3-yl)-4-(2-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxamide

[0110] A super dry tetrahydrofuran solution (10 mL) containing pyridine-3-amine (5, 0.15 g, 1.58 mmol), 4-(2-(trifluoromethyl)benzoyl)-1H-pyridine-2-carboxylic acid (9, 0.45 g, 1.58 mmol), 1-propylphosphonic anhydride (50 wt.% in ethyl acetate, 1.88 mL, 3.16 mmol) and 4-dimethylaminopyridine (0.18 g, 3.16 mmol) was stirred at room temperature for 12 hours. The mixture was quenched with aqueous hydrochloric acid and the solvent was removed under reduced pressure. The residue was loaded on silica gel and purified by column chromatography (petroleum ether / ethyl acetate = 1:5) to obtain a white solid with a yield of 85%, which was compound 2. 1 H NMR (400MHz, DMSO-d6) δ12.63(s,1H),10.24(s,1H),8.90(d,J=2.5Hz,1H),8.30(dd,J=4.6,1.4Hz,1H),8.14(dt,J=8.5,2.0Hz,1H) ,7.89(d,J=7.7Hz,1H),7.79(dt,J=15.6,7.5Hz,2H),7.63(d,J=7.4Hz,1H),7.50(s,1H),7.39(dd,J=8.3,4.7Hz,1H),7.34(s,1H). 13 C NMR(101MHz,DMSO-d6)δ189.53,159.30,144.83,142.06,139.45,139.43,136.03,132.80,130.54,129.80,128 .63,128.23,127.43,127.11,127.06,126.62,126.31,125.64,124.04,122.93,112.59.HRMS(m / z):calculated for C 18 H 12 F3N3O2 + [M+H] + 360.0949;found,360.0952.

[0111] Table 1 NMR and HRMS of compounds 3 to 153

[0112] Evaluation of compound pharmacological activity

[0113] 1. In vitro enzyme level experiments of 1H-pyrrole-2-carboxamide series derivatives

[0114] The in vitro enzyme level test uses a fluorescence polarization method. The experimental method is briefly described as follows: First, 30nM GST-YTHDC1 (345-509) protein and a series of concentration gradients of the small molecule to be tested were incubated for 30 minutes, and then FAM fluorescently labeled m 6 A modified single-stranded oligonucleotide (5'-AAGAACCGGACUAAGCU-3') (from 5' to 3', the first base A was FAM fluorescently labeled, and the 6th position of the 10th base A was methyl-modified) was incubated at 18°C ​​for 4 hours. Finally, the fluorescence polarization value of each well was read on a microplate reader and the inhibition rate was calculated. The IC was then calculated using Graphpad 8.0. 50 .

[0115] Table 2 Inhibitory activity of the compounds of the present invention against YTHDC1

[0116] 2. In vitro cell experiments

[0117] 2.1 Experimental Materials

[0118] Key instruments: Biosafety cabinet, CO2 cell culture incubator, flow cytometer, inverted fluorescence microscope, multifunctional microplate reader, precision electronic balance. Key consumables: Cell culture dishes, 12-well plates, 96-well plates, and 384-well plates. Key reagents: 1640 complete culture medium, fetal bovine serum (Hyclone, South America), penicillin-streptomycin double antibody solution. Cell cycle and apoptosis kits, PE-CD11b and APC-CD14 flow cytometry antibodies, MTT powder, and SDS powder. Cell lines: Acute myeloid leukemia cells (MV4-11, HL-60, MOLM-13, THP-1, KG-1, U937, and OCI-AML3).

[0119] 2.2 Experimental methods

[0120] (1) MTT assay for cell proliferation:

[0121] AML cells (MV4-11, HL-60, MOLM-13, THP-1, KG-1, U937, and OCI-AML3) were plated in 96-well plates at 10,000-15,000 cells per well. A series of concentration gradients of YL-5092 (i.e., compound 29) were then added and cultured for 72 h. 20 μL of MTT solution (5 mg / L) was added to each well and incubated for 2-4 hours. 50 μL of 20% SDS solution was then added and incubated overnight to dissolve the formazan. The absorbance was then read at 570 nm on a microplate reader, and the IC of YL-5092 was calculated using GraphPad Prism 8.0. 50 The results are shown in Figure 1a.

