WO2024260445A1 - Thiazolidinedione compound and pharmaceutical composition and use thereof - Google Patents

Abstract

Disclosed are a thiazolidinedione compound and a pharmaceutical composition and a use thereof. The present invention provides a use of a compound as shown in formula I or a pharmaceutically acceptable salt thereof in the preparation of a DNA methyltransferase 3A inhibitor. The thiazolidinedione compound provided by the present invention has excellent inhibitory activity against the DNA methyltransferase DNMT3A.

Description

A thiazolidinedione compound, its pharmaceutical composition and its use

This application claims the priority of Chinese Patent Application No. 2023107433385 filed on June 21, 2023. This application cites the entire text of the above Chinese Patent Application.

Technical Field

The present invention belongs to the field of biomedicine, and specifically relates to a thiazolidinedione compound, a pharmaceutical composition thereof and a use thereof.

Background Art

DNA methyltransferase DNMT3A is an important epigenetic modification enzyme responsible for de novo DNA methylation in eukaryotes. DNMT3A consists of a flexible N-terminus, a PWWP domain (Pro-Trp-Trp-Pro domain), an ADD domain (ATRX-DNMT3-DNMT3L domain) and a catalytic domain (Methyltransferase domain, MT). Mutations at specific MT sites not only lead to developmental diseases such as Tatton-Brown-Rahman syndrome (TBRS), but are also closely related to tumors such as acute myeloid leukemia (AML). Studies have shown that MT mutations in DNMT3A can cause significant changes in epigenetic regulatory patterns such as DNA methylation, thereby affecting the expression of a series of related genes, ultimately affecting the differentiation and proliferation of specific cells, and leading to the occurrence of diseases.

Summary of the invention

The technical problem to be solved by the present invention is that there are few inhibitors of DNA methyltransferase DNMT3A in the prior art. To this end, the present invention provides a thiazolidinedione compound, a pharmaceutical composition thereof and a use thereof. The thiazolidinedione compound provided by the present invention has good inhibitory activity on DNA methyltransferase 3A (DNMT3A).

The present invention provides a use of a compound as shown in formula I or a pharmaceutically acceptable salt thereof in the preparation of a DNA methyltransferase 3A (DNMT3A) inhibitor.

in,

n is 1, 2, 3, 4 or 5;

Each R ¹ is independently C _1-6 alkyl or C _1-6 alkoxy;

_X1 and _X2 are independently O or S;

is a single bond or a double bond;

Ring A is a C _6-10 aromatic ring or a 5-10 membered heteroaromatic ring; the heteroatoms of the 5-10 membered heteroaromatic ring are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3;

L is a C _6-10 aryl substituted by one or more R ^L-1 , a 3-10 membered heterocycloalkenyl substituted by one or more R ^L-2 , a C _1-6 heteroalkyl substituted by one or more R ^L-3 , or a benzo 3-10 membered heterocycloalkenyl substituted by one or more R ^L-4 ; the 3-10 membered heterocycloalkenyl The heteroatoms of the benzo-3-10 membered heterocycloalkenyl group, the C _1-6 heteroalkyl group and the 3-10 membered heterocycloalkenyl group are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

Each of RL ^-1 , RL ^-2 , ^RL-3 and ^RL-4 is independently carboxyl, oxo (=O), _C1-6 alkyl, or a 5-10 membered heteroaryl group, wherein the heteroatoms of the 5-10 membered heteroaryl group are selected from one, two or three of N, O and S, and the number of the heteroatoms is 1, 2 or 3;

each of RL ^-1-1 and ^RL-1-2 is independently _C1-6 alkyl, _C6-10 aryl, _C1-6 alkyl substituted by one or more ^RL-1-1-1 , or _C6-10 aryl substituted by one or more ^RL-1-1-2 ;

Each of ^RL-1-1-1 and RL ^-1-1-2 is independently _C1-6 alkyl, _C1-6 alkoxy, nitro or _C2-6 alkynyl.

In a preferred embodiment, in each R ¹ , the C _1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example, methyl.

In a preferred embodiment, in each R ¹ , the C _1-6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy, such as methoxy.

In a preferred embodiment, in ring A, the C _6-10 aromatic ring is a benzene ring or a naphthalene ring, such as a benzene ring. In a preferred embodiment, when ring A is a C _6-10 aromatic ring, for

In a preferred embodiment, in ring A, the heteroatom of the 5-10 membered heteroaromatic ring is O, and the number of heteroatoms is 1, 2 or 3; for example, the heteroatom is O, and the number of heteroatoms is 1.

In a preferred embodiment, in ring A, the 5-10 membered heteroaromatic ring is a 5-6 membered heteroaromatic ring, such as a furan ring.

In a preferred embodiment, when ring A is a 5-10 membered heteroaromatic ring, for

In a preferred embodiment, in L, the C _6-10 aryl group in the C _6-10 aryl group substituted by one or more R ^L-1 is phenyl or naphthyl, for example phenyl.

In a preferred embodiment, in L, the number of double bonds in the 3-10 membered heterocycloalkenyl group substituted by one or more R ^L-2 and the 3-10 membered heterocycloalkenyl group in the benzo 3-10 membered heterocycloalkenyl group substituted by one or more R ^L-4 is independently 1, 2 or 3, for example 2.

In a preferred embodiment, in L, the 3-10 membered heterocycloalkenyl substituted by one or more RL ^-2 and the 3-10 membered heterocycloalkenyl in the benzo 3-10 membered heterocycloalkenyl substituted by one or more ^RL-4 are independently 5-6 membered heterocycloalkenyl.

In a preferred embodiment, in L, the heteroatom of the 3-10 membered heterocycloalkenyl substituted by one or more RL ^-2 and the 3-10 membered heterocycloalkenyl in the benzo 3-10 membered heterocycloalkenyl substituted by one or more RL ^-4 is N, and the number of heteroatoms is 1, 2 or 3; for example, the heteroatom is N, and the number of heteroatoms is 1.

In a preferred embodiment, in L, the 3-10 membered heterocycloalkenyl group in the 3-10 membered heterocycloalkenyl group substituted by one or more R ^L-2 is For example

In a preferred embodiment, in L, the benzo 3-10 membered heterocycloalkenyl group in the benzo 3-10 membered heterocycloalkenyl group substituted by one or more R ^L-4 is For example

In a preferred embodiment, in L, the heteroatom of the _C1-6 heteroalkyl group substituted by one or more RL ^-3 is selected from one or _two of N, O and S, and the number of heteroatoms is 1, 2 or 3; for example, the heteroatom is selected from one or two of N and O, and the number of heteroatoms is 2; for another example, the heteroatom is N and O, and the number of heteroatoms is 2.

In a preferred embodiment, in L, the C _1-6 heteroalkyl group in the C _1-6 heteroalkyl group substituted by one or more ^RL-3 is a straight-chain heteroalkyl group.

In a preferred embodiment, in L, the C _1-6 heteroalkyl group in the C _1-6 heteroalkyl group substituted by one or more ^RL-3 is a C _1-4 heteroalkyl group, for example

In a preferred embodiment, in each of RL ^-1 , ^RL-2 , ^RL-3 and RL ^-4 , the _C1-6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, such as methyl.

In a preferred embodiment, in each of RL ^-1 , ^RL-2 , ^RL-3 and RL ^-4 , the heteroatom of the 5-10 membered heteroaryl is independently N, and the number of heteroatoms is independently 1, 2 or 3; for example, the heteroatom is N, and the number of heteroatoms is 1.

In a preferred embodiment, in each of RL ^-1 , ^RL-2 , ^RL-3 and RL ^-4 , the 5-10 membered heteroaryl group is independently a 5-6 membered heteroaryl group, for example, independently a pyridyl group, for example

In a preferred embodiment, in each of ^RL-1-1 and RL ^-1-2 , the _C1-6 alkyl group and the _C1-6 alkyl group substituted by one or more ^RL-1-1-1 _are independently methyl, ethyl, n _- propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; for example, methyl, ethyl, n-propyl or isobutyl.

In a preferred embodiment, in each of ^RL-1-1 and RL ^-1-2 , the _{C6-10 aryl} group and the _C6-10 aryl group substituted by one or more ^RL-1-1-2 _are independently phenyl or naphthyl, for example phenyl.

In a preferred embodiment, each plurality is independently 2 or 3.

In a preferred embodiment, in each of ^RL-1-1-1 and ^RL-1-1-2 , the _C1-6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl.

In a preferred embodiment, in each of ^RL-1-1-1 and RL ^-1-1-2 , the _C1-6 alkoxy group is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy, for example methoxy.

In a preferred embodiment, in each of RL ^-1-1-1 and ^RL-1-1-2 , the _C2-6 alkynyl group is independently ethynyl, propynyl or butynyl, for example

In a preferred embodiment, n is 1 or 2.

In a preferred embodiment, _X1 is O.

In a preferred embodiment, _X2 is O or S.

In a preferred embodiment, ring A is a 5-6 membered heteroaromatic ring; the heteroatom of the 5-6 membered heteroaromatic ring is selected from one of N, O and S. There are 1, 2 or 3 heteroatoms.

In a preferred embodiment, L is a C _6-10 aryl group substituted by one or more ^RL-1 , a 3-10 membered heterocycloalkenyl group substituted by one or more ^RL-2 , or a benzo 3-10 membered heterocycloalkenyl group substituted by one or more ^RL-4 ; preferably, L is a C _6-10 aryl group substituted by one or more ^RL-1 , a 5-6 membered heterocycloalkenyl group substituted by one or more ^RL-2, or a benzo 5-6 membered heterocycloalkenyl group substituted by one or more RL ^-4 , and the heteroatom of the 5-6 membered heterocycloalkenyl group and the 5-6 membered heterocycloalkenyl in the benzo 5-6 membered heterocycloalkenyl is N, and the number of heteroatoms is 1, 2 or 3.

