Thiazolidinedione compound as well as pharmaceutical composition and application thereof

Abstract

The invention discloses a thiazolidinedione compound as well as a pharmaceutical composition and application thereof. The invention provides application of a compound shown as a formula I or pharmaceutically acceptable salt thereof in preparation of a DNA methyltransferase 3A inhibitor. The thiazolidinedione compound provided by the invention has good inhibitory activity on DNA (Deoxyribose Nucleic Acid) methyltransferase DNMT3A. # imgabs0 #

Description

[0001] 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

[0002] 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

[0003] 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 in specific MT sites not only lead to development-related 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

[0004] 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).

[0005] 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.

[0006]

[0007] in,

[0008] n is 1, 2, 3, 4 or 5;

[0009] Each R 1 Independently for C 1-6 Alkyl or C 1-6 Alkoxy;

[0010] X1 and X2 are independently O or S;

[0011] is a single bond or a double bond;

[0012] Ring A is C 6-10 Aromatic ring or 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;

[0013] L is one or more R L-1 Substituted C 6-10 Aryl, one or more R L-2 substituted 3-10 membered heterocycloalkenyl, substituted by one or more R L-3 Substituted C 1-6 Heteroalkyl or one or more R L-4 Substituted benzo 3-10 membered heterocycloalkenyl; the 3-10 membered heterocycloalkenyl, the C 1-6 The heteroatoms of the 3-10-membered heterocycloalkenyl in the 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;

[0014] Each R L-1 , R L-2 , R L-3 and R L-4 are independently carboxyl, oxo (=O), C 1-6 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;

[0015] Each R L-1-1 and R L-1-2 Independently for C 1-6 Alkyl, C 6-10 Aryl, one or more R L-1-1-1 Substituted C 1-6 Alkyl or one or more R L-1-1-2 Substituted C 6-10 Aryl;

[0016] Each R L-1-1-1 and R L-1-1-2 Independently for C 1-6 Alkyl, C 1-6 Alkoxy, nitro or C 2-6 Alkynyl.

[0017] In a preferred embodiment, each R 1 In the C 1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl.

[0018] In a preferred embodiment, each R 1 In the C 1-6 Alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy, for example methoxy.

[0019] In a preferred embodiment, in ring A, the C 6-10 The aromatic ring is a benzene ring or a naphthalene ring, for example a benzene ring. for

[0020] 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.

[0021] 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.

[0022] In a preferred embodiment, when ring A is a 5-10 membered heteroaromatic ring, for

[0023] In a preferred embodiment, in L, the one or more R L-1 Substituted C 6-10 C in aromatic groups 6-10 Aryl is phenyl or naphthyl, for example phenyl.

[0024] In a preferred embodiment, in L, the one or more R L-2 The substituted 3-10 membered heterocycloalkenyl and the L-4 The number of double bonds in the 3-10-membered heterocycloalkenyl group in the substituted benzo3-10-membered heterocycloalkenyl group is independently 1, 2 or 3, for example 2.

[0025] In a preferred embodiment, in L, the one or more R L-2 The substituted 3-10 membered heterocycloalkenyl and the L-4 The 3-10-membered heterocycloalkenyl group in the substituted benzo 3-10-membered heterocycloalkenyl group is independently a 5-6-membered heterocycloalkenyl group.

[0026] In a preferred embodiment, in L, the one or more R L-2 The substituted 3-10 membered heterocycloalkenyl and the L-4The heteroatom of the 3-10-membered heterocycloalkenyl in the substituted benzo 3-10-membered heterocycloalkenyl is N, and the number of the heteroatoms is 1, 2 or 3; for example, the heteroatom is N, and the number of the heteroatoms is 1.

[0027] In a preferred embodiment, in L, the one or more R L-2 The 3-10 membered heterocycloalkenyl in the substituted 3-10 membered heterocycloalkenyl is For example

[0028] In a preferred embodiment, in L, the one or more R L-4 The benzo 3-10 membered heterocycloalkenyl group in the substituted benzo 3-10 membered heterocycloalkenyl group is For example

[0029] In a preferred embodiment, in L, the one or more R L-3 Substituted C 1-6 C in heteroalkyl 1-6 The heteroatoms of the heteroalkyl group are 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 selected from one or two of N and O, and the number of heteroatoms is 2; for another example, the heteroatoms are N and O, and the number of heteroatoms is 2.

[0030] In a preferred embodiment, in L, the one or more R L-3 Substituted C 1-6 C in heteroalkyl 1-6 Heteroalkyl is a straight chain heteroalkyl.

[0031] In a preferred embodiment, in L, the one or more R L-3 Substituted C 1-6 C in heteroalkyl 1-6 Heteroalkyl is C 1-4 Heteroalkyl, e.g.

[0032] In a preferred embodiment, each R L-1 , R L-2 , R L-3 and R L-4 In the C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl.

[0033] In a preferred embodiment, each R L-1 , R L-2 , R L-3 and R L-4In the 5-10 membered heteroaryl, the heteroatom 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.

[0034] In a preferred embodiment, each R L-1 , R L-2 , R L-3 and R L-4 In the above, the 5-10 membered heteroaryl is independently a 5-6 membered heteroaryl, for example, independently a pyridyl, for example

[0035] In a preferred embodiment, each R L-1-1 and R L-1-2 In the C 1-6 Alkyl and said one or more R L-1-1-1 Substituted C 1-6 C in the alkyl group 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; for example methyl, ethyl, n-propyl or isobutyl.

[0036] In a preferred embodiment, each R L-1-1 and R L-1-2 In the C 6-10 The aryl group and the one or more R L -1-1-2 Substituted C 6-10 C in aromatic groups 6-10 Aryl is independently phenyl or naphthyl, for example phenyl.

[0037] In a preferred embodiment, each plurality is independently 2 or 3.

[0038] In a preferred embodiment, each R L-1-1-1 Duhe R L-1-1-2 In the C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl.

