Compound, and pharmaceutical composition and application thereof

Abstract

The invention provides a compound as well as a pharmaceutical composition and application thereof. The compound has a structure as shown in a formula I, wherein each substituent group is described in the specification. The compound provided by the invention can interfere with the interaction between the menin protein and MLL1 or MLL2 or MLL-fusion oncoprotein, and is expected to become a medicine for treating tumors, diabetes mellitus and other diseases depending on the activity of MLL1, MLL2, MLL fusion protein and / or the menin protein. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a class of compounds, pharmaceutical compositions and applications thereof. Background Art

[0002] Mixed-lineage leukemia (MLL) protein is a histone methyltransferase that plays an important role in gene transcription regulation. In most acute leukemias, including acute myeloblastic leukemia (AML), acute lymphoblastic leukemia (ALL) and mixed-lineage leukemia, the MLL gene located at the q23 band of chromosome 11 is often translocated to form an MLL fusion (MLL-r) protein with one of about 80 proteins (such as AF4, AF9, ENL, AF10, ELL, AF6, AF1p, GAS7, etc.). The MLL-r protein retains approximately 1,400 amino acid sequences at the N-terminus of the MLL protein, but lacks the C-terminal methyltransferase activity region, and can abnormally regulate the transcription of multiple oncogenes including HOX and MEIS1, promote cell proliferation, and ultimately lead to the occurrence of cancer. Leukemia patients with MLL gene chromosomal translocation usually have a poor prognosis, with a 5-year survival rate of less than 40%.

[0003] Menin protein, encoded by the Multiple Endocrine Neoplasia (MEN) gene, is a widely expressed nuclear protein that interacts with DNA replication and repair proteins, chromatin modification proteins, and multiple transcription factors. Menin protein can bind to the N-terminus of MLL proteins including MLL1, MLL2, and MLL-r proteins, and this binding is necessary for the oncogenic activity of MLL proteins. Interfering with the interaction between menin and MLL-r proteins can selectively inhibit the proliferation of MLL-r leukemia cells in vivo and in vitro.

[0004] In certain hematological tumors, there are certain specific gene abnormalities or mutations, such as nucleoporin 98 (NUP98) gene fusion, nucleophosmin (NPM1) gene mutation, DNA methyltransferase 3A (DNMT3A) mutation, MLL gene amplification, etc. These abnormalities or mutations are often accompanied by high levels of HOX gene expression. In Ewing's sarcoma, HOXD genes, especially HOXD13, are abnormally overexpressed, accompanied by high levels of meinin and MLL1 proteins, and HOXD13 is a downstream gene regulated by menin and MLL1.

[0005] In addition, hERG potassium channels are essential for normal electrical activity of the heart. Inhibition of hERG can lead to prolonged QT interval, a fatal arrhythmia disease. This side effect is a common cause of drug failure in preclinical safety trials, and compounds that reduce targeted hERG binding are of great significance in drug design. Therefore, in drug development, it is very important to determine the ability of candidate compounds to inhibit hERG channels, but this property is not easy to determine from the structure of the compound, and compounds with similar structures may have huge differences in their ability to block hERG channels. Therefore, there is an urgent need to develop effective compounds that can block hERG channels as little as possible.

[0006] WO2023078426 reports a class of inhibitors based on pyrimidine pyridazine nuclei that interfere with the interaction between menin and MLL proteins, such as the compound in Example 3. However, the compound has poor metabolic properties in vivo and has a strong inhibitory effect on hERG ion channels.

[0007]

[0008] Therefore, there is an urgent need to develop small molecule compounds that can interfere with the interaction between menin and MLL proteins without inhibiting hERG ion channels for the treatment of tumors, diabetes and other diseases related to the activity of MLL1, MLL2, MLL fusion proteins, and / or menin proteins. Summary of the invention

[0009] The purpose of the present invention is to provide compounds that can interfere with the interaction between menin and MLL protein.

[0010] In a first aspect of the present invention, a compound is provided, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated substance or combination thereof, wherein the compound has a structure as shown in Formula I:

[0011]

[0012] in,

[0013] R 1 Selected from the group consisting of: -C(O)(NR a R b ), phenyl and 5-6 membered heteroaryl; wherein the phenyl or heteroaryl may be optionally replaced by R 1a replace;

[0014] R a and R bEach is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted 3-8 membered cycloalkyl or optionally substituted 4-8 membered heterocyclyl; or R a With R b and the N atoms connected to them together form an optionally substituted 4-8 membered heterocyclic ring; wherein, in addition to the connected N atoms, the heterocyclic ring further comprises 0-2 heteroatoms selected from N, O, S and P; wherein the substitution means that H in the group is replaced by one or more R;

[0015] Each R 1a Independently selected from the group consisting of H, cyano, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, halogenated C1-C3 alkoxy, and C3-C5 cycloalkyl;

[0016] R 2 Selected from the group consisting of H, halogen, methyl and trifluoromethyl;

[0017] R 3 represents 0, 1, 2 or 3 groups each independently selected from the group consisting of H, halogen, C1-C3 alkyl, and halogenated C1-C3 alkyl;

[0018] R 4 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted (C1-C4 alkyl)2amino, halogen, -NH2, -NO2, -COOH, -CN, -OH, optionally substituted C1-C6 alkylsulfone, optionally substituted C1-C6 alkylsulfoxide, optionally substituted C1-C6 alkylthio, -NHCOCR 4a =CH2, -NHCOCHR 4a R 4b 、-SO2C(R 4a )=CH2、-NHSO2 CR 4a =CH2 or -NHSO2 CHR 4a R 4b ; Among them, R 4a are each independently selected from the group consisting of H, methyl and fluoro; R 4b are each independently a chlorine or bromine atom; wherein the substitution means that the H in the group is replaced by one or more (such as 1, 2 or 3) R;