In a preferred embodiment, the C _6-10 aryl group substituted by one or more R ^L-1 is

In a preferred embodiment, each ^RL-1 is independently a carboxyl group,

In a preferred embodiment, each ^RL-1 is independently a carboxyl group or Preferably

In a preferred embodiment, each ^RL-1-1 is independently a _C1-6 alkyl group or a _C1-6 alkyl group substituted by one or more ^{RL-1-1-1 groups} .

In a preferred embodiment, each ^RL-1-2 is independently a C _1-6 alkyl group or a C _1-6 alkyl group substituted by one or more ^RL-1-1-1 ; preferably, it is a C _1-6 alkyl group substituted by one or more ^RL-1-1-1 .

In a preferred embodiment, each ^RL-1-1-1 is independently _C1-6 alkyl or _C2-6 alkynyl.

In a preferred embodiment, each RL ^-1-1-1 is independently a _C2-6 alkynyl group.

In a preferred embodiment, each ^RL-1-1-2 is independently _C1-6 alkyl, _C1-6 alkoxy or nitro.

In a preferred embodiment, the 3-10 membered heterocycloalkenyl substituted by one or more R ^L-2 is

In a preferred embodiment, each RL ^-2 is oxo.

In a preferred embodiment, the C _1-6 heteroalkyl substituted by one or more R ^L-3 is

In a preferred embodiment, each RL ^-3 is independently a _C1-6 alkyl group or a 5-10 membered heteroaryl group, wherein the heteroatoms of the 5-10 membered heteroaryl group are selected from one, two or three of N, O and S, and the number of the heteroatoms is 1, 2 or 3.

In a preferred embodiment, each RL ^-3 is independently a _C1-6 alkyl group or a 5-6 membered heteroaryl group, wherein the heteroatoms of the 5-6 membered heteroaryl group are selected from one, two or three of N, O and S, and the number of the heteroatoms is 1, 2 or 3.

In a preferred embodiment, the benzo 3-10 membered heterocycloalkenyl group substituted by one or more R ^L-4 is

In a preferred embodiment, each RL ^-4 is oxo.

In a preferred embodiment, each RL ^-1 is independently For example

In a preferred embodiment, each RL ^-1 is independently For example

In a preferred embodiment, each RL ^-1 is independently

In a preferred embodiment, for Preferably for

In a preferred embodiment, for

In a preferred embodiment, for Preferably,

In a preferred embodiment, ring A is Preferably, for Preferably,

In a preferred embodiment, L is Preferably, L is

In a preferred embodiment, L is More preferably,

In a preferred embodiment;

n is 1 or 2;

Each R ¹ is independently C _1-6 alkyl or C _1-6 alkoxy;

_X1 and _X2 are independently O or S;

is a single bond or a double bond;

Ring A is a C _6-10 aromatic ring or a 5-10 membered heteroaromatic ring; the heteroatom of the 5-10 membered heteroaromatic ring is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

L is a C _6-10 aryl substituted by one or more R ^L-1 , a 3-10 membered heterocycloalkenyl substituted by one or more R ^L-2 , a C _1-6 heteroalkyl substituted by one or more R ^L-3 , or a benzo 3-10 membered heterocycloalkenyl substituted by one or more R ^L-4 ; the heteroatoms of the 3-10 membered heterocycloalkenylene and the C _1-6 heteroalkyl are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

Each RL ^-1 is independently a carboxyl group,

Each RL ^-2 is oxo;

Each RL ^-3 is independently a _C1-6 alkyl group or a 5-10 membered heteroaryl group, wherein the heteroatoms of the 5-10 membered heteroaryl group are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3;

Each RL ^-4 is oxo;

Each RL ^-1-1 is independently _C1-6 alkyl or _C1-6 alkyl substituted by one or more RL ^-1-1-1 ;

each RL ^-1-2 is independently _C1-6 alkyl, 6-10 membered aryl, _C1-6 alkyl substituted with one or more ^RL-1-1-1 , or 6-10 membered aryl substituted with one or more RL ^-1-1-2 ;

Each ^RL-1-1-1 is independently _C1-6 alkyl or _C2-6 alkynyl;

Each RL ^-1-1-2 is independently _C1-6 alkyl, _C1-6 alkoxy or nitro.

In a preferred embodiment, Ring A is a C _6-10 aromatic ring.

In a preferred embodiment, ring A is a 5-10 membered heteroaromatic ring; the heteroatoms of the 5-10 membered heteroaromatic ring are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3.

In a preferred embodiment, ring A is a C _6-10 aromatic ring; and L is a C _1-6 heteroalkyl group substituted by one or more RL ^{-3 groups} .

In a preferred embodiment, ring A is a 5-10 membered heteroaromatic ring, L is a C _6-10 aryl group substituted by one or more R ^L-1 , each R ^L-1 is

In a preferred embodiment, ring A is a 5-10 membered heteroaromatic ring, L is a C _6-10 aryl group substituted by one or more R ^L-1 , each R ^L-1 is

In a preferred embodiment, ring A is a 5-10 membered heteroaromatic ring, L is a 3-10 membered heterocycloalkenyl substituted by one or more ^RL-2 or a benzo 3-10 membered heterocycloalkenyl substituted by one or more RL ^-4 ; the heteroatoms of each 3-10 membered heterocycloalkenylene group are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

In a preferred embodiment, the compound as shown in formula I is any of the following embodiments:

Solution (1):

n is 1 or 2;

Each R ¹ is independently C _1-6 alkyl or C _1-6 alkoxy;

_X1 and _X2 are independently O or S;

is a single bond or a double bond;

Ring A is a C _6-10 aromatic ring;

L is a C _1-6 heteroalkyl group substituted by one or more R ^L-3 ; the heteroatoms of the C _1-6 heteroalkylene group are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3;

Each RL ^-3 is independently a _C1-6 alkyl group or a 5-10 membered heteroaryl group, wherein the heteroatom of the 5-10 membered heteroaryl group is selected from N, O and S. One, two or three kinds of heteroatoms, the number of heteroatoms is 1, 2 or 3;

Solution (2):

n is 1 or 2;

Each R ¹ is independently C _1-6 alkyl or C _1-6 alkoxy;

_X1 and _X2 are independently O or S;

is a single bond or a double bond;

Ring A is a 5-10 membered heteroaromatic ring; the heteroatoms of the 5-10 membered heteroaromatic ring are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3;

L is a C _6-10 aryl group substituted by one or more R ^L-1 , each R ^L-1 being

Each RL ^-1-1 is independently _C1-6 alkyl or _C1-6 alkyl substituted by one or more RL ^-1-1-1 ;

Each ^RL-1-1-1 is independently _C1-6 alkyl or _C2-6 alkynyl.

Solution (3):

n is 1 or 2;

Each R ¹ is independently C _1-6 alkyl or C _1-6 alkoxy;

_X1 and _X2 are independently O or S;

is a single bond or a double bond;

Ring A is a 5-10 membered heteroaromatic ring; the heteroatoms of the 5-10 membered heteroaromatic ring are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3;

L is a C _6-10 aryl group substituted by one or more R ^L-1 ; each R ^L-1 is

each RL ^-1-2 is independently _C1-6 alkyl, 6-10 membered aryl, _C1-6 alkyl substituted with one or more ^RL-1-1-1 , or 6-10 membered aryl substituted with one or more RL ^-1-1-2 ;

Each ^RL-1-1-1 is independently _C1-6 alkyl or _C2-6 alkynyl;

Each RL ^-1-1-2 is independently _C1-6 alkyl, _C1-6 alkoxy or nitro;

Solution (4):

n is 1 or 2;

Each R ¹ is independently C _1-6 alkyl or C _1-6 alkoxy;

_X1 and _X2 are independently O or S;

is a single bond or a double bond;

Ring A is a 5-10 membered heteroaromatic ring; the heteroatoms of the 5-10 membered heteroaromatic ring are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3;

L is a 3-10 membered heterocycloalkenyl group substituted by one or more R ^L-2 or a benzo 3-10 membered heterocycloalkenyl group substituted by one or more R ^L-4 ; the heteroatoms of the 3-10 membered heterocycloalkenylene group are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3;

Each of ^RL-2 and ^RL-4 is oxo.

In a preferred embodiment,

n is 1, 2, 3, 4 or 5;

Each R ¹ is independently C _1-6 alkyl or C _1-6 alkoxy;

_X1 and _X2 are independently O or S;

is a single bond or a double bond;

Ring A is a C _6-10 aromatic ring or a 5-10 membered heteroaromatic ring; the heteroatoms of the 5-10 membered heteroaromatic ring are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3;

L is a C _6-10 aryl substituted by one or more R ^L-1 , a 3-10 membered heterocycloalkenyl substituted by one or more R ^L-2 , a C _1-6 heteroalkyl substituted by one or more R ^L-3 , or a benzo 3-10 membered heterocycloalkenyl substituted by one or more R ^L-4 ; the heteroatoms of the 3-10 membered heterocycloalkenyl, the C _1-6 heteroalkyl and the benzo 3-10 membered heterocycloalkenyl are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

Each ^RL-1 is independently carboxyl or

Each RL ^-2 is oxo;

Each RL ^-3 is independently a _C1-6 alkyl group or a 5-10 membered heteroaryl group, wherein the heteroatoms of the 5-10 membered heteroaryl group are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3;

Each RL ^-4 is oxo;

Each RL ^-1-2 is independently _C1-6 alkyl or _C1-6 alkyl substituted with one or more RL ^-1-1-1 .

Each ^RL-1-1-1 is independently _C1-6 alkyl or _C2-6 alkynyl.