[0039] In a preferred embodiment, each R L-1-1-1 Duhe R L-1-1-2 In the C 1-6 Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy, for example methoxy.

[0040] In a preferred embodiment, each R L-1-1-1 and R L-1-1-2 In the C 2-6 Alkynyl is independently ethynyl, propynyl or butynyl, for example

[0041] In a preferred embodiment, n is 1 or 2.

[0042] In a preferred embodiment, X1 is O.

[0043] In a preferred embodiment, X2 is O or S.

[0044] In a preferred embodiment, 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.

[0045] In a preferred embodiment, L is one or more R L-1 Substituted C 6-10 Aryl, one or more R L-2 substituted 3-10 membered heterocycloalkenyl or one or more R L-4 substituted benzo 3-10 membered heterocycloalkenyl; preferably, L is replaced by one or more R L-1 Substituted C 6-10 Aryl, one or more R L-2 substituted 5-6 membered heterocycloalkenyl or one or more R L-4 The substituted benzo 5-6 membered heterocycloalkenyl group, wherein the hetero atom of the 5-6 membered heterocycloalkenyl group and the 5-6 membered heterocycloalkenyl in the benzo 5-6 membered heterocycloalkenyl group is N, and the number of the hetero atoms is 1, 2 or 3.

[0046] In a preferred embodiment, one or more R L-1 Substituted C 6-10 Aryl

[0047] In a preferred embodiment, each R L-1 are independently carboxyl,

[0048] In a preferred embodiment, each R L-1 are independently carboxyl or Preferably

[0049] In a preferred embodiment, each R L-1-1 Independently for C 1-6 Alkyl or one or more R L-1-1-1 Substituted C 1-6 alkyl.

[0050] In a preferred embodiment, each R L-1-2 Independently for C 1-6 Alkyl or one or more R L-1-1-1 Substituted C 1-6 Alkyl; preferably, one or more RL-1-1-1 Substituted C 1-6 alkyl.

[0051] In a preferred embodiment, each R L-1-1-1 Independently for C 1-6 Alkyl or C 2-6 Alkynyl.

[0052] In a preferred embodiment, each R L-1-1-1 Independently for C 2-6 Alkynyl.

[0053] In a preferred embodiment, each R L-1-1-2 Independently for C 1-6 Alkyl, C 1-6 Alkoxy or nitro.

[0054] In a preferred embodiment, one or more R L-2 The substituted 3-10 membered heterocycloalkenyl group is

[0055] In a preferred embodiment, each R L-2 For oxygen.

[0056] In a preferred embodiment, one or more R L-3 Substituted C 1-6 Heteroalkyl is

[0057] In a preferred embodiment, each R L-3 Independently for C 1-6 An 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.

[0058] In a preferred embodiment, each R L-3 Independently for C 1-6 Alkyl or 5-6 membered heteroaryl, wherein the heteroatoms of the 5-6 membered heteroaryl are selected from one, two or three of N, O and S, and the number of the heteroatoms is 1, 2 or 3.

[0059] In a preferred embodiment, one or more R L-4 The substituted benzo 3-10 membered heterocycloalkenyl is

[0060] In a preferred embodiment, each R L-4 For oxygen.

[0061] In a preferred embodiment, each R L-1 Independently For example

[0062] In a preferred embodiment, each R L-1 Independently For example

[0063] In a preferred embodiment, each R L-1 Independently

[0064] In a preferred embodiment, for Preferably for

[0065] In a preferred embodiment, for

[0066] In a preferred embodiment, for Preferably,

[0067] In a preferred embodiment, ring A is Preferably, for Preferably,

[0068] In a preferred embodiment, L is

[0069] Preferably, L is

[0070] In a preferred embodiment, L is More preferably,

[0071] In a preferred embodiment;

[0072] n is 1 or 2;

[0073] Each R 1 Independently for C 1-6 Alkyl or C 1-6 Alkoxy;

[0074] X1 and X2 are independently O or S;

[0075] is a single bond or a double bond;

[0076] Ring A is C 6-10Aromatic ring or 5-10 membered heteroaromatic ring; the heteroatoms of the 5-10 membered heteroaromatic ring are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0077] L is one or more R L-1 Substituted C 6-10 Aryl, one or more R L-2 substituted 3-10 membered heterocycloalkenyl, substituted by one or more R L-3 Substituted C 1-6 Heteroalkyl or one or more R L-4 Substituted benzo 3-10 membered heterocycloalkenyl; the 3-10 membered heterocycloalkenylene and the C 1-6 The heteroatoms of the heteroalkyl 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;

[0078] Each R L-1 are independently carboxyl,

[0079] Each R L-2 For oxygen generation;

[0080] Each R L-3 Independently for C 1-6 Alkyl or 5-10 membered heteroaryl, wherein the heteroatoms of the 5-10 membered heteroaryl are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0081] Each R L-4 For oxygen generation;

[0082] Each R L-1-1 Independently for C 1-6 Alkyl or one or more R L-1-1-1 Substituted C 1-6 alkyl;

[0083] Each R L-1-2 Independently for C 1-6 Alkyl, 6-10 membered aryl, one or more R L-1-1-1 Substituted C 1-6 Alkyl or one or more R L-1-1-2 Substituted 6-10 membered aryl;

[0084] Each R L-1-1-1 Independently for C 1-6 Alkyl or C 2-6 Alkynyl;

[0085] Each R L-1-1-2 Independently for C 1-6 Alkyl, C 1-6 Alkoxy or nitro.

[0086] In a preferred embodiment, ring A is C 6-10 Aromatic ring.

[0087] 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.

[0088] In a preferred embodiment, ring A is C 6-10 Aromatic ring; L is one or more R L-3 Substituted C 1-6 Heteroalkyl.