[0019] X 1 and X 2 Each independently selected from N or CR X ; Among them, R XSelected from the following group: H, halogen, -CN, -OH, -NH2, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, and optionally substituted (C1-C4 alkyl)2amino; wherein the substitution means that H in the group is replaced by one or more R;

[0020] Ring B is a 4-12 membered saturated or partially saturated nitrogen-containing heterocyclic ring; wherein the nitrogen-containing heterocyclic ring may be optionally replaced by R B Substitution, the nitrogen-containing heterocycle includes at least one N atom and 0-2 heteroatoms selected from N, O and S;

[0021] Each R B Independently selected from the group consisting of deuterium, halogen, oxo, C1-C3 alkyl, halogenated C1-C3 alkyl or cyano;

[0022] L 1 Selected from: absence (i.e. single bond), -(CR La R Lb )-、-(CR La R Lb )2-; where R La and R Lb are independently selected from the group consisting of H, deuterium, optionally substituted C1-C4 alkyl and halogen, or R La and R Lb and the carbon atoms connected to them together form an optionally substituted 3-8 membered saturated or unsaturated carbon alkyl group, an optionally substituted 4-8 membered saturated or unsaturated heterocyclic group; wherein the heterocyclic ring contains 1-3 heteroatoms selected from N, O, S, and P;

[0023] R 5 Selected from the following group: optionally substituted C1-C4 alkyl, optionally substituted 3-8 membered saturated or unsaturated carbon alkyl, optionally substituted 4-8 membered saturated or unsaturated heterocyclic group; wherein the heterocyclic ring contains 1-3 heteroatoms selected from N, O, S, and P; wherein the substitution refers to substitution by one or more R;

[0024] Y is selected from: -C1-C6 alkylene-NR Y1 R Y2 、-3-6 membered cycloalkylene-NR Y1 R Y2 , an optionally substituted 4-8 membered heterocyclic group; wherein the substitution refers to substitution by one or more R;

[0025] R Y1 Selected from the group consisting of: H, C1-C4 alkyl; wherein the alkyl is optionally further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, C1-C4 alkoxy and cyano;

[0026] R Y2 For -L 2 -R Y3 ; where L 2 Selected from: absent and C1-C6 alkylene; R Y3 Selected from the following group: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, optionally substituted saturated or unsaturated 3-8 membered carbocyclic group, or optionally substituted saturated or unsaturated 4-12 membered heterocyclic group; wherein, the substitution refers to substitution by one or more R;

[0027] or R Y1 With R Y2 and the N atoms connected to them together form an optionally substituted 4-10-membered nitrogen-containing heterocyclic ring; the nitrogen-containing heterocyclic ring includes at least one N atom and 0-2 heteroatoms selected from N, O and S, wherein the substitution refers to the replacement of H in the group by one or more R;

[0028] Each R is independently selected from the group consisting of deuterium, halogen, -OH, oxo, mercapto, cyano, -CD3, -C1-C6 alkyl, methylene, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 6-10 membered aryl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl, 6-10 membered aryl-C1-C6 alkylene-, 5-10 membered heteroaryl-C1-C6 alkylene-, C3-C8 cycloalkyl-C1-C6 alkylene-, 4-12 membered heterocyclyl-C1-C6 alkylene-, C1-C6 haloalkyl-, -OC1-C6 alkyl, -OC2-C6 alkenyl, C3-C8 cycloalkyl-O-, 4-12 membered heterocyclyl-O-, 6-10 -C1-C6 alkyl-NH2, -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkylphenyl), -NH(C1-C6 alkylphenyl), -N(C1-C6 alkyl)(6-10 membered aryl), -NH(6-10 membered aryl), nitro, -C(O)-OH, -C(O)OC1-C6 alkyl, -CONR i R ii, -NHC(O)(C1-C6 alkyl), -NHC(O)(phenyl), -N(C1-C6 alkyl)C(O)(C1-C6 alkyl), -N(C1-C6 alkyl)C(O)(phenyl), -C(O)C1-C6 alkyl, 5-10 membered heteroaryl C(O)-, -C(O)C1-C6 alkylphenyl, -C(O)C1-C6 haloalkyl, -OC(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl, -S(O)-C1-C6 -S(O)2-phenyl, -S(O)2-C1-C6 haloalkyl, -S(O)2NH2, -S(O)2NH(C1-C6 alkyl), -S(O)2NH(phenyl), -NHS(O)2(C1-C6 alkyl), -NHS(O)2(phenyl) and -NHS(O)2(C1-C6 haloalkyl); wherein each hydrogen in the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, aryl, heterocyclyl and heteroaryl is optionally replaced by one or more selected from the following Substituents further substituted: halogen, -OH, oxo (=O), -NH2, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C1-C4 alkyl, C1-C4 haloalkyl-, -OC1-C4 alkyl, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, cyano, nitro, -C(O)-OH, -C(O)OC1-C6 alkyl, -CON(C1-C6 alkyl)2, -CONH(C1-C6 alkyl) -C6 alkyl), -CONH2, -NHC(O)(C1-C6 alkyl), -NH(C1-C6 alkyl)C(O)(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2(phenyl), -SO2(C1-C6 haloalkyl), -SO2NH2, -SO2NH(C1-C6 alkyl), -SO2NH(phenyl), -NHSO2(C1-C6 alkyl), -NHSO2(phenyl) and -NHSO2(C1-C6 haloalkyl); R i and R ii Each is independently H, deuterium or C1-C6 alkyl.

[0029] In another preferred embodiment,

[0030] R 1 Selected from the group consisting of: -C(O)(NR a R b ) and a 5-6 membered heteroaryl; wherein the heteroaryl is optionally replaced by R 1a replace;

[0031] R a and R b Each is independently selected from the following group: H, optionally substituted C1-C6 alkyl, optionally substituted 3-8 membered cycloalkyl;

[0032] Each R 1a Independently selected from the group consisting of H, cyano, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy and C3-C5 cycloalkyl.