[0122] (2) Flow cytometry detection of cell cycle, apoptosis, and differentiation:

[0123] To test the effect of the small molecule YL-5092 on the cell cycle of leukemia MOLM-13 cells, MOLM-13 cells were plated in 12-well plates and treated with different concentrations of YL-5092 (0.5-2 μM) for 48 hours. After collection, the cells were washed once with ice-cold PBS and fixed with 70% ice-cold ethanol for 12 hours. Before flow cytometry analysis, the cells were washed twice with ice-cold PBS and incubated in the dark with PI reagent for 30 minutes. The results are shown in Figure 1b.

[0124] To detect the effect of the small molecule YL-5092 on the differentiation of leukemia MOLM-13 cells, MOLM-13 cells were evenly plated in 12-well plates and treated with different concentrations of YL-5092 (0.5-2 μM) for 5 days. After collection, the cells were washed twice with ice-cold PBS and incubated in the dark for 30 minutes with 2 μL PE-CD11b antibody and 2 μL APC-CD14 antibody. The cells were then washed twice with ice-cold PBS and analyzed by flow cytometry. The results are shown in Figure 1c.

[0125] To examine the effect of the small molecule YL-5092 on apoptosis in leukemia cells (MOLM-13, MV4-11, THP-1, and U937), we plated MOLM-13, MV4-11, THP-1, and U937 cells in 12-well plates and treated them with varying concentrations of YL-5092 (0.5–2 μM) for 5 days. Cells were harvested, washed twice with ice-cold PBS, and incubated with 5 μL of APC-Annexin V antibody and 5 μL of 7-AAD in the dark for 15–30 minutes before analysis by flow cytometry. The results are shown in Figure 1d.

[0126] 2.3 Experimental Results

[0127] YL-5092 can significantly inhibit the proliferation of AML cells (MV4-11, HL-60, MOLM-13, THP-1, KG-1, U937, OCI-AML3), IC 50 The values ​​ranged from 0.28 to 2.87 μM (Figure 1a). Flow cytometry analysis revealed that YL-5092 could significantly induce AML cell cycle arrest at the G0 / G1 phase (Figure 1b), induce AML cell differentiation (Figure 1c) and apoptosis (Figure 1d).

Claims

1. A compound represented by formula I or a hydrate thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The structure is as follows: wherein Ring A is selected from a 6- to 10-membered aromatic ring and a 5- to 10-membered heteroaromatic ring; In ring A, the 5- to 10-membered heteroaromatic ring contains 1 to 3 heteroatoms, and the heteroatoms are selected from N, S, and O; R 1 Selected from H, halogen, cyano, halogen-substituted or unsubstituted C1-C8 alkyl, halogen-substituted or unsubstituted C1-C8 alkoxy, halogen-substituted or unsubstituted C2-C8 alkanoyl, halogen-substituted or unsubstituted C2-C8 alkoxycarbonyl, halogen-substituted or unsubstituted 3-8-membered cycloalkyl, substituted or unsubstituted 6-10-membered aryl, substituted or unsubstituted 5-10-membered heteroaryl; R 1 In the above, the 5- to 10-membered heteroaryl group contains 1 to 3 heteroatoms, and the heteroatoms are selected from N, S, and O; R 1 wherein the substituents of the substituted or unsubstituted 6- to 10-membered aryl group or the substituted or unsubstituted 5- to 10-membered heteroaryl group are selected from cyano, halogen-substituted or unsubstituted C1- to C6-alkyl, -NR 13 R 14 at least one of; R 13 ~R 14 are independently selected from H, halogen-substituted or unsubstituted C1-C4 alkyl, or R 13 , R 14 With -NR 13 R 14 The N in the group is connected to form a halogen-substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, wherein the 3- to 8-membered heterocycloalkyl group contains 0 to 2 heteroatoms in addition to the aforementioned N, and the heteroatoms are selected from N, S, and O; Ring B is selected from R 2 ~R 6 Independently selected from H, halogen, halogen-substituted or unsubstituted C1-C8 alkyl, halogen-substituted or unsubstituted C1-C8 alkoxy; R 7 ~R 9 , R 11 Independently selected from H, halogen, halogen-substituted or unsubstituted C1-C6 alkyl; R 10 , R 12 Independently selected from substituted or unsubstituted 6- to 10-membered aryl, substituted or unsubstituted 5- to 10-membered heteroaryl; R 10 , R 12 In the above, the 5- to 10-membered heteroaryl group contains 1 to 3 heteroatoms, and the heteroatoms are selected from N, S, and O; R 10 , R 12 wherein the substituents of the substituted 6- to 10-membered aryl group and the substituted 5- to 10-membered heteroaryl group are selected from cyano, halogen, substituted or unsubstituted C1- to C6 alkyl, substituted or unsubstituted C1- to C6 alkoxy, -NR 15 R 16 、-SO2R 17 ; R 10 , R 12 wherein the substituents of the substituted C1-C6 alkyl and substituted C1-C6 alkoxy are selected from Hydroxyl, halogen; R 15 , R 16 , R 17 Independently selected from H, halogen-substituted or unsubstituted C1-C4 alkyl; X is selected from a bond, -CH(R 18 )(CH2) n -; n is an integer selected from 0 to 3; R 18 Selected from H, C1-C4 alkyl; Y is selected from -NH-; R 19 , R 20 Independently selected from H, hydroxyl, cyano, halogen, halogen-substituted or unsubstituted C1-C4 alkyl; Z and W are independently selected from N, CR 21 ; R 21 Selected from H, halogen.