[0089] In a preferred embodiment, ring A is a 5-10 membered heteroaromatic ring, L is a L-1 Substituted C 6-10 Aryl, each R L-1 for

[0090] In a preferred embodiment, ring A is a 5-10 membered heteroaromatic ring, L is a L-1 Substituted C 6-10 Aryl, each R L-1 for

[0091] In a preferred embodiment, ring A is a 5-10 membered heteroaromatic ring, L is a L-2 substituted 3-10 membered heterocycloalkenyl or one or more R L-4 Substituted benzo 3-10 membered heterocycloalkenyl; 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.

[0092] In a preferred embodiment, the compound as shown in formula I is any of the following embodiments:

[0093] Solution (1):

[0094] n is 1 or 2;

[0095] Each R 1 Independently for C 1-6 Alkyl or C 1-6 Alkoxy;

[0096] X1 and X2 are independently O or S;

[0097] is a single bond or a double bond;

[0098] Ring A is C 6-10 Aromatic rings;

[0099] L is one or more R L-3 Substituted C 1-6 heteroalkyl; said C 1-6 The heteroatoms of the heteroalkylene group are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0100] Each R L-3 Independently for C 1-6 Alkyl or 5-10 membered heteroaryl, wherein the heteroatoms of the 5-10 membered heteroaryl are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0101] Solution (2):

[0102] n is 1 or 2;

[0103] Each R 1 Independently for C 1-6 Alkyl or C 1-6 Alkoxy;

[0104] X1 and X2 are independently O or S;

[0105] is a single bond or a double bond;

[0106] 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;

[0107] L is one or more R L-1 Substituted C 6-10 Aryl, each R L-1 for

[0108] Each R L-1-1 Independently for C 1-6 Alkyl or one or more R L-1-1-1 Substituted C 1-6 alkyl;

[0109] Each R L-1-1-1 Independently for C 1-6 Alkyl or C 2-6 Alkynyl.

[0110] Solution (3):

[0111] n is 1 or 2;

[0112] Each R 1 Independently for C 1-6 Alkyl or C 1-6 Alkoxy;

[0113] X1 and X2 are independently O or S;

[0114] is a single bond or a double bond;

[0115] 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;

[0116] L is one or more R L-1 Substituted C 6-10 Aryl; each R L-1 for

[0117] Each R L-1-2 Independently for C 1-6 Alkyl, 6-10 membered aryl, one or more R L-1-1-1 Substituted C 1-6 Alkyl or one or more R L-1-1-2 Substituted 6-10 membered aryl;

[0118] Each R L-1-1-1 Independently for C 1-6 Alkyl or C 2-6 Alkynyl;

[0119] Each R L-1-1-2 Independently for C 1-6 Alkyl, C 1-6 Alkoxy or nitro;

[0120] Solution (4):

[0121] n is 1 or 2;

[0122] Each R 1 Independently for C 1-6 Alkyl or C 1-6 Alkoxy;

[0123] X1 and X2 are independently O or S;

[0124] is a single bond or a double bond;

[0125] 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;

[0126] L is one or more R L-2 substituted 3-10 membered heterocycloalkenyl or one or more R L-4 Substituted benzo 3-10 membered heterocycloalkenyl; 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;

[0127] Each R L-2 and R L-4 For oxygen.

[0128] In a preferred embodiment,

[0129] n is 1, 2, 3, 4 or 5;

[0130] Each R 1 Independently for C 1-6 Alkyl or C 1-6 Alkoxy;

[0131] X1 and X2 are independently O or S;

[0132] is a single bond or a double bond;

[0133] Ring A is C 6-10 Aromatic ring or 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;

[0134] L is one or more R L-1 Substituted C 6-10 Aryl, one or more R L-2 substituted 3-10 membered heterocycloalkenyl, substituted by one or more R L-3 Substituted C 1-6 Heteroalkyl or one or more R L-4 Substituted benzo 3-10 membered heterocycloalkenyl; the 3-10 membered heterocycloalkenyl, the C 1-6 The heteroatoms of the 3-10-membered heterocycloalkenyl in the 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;

[0135] Each R L-1 are independently carboxyl or

[0136] Each R L-2 For oxygen generation;

[0137] Each R L-3 Independently for C 1-6 Alkyl or 5-10 membered heteroaryl, wherein the heteroatoms of the 5-10 membered heteroaryl are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0138] Each R L-4 For oxygen generation;

[0139] Each R L-1-2 Independently for C 1-6 Alkyl or one or more R L-1-1-1Substituted C 1-6 alkyl.

[0140] Each R L-1-1-1 Independently for C 1-6 Alkyl or C 2-6 Alkynyl.

[0141] In a preferred embodiment, n is 1, 2, 3, 4 or 5;

[0142] Each R 1 Independently for C 1-6 Alkyl or C 1-6 Alkoxy;

[0143] X1 and X2 are independently O or S;

[0144] is a double bond;

[0145] 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;

[0146] L is one or more R L-1 Substituted C 6-10 Aryl, one or more R L-2 substituted 5-6 membered heterocycloalkenyl or one or more R L-4 Substituted benzo 5-6 membered heterocycloalkenyl, wherein the heteroatom of the 5-6 membered heterocycloalkenyl 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;

[0147] Each R L-1 for Each R L-1-2 Independently for one or more R L-1-1-1 Substituted C 1-6 Alkyl, each R L-1-1-1 Independently for C 2-6 Alkynyl;

[0148] Each R L-2 For oxygen generation;

[0149] Each R L-4 For oxygen.

[0150] In a preferred embodiment, the compound shown in formula I is any of the following compounds:

[0151]

[0152] 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.

[0153] The present invention provides a compound as shown in formula I' or a pharmaceutically acceptable salt thereof,

[0154]

[0155] in,

[0156] n、R 1 , X1, X2, 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

[0157] The present invention also provides a pharmaceutical composition comprising:

[0158] (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;

[0159] (2) Pharmaceutically acceptable excipients.