[0033] In another preferred embodiment, R 1 Selected from the group consisting of: -C(O)(NR a R b ) and a 5-6 membered heteroaryl; wherein the heteroaryl is optionally replaced by R 1a replace;

[0034] R a and R b Each is independently selected from the following group: H, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0035] Each R 1a Independently selected from the group consisting of H, cyano, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy and C3-C5 cycloalkyl.

[0036] In another preferred embodiment, R 1 Selected from the group consisting of: -C(O)(NR a R b )and Among them, the Optionally R 1a replace;

[0037] R a and R b Each is independently selected from the group consisting of H, ethyl, isopropyl, and cyclopropyl;

[0038] Each R 1a Independently selected from the group consisting of H, cyano, methyl and cyclopropyl.

[0039] In another preferred embodiment, R 2 is selected from the group consisting of H, halogen, methyl and trifluoromethyl, preferably, R 2 Selected from the group consisting of: H, F.

[0040] In another preferred embodiment, R 3 For H.

[0041] In another preferred embodiment, R 4 Selected from the following group: H, C1-C6 alkyl, C1-C4 alkoxy, halogen, -NH2, -NO2, -COOH, -CN, -OH.

[0042] In another preferred embodiment, R 4 For H.

[0043] In another preferred embodiment, ring B is a 4-11-membered saturated or partially saturated nitrogen-containing heterocyclic ring, wherein the nitrogen-containing heterocyclic ring includes at least one N atom and 0-2 heteroatoms selected from N, O and S; wherein the nitrogen-containing heterocyclic ring may be optionally replaced by R B Replace; each R B Independently selected from the group consisting of deuterium, halogen, oxo, C1-C3 alkyl, halogenated C1-C3 alkyl or cyano.

[0044] In another preferred embodiment, the B ring is selected from the following groups:

[0045]

[0046] Wherein, the B ring is optionally R B Replace; each R B are independently deuterium, halogen, oxo, C1-C3 alkyl, halogenated C1-C3 alkyl or cyano.

[0047] In another preferred embodiment, ring B is a 4-7 membered saturated nitrogen-containing heterocyclic ring, wherein the nitrogen-containing heterocyclic ring includes at least one N atom and 0-2 heteroatoms selected from N and O; wherein the nitrogen-containing heterocyclic ring may be optionally replaced by R B Replace; each R B Independently selected from the group consisting of deuterium, halogen, oxo, C1-C3 alkyl, halogenated C1-C3 alkyl or cyano.

[0048] In another preferred embodiment, the B ring is selected from the following group: Wherein, the B ring is optionally R B Replace; each R B are independently deuterium, halogen, oxo, C1-C3 alkyl, halogenated C1-C3 alkyl or cyano.

[0049] In another preferred embodiment, ring B is a 5-6 membered saturated nitrogen-containing heterocyclic ring; wherein the nitrogen-containing heterocyclic ring may be optionally replaced by R B Replace; each R B Independently selected from the group consisting of H, deuterium, halogen, C1-C3 alkyl.

[0050] In another preferred embodiment, ring B is a 5-membered saturated nitrogen-containing heterocyclic ring; wherein the nitrogen-containing heterocyclic ring may be optionally replaced by R B Replace; each R B Independently selected from the group consisting of H, deuterium, halogen, C1-C3 alkyl.

[0051] In another preferred embodiment, Ring B is unsubstituted.

[0052] In another preferred embodiment, ring B is selected from

[0053] In another preferred embodiment, L1 Select from: absence (i.e. single bond), -(CR La R Lb )-; where R La and R Lb are each independently selected from the group consisting of H, deuterium, optionally substituted C1-C4 alkyl and halogen.

[0054] In another preferred embodiment, L 1 Does not exist.

[0055] In another preferred embodiment, R 5 Selected from the group consisting of C1-C4 alkyl.

[0056] In another preferred embodiment, R 5 Selected from isopropyl.

[0057] In another preferred embodiment, X 1 and X 2 Each independently selected from N or CR X ; Among them, R X Selected from the following group: H, halogen, -CN, -OH, -NH2, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy; wherein the substitution means that H in the group is replaced by one or more R.

[0058] In another preferred embodiment, X 1 and X 2 are each independently selected from N.

[0059] In another preferred embodiment, X 1 N; X 2 is N or CH.

[0060] In another preferred embodiment, Y is selected from: -C1-C6 alkylene-NR Y1 R Y2 、-3-6 membered cycloalkylene-NR Y1 R Y2 ;

[0061] R Y1 Selected from the group consisting of: H, C1-C4 alkyl; wherein the alkyl is optionally further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, C1-C4 alkoxy and cyano;

[0062] R Y2 For -L 2 -R Y3 ; where L 2 Selected from: absent and C1-C6 alkylene; R Y3Selected from the following group: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, optionally substituted saturated or unsaturated 3-6-membered carbocyclic group, or optionally substituted saturated or unsaturated 4-6-membered heterocyclic group; wherein the substitution refers to substitution by one or more R;

[0063] or R Y1 With R Y2 and the N atoms connected to them together form an optionally substituted 4-9 membered nitrogen-containing heterocycle; the nitrogen-containing heterocycle includes at least one N atom and 0-2 heteroatoms selected from N and O, wherein the substitution means that the H in the group is replaced by one or more R; R is as described in the first aspect of the present invention.