In a preferred embodiment, n is 1, 2, 3, 4 or 5;

Each R ¹ is independently C _1-6 alkyl or C _1-6 alkoxy;

_X1 and _X2 are independently O or S;

is a double bond;

Ring A is a 5-6 membered heteroaromatic ring; the heteroatoms of the 5-6 membered heteroaromatic ring are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3;

L is a C _6-10 aryl group substituted by one or more R ^L-1 , a 5-6 membered heterocycloalkenyl group substituted by one or more R ^L-2, or a benzo 5-6 membered heterocycloalkenyl group substituted by one or more R ^L-4 , wherein the heteroatom of the 5-6 membered heterocycloalkenyl group and the benzo 5-6 membered heterocycloalkenyl group is N, and the number of heteroatoms is 1, 2 or 3;

Each R ^L-1 is each ^RL-1-2 is independently a _C1-6 alkyl substituted by one or more ^RL-1-1-1 , and each RL ^{- 1-1-1} is independently a _C2-6 alkynyl;

Each RL ^-2 is oxo;

Each RL ^-4 is oxo.

In a preferred embodiment, the compound shown in formula I is any of the following compounds:

In a preferred embodiment, in the application, the DNA methyltransferase 3A inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of DNA methyltransferase 3A inhibitory effects.

The present invention provides a compound as shown in formula I' or a pharmaceutically acceptable salt thereof,

in,

n、R ¹ 、X ₁ 、X ₂ 、 The definitions of ring A and L are as described in any embodiment of the present invention, and the compound shown in formula I' is not

The present invention also provides a pharmaceutical composition comprising:

(1) (a therapeutically effective amount) a compound represented by formula I' or a pharmaceutically acceptable salt thereof according to any embodiment of the present invention;

(2) Pharmaceutically acceptable excipients.

The present invention also provides a use of a compound as shown in Formula I or Formula I' as described in any embodiment of the present invention (in a therapeutically effective amount), a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a drug for treating and/or preventing diseases related to DNA methylation.

In a preferred embodiment, the disease associated with DNA methylation is overgrowth syndrome or acute myeloid leukemia.

In a preferred embodiment, the acute myeloid leukemia is monocytic leukemia.

The present invention also provides a method for preparing a drug for treating and/or preventing overgrowth syndrome or acute myeloid leukemia using a compound of formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as described in any scheme of the present invention (in a therapeutically effective amount) or a pharmaceutical composition thereof as shown in formula I' or a pharmaceutically acceptable salt thereof.

The present invention provides a method for preventing and/or treating diseases related to DNA methylation, comprising administering to a patient a therapeutically effective amount of a compound as shown in Formula I or Formula I' as described in any embodiment of the present invention, a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

The present invention provides a method for preventing and/or treating overgrowth syndrome or acute myeloid leukemia, comprising administering to a patient a therapeutically effective amount of a compound as shown in Formula I or Formula I' as described in any scheme of the present invention, a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

Unless otherwise specified, the terms used in the present invention have the following meanings:

It will be understood by those skilled in the art that the structural formulas used in the present invention to describe groups are based on the conventions used in the art. It means that the corresponding group is connected to other fragments and groups in the compound through this site.

The term "pharmaceutically acceptable" means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for use by patients.

The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention and a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes an inorganic acid. The pharmaceutically acceptable acid includes an organic acid. When the compound of the present invention contains relatively acidic and relatively basic functional groups, it can be converted into a base addition salt or an acid addition salt.

The terms "compound" and "pharmaceutically acceptable salt" may exist as single stereoisomers or mixtures thereof (eg, racemates), if stereoisomers exist.

The term "compound" or "pharmaceutically acceptable salt" may exist in the form of a single tautomer or a mixture thereof if tautomers exist, preferably in the form in which the more stable tautomer is predominant.

When any variable (e.g., R ¹ ) appears multiple times in the definition of a compound, the definition of the variable at each position is independent of the definitions at the remaining positions, and their meanings are independent of each other. Therefore, if a group is substituted with 1, 2, or 3 R ¹ groups, that is, the group may be substituted with up to 3 R ^1s , the definition of R ¹ at that position is independent of the definitions of R ¹ at the remaining positions. In addition, combinations of substituents and/or variables are allowed only if the combination results in a stable compound.

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

The term "alkynyl" refers to a straight or branched hydrocarbon group (e.g., _C2 - _C8 alkynyl, or _C2 - _C4 alkynyl) having one or more triple bonds to a specified number of carbon atoms. The one or more carbon-carbon triple bonds may be internal or terminal, such as propynyl with an internal triple bond. or a propynyl group with a triple bond at the terminal wait.

The term "alkoxy" refers to a group _-ORX , wherein _RX is alkyl as defined above.

The term "heteroalkyl" refers to a group in which a carbon atom at a certain position in the parent structure of a straight or branched alkyl group is replaced by a heteroatom, and has a specified number of carbon atoms (e.g., C ₁ to C ₆ ), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). Heteroalkyl groups include, but are not limited to wait.

The term "aryl" refers to a cyclic group consisting of only carbon atoms, having a specified number of carbon atoms (e.g., C _6-10 ), which is monocyclic or polycyclic, and each ring is aromatic (complying with Huckel's rule). Aryl includes, but is not limited to, phenyl and naphthyl.

The term "aromatic ring" refers to a cyclic group consisting of only carbon atoms with a specified number of carbon atoms (e.g. C _6-10 ), which is monocyclic or polycyclic, and each ring is aromatic (complying with Huckel's rule). Aromatic rings include, but are not limited to, benzene rings and naphthalene rings.

The term "heteroaryl" refers to a cyclic aromatic group having a specified number of ring atoms (e.g., 5-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (1, 2, or 3 of N, O, and S). It is monocyclic or bicyclic. When it is bicyclic, each ring is aromatic, for example, furanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benzisothiazolyl, quinolyl, isoquinolyl, and the like.

The term "heteroaromatic ring" refers to a cyclic aromatic group having a specified number of ring atoms (e.g., 5-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (1, 2, or 3 of N, O, and S), which is monocyclic or bicyclic. When it is bicyclic, each ring is aromatic, for example, furan ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, thiophene ring, isoxazole ring, oxadiazole ring, imidazole ring, pyrrole ring, pyrazole ring, triazole ring, tetrazole ring, thiazole ring, isothiazole ring, thiadiazole ring, benzimidazole ring, indole ring, indazole ring, benzothiazole ring, benzisothiazole ring, quinoline ring, isoquinoline ring and the like.

The term "heterocycloalkenyl" refers to a cyclic group with a specified number of ring atoms (e.g., 3-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (1, 2, or 3 of N, O, and S), which is a monocyclic, bridged, or spirocyclic group, and at least one of the rings contains one or more "double bonds". The "heterocycloalkenyl" does not contain a closed cyclic conjugated system, but only isolated π bonds or discontinuous conjugated π bonds; for example wait.

The term "oxo" refers to the replacement of hydrogen or lone pair electrons on non-oxygen atoms with oxygen, e.g. After being oxidized After being oxidized

The term "pharmaceutically acceptable excipients" refers to excipients and additives used in the production of medicines and the preparation of prescriptions. It is all substances contained in pharmaceutical preparations except the active ingredients.

The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) ameliorating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

The term "therapeutically effective amount" refers to an amount of a compound that is sufficient to effectively treat a disease or condition described herein when administered to a patient."Therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art.

The term "patient" refers to any animal, preferably a mammal, most preferably a human, who is about to be or has been administered the compound or composition according to the embodiments of the present invention.

The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.

Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

The reagents and raw materials used in the present invention are commercially available.

The positive and progressive effects of the present invention are that the thiazolidinedione compounds provided by the present invention are designed and synthesized for the binding pocket characteristics of the MT domain substrate, and have good inhibitory activity against DNMT3A. Through in vitro biochemical and cell experiments, they are proven to have low toxicity, high inhibition rate and high specificity. These compounds can not only be used to further clarify the molecular mechanism of DNMT3A structure and its DNA methylation function, but also provide new drugs for DNA methylation-related diseases, especially cancers such as acute myeloid leukemia AML.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Statistical analysis of IC50 of compounds in A549, MOLM-13 and Thp-1 cell lines (ns indicates no significance (p>0.05), * indicates p<0.05, ** indicates p<0.01, *** indicates p<0.001, **** indicates p<0.0001).

Figure 2: Western blotting was used to identify the expression of DNMT3A protein in J1-890 and J1-890Dnmt3a-/- cell lines.

Figure 3: Statistical analysis of compound IC50 in J1-890Dnmt3a-/- and J1-890 cell lines.

DETAILED DESCRIPTION

The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

Intermediate Preparation Example 1: Preparation of C1

C1: 5-Formaldehydefuran-2-boronic acid C1-1 (140 mg, 1 mmol) and 3-bromobenzoic acid C1-2 (201 mg, 1.1 mmol) were dissolved in DMF solution (2 ml), K ₂ CO ₃ (138 mg, 2 mmol) was added, and finally (pph ₃ ) ₂ pdcl ₂ (3.5 mg, 0.005 mmol) was added, and heated to 100° C. and refluxed for 5 h. After the reaction was completed, it was cooled to room temperature, extracted three times with DCM:H ₂ O (1:20), and the organic phases were combined, evaporated under reduced pressure, and purified by Flash column to obtain yellow solid C1 (110 mg, 51%).

HRMS calculated mass-to-charge ratio of [C ₂ H ₈ O ₄ ] ⁺ [M+H] ⁺ 216.0423, LC-MS showed mass-to-charge ratio of [C ₂ H ₈ O ₄ ] ⁺ [M+H] ⁺ 217.4.

¹ H NMR (500MHz, DMSO) δ9.66 (s, 1H), 8.39 (s, 1H), 8.14 (d, J = 7.8Hz, 1H), 8.01 (d, J = 7.7Hz, 1H), 7.75– 7.61(m,2H),7.44(d,J=3.7Hz,1H).