[0160] The present invention also provides a use of a compound (therapeutically effective amount) of formula I or formula I' as described in any embodiment of the present invention, a pharmaceutically acceptable salt thereof or the above pharmaceutical composition in the preparation of a drug for treating and / or preventing diseases related to DNA methylation.

[0161] In a preferred embodiment, the disease associated with DNA methylation is overgrowth syndrome or acute myeloid leukemia.

[0162] In a preferred embodiment, the acute myeloid leukemia is monocytic leukemia.

[0163] The present invention also provides a use of a compound of formula I or a pharmaceutically acceptable salt thereof or formula I' or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition (in a therapeutically effective amount) as described in any scheme of the present invention in the preparation of a drug for treating and / or preventing overgrowth syndrome or acute myeloid leukemia.

[0164] The present invention provides a method for preventing and / or treating diseases associated with 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 pharmaceutical composition.

[0165] 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 embodiment of the present invention, a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

[0166] Unless otherwise specified, the terms used in the present invention have the following meanings:

[0167] 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.

[0168] The term "pharmaceutically acceptable" means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for use by patients.

[0169] 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.

[0170] The terms "compound" and "pharmaceutically acceptable salt" may exist as single stereoisomers or mixtures thereof (eg, racemates), if stereoisomers exist.

[0171] 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.

[0172] When any variable (such as R 1 ) appears multiple times in the definition of a compound, the definition of the variable at each position is independent of the definition of the other positions, and their meanings are independent of each other and do not affect each other. 1 group-substituted, that is, the group may be replaced by up to 3 R 1 Replace, the position R 1Definition and other positions R 1 In addition, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0173] 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.

[0174] 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 with 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.

[0175] The term "alkoxy" refers to the group -OR X , where R X is alkyl as defined above.

[0176] 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., C1 to C6), 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.

[0177] The term "aryl" refers to a radical having a specified number of carbon atoms (e.g. 6-10 ) is a cyclic group consisting only of carbon atoms, which is monocyclic or polycyclic, and each ring is aromatic (conforming to Huckel's rule). Aryl includes but is not limited to phenyl and naphthyl.

[0178] The term "aromatic ring" refers to a ring having a specified number of carbon atoms (e.g., C 6-10 ) is a cyclic group consisting only of carbon atoms, which is a monocyclic or polycyclic ring, and each ring is aromatic (conforming to Huckel's rule). Aromatic rings include but are not limited to benzene rings and naphthalene rings.

[0179] 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.

[0180] 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). It is monocyclic or bicyclic. When it is bicyclic, each ring is aromatic, such as 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, etc.

[0181] 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.

[0182] The term "oxo" refers to the replacement of hydrogen or lone pair electrons on a non-oxygen atom with oxygen, e.g. After being oxidized After being oxidized

[0183] 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.

[0184] 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.

[0185] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] The reagents and raw materials used in the present invention are commercially available.

[0191] 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

[0192] Figure 1 : Statistical analysis of IC50 of compounds in A549, MOLM-13 and Thp-1 cell lines (ns indicates no significant difference (no significance, p>0.05), * indicates p<0.05, ** indicates p<0.01, *** indicates p<0.001, **** indicates p<0.0001).

[0193] Figure 2 : Western blotting was used to identify the expression of DNMT3A protein in J1-890 and J1-890 Dnmt3a- / - cell lines.

[0194] Figure 3 : Statistical analysis of compound IC50 in J1-890 Dnmt3a- / - and J1-890 cell lines. DETAILED DESCRIPTION

[0195] 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.

[0196] Intermediate Preparation Example 1: Preparation of C1

[0197]

[0198] C1: 5-formaldehyde furan-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), K2CO3 (138 mg, 2 mmol) was added, and finally (pph3)2PDCl2 (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:H2O (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%).

[0199] HRMS calculated [C2H8O4] + [M+H] + Mass-to-charge ratio 216.0423, LC-MS shows [C2H8O4] + [M+H] + Mass-to-charge ratio 217.4.

[0200] 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).

[0201] Intermediate Preparation Example 2: Preparation of C2

[0202]

[0203] 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 K2CO3 (2.7g, 20mmol) was added, and stirred at room temperature overnight. The next day, Na2S4O8 (2.38g, 10mmol), K2CO3 (1.38g, 10mmol), water (2ml) were added, and 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.

[0204] HRMS calculated [C 11 H 11 NOS2] + [M+H] + Mass-to-charge ratio 237.0282. LC-MS showed [C 11 H 11 NOS2] + [M+H] + Mass-to-charge ratio 238.3.

[0205] 1 H NMR (500MHz, CDCl3) 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).

[0206] Example 1: Compound 1

[0207]

[0208] 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 H2O 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%).

[0209] HRMS calculated [C 23 H 17 NO4S2]+ [M+H] + Mass-to-charge ratio 435.0599.

[0210] LC-MS showed [C 23 H 17 NO4S2] + [M+H] + Mass-to-charge ratio 435.3.

[0211] 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).

[0212] Example 2: Compound 4

[0213]

[0214] 1 (43.5 mg, 0.1 mmol) was dissolved in acetone (4 ml), iodoethane (20 μl, 0.25 mmol) was added, and then K2CO3 (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 H2O were added to extract three times, the organic phases were combined, evaporated under reduced pressure, and purified by Flash column to obtain yellow solid 4 (41 mg, 91%).

[0215] HRMS calculated [C 25 H 21 NO4S2] + [M+H] + Mass-to-charge ratio 463.0912.

[0216] LC-MS showed [C 25 H 21 NO4S2] + [M+H] + Mass-to-charge ratio 464.3.

[0217] 1H 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).

[0218] Example 3: Compound 5:

[0219]

[0220] 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:H2O (1:20), and the organic phases were combined, evaporated under reduced pressure, and purified by Flash column to obtain yellow solid 5 (30 mg, 61%).