[0064] In another preferred embodiment, Y is selected from: -C1-C4 alkylene-NR Y1 R Y2 、-3-6 membered cycloalkylene-NR Y1 R Y2 ;

[0065] R Y1 Selected from the group consisting of: H, C1-C4 alkyl; wherein the alkyl is optionally further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, C1-C4 alkoxy and cyano;

[0066] R Y2 For -L 2 -R Y3 ; where L 2 Selected from: absent and C1-C4 alkylene; R Y3 Selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy;

[0067] or R Y1 With R Y2 and the N atoms connected to them together form an optionally substituted 4-10 membered nitrogen-containing heterocycle; the nitrogen-containing heterocycle includes at least one N atom and 0-2 heteroatoms selected from N and O, wherein the substitution means that the H in the group is replaced by one or more R, and R is as described in the first aspect of the present invention.

[0068] In another preferred embodiment, the nitrogen-containing heterocycle is a monocyclic ring, a fused ring, a bridged ring or a spirocyclic ring.

[0069] In another preferred embodiment, the nitrogen-containing heterocycle is unsubstituted.

[0070] In another preferred embodiment, R Y1 Selected from methyl.

[0071] In another preferred embodiment, L 2 Selected from: absent and C1-C6 alkylene; preferably absent or ethylene.

[0072] In another preferred embodiment, R Y3 Selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, preferably, R Y3 Selected from the group consisting of hydrogen, methyl, methoxy.

[0073] In another preferred embodiment, L 1 Does not exist; R 5 for

[0074] Y is Wherein, n is selected from: 0, 1, 2; m is selected from 1, 2;

[0075] R Y1 and R Y2 As defined in the first aspect of the present invention.

[0076] In another preferred embodiment,

[0077] When R Y1 With R Y2 When the N atom to which they are connected together forms an optionally substituted 4-10 membered nitrogen-containing heterocyclic ring, the 4-10 membered heterocyclic ring is selected from the following group:

[0078] The substitution means that H in the group is replaced by one or more R; wherein R is as described in the first aspect of the present invention. In another preferred embodiment, the compound is selected from Table A:

[0079] Table A

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092] In another preferred embodiment, the compound is selected from Table B:

[0093] Table B

[0094]

[0095] In the second aspect of the present invention, a pharmaceutical composition is provided, comprising a safe and effective amount of one or more compounds as described in the first aspect of the present invention and a pharmaceutically acceptable carrier.

[0096] In another preferred embodiment, in the composition, the compound accounts for 0.001-99.999wt% of the total weight of the composition; preferably 0.01-99.99wt%; more preferably 0.1-90wt%.

[0097] In another preferred embodiment, the pharmaceutical composition is in the form of an injection, tablet, capsule, pill, suspension or emulsion.

[0098] In the third aspect of the present invention, there is provided a use of the compound according to the first aspect of the present invention or the pharmaceutical composition according to the second aspect of the present invention, wherein the use is selected from any one or more of the following (a)-(c):

[0099] (a) preparing a drug for preventing or treating a disease associated with the activity of MLL1, MLL2, MLL fusion protein, and / or menin protein;

[0100] (b) preparing inhibitors related to the activity of MLL1, MLL2, MLL fusion protein, and / or menin protein for non-therapeutic use in vitro;

[0101] (c) Preparation of proliferation inhibitors for non-therapeutic tumor cells in vitro.

[0102] In another preferred embodiment, the disease related to the activity of MLL1, MLL2, MLL fusion protein, and / or menin protein is selected from the following group: tumor, diabetes and other diseases related to the activity of MLL1, MLL2, MLL fusion protein, and / or menin protein.

[0103] In another preferred embodiment, the tumor associated with MLL1, MLL2, MLL fusion protein, and / or menin protein activity is selected from the following group: leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T cell lymphoma, B cell lymphoma, malignant rhabdoid tumor, synovial sarcoma, colorectal cancer, endometrioma, gastric cancer, liver cancer, kidney cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, glioma, bile duct cancer, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer.

[0104] In another preferred embodiment, the other diseases related to the activity of MLL1, MLL2, MLL fusion protein, and / or menin protein are selected from the following group: autoimmune diseases and non-alcoholic hepatitis.

[0105] In another preferred embodiment, the pharmaceutical composition further comprises other therapeutic agents.

[0106] In another preferred embodiment, the other therapeutic agent is other anti-tumor drugs.

[0107] In another preferred embodiment, the other therapeutic agents include: anti-tumor drugs that act on the chemical structure of DNA, such as cisplatin; anti-tumor drugs that affect nucleic acid synthesis, such as methotrexate (MTX) and 5-fluorouracil (5FU); anti-tumor drugs that affect nucleic acid transcription, such as doxorubicin, epirubicin, aclarubicin, and mithramycin; anti-tumor drugs that act on microtubule synthesis, such as paclitaxel and vinorelbine; aromatase inhibitors, such as aminoglutethimide, lantron, letrozole, and arimidex; cell signaling pathway inhibitors, such as epidermal growth factor receptor inhibitors imatinib, gefitinib, erlotinib, and lapatinib.

[0108] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0109] The inventors of the present invention have obtained a new class of compounds that interfere with the interaction between menin and MLL proteins by rational design and comprehensive consideration of the target-related activity of the compound, the inhibitory activity on the hERG channel and the pharmacokinetic properties. This type of compound shows good MV-411 cell proliferation inhibitory activity, significantly reduced inhibitory activity on hERG, and has very good metabolic properties in animals. Compared with the compounds reported in WO2023078426, it has obvious advantages and is expected to be developed into a new drug for the treatment of tumors, diabetes and other diseases. On this basis, the inventors completed the present invention.

[0110] the term

[0111] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0112] As used herein, the term "comprising" or "including (comprising)" may be open, semi-closed and closed. In other words, the term also includes "consisting essentially of" or "consisting of".

[0113] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0114] It should be understood that when a group is present in multiple different positions of a compound at the same time, its definition at each position is independent of each other and may be the same or different. That is, the term "selected from the following group:" has the same meaning as the term "independently selected from the following group:".

[0115] Unless otherwise specified, the structural formulas described in the present invention are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, etc. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers or geometric isomers (or conformational isomers) are all within the scope of the present invention.