2. The compound according to claim 1, characterized in that: Ring A is selected from a 6- to 10-membered aromatic ring and a 5- to 6-membered heteroaromatic ring; in Ring A, the 5- to 6-membered heteroaromatic ring contains 1 to 2 heteroatoms selected from N, S, and O; Preferably, ring A is selected from a benzene ring and a pyridine ring; Most preferably, Ring A is selected from 3. The compound according to claim 1, characterized in that: R 1 R is selected from H, halogen, cyano, halogen-substituted or unsubstituted C1-C6 alkyl, halogen-substituted or unsubstituted C1-C6 alkoxy, halogen-substituted or unsubstituted C2-C6 alkanoyl, halogen-substituted or unsubstituted C2-C6 alkoxycarbonyl, halogen-substituted or unsubstituted 3-6-membered cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6-membered heteroaryl; 1 In the above, the 5-6 membered heteroaryl group contains 1-2 heteroatoms, and the heteroatoms are selected from N, S, and O; Preferably, R 1 R is selected from H, halogen, cyano, halogen-substituted or unsubstituted C1-C4 alkyl, halogen-substituted or unsubstituted C1-C4 alkoxy, halogen-substituted or unsubstituted C2-C4 alkanoyl, halogen-substituted or unsubstituted C2-C5 alkoxycarbonyl, halogen-substituted or unsubstituted 3-6-membered cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6-membered heteroaryl; 1 In the above, the 5-6 membered heteroaryl group contains 1-2 heteroatoms, and the heteroatoms are selected from N, S, and O; More preferably, R 1 R is selected from H, F, Cl, Br, cyano, fluorine-substituted or unsubstituted C1-C4 alkyl, fluorine-substituted or unsubstituted C1-C4 alkoxy, fluorine-substituted or unsubstituted C2-C4 alkanoyl, fluorine-substituted or unsubstituted C2-C5 alkoxycarbonyl, fluorine-substituted or unsubstituted 3-6-membered cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6-membered heteroaryl; 1 In the above, the 5-6 membered heteroaryl group contains 1-2 heteroatoms, and the heteroatoms are selected from N, S, and O; Further preferably, R 1 R is selected from H, F, Cl, Br, cyano, fluorine-substituted or unsubstituted C1-C4 alkyl, fluorine-substituted or unsubstituted C1-C4 alkoxy, fluorine-substituted or unsubstituted C2-C4 alkanoyl, fluorine-substituted or unsubstituted C2-C5 alkoxycarbonyl, fluorine-substituted or unsubstituted 3-6-membered cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6-membered heteroaryl; 1 wherein the 5- to 6-membered heteroaryl group is selected from pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, and pyrazolyl; Most preferably, R 1 R is selected from H, F, Cl, Br, methyl, trifluoromethyl, methoxy, trifluoromethoxy, acetyl, ethoxycarbonyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; 1 wherein the 5- to 6-membered heteroaryl group is selected from 4. The compound according to any one of claims 1 to 3, characterized in that: R 1 wherein the substituent of the substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl is selected from cyano, halogen substituted or unsubstituted C1-C4 alkyl, -NR 13 R 14 At least one of R 13 ~R 14 independently selected from halogen-substituted or unsubstituted C1-C4 alkyl, or R 13 , R 14 With -NR 13 R 14 The N in the group is connected to form a halogen-substituted or unsubstituted 3- to 6-membered heterocycloalkyl group, wherein the 3- to 6-membered heterocycloalkyl group contains 0 to 1 heteroatom in addition to the aforementioned N, and the heteroatom is selected from N, S, and O; Preferably, R 1 wherein the substituent of the substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl is selected from cyano, fluorine-substituted or unsubstituted C1-C4 alkyl, -NR 13 R 14 At least one of R 13 ~R 14 are independently selected from fluorine-substituted or unsubstituted C1-C4 alkyl, or R 13 , R 14 With -NR 13 R 14 The N in the group is connected to form a fluorine-substituted or unsubstituted 3- to 6-membered heterocycloalkyl group, wherein the 3- to 6-membered heterocycloalkyl group contains 0 to 1 heteroatom in addition to the aforementioned N, and the heteroatom is selected from S and O; More preferably, R 1 wherein the substituent of the substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl is selected from cyano, methyl, trifluoromethyl, -NR 13 R 14 At least one of R 13 ~R 14 are independently selected from methyl, trifluoromethyl, or R 13 , R 14 With -NR 13 R 14 The N in the group is connected to form a fluorine-substituted or unsubstituted 3-6-membered heterocycloalkyl group, wherein the 3-6-membered heterocycloalkyl group is selected from Most preferably, R 1 wherein the substituent of the substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl is selected from cyano, methyl, trifluoromethyl, 5. The compound according to any one of claims 1 to 4, characterized in that: Structural unit Selected from:

6. The compound according to claim 1, characterized in that: R 2 ~R 6 Independently selected from H, halogen, halogen-substituted or unsubstituted C1-C6 alkyl, halogen-substituted or unsubstituted C1-C6 alkoxy; Preferably, R 2 ~R 6 Independently selected from H, halogen, halogen-substituted or unsubstituted C1-C4 alkyl, halogen-substituted or unsubstituted C1-C4 alkoxy; More preferably, R 2 ~R 6 Independently selected from H, F, Cl, Br, fluorine-substituted or unsubstituted C1-C4 alkyl, fluorine-substituted or unsubstituted C1-C4 alkoxy; Further preferably, R 2 ~R 6 are independently selected from H, F, Cl, Br, fluorine-substituted or unsubstituted C1-C4 alkyl, fluorine-substituted or unsubstituted C1-C4 alkoxy, and R 2 and R 6 Not at the same time H; Most preferably, R 2 is selected from H, F, Cl, Br, methyl, trifluoromethyl, ethyl, tert-butyl, methoxy, trifluoromethoxy, ethoxy, R 3 Selected from H, F, Cl, Br, R 4 is selected from H, F, Cl, Br, methyl, trifluoromethyl, R 5 Selected from H, F, Cl, Br, R 6 is selected from H, F, Cl, Br, methyl, trifluoromethyl, ethyl, tert-butyl, methoxy, trifluoromethoxy, ethoxy, and R 2 and R 6 Not H at the same time.

7. The compound according to claim 1 or 6, characterized in that: Structural unit Selected from:

8. The compound according to claim 1, characterized in that: Y is selected from -NH-; R 19 , R 20 Independently selected from H, hydroxyl, cyano, F, F-substituted or unsubstituted C1-C4 alkyl; Preferably, Y is selected from -NH-; R 19 , R 20 Independently selected from H, hydroxy, cyano, F, methyl, trifluoromethyl; Most preferably, Y is selected from -NH-.

9. The compound according to claim 1, characterized in that: R 7 ~R 9 , R 11 Independently selected from H, halogen, halogen-substituted or unsubstituted C1-C4 alkyl; Preferably, R 7 ~R 9 , R 11 Independently selected from H, F, F-substituted or unsubstituted C1-C4 alkyl; Most preferably, R 7 ~R 9 , R 11 Independently selected from H, F, methyl, trifluoromethyl.