[0221] HRMS calculated [C 27 H 26 N2O3S2] + [M+H] + Mass-to-charge ratio 490.1385.

[0222] LC-MS showed [C 27 H 26 N2O3S2] + [M+H] + Mass-to-charge ratio 491.4.

[0223] 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).

[0224] Example 4: Compound 6:

[0225]

[0226] 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:H2O (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%).

[0227] HRMS calculated [C 27 H 26 N2O3S2] + [M+H] + Mass-to-charge ratio 490.6360.

[0228] LC-MS showed [C 27 H 26 N2O3S2] + [M+H] + Mass-to-charge ratio 491.2.

[0229] 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).

[0230] Example 5: Compound 7:

[0231]

[0232] 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:H2O (1:20), and the organic phases were combined and evaporated under reduced pressure. After purification by Flash column, yellow solid 7 (33 mg, 61%) was obtained.

[0233] HRMS calculated [C 30 H 24 N2O4S2] + [M+H] + Mass-to-charge ratio 540.1177.

[0234] LC-MS showed [C 30 H 24 N2O4S2] + [M+H] + Mass-to-charge ratio 541.3.

[0235] 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=26.9Hz,3H).

[0236] Example 6: Compound 8

[0237]

[0238] 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:H2O (1:20), and the organic phases were combined, evaporated under reduced pressure, and purified by Flash column to obtain a yellow solid (34 mg, 61%). HRMS calculated [C 29 H 21 N3O5S2] + [M+H] + Mass-to-charge ratio 555.0923. LC-MS showed [C 29 H 21N3O5S2] + [M+H] + Mass-to-charge ratio 556.4.

[0239] 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=1.9Hz,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).

[0240] Example 7: Compound 9:

[0241]

[0242] 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:H2O (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%).

[0243] HRMS calculated [C 26 H 20 N2O3S2] + [M+H] + Mass-to-charge ratio 472.0915.

[0244] LC-MS showed [C 26 H 20 N2O3S2] + [M+H] + Mass-to-charge ratio 473.2.

[0245] 1H 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).

[0246] Example 8: Compound 10:

[0247]

[0248] C3 (43.5 mg, 0.1 mmol) was dissolved in DMF (3 ml), 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:H2O (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%).

[0249] HRMS calculated [C 29 H 22 N2O3S2] + [M+H] + Mass-to-charge ratio 510.1072.

[0250] LC-MS showed [C 29 H 22 N2O3S2] + [M+H] + Mass-to-charge ratio 511.3.

[0251] 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).

[0252] Example 9: Compound 11:

[0253]

[0254] 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:H2O (1:20), and the organic phases were combined and evaporated under reduced pressure. After purification by Flash column, yellow solid 11 (32 mg, 61%) was obtained.

[0255] HRMS calculated [C 30 H 24 N2O3S2] + [M+H] + Mass-to-charge ratio 524.1228.

[0256] LC-MS showed [C 30 H 24 N2O3S2] + [M+H] + Mass-to-charge ratio 525.3.

[0257] 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=7.9,1.4Hz,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).

[0258] Example 10: Compound 12:

[0259]

[0260] 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.

[0261] HRMS calculated [C 20 H 16 N2O3S2] + [M+H] + Mass-to-charge ratio 408.0602.

[0262] LC-MS showed [C 20 H 16 N2O3S2] + [M+H] + Mass-to-charge ratio 409.2.

[0263] 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).

[0264] Example 11: Compound 13:

[0265]

[0266] 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), 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 13 (183.6 mg, 90%) was obtained.

[0267] HRMS calculated [C 20 H 16 N2O3S2]+[M+H]+mass-to-charge ratio 408.0602.

[0268] LC-MS showed [C 20 H 16 N2O3S2]+[M+H]+mass-to-charge ratio 409.6.

[0269] 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).

[0270] Example 12: Compound 14:

[0271]

[0272] 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), 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 (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 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 14 (206.1 mg, 90%) was obtained.

[0273] HRMS calculated [C 25 H 18 N2O3S2] + [M+H] + Mass-to-charge ratio 458.0759.

[0274] LC-MS showed [C 25 H 18 N2O3S2] + [M+H] + Mass-to-charge ratio 459.1.

[0275] 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).

[0276] Example 13: Compound 15:

[0277]

[0278] 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), diphenyl iodonium salt (101.1 mg, 3.0 mmol), Cu(NO3)2 (5.8, 0.05 mmol), and finally TEA (7 μl) were added, 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 H2O, the organic phases were combined, evaporated under reduced pressure, and purified by Flash column to obtain yellow solid 15 (36.9 mg, 80%).

[0279] HRMS calculated [C 26 H 27 N3O3S] + [M+H] + Mass-to-charge ratio 461.1773.

[0280] LC-MS showed [C 26 H 27 N3O3S] + [M+H] + Mass-to-charge ratio 462.4.

[0281] 1 H NMR(500MHz, CDCl3)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),3.54–3.39(m,3H),3.26(ddd,J=55.9,14.1,8.4Hz,2H),2.35(s,3H),1.98(d,J=122.2Hz,3H).

[0282] Effect Embodiment Section

[0283] 1. Activity determination method:

[0284] (I) Using MTase-Glo TM Methyltransferase Assay (V7601) kit was used to determine the inhibition of compounds on methyltransferase.

[0285] 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.

[0286] 2. Add 4 μL of substrate (see Table 1) to each well of a 384-well plate, and then add 4 μL of the 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.

[0287] Table 1 Methylation reaction substrate system

[0288]

[0289] 3. Add 2 μL 5x MTase-Glo to each well TM Reagent, centrifuge at 2200 rpm for 30 s, shake at 250 rpm for 90 s, and react at room temperature for 30 min.

[0290] 4. Add 10 μL MTase-Glo to each well TM Detection Solution, centrifuge at 2200 rpm for 30 s, shake at 250 rpm for 90 s, and react at room temperature for 30 min.