[0116] The compounds of the present application can be prepared by a variety of synthesis methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining specific embodiments with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0117] Group Definition

[0118] Definitions of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4THED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise stated, conventional methods within the technical scope of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy and pharmacological methods, are used. Unless specifically defined, the terms used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and drugs and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for the use of the kit can be used, or the reaction and purification can be carried out in a manner known in the art or in accordance with the description of the present invention. The above-mentioned techniques and methods can usually be implemented according to the descriptions in the multiple summary and more specific documents cited and discussed in this specification, according to conventional methods well known in the art. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural parts and compounds.

[0119] When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0120] The section headings used herein are only for the purpose of organizing the article and should not be interpreted as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals and papers, are incorporated herein by reference in their entirety.

[0121] Certain chemical groups defined herein are preceded by simplified symbols to indicate the total number of carbon atoms present in the group. For example, a C1-C6 alkyl group refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the simplified symbols does not include carbons that may be present in substituents of the group.

[0122] In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0123] Unless otherwise specified, in this application, the term "halogen" refers to fluorine, chlorine, bromine or iodine; "hydroxy" refers to an -OH group; "hydroxyalkyl" refers to an alkyl group as defined below substituted by a hydroxyl (-OH); "carbonyl" refers to a -C(=O)- group; "nitro" refers to -NO2; "cyano" refers to -CN; "amino" refers to -NH2; "alkylamino" or "alkylamino" refers to an amino group in which one or both hydrogens are replaced by an alkyl group as defined below (e.g., -NH(CH3) or -N(CH3)2); "alkylsulfone" refers to an -SO2-alkyl group; "alkylsulfoxide" refers to an -SO-alkyl group; and "carboxyl" refers to -COOH.

[0124] "Substituted amino" refers to an amino group substituted with one or two alkyl groups, alkylcarbonyl groups, arylalkyl groups, heteroarylalkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkylacylamino, arylalkylamino, heteroarylalkylamino.

[0125] In the present application, as a separate group or as part of other groups (for example, in groups such as halogen-substituted alkyl), the term "alkyl" refers to a fully saturated straight or branched hydrocarbon chain radical consisting only of carbon atoms and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6, such as 1, 2, 3, or 4) carbon atoms, and connected to the rest of the molecule by one or more single bonds, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl, etc. For the purposes of the present invention, the term "alkyl" preferably refers to an alkyl group containing 1 to 6 carbon atoms.

[0126] In the present application, the term "alkenyl", as a separate group or as part of other groups, means a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6, such as 2, 3, or 4) carbon atoms and connected to the rest of the molecule by one or more single bonds, such as but not limited to ethenyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, etc.

[0127] As used herein, the term "alkynyl" as a separate group or as part of other groups refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6, such as 2, 3, or 4) carbon atoms and connected to the rest of the molecule by one or more single bonds, such as, but not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0128] In the present application, as a separate group or as part of other groups, the term "carbocyclic (radical)" means a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting only of carbon atoms and hydrogen atoms, which may include a fused ring system, a bridged ring system or a spirocyclic system, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms, and which is a saturated or unsaturated ring (i.e., cycloalkyl, cycloalkenyl, etc.) and may be connected to the rest of the molecule via one or more single bonds via any suitable carbon atom. Unless otherwise specifically indicated in the specification, the carbon atoms in the carbocyclic radical may be optionally oxidized. Examples of carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, 2,3-dihydroindanyl, octahydro-4,7-methylene-1H-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, 1H-indenyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocyclohepten-5, 5,6,7,8-tetrahydro-1H-benzocyclohepten-6-yl, 1,2,3,4 ... 6,7,8,9,10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl and octahydro-2,5-methylene-pentalenyl, etc.

[0129] In the present application, as a separate group or as part of other groups, the term "heterocyclic (base)" means a stable 3- to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. Unless otherwise specified in this specification, the heterocyclic group can be a monocyclic, bicyclic, tricyclic or more ring system, which can include a fused ring system, a bridged ring system or a spirocyclic system; the nitrogen, carbon or sulfur atoms in the heterocyclic group can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclic group can be partially or fully saturated. The heterocyclic group can be connected to the rest of the molecule via a carbon atom or a heteroatom and by one or more single bonds. In a heterocyclic group containing a fused ring, one or more rings can be an aryl or heteroaryl group as defined below, provided that the point of connection with the rest of the molecule is a non-aromatic ring atom. For the purpose of the present invention, the heterocyclic group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2-azabicyclo[2.2.2]octanyl, 2,7-diaza-spiro[3.5]nonan-7-yl, 2-oxa-6-aza-spiro[3.3]heptan-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxolane, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, dihydroindolyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimido, and the like.

[0130] In the present application, the term "aryl" as a separate group or as part of another group means a conjugated hydrocarbon ring system radical having 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms. For the purposes of the present invention, aryl can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused to a carbocyclic or heterocyclic group as defined above, provided that the aryl is connected to the rest of the molecule via one or more single bonds via atoms on the aromatic ring. Examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazolin-3(4H)-one-7-yl, and the like.

[0131] In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted by an aryl group as defined above.

[0132] In the present application, as a separate group or as part of another group, the term "heteroaryl" means a 5- to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specified in this specification, the heteroaryl group may be a monocyclic, bicyclic, tricyclic or more ring system, and may also be fused to a carbocyclic or heterocyclic group as defined above, provided that the heteroaryl group is connected to the rest of the molecule through one or more single bonds via atoms on the heteroaromatic ring. The nitrogen, carbon or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atom may be optionally quaternized. For the purpose of the present invention, heteroaryl is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5- to 10-membered aromatic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolyl, isoquinolyl, naphthazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothiophenyl, oxatriol, oxazolyl, cinnolinyl, quinazolinyl, phenylthio, indolizinyl, o-phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridinyl, [1,2,4]triazolo[4,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine, etc.