Intermediate Preparation Example 2: Preparation of C2

C2: 2,4-dimethylaniline C2-1 (1.2ml, 10mmol) was dissolved in water (10ml), carbon disulfide (1.8ml, 25mmol) was added via a syringe, and then K ₂ CO ₃ (2.7g, 20mmol) was added, and the mixture was stirred overnight at room temperature. The next day, Na ₂ S ₄ O ₈ (2.38g, 10mmol), K ₂ CO ₃ (1.38g, 10mmol) were added, and water (2ml) was added, and the mixture was stirred for 2h. After the reaction was completed, PE was used for extraction three times, and the organic phases were combined, evaporated under reduced pressure, and purified by Flash column to obtain a white solid (900mg, 75%). The obtained product (149mg, 1mmol) was dissolved in DCM, methyl thioglycolate (106mg, 1.0mmol) was added, and triethylamine (40μl, 0.3mmol) was added, and the reaction was carried out for 3h. After the reaction was completed, the mixture was extracted three times with PE, and the organic phases were combined and evaporated under reduced pressure. After purification by Flash column, a yellow solid C2 (201 mg, 85%) was obtained.

HRMS calculated mass-to-charge ratio for [C ₁₁ H ₁₁ NOS ₂ ] ⁺ [M+H] ⁺ 237.0282. LC-MS showed mass-to-charge ratio for [C ₁₁ H ₁₁ NOS ₂ ] ⁺ [M+H] ⁺ 238.3.

¹ H NMR (500MHz, CDCl ₃ ) δ7.13–7.06 (m, 2H), 6.88 (d, J = 7.9Hz, 1H), 4.15–4.12 (m, 2H), 2.31 (s, 3H), 2.01 ( s,3H).

Example 1: Compound 1

Dissolve C1 (216 mg, 1.0 mmol) and C2 (237 mg, 1.0 mmol) in ethanol (2 ml), add 3 drops of tetramethylpiperidine, heat to 80°C and reflux, and react for 4 hours. After the reaction is completed, evaporate under reduced pressure. Add DCM and H ₂ O to extract three times, combine the organic phases, evaporate under reduced pressure, and purify with a Flash column to obtain a yellow solid 1 (391 mg, 90%).

HRMS calculated mass-to _{-charge ratio for [C23H17NO4S2 ] +} ^[ M+ _H ] ⁺ : 435.0599.

LC-MS showed a mass-to-charge ratio of [C ₂₃ H ₁₇ NO ₄ S ₂ ] ⁺ [M+H] ⁺ of 435.3.

¹ H NMR (500MHz, DMSO) δ8.45(d,J＝1.7Hz,1H),8.15–8.11(m,1H),8.00(d,J＝7.7Hz,1H),7.77(d,J＝1.5Hz, 1H),7.73(d,J＝7 .8Hz,1H),7.50(dd,J＝3.8,1.8Hz,1H),7.43(d,J＝3.8Hz,1H),7.24(s,1H),7.21–7.18(m,2H),2.36( s,3H),2.02(s,3H).

Example 2: Compound 4

1 (43.5 mg, 0.1 mmol) was dissolved in acetone (4 ml), iodoethane (20 μl, 0.25 mmol) was added, and then K ₂ CO ₃ (69.1 mg, 0.5 mmol) was added, and stirred at room temperature overnight. After the reaction was completed, it was evaporated under reduced pressure. DCM and H ₂ O were added to extract three times, and the organic phases were combined and evaporated under reduced pressure. After purification by Flash column, a yellow solid 4 (41 mg, 91%) was obtained.

HRMS calculated mass-to-charge ratio for [ _{C25H21NO4S2 ]} ⁺ [M _{+ H} ] ⁺ : 463.0912.

LC-MS showed a mass-to-charge ratio of [C ₂₅ H ₂₁ NO ₄ S ₂ ] ⁺ [M+H] ⁺ of 464.3.

¹ H NMR (500MHz, DMSO) δ8.46(t,J＝1.8Hz,1H),8.16(dt,J＝7.9,1.5Hz,1H),8.01(dt,J＝7.8,1.4Hz,1H),7.76( s,1H),7.72(t,J＝7.8Hz,1H),7.48( d,J＝3.8Hz,1H),7.42(d,J＝3.8Hz,1H),7.24(s,1H),7.19(d,J＝2.6Hz,2 H),4.38(q,J＝7.1Hz,2H),2.36(s,3H),2.02(s,3H),1.42–1.39(m,3H).

Example 3: Compound 5:

1 (43.5 mg, 0.1 mmol) was dissolved in DMF (3 ml), and isopropylamine (7.2 mg, 0.1 mmol) was added, followed by HATU (38 mg, 0.1 mmol) and DIPEA (17.3 μl, 0.1 mmol), and the mixture was stirred at room temperature for 3 h. The mixture was extracted three times with DCM:H ₂ O (1:20), and the organic phases were combined and evaporated under reduced pressure. After purification by Flash column, a yellow solid 5 (30 mg, 61%) was obtained.

HRMS calculated mass-to _- charge ratio for [ _{C27H26N2O3S2 ]} ⁺ [M _{+ H} ] ⁺ : 490.1385.

LC-MS showed a mass-to-charge ratio of [C ₂₇ H ₂₆ N ₂ O ₃ S ₂ ] ⁺ [M+H] ⁺ of 491.4.

¹ H NMR (500MHz, DMSO) δ8.42–8.29(m,2H),8.01(dt,J＝7.8,1.4Hz,1H),7.88(dt,J＝7.8,1.5Hz,1H),7.78(s,1H ),7.67(t,J＝7 .8Hz,1H),7.44(s,2H),7.26–7.15(m,3H),4.13(dq,J＝13.5,6.5Hz,1H),2.36(s,3H),2.02(s,3H), 1.21(d,J＝6.6Hz,7H).

Example 4: Compound 6:

1 (43.5 mg, 0.1 mmol) was dissolved in DMF (3 ml), and n-butylamine (7.2 mg, 0.1 mmol) was added, followed by HATU (38 mg, 0.1 mmol) and DIPEA (17.3 μl, 0.1 mmol), and the mixture was stirred at room temperature for 3 h. The mixture was extracted three times with DCM:H ₂ O (1:20), and the organic phases were combined, evaporated under reduced pressure, and purified by Flash column to obtain yellow solid 6 (30 mg, 61%).

HRMS calculated mass-to _- charge ratio for [ _{C27H26N2O3S2 ]} ⁺ [M _{+ H} ] ⁺ : 490.6360.

LC-MS showed a mass-to-charge ratio of [C ₂₇ H ₂₆ N ₂ O ₃ S ₂ ] ⁺ [M+H] ⁺ of 491.2.

¹ H NMR(500MHz,DMSO)δ8.59(t,J＝5.6Hz,1H),8.32(t,J＝1.9Hz,1H),8.01(dt, J＝7.7,1.5Hz,1H),7.87(dt,J＝7.8,1.4Hz,1H),7.78(s,1H),7.68(t,J＝7.8H z,1H),7.46–7.42(m,2H),7.27–7.15(m,3H),3.33–3.29(m,2H),2.36(s,3H) ),2.02(s,3H),1.60–1.51(m,2H),1.41–1.33(m,2H),0.92(t,J=7.3Hz,3H).

Example 5: Compound 7:

C3 (43.5 mg, 0.1 mmol) was dissolved in DMF (3 ml), 2-methoxyaniline (12.2 mg, 0.1 mmol) was added, followed by HATU (38 mg, 0.1 mmol) and DIPEA (17.3 μl, 0.1 mmol), and the mixture was stirred at room temperature for 3 h. The mixture was extracted three times with DCM:H ₂ O (1:20), and the organic phases were combined and evaporated under reduced pressure. After purification by Flash column, a yellow solid 7 (33 mg, 61%) was obtained.

HRMS calculated mass-to-charge ratio for [C ₃₀ H ₂₄ N ₂ O ₄ S ₂ ] ⁺ [M+H] ⁺ 540.1177.

LC-MS showed a mass-to-charge ratio of [C ₃₀ H ₂₄ N ₂ O ₄ S ₂ ] ⁺ [M+H] ⁺ of 541.3.

¹ H NMR (500MHz, DMSO) δ9.64 (s, 1H), 8.45 (t, J = 1.8Hz, 1H), 8.12–7.99 (m, 2H), 7.82–7.72 (m, 3H), 7.51–7.43 (m,2H),7.25–7.10(m,5H),7.00(td,J＝7.6,1.4Hz,1H),3.85(s,3H),2.36(s,3H),2.05(d,J＝26.9 Hz,3H).

Example 6: Compound 8

C3 (43.5 mg, 0.1 mmol) was dissolved in DMF (3 ml), p-nitroaniline (13.7 mg, 0.1 mmol) was added, followed by HATU (38 mg, 0.1 mmol) and DIPEA (17.3 μl, 0.1 mmol), and the mixture was stirred at room temperature for 3 h. The mixture was extracted three times with DCM:H ₂ O (1:20), and the organic phases were combined, evaporated under reduced pressure, and purified by Flash column to give a yellow solid (34 mg, 61%). The mass-to-charge ratio of [C ₂₉ H ₂₁ N ₃ O ₅ S ₂ ] ⁺ [M+H] ⁺ calculated by HRMS was 555.0923. The mass-to-charge ratio of [C ₂₉ H ₂₁ N ₃ O ₅ S ₂ ] ⁺ [M+H] ⁺ shown by LC-MS was 556.4.