10. The compound according to claim 1, characterized in that: R 10 , R 12 R is independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; 10 , R 12 In the above, the 5-6 membered heteroaryl group contains 1-2 heteroatoms, and the heteroatoms are selected from N, S, and O; Preferably, R 10 , R 12 R is independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; 10 , R 12 wherein the 5- to 6-membered heteroaryl group is selected from pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, and pyrazolyl; Most preferably, R 10 , R 12 R is independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; 10 , R 12 wherein the 5- to 6-membered heteroaryl group is selected from 11. The compound according to claim 1 or 10, characterized in that: R 10 , R 12 wherein the substituent of the substituted aryl or substituted heteroaryl is selected from cyano, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, -NR 15 R 16 、-SO2R 17 ; R 10 , R 12 wherein the substituent of the substituted C1-C4 alkyl and substituted C1-C4 alkoxy is selected from hydroxyl and halogen; R 15 , R 16 , R 17 Independently selected from H, halogen-substituted or unsubstituted C1-C4 alkyl; Preferably, R 10 , R 12 wherein the substituent of the substituted aryl or substituted heteroaryl is selected from cyano, F, Cl, Br, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, -NR 15 R 16 , -SO2R 17 ; R 10 , R 12 wherein the substituents of the substituted C1-C4 alkyl and substituted C1-C4 alkoxy are selected from hydroxyl, F; R 15 , R 16 , R 17 Independently selected from H, fluorine-substituted or unsubstituted C1-C4 alkyl; Most preferably, R 10 , R 12 In the above, the substituents of the substituted aryl and substituted heteroaryl are selected from cyano, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, hydroxymethyl, trifluoromethyl, methoxy, trifluoromethoxy, amino, -SO2CF3, and -SO2CH3.

12. The compound according to claim 1, characterized in that: X is selected from a bond, -CH(R 18 )(CH2) n -; n is an integer selected from 0 to 1; R 18 Selected from H, C1-C4 alkyl; Preferably, X is selected from a bond, -CH(CH3)-, -CH2-.

13. The compound according to claim 1, characterized in that: Z and W are independently selected from N, CR 21 ; R 21 Selected from H, F; Preferably, Z is selected from N, CH, CF, and W is selected from N.

14. The compound according to any one of claims 1 to 13, characterized in that: At least one of the following is met: Selected from: Selected from: Selected from:

15. The compound according to any one of claims 1 to 14, characterized in that: The structural formula is as follows:

16. The compound according to claim 1 or 2, characterized in that: Structural unit Selected from:

17. The compound according to any one of claims 1, 2, 9, 12 to 13 or 16, characterized in that: Selected from:

18. The compound according to any one of claims 1, 2, 9, 12-13 or 16-17, characterized in that: The structural formula is as follows:

19. The compound according to claim 1, characterized in that: The structural formula is as follows:

20. The compound according to claim 1 or 2, characterized in that: Structural unit Selected from:

21. The compound according to any one of claims 1, 2 or 20, characterized in that: Structural unit Selected from:

22. The compound according to any one of claims 1, 2, 8, 9, 12 or 20 to 21, characterized in that: Selected from:

23. The compound according to any one of claims 1, 2, 8, 9, 12 or 20 to 22, characterized in that: The structural formula is as follows:

24. The compound according to claim 1, characterized in that: The structural formula is as follows:

25. A pharmaceutical composition, comprising the compound according to any one of claims 1 to 24 and its hydrate or pharmaceutically acceptable salt as an active ingredient, and pharmaceutically acceptable auxiliary ingredients.

26. Use of the compound according to any one of claims 1 to 24, its hydrate, pharmaceutically acceptable salt, and the pharmaceutical composition according to claim 25 in the preparation of a YTHDC1 small molecule inhibitor.

27. Use of the compound according to any one of claims 1 to 26, its hydrate, pharmaceutically acceptable salt, and the pharmaceutical composition according to claim 32 in the preparation of a drug for treating and / or preventing YTHDC1-related diseases; preferably, the YTHDC1-related diseases include: Acute myeloid leukemia, T-cell lymphoma, liver cancer, pancreatic cancer, breast cancer, glioma or hepatitis B; more preferably, the YTHDC1-related disease includes acute myeloid leukemia or T-cell lymphoma.

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