[0133] In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted by a heteroaryl group as defined above.

[0134] In the present application, the term "absent" means that the two sides of the group defined above are directly connected by a chemical bond. For example, "ABC in which B is absent" means "AC".

[0135] In this application, the term "-[CH2] n "-" means that the two sides of the group defined above are connected by a methylene group having a number n. When n is 0, it means that the two sides of the group defined above are directly connected by a chemical bond.

[0136] In this application, In Indicates the attachment position of the group R.

[0137] In this application, unless otherwise specified, "optionally" or "optionally" means that the event or situation described later may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation. For example, "optionally substituted aryl" means that the hydrogen on the aryl is substituted or unsubstituted, and the description includes both substituted aryl and unsubstituted aryl. For example, in the absence of explicit listing of substituents, the terms "optionally substituted", "substituted" or "substituted by" as used herein mean that one or more hydrogen atoms on a given atom or group are independently replaced by one or more, e.g., 1, 2, 3 or 4, substituents independently selected from the group consisting of: deuterium (D), halogen, -OH, oxo (=O), mercapto, cyano, -CD3, -C1-C6 alkyl (preferably -C1-3 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl (preferably C3-C8 cycloalkyl), aryl, heterocyclyl (preferably 3-8 membered heterocyclyl), heteroaryl, aryl-C1-C6 alkyl-, heteroaryl-C1-C6 alkyl-, C1-C6 haloalkyl-, -OC1-C6 alkyl (preferably -OC1-C3 alkyl), -OC2-C6 alkenyl, -O cycloalkyl, -O heterocyclyl, -O aromatic alkyl), -O heteroaryl, -OC1-C6 alkylphenyl, -C1-C6 alkyl-OH (preferably -C1-C4 alkyl-OH), -C1-C6 alkyl-SH, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 haloalkyl, -NH2, -C1-C6 alkyl-NH2 (preferably -C1-C3 alkyl-NH2), -N(C1-C6 alkyl)2 (preferably -N(C1-C3 alkyl)2), -NH(C1-C6 alkyl) (preferably -NH(C1-C3 alkyl)), -N(C1-C6 alkyl)(C1-C6 alkylphenyl), -NH(C1-C6 alkylphenyl), -N(C1-C6 alkyl)(aryl), -NH(aryl), nitro, -C(O)-OH, -C(O)OC1-C6 alkyl (preferably -C(O)OC1-C3 alkyl), -CONR i R ii (where R i and R iiis H, D and C1-6 alkyl, preferably C1-3 alkyl), -NHC(O)(C1-C6 alkyl), -NHC(O)(phenyl), -N(C1-C6 alkyl)C(O)(C1-C6 alkyl), -N(C1-C6 alkyl)C(O)(phenyl), -C(O)C1-C6 alkyl, -C(O)heteroaryl (preferably -C(O)-5-7 membered heteroaryl), -C(O)C1-C6 alkylphenyl, -C(O)C1-C6 haloalkyl, -OC(O)C1-C6 alkyl (preferably -O C(O)2-C1-C3 alkyl), -S(O)2-C1-C6 alkyl, -S(O)-C1-C6 alkyl, -S(O)2-phenyl, -S(O)2-C1-C6 haloalkyl, -S(O)2NH2, -S(O)2NH(C1-C6 alkyl), -S(O)2NH(phenyl), -NHS(O)2(C1-C6 alkyl), -NHS(O)2(phenyl) and -NHS(O)2(C1-C6 haloalkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, aromatic Each of the alkyl, heterocyclyl and heteroaryl groups is optionally further substituted by one or more substituents selected from the group consisting of halogen, -OH, oxo (=O), -NH2, cycloalkyl, 3-8 membered heterocyclyl, C1-C4 alkyl, C1-C4 haloalkyl-, -OC1-C4 alkyl, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, cyano, nitro, -C(O)-OH, -C(O)OC1-C6 alkyl, -CON(C1-C6 alkyl)2, -CONH(C1-C6 alkyl), -CONH2, -NHC(O)(C1-C6 alkyl), -NH(C1-C6 alkyl)C(O)(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2(phenyl), -SO2(C1-C6 haloalkyl), -SO2NH2, -SO2NH(C1-C6 alkyl), -SO2NH(phenyl), -NHSO2(C1-C6 alkyl), -NHSO2(phenyl) and -NHSO2(C1-C6 haloalkyl). When an atom or group is substituted with multiple substituents, the substituents may be the same or different. As used herein, the terms "part", "structural part", "chemical part", "group", "chemical group" refer to a specific fragment or functional group in a molecule. A chemical part is generally considered to be a chemical entity embedded in or attached to a molecule.

[0138] In the present invention, (C1-C4 alkyl)2amino represents amines substituted by two identical or different C1-C4 alkyl groups, for example, wait.

[0139] Unless otherwise specified, "plurality" herein means 2, 3 or 4.

[0140] Active ingredients

[0141] As used herein, "compound of the present invention" or "active ingredient" refers to the compound shown in Formula I, and also includes pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, cis-trans isomers, solvates, polymorphs, deuterated substances or combinations thereof.

[0142] "Stereoisomers" refer to compounds composed of the same atoms, bonded by the same bonds, but having different three-dimensional structures. The present invention is intended to encompass various stereoisomers and mixtures thereof.

[0143] When the compounds of the present invention contain olefinic double bonds, and unless specified otherwise, it is intended that the compounds of the present invention include both E- and Z- geometric isomers.

[0144] "Tautomer" refers to an isomer formed when a proton is shifted from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present invention are intended to be encompassed within the scope of the present invention.