¹ H NMR (500MHz, DMSO) δ13.79(s,1H),8.77(dd,J＝4.5,1.4Hz,1H),8.54(dd,J＝8.4,1.4Hz,1H),8.44(d,J＝1.9 Hz,1H),8.16–8.07(m,1H ),8.02–7.98(m,1H),7.77(s,1H),7.72(t,J＝7.8Hz,1H),7.54–7.41(m,3H),7.26–7.15(m,3H),2.36( s,3H),2.02(d,J＝4.9Hz,3H).

Example 7: Compound 9:

C3 (43.5 mg, 0.1 mmol) was dissolved in DMF (3 ml), propargylamine (5.4 mg, 0.1 mmol) was added, followed by HATU (38 mg, 0.1 mmol) and DIPEA (17.3 μl, 0.1 mmol), and the mixture was stirred at room temperature for 3 h. The mixture was extracted three times with DCM:H ₂ O (1:20), and the organic phases were combined, evaporated under reduced pressure, and purified by Flash column to obtain a yellow solid (28.7 mg, 61%).

HRMS calculated mass-to _- charge ratio for [ _{C26H20N2O3S2 ]} ⁺ [M _{+ H} ] ⁺ : 472.0915.

LC-MS showed a mass-to-charge ratio of [C ₂₆ H ₂₀ N ₂ O ₃ S ₂ ] ⁺ [M+H] ⁺ of 473.2.

¹ H NMR (500MHz, DMSO) δ9.10(t,J＝5.6Hz,1H),8.37(t,J＝1.8Hz,1H),8.04(dt,J＝7.8,1.4Hz,1H),7.90(dt, J＝7.7,1.4Hz,1H),7.78(s,1H ),7.71(t,J＝7.8Hz,1H),7.44(s,2H),7.25–7.16(m,3H),4.12(dd,J＝5.5,2.5Hz,2H),3.17(t,J＝ 2.5Hz,1H),2.36(s,3H),2.02(s,3H).

Example 8: Compound 10:

C3 (43.5 mg, 0.1 mmol) was dissolved in DMF (3 ml), and aniline (9.2 mg, 0.1 mmol) was added, followed by HATU (38 mg, 0.1 mmol) and DIPEA (17.3 μl, 0.1 mmol), and the mixture was stirred at room temperature for 3 h. The mixture was extracted three times with DCM:H ₂ O (1:20), and the organic phases were combined, evaporated under reduced pressure, and purified by Flash column to obtain a yellow solid (31.1 mg, 61%).

HRMS calculated mass-to-charge ratio for [C ₂₉ H ₂₂ N ₂ O ₃ S ₂ ] ⁺ [M+H] ⁺ 510.1072.

LC-MS showed a mass-to-charge ratio of [C ₂₉ H ₂₂ N ₂ O ₃ S ₂ ] ⁺ [M+H] ⁺ of 511.3.

¹ H NMR(500MHz,DMSO)δ10.44(s,1H),8.46–8.35(m,1H),8.13–8.05(m,1H),7.98(dd,J＝20.7,7.8Hz,1H),7.85– 7.72(m,4H),7.52–7.42(m,2H),7.38(t,J＝7.9Hz,2H),7.26–7.11(m,4H),2.36(s,3H),2.02(d,J＝ 3.7Hz,3H).

Example 9: Compound 11:

C3 (43.5 mg, 0.1 mmol) was dissolved in DMF (3 ml), p-methylaniline (10.6 mg, 0.1 mmol) was added, followed by HATU (38 mg, 0.1 mmol) and DIPEA (17.3 μl, 0.1 mmol), and the mixture was stirred at room temperature for 3 h. The mixture was extracted three times with DCM:H ₂ O (1:20), and the organic phases were combined and evaporated under reduced pressure. After purification by Flash column, a yellow solid 11 (32 mg, 61%) was obtained.

HRMS calculated mass-to-charge ratio for [C ₃₀ H ₂₄ N ₂ O ₃ S ₂ ] ⁺ [M+H] ⁺ 524.1228.

LC-MS showed a mass-to-charge ratio of [C ₃₀ H ₂₄ N ₂ O ₃ S ₂ ] ⁺ [M+H] ⁺ of 525.3.

¹ H NMR (500MHz, DMSO) δ10.37(s,1H),8.43(t,J＝1.8Hz,1H),8.08(dt,J＝7.8,1.4Hz,1H),7.99(dt,J＝7.9,1.4 Hz,1 H),7.80–7.67(m,4H),7.48(dd,J＝24.8,3.7Hz,2H),7.27–7.15(m,5H),2.36(s,3H),2.29(s,3H),2.02 (s,3H).

Example 10: Compound 12:

5-Formaldehyde furan-2-boronic acid (140 mg, 1 mmol) and 3-bromodihydroxypyridine (172 mg, 1.1 mmol) were dissolved in DMF solution (2 ml), K2CO3 (138 mg, 2 mmol) was added, and (pph3)2PDCl2 (3.5 mg, 0.005 mmol) was added, and the mixture was heated to 100°C and refluxed for 5 h. After the reaction was completed, the mixture was cooled to room temperature, extracted three times with DCM:H2O (1:20), and the organic phases were combined, evaporated under reduced pressure, and purified by Flash column to obtain a yellow solid (96 mg, 51%). The product (96 mg, 0.5 mmol) and C2 (118.5 mg, 0.5 mmol) were then dissolved in ethanol (2 ml), 3 drops of tetramethylpiperidine were added, and the mixture was heated to 80°C and refluxed for 4 h. After the reaction was completed, the mixture was evaporated under reduced pressure. DCM and H2O were added to extract three times, and the organic phases were combined and evaporated under reduced pressure. After purification by Flash column, a yellow solid 12 (183.6 mg, 90%) was obtained.

HRMS calculated mass-to-charge ratio for [C ₂₀ H ₁₆ N ₂ O ₃ S ₂ ] ⁺ [M+H] ⁺ 408.0602.

LC-MS showed a mass-to-charge ratio of [C ₂₀ H ₁₆ N ₂ O ₃ S ₂ ] ⁺ [M+H] ⁺ of 409.2.

¹ H NMR (500MHz, DMSO) δ8.03(dd,J＝7.2,2.1Hz,1H),7.74(s,1H),7.57(dd,J＝6.4,2.1Hz,1H),7.50(d,J＝3.7 Hz,1H),7.39(d,J＝3.7Hz,1H),7.24(s,1H),7.18(s,2H),6.58(t,J＝6.8Hz,1H),2.35(s,3H), 2.01(s,3H).

Example 11: Compound 13:

5-Formaldehyde furan-2-boronic acid (140 mg, 1 mmol) and 4-bromopyridin-2-one (172 mg, 1.1 mmol) were dissolved in DMF solution (2 ml), K ₂ CO ₃ (138 mg, 2 mmol) was added, and finally (pph ₃ ) ₂ pdcl ₂ (3.5 mg, 0.005 mmol) was added, and the mixture was heated to 100°C and refluxed for 5 h. After the reaction was completed, the mixture was cooled to room temperature, extracted three times with DCM:H ₂ O (1:20), and the organic phases were combined, evaporated under reduced pressure, and purified by Flash column to obtain a yellow solid (96 mg, 51%). The product (96 mg, 0.5 mmol) and C2 (118.5 mg, 0.5 mmol) were then dissolved in ethanol (2 ml), 3 drops of tetramethylpiperidine were added, and the mixture was heated to 80°C and refluxed for 4 h. After the reaction was completed, the mixture was evaporated under reduced pressure. DCM and H2O were added to extract three times, and the organic phases were combined and evaporated under reduced pressure. After purification by Flash column, a yellow solid 13 (183.6 mg, 90%) was obtained.

The mass-to-charge ratio of [C ₂₀ H ₁₆ N ₂ O ₃ S ₂ ]+[M+H]+ calculated by HRMS is 408.0602.

LC-MS showed a mass-to-charge ratio of [C ₂₀ H ₁₆ N ₂ O ₃ S ₂ ]+[M+H]+ of 409.6.

¹ H NMR(500MHz,DMSO)δ7.76(s,1H),7.57–7.51(m,2H),7.40(d,J＝3.8Hz,1H),7.24(d,J＝1.6Hz,1H) ,7.22–7.16(m,2H),6.75(d,J＝1.7Hz,1H),6.65(dd,J＝6.8,1.8Hz,1H),2.35(s,3H),2.02(s,3H).

Example 12: Compound 14:

5-Formaldehyde furan-2-boronic acid (140 mg, 1 mmol) and 7-bromoisoquinolin-1-one (222 mg, 1.1 mmol) were dissolved in DMF solution (2 ml), K ₂ CO ₃ (138 mg, 2 mmol) was added, and finally (pph ₃ ) ₂ pdcl ₂ (3.5 mg, 0.005 mmol) was added, and the mixture was heated to 100°C and refluxed for 5 h. After the reaction was completed, the mixture was cooled to room temperature, extracted three times with DCM:H ₂ O (1:20), and the organic phases were combined, evaporated under reduced pressure, and purified by Flash column to obtain a yellow solid (121.9 mg, 51%). The product (121 mg, 0.5 mmol) and C2 (118 mg, 0.5 mmol) were then dissolved in ethanol (2 ml), 3 drops of tetramethylpiperidine were added, and the mixture was heated to 80°C and refluxed for 4 h. After the reaction was completed, the mixture was evaporated under reduced pressure. DCM and H ₂ O were added for extraction three times, and the organic phases were combined and evaporated under reduced pressure. After purification by Flash column, a yellow solid 14 (206.1 mg, 90%) was obtained.

HRMS calculated mass-to _- charge ratio for [ _{C25H18N2O3S2 ]} ⁺ [M _{+ H} ] ⁺ : 458.0759.

LC-MS showed a mass-to-charge ratio of [C ₂₅ H ₁₈ N ₂ O ₃ S ₂ ] ⁺ [M+H] ⁺ of 459.1.