[0291] 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:

[0292] Table 2

[0293] Compound Compound 1 Compound 2 Compound 3 Well 1 inhibition rate 56.0％ 34.3％ 16.1％ Well 2 inhibition rate 54.1％ 36.5％ 14.1％ Well 3 inhibition rate 55.0％ 40.0％ 20.8％ Well 4 inhibition rate 55.0％ 36.9％ 17.0％ Average inhibition rate 55.0％ 36.9％ 17.0％ Standard Deviation 0.8％ 2.3％ 2.8％

[0294] (ii) The growth inhibition of the compound on the tumor cell line A549 was determined using the Cell Counting Kit-8 (HY-K0301) kit.

[0295] Tumor cell line A549 was obtained from ATCC.

[0296] (1) Drawing of standard curve

[0297] 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.

[0298] 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).

[0299] 3. After incubation in the incubator for 2 hours, measure the absorbance at 450 nm using an enzyme reader and draw a standard curve.

[0300] (2) Growth inhibition measurement

[0301] 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.

[0302] 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.

[0303] 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).

[0304] 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.

[0305] (3) Inhibition rate determination

[0306] 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.

[0307] 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.

[0308] 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).

[0309] 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.

[0310] Table 3

[0311] Compound <![CDATA[IC 50 (μM)]]> Compound 1 53.6 Compound 5 More than 200 Compound 8 89.15 Compound 12 26.76

[0312] It can be seen from the data in the above table that the compounds of the present application have good safety to cells.

[0313] (III) Growth inhibition of compounds on AML-related cell lines

[0314] The Cell Counting Kit-8 (HY-K0301) was used to measure the growth inhibition of the compound on the cell line.

[0315] 1. Drawing of standard curves of Thp-1, MOLM-13 and A549 cell concentrations

[0316] First, prepare a cell suspension with a doubling dilution gradient concentration, a total of 6 concentration gradients, 3 replicates for each concentration, where the starting concentrations of Thp-1 and MOLM-13 are 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 directly added 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 two cell lines were inoculated in each well according to the standard curve to determine 10,000 cells and 5,000 cells, and the CCK-8 incubation time was 1h.

[0317] 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.

[0318] The experimental group consisted of 50 μL cells + 50 μL culture medium diluted with gradient concentration compounds (24 nM to 50 μM dilutions). After continued culture in the incubator for 72 hours, 10 μL of 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 a microplate reader. 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 cells treated with the compound at that concentration / the proliferation rate of the cells treated with DMSO at the same concentration. The results are shown in Tables 4 and Figure 1 shown.

[0319] Table 4

[0320]

[0321] 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.

[0322] 4. Drawing of standard curve of J1-890 Dnmt3a- / - and J1-890 cell concentration

[0323] The steps are basically the same as the A549 cell line, but the starting cell concentration is 4.8*10^4 cells / well, which are inoculated into a matrigel-coated plate. After 72 hours of culture, the culture medium is replaced with 105μL of CCK-8 diluent (95μL culture medium + 10μL CCK solution). 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.

[0324] (IV) Off-target effect testing of compounds

[0325] 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 J1-890 Dnmt3a- / - and wild-type J1-890 cell lines after administration.

[0326] J1-890 Dnmt3a- / - 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 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.

[0327] Table 5

[0328]

[0329] Compared with the wild-type J1-890 cell line, DNMT3A protein was barely expressed in J1-890 Dnmt3a- / - cells. Figure 2 and Figure 3 As shown; however, Dnmt3a2 knockout did not affect the IC50 of these four drugs.

[0330] In summary, these compounds work by targeting DNMT3A protein and do not cause off-target effects.

Claims

1. 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 Independently for 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 C 6-10 Aromatic ring or 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 one or more R L-1 Substituted C 6-10 Aryl, one or more R L-2 substituted 3-10 membered heterocycloalkenyl, substituted by one or more R L-3 Substituted C 1-6 Heteroalkyl or one or more R L-4 Substituted benzo 3-10 membered heterocycloalkenyl; the 3-10 membered heterocycloalkenyl, the C 1-6 The heteroatoms of the 3-10-membered heterocycloalkenyl in the 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 R L-1 , R L-2 , R L-3 and R L-4 are independently carboxyl, oxo, C 1-6 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 R L-1-1 and R L-1-2 Independently for C 1-6 Alkyl, C 6-10 Aryl, one or more R L-1-1-1 Substituted C 1-6 Alkyl or one or more R L-1-1-2 Substituted C 6-10 Aryl; Each R L-1-1-1 and R L-1-1-2 Independently for C 1-6 Alkyl, C 1-6 Alkoxy, nitro or C 2-6 Alkynyl.