[0145] The compounds of the present invention or their pharmaceutically acceptable salts may contain one or more chiral carbon atoms and may therefore give rise to enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom may be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the present invention may be prepared using racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0146] Conventional techniques for preparing / isolating individual isomers include chiral synthesis from appropriate optically pure precursors, or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography, see, for example, Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; A. M. Stalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3: 341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5. sup. TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128.

[0147] In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0148] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetates, trifluoroacetates, propionates, caproates, caprylates, decanoates, undecylenates, glycolates, gluconates, lactates, sebacates, adipates, glutarates, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamate, pyroglutamate, aspartate, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginate, ascorbate, salicylates, 4-aminosalicylates, naphthalene disulfonates, and the like. These salts may be prepared by methods known in the art.

[0149] "Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts, and magnesium salts. The salt derived from organic base includes but is not limited to the following salt: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the profession.

[0150] It should be understood that the specific preparation method of the compound of formula (I) of the present invention does not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combination can be easily performed by a person skilled in the art to which the present invention belongs.

[0151] Typically, the compounds of the present invention can be prepared by the process described in the examples, wherein the raw materials and reagents used can be purchased from commercial sources unless otherwise specified.

[0152] Pharmaceutical compositions and methods of administration

[0153] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compound of the present invention or, or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof.

[0154] Since the compounds of the present invention have excellent anti-tumor activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate tumor-related diseases.

[0155] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0156] In this application, "pharmaceutical composition" refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering the biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote administration of the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0157] The term "pharmaceutically acceptable" as used herein refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to a subject without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.

[0158] In the present application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant regulatory authorities as acceptable for human or livestock use.

[0159] The "tumor" mentioned in the present invention includes but is not limited to lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdoid tumor, synovial sarcoma, endometrioma, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, glioma, bile duct cancer, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer.

[0160] In a preferred example, the tumor associated with MLL1, MLL2, MLL fusion protein, and / or menin protein activity is selected from the following group: leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdoid tumor, synovial sarcoma, colorectal cancer, endometrioma, gastric cancer, liver cancer, kidney cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, glioma, bile duct cancer, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer; related "other diseases" include but are not limited to autoimmune diseases, non-alcoholic hepatitis, etc.

[0161] As used herein, the terms "prophylactic," "prevention," and "prevention" include reducing the likelihood of a disease or condition occurring or becoming worse in a patient.

[0162] As used herein, the term "treatment" and other similar synonyms include the following meanings:

[0163] (i) preventing a disease or condition from occurring in a mammal, particularly where such mammal is susceptible to the disease or condition but has not yet been diagnosed as having the disease or condition;

[0164] (ii) inhibiting a disease or condition, i.e. arresting its development;

[0165] (iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

[0166] (iv) alleviating the symptoms caused by the disease or condition.

[0167] As used herein, the term "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" refers to an amount of at least one agent or compound sufficient to relieve to some extent one or more symptoms of the disease or condition being treated after administration. The result can be a reduction and / or alleviation of signs, symptoms or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant relief of the condition. Techniques such as dose escalation trials can be used to determine the effective amount appropriate for any individual case.

[0168] As used herein, the terms "administering", "administering", "dosing", etc. refer to methods that can deliver a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used for the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

[0169] As used herein, the terms "drug combination", "drug combination", "combination therapy", "administration of other treatments", "administration of other therapeutic agents" and the like refer to drug treatments obtained by mixing or combining more than one active ingredient, including fixed and non-fixed combinations of the active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form. The term "non-fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of separate entities, in combination or sequentially at variable intervals. These also apply to cocktail therapies, for example the administration of three or more active ingredients.

[0170] Preferably, the pharmaceutical composition further comprises other pharmaceutically acceptable therapeutic agents, in particular other anti-tumor drugs. The therapeutic agents include but are not limited to: anti-tumor drugs such as cisplatin that act on the chemical structure of DNA, anti-tumor drugs that affect nucleic acid synthesis such as methotrexate (MTX), 5-fluorouracil (5FU), etc., anti-tumor drugs that affect nucleic acid transcription such as doxorubicin, epirubicin, aclarubicin, mithramycin, etc., anti-tumor drugs that act on microtubule synthesis such as paclitaxel, vinorelbine, etc., aromatase inhibitors such as aminoglutethimide, lantron, letrozole, arimide, etc., cell signaling pathway inhibitors such as epidermal growth factor receptor inhibitors imatinib (Imatinib), gefitinib (Gefitinib), erlotinib (Erlotinib), lapatinib (Lapatinib), etc.

[0171] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0172] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0173] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0174] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0175] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0176] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0177] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0178] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0179] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0180] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0181] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0182] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0183] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0184] Compared with the prior art, the main advantages of the present invention include:

[0185] (1) The present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof;

[0186] (2) The present invention provides a compound as shown in Formula I for use in preparing a pharmaceutical composition for preventing and treating diseases related to the activity of MLL1, MLL2, MLL fusion protein, and / or menin protein.

[0187] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or under conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0188] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0189] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.

[0190] In each embodiment, 1 H NMR was recorded by a BRUKER AVANCE NEO 400 MHz nuclear magnetic resonance instrument, and the chemical shift was expressed in δ (ppm). Liquid chromatography-mass spectrometry (LCMS) was recorded by Shimadzu LC-20AD, SIL-20A, CTO-20AC, SPD-M20A, CBM-20A, LCMS-2020 mass spectrometers. Preparative HPLC separation used a Gilson-281 liquid chromatograph.

[0191] Example 1

[0192]

[0193] The synthetic route of compound 1 is as follows:

[0194]

[0195] (1) Ethyl diisopropylamine (8.92 g, 69.0 mmol, 12.0 mL), 1-hydroxybenzotriazole (3.73 g, 27.6 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.29 g, 27.6 mmol) were added to a solution of compound 1-1 (5.00 g, 23.0 mmol) in dichloromethane (80.0 mL), and the reaction solution was stirred at 25°C for 1 hour. N,O-dimethylhydroxylamine (4.49 g, 46.0 mmol) was then added, and the reaction solution was stirred at 25°C for 5 hours. A citric acid aqueous solution (50.0 mL) was added for washing, and the organic phase was washed with a sodium bicarbonate aqueous solution (50.0 mL) and water (50.0 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-2.