¹ H NMR (500MHz, DMSO) δ11.45(d,J＝5.8Hz,1H),8.66(d,J＝1.8Hz,1H),8.17(dd,J＝8.3,2.0Hz,1H),7.84(d, J＝8.4Hz,1H),7.7 7(s,1H),7.51(d,J＝3.7Hz,1H),7.44(d,J＝3.8Hz,1H),7.29–7.16(m,4H),6.61(d,J＝7.1Hz,1H ),2.36(s,3H),2.03(s,3H).

Example 13: Compound 15:

5-((4-(2-(methyl-2-pyridinylamino)ethoxy)phenyl)methyl)-2,4-thiazolidinedione (35.7 mg, 0.1 mmol) was dissolved in toluene (3.3 ml), and diphenyliodonium salt (101.1 mg, 3.0 mmol) and Cu(NO ₃ ) ₂ (5.8, 0.05 mmol) were added, and finally TEA (7 μl) was added, and the mixture was heated to 70° C. and reacted for 8 h. After the reaction was completed, the mixture was evaporated under reduced pressure, extracted three times with DCM and H ₂ O, and the organic phases were combined and evaporated under reduced pressure. After purification by Flash column, a yellow solid 15 (36.9 mg, 80%) was obtained.

HRMS calculated mass-to-charge ratio for [C ₂₆ H ₂₇ N ₃ O ₃ S] ⁺ [M+H] ⁺ 461.1773.

LC-MS showed a mass-to-charge ratio of [C ₂₆ H ₂₇ N ₃ O ₃ S] ⁺ [M+H] ⁺ of 462.4.

¹ H NMR (500MHz, CDCl ₃ )δ8.25(s,1H),7.86(s,1H),7.23–6.99(m,4H),6.99–6.62(m,5H),4.73–4.12(m,5H),3.5 4–3.39(m,3H),3.26(ddd,J＝55.9,14.1,8.4Hz,2H),2.35(s,3H),1.98(d,J＝122.2Hz,3H).

Effect Embodiment Section

1. Activity determination method:

(I) The inhibition of the compounds on methyltransferase was determined using the MTase-Glo ^TM Methyltransferase Assay (V7601) kit.

1. Mix 3 μL of protein of appropriate concentration with 1 μL of compound of appropriate concentration and let stand on ice for 15 min.

2. Add 4 μL of substrate (see Table 1) to each well of a 384-well plate, and then add 4 μL of a mixture of protein and compound. Centrifuge at 2200 rpm for 30 s, shake at 250 rpm for 90 s, and react at 37°C for 1 h. The formula of 4x reaction buffer is: 80 mM Tris-HCl, pH 8.0, 200 mM NaCl, 4 mM EDTA, 12 mM MgCl2, 0.4 mg/mL BSA, 4 mM DTT.

Table 1 Methylation reaction substrate system

3. Add 2 μL 5x MTase-Glo ^TM Reagent to each well, centrifuge at 2200 rpm for 30 s, shake at 250 rpm for 90 s, and react at room temperature for 30 min.

4. Add 10 μL MTase-Glo ^TM Detection Solution to each well, centrifuge at 2200 rpm for 30 seconds, shake at 250 rpm for 90 seconds, and react at room temperature for 30 minutes.

5. Read the luminescence value of the 384-well plate and calculate the compound inhibition rate. When the drug concentration is 5 μM, the inhibition rate of compound 1-3 on DNMT3A is shown in Table 2:

Table 2

(ii) The Cell Counting Kit-8 (HY-K0301) was used to determine the growth inhibition of the compounds on the tumor cell line A549.

Tumor cell line A549 was obtained from ATCC.

(1) Drawing of standard curve

1. Inoculate a 96-well plate with a 2-fold gradient dilution of the cell suspension (100 μL/well, the highest concentration is 30,000 cells/well) and place it in an incubator for 4 hours to allow the cells to adhere.

2. Aspirate the supernatant from the wells and add 110 μL of a mixture of CCK-8 reagent and culture medium to each well (mix 10 μL of CCK solution with every 100 μL of culture medium).

3. After incubation in the incubator for 2 hours, measure the absorbance at 450 nm using an enzyme reader and draw a standard curve.

(2) Growth inhibition measurement

1. Inoculate the cell suspension in a 96-well plate (100 μL/well, 3000 cells in total) and culture in an incubator for 24 hours.

2. Remove the supernatant from the wells, add culture medium mixed with the compound (100 μL/well), and continue culturing in the incubator for 24, 48, and 72 hours.

3. Aspirate the supernatant from the wells and add 110 μL of a mixture of CCK-8 reagent and culture medium to each well (mix 10 μL of CCK solution with every 100 μL of culture medium).

4. After incubation in the incubator for 2 hours, measure the absorbance at 450 nm using an ELISA reader. Calculate the inhibitory effect of the compound on cell growth based on the standard curve.

(3) Inhibition rate determination

1. Inoculate the cell suspension in a 96-well plate (100 μL/well, 3000 cells in total) and place it in an incubator for 4 hours to allow the cells to adhere.

2. The supernatant in the wells was aspirated, and culture medium (100 μL/well) mixed with compounds (compound gradient concentration was 11.85-202.5 μM) was added, and the cells were cultured in an incubator for 24 hours.

3. Aspirate the supernatant from the wells and add 110 μL of a mixture of CCK-8 reagent and culture medium to each well (mix 10 μL of CCK solution with every 100 μL of culture medium).

4. After incubation in the incubator for 2 hours, the absorbance at 450 nm was measured using an enzyme-labeled instrument to calculate the inhibition rate of the compound on the cells, as shown in Table 3.

Table 3

It can be seen from the data in the above table that the compounds of the present application have good safety to cells.

(III) Growth inhibition of compounds on AML-related cell lines

The Cell Counting Kit-8 (HY-K0301) was used to measure the growth inhibition of the compounds on the cell lines.

1. Drawing of standard curves of Thp-1, MOLM-13 and A549 cell concentrations

First, prepare the cell suspension with a dilution gradient, a total of 6 concentration gradients, 3 replicates for each concentration, including Thp-1 and The starting concentrations of MOLM-13 were 5*10^4 cells/well and 6*10^4 cells/well, respectively. The gradient diluted cells were inoculated in a 96-well plate at 100μL/well and placed in an incubator for 72h. 10μL CCK solution was added directly to each well. After continuing to incubate in the incubator for 30 minutes, 1h, 2h, 3h, and 4h, the absorbance at 450nm (hereinafter referred to as OD450 value) was measured with an enzyme reader, and a standard curve was drawn. In subsequent experiments, the inoculation amount of each well of the two cell lines was determined to be 10,000 cells and 5,000 cells according to the standard curve, and the CCK-8 incubation time was 1h.

3. Determination of Thp-1 and MOLM-13 proliferation inhibition rate: Slightly different from the A549 cell line, since it is inconvenient to change the medium of suspended cells, we selected a cell-free gradient concentration compound group (denoted as the pure compound control group) as the drug background control.

The experimental group consisted of 50 μL cells + 50 μL culture medium diluted with gradient concentration compounds (24 nM to 50 μM dilutions). After continuing to culture in the incubator for 72 hours, 10 μL CCK solution was directly added. After incubation in the incubator for 1 hour, the OD450 value and the reference wavelength OD620 value were measured using an enzyme marker. First, the OD450 value was deducted from the OD620 value and the value was recorded as the OD’450 value. Proliferation rate = (OD’450 value of the experimental group - OD’450 value of the pure compound control group) / (OD’450 value of the no compound control group - blank OD’450 value). (5) Determination of proliferation inhibition rate: The proliferation rate of the compound at each concentration = the proliferation rate of the compound-treated cells at that concentration / the proliferation rate of the DMSO-treated cells at the same concentration. The results are shown in Table 4 and Figure 1.

Table 4

The IC50 values of the above compounds in AML-related cell lines (THP-1, MOLM-13) are 1.7-25 times lower than those in non-target cells (A549), indicating that they have a good effect in inhibiting the proliferation of AML cells. Among them, the IC50 of compound 14 in Thp-1 is only 0.5784 μM, and the effect of inhibiting cell proliferation is more obvious.

4. Drawing of standard curve of J1-890Dnmt3a-/- and J1-890 cell concentration

The steps are basically the same as the A549 cell line, but the starting cell concentration is 4.8*10^4 cells/well, inoculated into a matrigel-coated plate, and the culture medium is replaced with 105μL of CCK-8 diluent (95μL culture medium + 10μL CCK solution) after 72h of culture. The subsequent experiments are based on the standard curve to determine the inoculation amount per well as 3,000 cells, and the CCK-8 incubation time is 1h. Data processing is the same as the A549 cell line.

(IV) Off-target effect testing of compounds

In order to determine whether the mechanism by which compounds 9, 12, 13, and 14 inhibit cell proliferation has off-target effects, we compared the proliferation of the Dnmt3a2 knockout mouse embryonic stem cell line J1-890Dnmt3a-/- and wild-type J1-890 cell lines after administration.

J1-890Dnmt3a-/- and J1-890 cell lines proliferation inhibition rate determination: The basic steps are the same as A549 operation, but the inoculation amount per well is 3,000 cells, and the medium is replaced with a medium diluted with gradient concentration compounds after overnight culture (about 12 hours). Data processing is the same as A549 cell line. The results are shown in Table 5.

Table 5

Compared with the wild-type J1-890 cell line, DNMT3A protein was hardly expressed in J1-890Dnmt3a-/-, as shown in Figures 2 and 3; and Dnmt3a2 knockout did not affect the IC50 of these four drugs.

In summary, these compounds work by targeting DNMT3A protein and do not cause off-target effects.