2. Use of the compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1 in the preparation of a DNA methyltransferase 3A inhibitor, characterized in that: It meets one or more of the following conditions: (1) Each R 1 In the C 1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl; (2) Each R 1 In the C 1-6 Alkoxy 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 The 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 one or more R L-1 Substituted C 6-10 C in aromatic groups 6-10 Aryl is phenyl or naphthyl, for example phenyl; (7) In L, the one or more R L-2 The substituted 3-10 membered heterocycloalkenyl and the L-4 replace Benzene and the number of double bonds in the 3-10 membered heterocycloalkenyl group is independently 1, 2 or 3, for example 2; (8) In L, the one or more R L-2 The substituted 3-10 membered heterocycloalkenyl and the L-4 The 3-10-membered heterocycloalkenyl group in the substituted benzo 3-10-membered heterocycloalkenyl group is independently a 5-6-membered heterocycloalkenyl group; (9) In L, the one or more R L-2 The substituted 3-10 membered heterocycloalkenyl and the L-4 The heteroatom of the 3-10 membered heterocycloalkenyl in the substituted benzo 3-10 membered heterocycloalkenyl 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 one or more R L-3 Substituted C 1-6 C in heteroalkyl 1-6 The heteroatoms of the heteroalkyl group are 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 one or more R L-3 Substituted C 1-6 C in heteroalkyl 1-6 Heteroalkyl is a straight chain heteroalkyl; (12) In L, the one or more R L-3 Substituted C 1-6 C in heteroalkyl 1-6 Heteroalkyl is C 1-4 heteroalkyl; (13) Each R L-1 , R L-2 , R L-3 and R L-4 In the C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl; (14) Each R L-1 , R L-2 , R L-3 and R L-4 In the 5-10 membered heteroaryl, the heteroatom 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) Each R L-1 , R L-2 , R L-3 and R L-4 In the above, the 5-10 membered heteroaryl group is independently a 5-6 membered heteroaryl group; (16) Each R L-1-1 and R L-1-2 In the C 1-6 Alkyl and said one or more R L-1-1-1 Substituted C 1-6 C in the alkyl group 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; for example, methyl, ethyl, n-propyl or isobutyl; (17) Each R L-1-1 and R L-1-2 In the C 6-10 The aryl group and the one or more R L-1-1-2 Substituted C 6-10 C in aromatic groups 6-10 Aryl is independently phenyl or naphthyl, for example phenyl; (18) each plurality is independently 2 or 3; (19) Each R L-1-1-1 Duhe R L-1-1-2 In the C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl; (20) Each R L-1-1-1 Duhe R L-1-1-2 In the C 1-6 Alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy, for example methoxy; and (21) Each R L-1-1-1 and R L-1-1-2 In the C 2-6 Alkynyl is ethynyl, propynyl or butynyl, e.g.

3. Use of the compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 2 in the preparation of a DNA methyltransferase 3A inhibitor, characterized in that: It meets 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 one or more R L-2 The 3-10 membered heterocycloalkenyl in the substituted 3-10 membered heterocycloalkenyl is For example (3) In L, the one or more R L-4 The benzo 3-10 membered heterocycloalkenyl group in the substituted benzo 3-10 membered heterocycloalkenyl group is For example (4) In L, the one or more R L-3 Substituted C 1-6 C in heteroalkyl 1-6 Heteroalkyl is and (5) Each R L-1 , R L-2 , R L-3 and R L-4 In the above, the 5-10 membered heteroaryl groups are independently pyridyl groups, for example 4. 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 meets one or more of the following conditions: (1) By one or more R L-1 Substituted C 6-10 Aryl (2) By one or more R L-2 The substituted 3-10 membered heterocycloalkenyl group is (3) By one or more R L-3 Substituted C 1-6 Heteroalkyl is (4) By one or more R L-4 The substituted benzo 3-10 membered heterocycloalkenyl is (5) When ring A is C 6-10 Aromatic ring, for and (6) When ring A is a 5-10 membered heteroaromatic ring, for 5. Use of the compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1 in the preparation of a DNA methyltransferase 3A inhibitor, characterized in that: It meets 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 R L-1 are independently carboxyl, Preferably, each R L-1 Independently (5) Each R L-1-1 Independently for C 1-6 Alkyl or one or more R L-1-1-1 Substituted C 1-6 alkyl; (6) Each R L-1-1-1 Independently for C 1-6 Alkyl or C 2-6 Alkynyl; (7) Each R L-1-1-2 Independently for C 1-6 Alkyl, C 1-6 Alkoxy or nitro; (8) Each R L-2 For oxygen generation; (9) Each R L-3 Independently for C 1-6 Alkyl or 5-10 membered heteroaryl, wherein the heteroatoms of the 5-10 membered heteroaryl are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3; (10) Each R L-4 For oxygen generation; (11) Ring A is C 6-10 Aromatic rings; 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.

6. Use of the compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1 in the preparation of a DNA methyltransferase 3A inhibitor, characterized in that: It meets 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 represented by one or more R L-1 Substituted C 6-10 Aryl, one or more R L-2 substituted 3-10 membered heterocycloalkenyl or one or more R L-4 substituted benzo 3-10 membered heterocycloalkenyl; preferably, L is replaced by one or more R L-1 Substituted C 6-10 Aryl, one or more R L-2 substituted 5-6 membered heterocycloalkenyl or one or more R L-4 Substituted benzo 5-6 membered heterocycloalkenyl, wherein the heteroatom of the 5-6 membered heterocycloalkenyl 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; (3) Each R L-1 are independently carboxyl or Preferably (4) Each R L-1-2 Independently for C 1-6 Alkyl or one or more R L-1-1-1 Substituted C 1-6 Alkyl; preferably, each R L -1-2 Independently for one or more R L-1-1-1 Substituted C 1-6 alkyl; (5) Each R L-1-1-1 Independently for C 2-6 Alkynyl; (6) Each R L-3 Independently for C 1-6 Alkyl or 5-6 membered heteroaryl, wherein the heteroatoms of the 5-6 membered heteroaryl are selected from one, two or three of N, O and S, and the number of the heteroatoms is 1, 2 or 3.

7. Use of the compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1 in the preparation of a DNA methyltransferase 3A inhibitor, characterized in that: It meets one or more of the following conditions: (1) for Preferably for (2) for (3) Ring A is Preferably, for (4) Each R L-1 are independently carboxyl, and (5) L is Preferably, L is 8. Use of the compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1 in the preparation of a DNA methyltransferase 3A inhibitor, characterized in that: It meets one or more of the following conditions: (1) Each R L-1 Independently (2) for (3) for (4) Ring A is (5) L is More preferably, L is 9. Use of the compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1 in the preparation of a DNA methyltransferase 3A inhibitor, characterized in that: It is any of the following: Case (1): Ring A is C 6-10 Aromatic ring; L is one or more R L-3 Substituted C 1-6 heteroalkyl; Case (2): Ring A is a 5-10 membered heteroaromatic ring, L is L-1 Substituted C 6-10 Aryl, each R L-1 for Case (3): Ring A is a 5-10 membered heteroaromatic ring, L is L-1 Substituted C 6-10 Aryl, each R L-1 for Case (4): Ring A is a 5-10 membered heteroaromatic ring, L is L-2 substituted 3-10 membered heterocycloalkenyl or one or more R L-4 Substituted benzo 3-10 membered heterocycloalkenyl; 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.