Claims (15)

Use of a compound as shown in formula I or a pharmaceutically acceptable salt thereof in the preparation of a DNA methyltransferase 3A inhibitor,
in, n is 1, 2, 3, 4 or 5; Each R ¹ is independently C _1-6 alkyl or C _1-6 alkoxy; _X1 and _X2 are independently O or S; is a single bond or a double bond; Ring A is a C _6-10 aromatic ring or a 5-10 membered heteroaromatic ring; the heteroatoms of the 5-10 membered heteroaromatic ring are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3; L is a C _6-10 aryl substituted by one or more R ^L-1 , a 3-10 membered heterocycloalkenyl substituted by one or more R ^L-2 , a C _1-6 heteroalkyl substituted by one or more R ^L-3 , or a benzo 3-10 membered heterocycloalkenyl substituted by one or more R ^L-4 ; the heteroatoms of the 3-10 membered heterocycloalkenyl, the C _1-6 heteroalkyl and the benzo 3-10 membered heterocycloalkenyl are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; Each of RL ^-1 , ^RL-2 , ^RL-3 and RL ^-4 is independently carboxyl, oxo, _C1-6 alkyl, or a 5-10 membered heteroaryl group, wherein the heteroatoms of the 5-10 membered heteroaryl group are selected from one, two or three of N, O and S, and the number of the heteroatoms is 1, 2 or 3; each of RL ^-1-1 and ^RL-1-2 is independently _C1-6 alkyl, _C6-10 aryl, _C1-6 alkyl substituted by one or more ^RL-1-1-1 , or _C6-10 aryl substituted by one or more ^RL-1-1-2 ; Each of ^RL-1-1-1 and RL ^-1-1-2 is independently _C1-6 alkyl, _C1-6 alkoxy, nitro or _C2-6 alkynyl. The use of the compound as shown in formula I or a pharmaceutically acceptable salt thereof in the preparation of a DNA methyltransferase 3A inhibitor according to claim 1, characterized in that it satisfies one or more of the following conditions: (1) In each R ¹ , the C _1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example, methyl; (2) In each R ¹ , the C _1-6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy, for example, methoxy; (3) In ring A, the C _6-10 aromatic ring is a benzene ring or a naphthalene ring, for example, a benzene ring; (4) In ring A, the heteroatom of the 5-10 membered heteroaromatic ring is O, and the number of heteroatoms is 1, 2 or 3; for example, the heteroatom is O, and the number of heteroatoms is 1; (5) In ring A, the 5-10 membered heteroaromatic ring is a 5-6 membered heteroaromatic ring; (6) In L, the C _6-10 aryl group in the C _6-10 aryl group substituted by one or more R ^L-1 is phenyl or naphthyl, for example, phenyl; (7) In L, the number of double bonds in the 3-10 membered heterocycloalkenyl substituted by one or more R ^L-2 and the 3-10 membered heterocycloalkenyl in the benzo 3-10 membered heterocycloalkenyl substituted by one or more R ^L-4 is independently 1, 2 or 3, for example 2; (8) In L, the 3-10-membered heterocycloalkenyl group substituted by one or more R ^L-2 and the 3-10-membered heterocycloalkenyl group in the benzo 3-10-membered heterocycloalkenyl group substituted by one or more R ^L-4 are independently 5-6-membered heterocycloalkenyl groups; (9) In L, the heteroatom of the 3-10 membered heterocycloalkenyl substituted by one or more R ^L-2 and the 3-10 membered heterocycloalkenyl in the benzo 3-10 membered heterocycloalkenyl substituted by one or more R ^L-4 is N, and the number of heteroatoms is 1, 2 or 3; for example, the heteroatom is N, and the number of heteroatoms is 1; (10) In L, the heteroatom of the C _1-6 heteroalkyl group substituted by one or more ^RL-3 is selected from one or two of N, O and S, and the number of heteroatoms is 1, 2 or 3; for example, the heteroatoms _are N and O, and the number of heteroatoms is 2; (11) In L, the C _1-6 heteroalkyl group substituted by one or more R _L ^-3 is a straight-chain heteroalkyl group; (12) In L, the C _1-6 heteroalkyl group substituted by one or more R _L ^-3 is a C _1-4 heteroalkyl group; (13) In each of RL ^-1 , ^RL-2 , ^RL-3 and RL ^-4 , the _C1-6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl; (14) In each of RL ^-1 , RL ^-2 , ^RL-3 and RL ^-4 , the heteroatom of the 5-10 membered heteroaryl group is independently N, and the number of heteroatoms is independently 1, 2 or 3; for example, the heteroatom is N, and the number of heteroatoms is 1; (15) In each of RL ^-1 , ^RL-2 , ^RL-3 and RL ^-4 , the 5-10 membered heteroaryl group is independently a 5-6 membered heteroaryl group; (16) In each of ^RL-1-1 and ^RL-1-2 , the _C1-6 alkyl group and the _{C1-6 alkyl} group substituted by one _or more ^RL-1-1-1s are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; for example, methyl, ethyl, n-propyl or isobutyl; (17) In each of ^RL-1-1 and RL ^-1-2 , the _C6-10 aryl group and the _{C6-10 aryl} group substituted by one or more ^RL-1-1-2 are independently phenyl or naphthyl, for example, phenyl; (18) each plurality is independently 2 or 3; (19) In each of RL ^-1-1-1 and RL ^-1-1-2 , the _C1-6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl; (20) In each of ^RL-1-1-1 and RL ^-1-1-2 , the _C1-6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy, for example, methoxy; and (21) In each of ^RL-1-1-1 and ^RL-1-1-2 , the _C2-6 alkynyl group is ethynyl, propynyl or butynyl, for example The use of a compound as shown in formula I or a pharmaceutically acceptable salt thereof in the preparation of a DNA methyltransferase 3A inhibitor as claimed in claim 2, characterized in that it satisfies one or more of the following conditions: (1) In ring A, the 5-10 membered heteroaromatic ring is a furan ring; (2) In L, the 3-10 membered heterocycloalkenyl group in the 3-10 membered heterocycloalkenyl group substituted by one or more R ^L-2 is For example (3) In L, the benzo 3-10 membered heterocycloalkenyl group in the benzo 3-10 membered heterocycloalkenyl group substituted by one or more R ^L-4 is For example (4) In L, the C _1-6 heteroalkyl group in the C _1-6 heteroalkyl group substituted by one or more R ^L-3 is and (5) In each of RL ^-1 , RL ^-2 , ^RL-3 and RL ^-4 , the 5-10 membered heteroaryl group is independently a pyridyl group, for example The use of a compound as shown in formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 in the preparation of a DNA methyltransferase 3A inhibitor, characterized in that it satisfies one or more of the following conditions: (1) The C _6-10 aryl group substituted by one or more R ^L-1 is (2) The 3-10 membered heterocycloalkenyl group substituted by one or more R ^L-2 is (3) C _1-6 heteroalkyl substituted by one or more R ^L-3 is (4) a benzo 3-10 membered heterocycloalkenyl group substituted by one or more R ^L-4 is (5) When ring A is a C _6-10 aromatic ring, for and (6) When ring A is a 5-10 membered heteroaromatic ring, for The use of the compound as shown in formula I or a pharmaceutically acceptable salt thereof in the preparation of a DNA methyltransferase 3A inhibitor according to claim 1, characterized in that it satisfies one or more of the following conditions: (1) n is 1 or 2; (2) _X1 is 0; (3) _X2 is O or S; (4) Each RL ^-1 is independently a carboxyl group, Preferably, each RL ^-1 is independently (5) each ^RL-1-1 is independently _C1-6 alkyl or _C1-6 alkyl substituted by one or more RL ^-1-1-1 ; (6) Each ^RL-1-1-1 is independently _C1-6 alkyl or _C2-6 alkynyl; (7) Each ^RL-1-1-2 is independently _C1-6 alkyl, _C1-6 alkoxy or nitro; (8) each ^RL-2 is oxo; (9) Each RL ^-3 is independently a _C1-6 alkyl group or a 5-10 membered heteroaryl group, wherein the heteroatoms of the 5-10 membered heteroaryl group are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3; (10) each ^RL-4 is oxo; (11) Ring A is a C _6-10 aromatic ring; and (12) Ring A is a 5-10 membered heteroaromatic ring; the heteroatoms of the 5-10 membered heteroaromatic ring are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3. The use of the compound as shown in formula I or a pharmaceutically acceptable salt thereof in the preparation of a DNA methyltransferase 3A inhibitor according to claim 1, characterized in that it satisfies one or more of the following conditions: (1) Ring A is a 5-6 membered heteroaromatic ring; the heteroatoms of the 5-6 membered heteroaromatic ring are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3; (2) L is a C _6-10 aryl group substituted by one or more R ^L-1 , a 3-10 membered heterocycloalkenyl group substituted by one or more R ^L-2, or a benzo 3-10 membered heterocycloalkenyl group substituted by one or more R ^L-4 ; preferably, L is a C _6-10 aryl group substituted by one or more R ^L-1 , a 5-6 membered heterocycloalkenyl group substituted by one or more R ^L-2, or a benzo 5-6 membered heterocycloalkenyl group substituted by one or more R ^L-4 , and the heteroatom of the 5-6 membered heterocycloalkenyl group and the benzo 5-6 membered heterocycloalkenyl group is N, and the number of heteroatoms is 1, 2 or 3; (3) Each RL ^-1 is independently a carboxyl group or Preferably (4) Each ^RL-1-2 is independently a C _1-6 alkyl group or a C _1-6 alkyl group substituted by one or more ^RL-1-1-1 ; preferably, each ^RL-1-2 is independently a C _1-6 alkyl group substituted by one or more RL ^- 1-1-1; (5) each R ^L-1-1-1 is independently a C _2-6 alkynyl group; (6) Each RL ^-3 is independently a _C1-6 alkyl group or a 5-6 membered heteroaryl group, wherein the heteroatom of the 5-6 membered heteroaryl group is selected from one, two or three of N, O and S, and the number of the heteroatoms is 1, 2 or 3. The use of