10. The compound as described in claim 1 or a pharmaceutically acceptable salt thereof as shown in formula I in the preparation of DNA methyl transfer 3A inhibitor The use in a preparation is characterized in that It is any of the following: Solution (1): n is 1 or 2; Each R 1 Independently for 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 C 6-10 Aromatic rings; L is one or more R L-3 Substituted C 1-6 heteroalkyl; said C 1-6 The heteroatoms of the heteroalkylene group are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3; R L-3 C 1-6 Alkyl or 5-10 membered heteroaryl, wherein the heteroatoms of the 5-10 membered heteroaryl 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 Independently for 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 one or more R L-1 Substituted C 6-10 Aryl, each R L-1 for R L-1-1 C 1-6 Alkyl or one or more R L-1-1-1 Substituted C 1-6 alkyl; Each R L-1-1-1 Independently for C 1-6 Alkyl or C 2-6 Alkynyl; Solution (3): n is 1 or 2; Each R 1 Independently for 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 one or more R L-1 Substituted C 6-10 Aryl; each R L-1 for R L-1-2 C 1-6 Alkyl, 6-10 membered aryl, one or more R L-1-1-1 Substituted C 1-6 Alkyl or one or more R L -1-1-2 Substituted 6-10 membered aryl; Each R L-1-1-1 Independently for C 1-6 Alkyl or C 2-6 Alkynyl; Each R L-1-1-2 Independently for C 1-6 Alkyl, C 1-6 Alkoxy or nitro; Solution (4): n is 1 or 2; Each R 1 Independently for 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; By one or more R L-2 substituted 3-10 membered heterocycloalkenyl or one or more R L-4 Substituted benzo 3-10 membered heterocycloalkenyl; 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 R L-2 and R L-4 For oxygen generation; Solution (5): n is 1 or 2; Each R 1 Independently for C 1-6 Alkyl or C 1-6 Alkoxy; X1 and X2 are independently O or S; Ring A is C 6-10 Aromatic ring or 5-10 membered heteroaromatic ring; the heteroatoms of the 5-10 membered heteroaromatic ring are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; L is one or more R L-1 Substituted C 6-10 Aryl, one or more R L-2 substituted 3-10 membered heterocycloalkenyl, substituted by one or more R L-3 Substituted C 1-6 Heteroalkyl or one or more R L-4 Substituted benzo 3-10 membered heterocycloalkenyl; the 3-10 membered heterocycloalkenylene and the C 1-6 The heteroatoms of the heteroalkyl 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 R L-1 are independently carboxyl, Each R L-2 are independently oxo; Each R L-3 Independently for C 1-6 Alkyl or 5-10 membered heteroaryl, wherein the heteroatoms of the 5-10 membered heteroaryl are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3; Each R L-4 are independently oxo; R L-1-1 C 1-6 Alkyl or one or more R L-1-1-1 Substituted C 1-6 alkyl; R L-1-2 Independently for C 1-6 Alkyl, 6-10 membered aryl, one or more R L-1-1-1 Substituted C 1-6 Alkyl or one or more R L-1-1-2 Substituted 6-10 membered aryl; Each R L-1-1-1 Independently for C 1-6 Alkyl or C 2-6 Alkynyl; Each R L-1-1-2 Independently for C 1-6 Alkyl, C 1-6 Alkoxy or nitro; Solution (6): n is 1, 2, 3, 4 or 5; Each R 1 Independently for 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 C 6-10 Aromatic ring or 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 one or more R L-1 Substituted C 6-10 Aryl, one or more R L-2 substituted 3-10 membered heterocycloalkenyl, substituted by one or more R L-3 Substituted C 1-6 Heteroalkyl or one or more R L-4 Substituted benzo 3-10 membered heterocycloalkenyl; the 3-10 membered heterocycloalkenyl, the C 1-6 The heteroatoms of the 3-10-membered heterocycloalkenyl in the 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 R L-1 are independently carboxyl or Each R L-2 For oxygen generation; Each R L-3 Independently for C 1-6 Alkyl or 5-10 membered heteroaryl, wherein the heteroatoms of the 5-10 membered heteroaryl are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3; Each R L-4 For oxygen generation; Each R L-1-2 Independently for C 1-6 Alkyl or one or more R L-1-1-1 Substituted C 1-6 alkyl; Each R L-1-1-1 Independently for C 1-6 Alkyl or C 2-6 Alkynyl; Solutions (7) n is 1, 2, 3, 4 or 5; Each R 1 Independently for 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 one or more R L-1 Substituted C 6-10 Aryl, one or more R L-2 substituted 5-6 membered heterocycloalkenyl or one or more R L-4 Substituted benzo 5-6 membered heterocycloalkenyl, wherein the heteroatom of the 5-6 membered heterocycloalkenyl 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; Each R L-1 for Each R L-1-2 Independently for one or more R L-1-1-1 Substituted C 1-6 Alkyl, each R L-1-1-1 Independently for C 2-6 Alkynyl; Each R L-2 For oxygen generation; Each R L-4 For oxygen.

11. Use of the compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1 in the preparation of a DNA methyltransferase 3A inhibitor, characterized in that: The compound as shown in formula I is any of the following compounds:

12. A compound as shown in formula I' or a pharmaceutically acceptable salt thereof, in, n、R 1 , X1, X2, 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 13. 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.

14. Use of a compound of formula I as described in any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, or a compound of 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.

15. Use of a compound of formula I as described in any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, or a compound of 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.

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