the compound as shown in formula I or a pharmaceutically acceptable salt thereof in the preparation of a DNA methyltransferase 3A inhibitor according to claim 1, characterized in that it satisfies one or more of the following conditions: (1) for Preferably for (2) for (3) Ring A is Preferably, for (4) Each RL ^-1 is independently a carboxyl group, and (5) L is Preferably, L is The use of the compound as shown in formula I or a pharmaceutically acceptable salt thereof in the preparation of a DNA methyltransferase 3A inhibitor according to claim 1, characterized in that it satisfies one or more of the following conditions: (1) Each RL ^-1 is independently (2) for (3) for (4) Ring A is (5) L is More preferably, L is The use of the compound as shown in formula I or a pharmaceutically acceptable salt thereof in the preparation of a DNA methyltransferase 3A inhibitor according to claim 1, characterized in that it is any of the following: Case (1): Ring A is a C _6-10 aromatic ring; L is a C _1-6 heteroalkyl group substituted by one or more R ^L-3 ; Case (2): Ring A is a 5-10 membered heteroaromatic ring, L is a C _6-10 aryl group substituted by one or more R ^L-1 , each R ^L-1 is Case (3): Ring A is a 5-10 membered heteroaromatic ring, L is a C _6-10 aryl group substituted by one or more R ^L-1 , each R ^L-1 is Case (4): Ring A is a 5-10 membered heteroaromatic ring, L is a 3-10 membered heterocycloalkenyl substituted by one or more R ^L-2 or a benzo 3-10 membered heterocycloalkenyl substituted by one or more R ^L-4 ; the heteroatoms of the 3-10 membered heterocycloalkenylene group are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3. The compound as described in claim 1 or a pharmaceutically acceptable salt thereof in the preparation of DNA methyltransferase 3A inhibitor The application in a preparation is characterized in that it is any of the following schemes: Solution (1): n is 1 or 2; Each R ¹ is independently C _1-6 alkyl or C _1-6 alkoxy; _X1 and _X2 are independently O or S; is a single bond or a double bond; Ring A is a C _6-10 aromatic ring; L is a C _1-6 heteroalkyl group substituted by one or more R ^L-3 ; the heteroatoms of the C _1-6 heteroalkylene group are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3; RL ^-3 is a _C1-6 alkyl group or a 5-10 membered heteroaryl group, wherein the heteroatoms of the 5-10 membered heteroaryl group are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3; Solution (2): n is 1 or 2; Each R ¹ is independently C _1-6 alkyl or C _1-6 alkoxy; _X1 and _X2 are independently O or S; is a single bond or a double bond; Ring A is a 5-10 membered heteroaromatic ring; the heteroatoms of the 5-10 membered heteroaromatic ring are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3; L is a C _6-10 aryl group substituted by one or more R ^L-1 , each R ^L-1 being RL ^-1-1 is _C1-6 alkyl or _C1-6 alkyl substituted by one or more RL ^-1-1-1 ; Each ^RL-1-1-1 is independently _C1-6 alkyl or _C2-6 alkynyl; Solution (3): n is 1 or 2; Each R ¹ is independently C _1-6 alkyl or C _1-6 alkoxy; _X1 and _X2 are independently O or S; is a single bond or a double bond; Ring A is a 5-10 membered heteroaromatic ring; the heteroatoms of the 5-10 membered heteroaromatic ring are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3; L is a C _6-10 aryl group substituted by one or more R ^L-1 ; each R ^L-1 is RL ^-1-2 is _C1-6 alkyl, 6-10 membered aryl, _C1-6 alkyl substituted by one or more ^RL-1-1-1 , or 6-10 membered aryl substituted by one or more RL ^-1-1-2 ; Each ^RL-1-1-1 is independently _C1-6 alkyl or _C2-6 alkynyl; Each RL ^-1-1-2 is independently _C1-6 alkyl, _C1-6 alkoxy or nitro; Solution (4): n is 1 or 2; Each R ¹ is independently C _1-6 alkyl or C _1-6 alkoxy; _X1 and _X2 are independently O or S; is a single bond or a double bond; Ring A is a 5-10 membered heteroaromatic ring; the heteroatoms of the 5-10 membered heteroaromatic ring are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3; A 3-10 membered heterocycloalkenyl group substituted by one or more R ^L-2 or a benzo 3-10 membered heterocycloalkenyl group substituted by one or more R ^L-4 ; the heteroatoms of the 3-10 membered heterocycloalkenylene group are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3; Each of ^RL-2 and ^RL-4 is oxo; Solution (5): n is 1 or 2; Each R ¹ is independently C _1-6 alkyl or C _1-6 alkoxy; _X1 and _X2 are independently O or S; Ring A is a C _6-10 aromatic ring or a 5-10 membered heteroaromatic ring; the heteroatom of the 5-10 membered heteroaromatic ring is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; L is a C _6-10 aryl substituted by one or more R ^L-1 , a 3-10 membered heterocycloalkenyl substituted by one or more R ^L-2 , a C _1-6 heteroalkyl substituted by one or more R ^L-3 , or a benzo 3-10 membered heterocycloalkenyl substituted by one or more R ^L-4 ; the heteroatoms of the 3-10 membered heterocycloalkenylene and the C _1-6 heteroalkyl are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; Each RL ^-1 is independently a carboxyl group, each ^RL-2 is independently oxo; Each RL ^-3 is independently a _C1-6 alkyl group or a 5-10 membered heteroaryl group, wherein the heteroatoms of the 5-10 membered heteroaryl group are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3; each ^RL-4 is independently oxo; RL ^-1-1 is _C1-6 alkyl or _C1-6 alkyl substituted by one or more RL ^-1-1-1 ; RL ^-1-2 is independently _C1-6 alkyl, 6-10 membered aryl, _C1-6 alkyl substituted by one or more ^RL-1-1-1 , or 6-10 membered aryl substituted by one or more ^RL - ^1-1-2 ; Each ^RL-1-1-1 is independently _C1-6 alkyl or _C2-6 alkynyl; Each RL ^-1-1-2 is independently _C1-6 alkyl, _C1-6 alkoxy or nitro; Solution (6): n is 1, 2, 3, 4 or 5; Each R ¹ is independently C _1-6 alkyl or C _1-6 alkoxy; _X1 and _X2 are independently O or S; is a single bond or a double bond; Ring A is a C _6-10 aromatic ring or a 5-10 membered heteroaromatic ring; the heteroatoms of the 5-10 membered heteroaromatic ring are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3; L is a C _6-10 aryl substituted by one or more R ^L-1 , a 3-10 membered heterocycloalkenyl substituted by one or more R ^L-2 , a C _1-6 heteroalkyl substituted by one or more R ^L-3 , or a benzo 3-10 membered heterocycloalkenyl substituted by one or more R ^L-4 ; the heteroatoms of the 3-10 membered heterocycloalkenyl, the C _1-6 heteroalkyl and the benzo 3-10 membered heterocycloalkenyl are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; Each ^RL-1 is independently carboxyl or Each RL ^-2 is oxo; Each RL ^-3 is independently a _C1-6 alkyl group or a 5-10 membered heteroaryl group, wherein the heteroatoms of the 5-10 membered heteroaryl group are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3; Each RL ^-4 is oxo; Each RL ^-1-2 is independently _C1-6 alkyl or _C1-6 alkyl substituted by one or more RL ^-1-1-1 ; Each ^RL-1-1-1 is independently _C1-6 alkyl or _C2-6 alkynyl; Solutions (7) n is 1, 2, 3, 4 or 5; Each R ¹ is independently C _1-6 alkyl or C _1-6 alkoxy; _X1 and _X2 are independently O or S; is a double bond; Ring A is a 5-6 membered heteroaromatic ring; the heteroatoms of the 5-6 membered heteroaromatic ring are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3; L is a C _6-10 aryl group substituted by one or more R ^L-1 , a 5-6 membered heterocycloalkenyl group substituted by one or more R ^L-2, or a benzo 5-6 membered heterocycloalkenyl group substituted by one or more R ^L-4 , wherein the heteroatom of the 5-6 membered heterocycloalkenyl group and the benzo 5-6 membered heterocycloalkenyl group is N, and the number of heteroatoms is 1, 2 or 3; Each R ^L-1 is each ^RL-1-2 is independently a _C1-6 alkyl substituted by one or more ^RL-1-1-1 , and each RL ^{- 1-1-1} is independently a _C2-6 alkynyl; Each RL ^-2 is oxo; Each RL ^-4 is oxo. The use of a compound as shown in formula I or a pharmaceutically acceptable salt thereof in the preparation of a DNA methyltransferase 3A inhibitor according to claim 1, characterized in that the compound as shown in formula I is any of the following compounds:

A compound as shown in formula I' or a pharmaceutically acceptable salt thereof,
in, n、R ¹ 、X ₁ 、X ₂ 、 The definitions of ring A and L are as described in any one of claims 1 to 11, and the compound shown in formula I' is not A pharmaceutical composition comprising: (1) The compound of formula I' as claimed in claim 12 or a pharmaceutically acceptable salt thereof; (2) Pharmaceutically acceptable excipients. A use of a compound as shown in formula I as described in any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, or a compound as shown in formula I' as described in claim 12, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 13 in the preparation of a medicament for treating or preventing a disease associated with DNA methylation; the disease associated with DNA methylation is overgrowth syndrome or acute myeloid leukemia; the acute myeloid leukemia may be monocytic leukemia. A use of a compound as shown in formula I as described in any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, or a compound as shown in formula I' as described in claim 12, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 13 in the preparation of a medicament for treating or preventing overgrowth syndrome or acute myeloid leukemia; the acute myeloid leukemia may be monocytic leukemia.