[0196] MS-ESI[M+H] + , calculated value 261, measured value 261.

[0197] 1H NMR (400MHz, CDCl3) δ3.67(s,3H),3.27(t,J=7.2Hz,2H),3.17(s,3H),2.84(s,3H),2.42(br t,J=7.2Hz,2H),1.83(m,2H),1.44(s,9H).

[0198] (2) Add isopropenylmagnesium bromide (1 mol / L, 19.2 mL) to a solution of compound 1-2 (2.00 g, 7.68 mmol) in tetrahydrofuran (60.0 mL) at 0°C, and stir the reaction solution at 0°C for 1 hour under nitrogen protection. Move to room temperature and continue the reaction for 12 hours. Add aqueous ammonium chloride solution (50.0 mL) to quench the reaction, extract the organic phase with ethyl acetate (50.0 mL), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the organic phase under reduced pressure to obtain compound 1-3.

[0199] MS-ESI[M- t Bu+H] + , calculated value 186, measured value 186.

[0200] 1 H NMR (400MHz, CDCl3) δ5.95 (s, 1H), 5.76 (s, 1H), 3.24 (t, J = 6.8Hz, 2H), 2.83 (s, 3H), 2.69 (t, J = 7.2Hz, 2H), 1.87 (s, 3H), 1.80-1.85 (m, 2H), 1.43-1.45 (m, 9H).

[0201] (3) Palladium carbon (10%, 200 mg) was added to a solution of compound 1-3 (2.00 g, 8.29 mmol) in methanol (20.0 mL), and the reaction solution was stirred at 25° C. for 2 hours under a hydrogen atmosphere. The reaction solution was filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 0:1) to obtain compound 1-4.

[0202] MS-ESI[M-Boc+H] + , calculated value 144, measured value 144.

[0203] 1 H NMR (400MHz, CDCl3) δ3.21(t,J=7.2Hz,2H),2.82(s,3H),2.58(dt,J=14.0,6.8Hz,1H) ,2.44(t,J=7.2Hz,2H),1.77(quin,J=7.2Hz,2H),1.45(s,9H),1.09(d,J=6.8Hz,6H).

[0204] (4) Add triethylamine to a solution of the hydrochloride of compound 1-5 (100 mg, 242 μmol, synthesis reference patent WO2023078426) in methanol (20.0 mL) to adjust the pH value to 8. Then add 1-4 (53.0 mg, 218 μmol) and zinc chloride (132 mg, 969 μmol), and stir the reaction solution at 80 ° C for 12 hours under nitrogen protection. Add sodium cyanoborohydride (121 mg, 1.94 mmol) and continue stirring for 72 hours. Add water (5.0 mL) to quench the reaction, extract with ethyl acetate (30.0 mL × 1), wash the combined organic phases with water (75.0 mL × 2) and saturated brine (75.0 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the organic phase under reduced pressure. The crude product is separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 10:1) to obtain compound 1-6.

[0205] MS-ESI[M+H] + , calculated value 640, measured value 640.

[0206] 1 H NMR (400MHz, CDCl3) δ7.98-8.14(m,1H),7.27-7.34(m,2H),7.11-7.20(m,1 H),7.00-7.10(m,1H),3.58-3.97(m,5H),3.39-3.57(m,3H),3.05-3.33(m, 4H),2.57-2.91(m,5H),2.07-2.42(m,2H),1.73(s,4H),1.43-1.47(m,9H), 1.23-1.30(m,2H),1.11-1.20(m,6H),1.02-1.08(m,3H),0.81-1.01(m,6H).

[0207] (5) Add dioxane hydrochloride (4 mol / L, 1.50 mL) to a solution of compound 1-6 (60.0 mg, 93.7 μmol) in dichloromethane (6.0 mL), and stir the reaction mixture under nitrogen at 25°C for 1 hour. Filter the reaction mixture and concentrate under reduced pressure to obtain the hydrochloride of compound 1-7.

[0208] MS-ESI[M+H] + , calculated value 540, measured value 540.

[0209] 1H NMR (400MHz, CDCl3) δ8.40-8.50(m,1H),7.52-7.66(m,1H),7.36-7.45(m,1H) ),6.91-7.33(m,2H),3.89-4.19(m,4H),3.68-3.87(m,3H),3.54-3.64(m,1H) ,3.34-3.51(m,3H),3.00-3.19(m,3H),2.72-2.76(m,3H),2.45-2.65(m,2H) ,2.25-2.41(m,1H),1.72-2.06(m,5H),1.17-1.27(m,6H),1.03-1.16(m,9H).

[0210] (6) Potassium carbonate (51.0 mg, 369 μmol) was added to a solution of compound 1-7 (35.0 mg, 64.8 μmol) in N,N-dimethylformamide (3.0 mL) at 0°C. Compound 1-8 (16.7 mg, 120 μmol, 11.3 μL) was then added, and the reaction solution was stirred at 50°C for 5 hours under nitrogen protection. The reaction solution was filtered and concentrated under reduced pressure. The crude product was separated by high performance liquid chromatography (Xtimate C18, 150 mm × 40 mm 10 μm, A: water (ammonium bicarbonate); B: acetonitrile, 44%-84%: 25 minutes) to obtain compound 1.

[0211] MS-ESI[M+H] + , calculated value 598, measured value 598.

[0212] 1H NMR (400MHz, MeOD) δ7.94-8.01(m,1H),7.41-7.53(m,1H),7.31(td,J=8.4,2.4Hz,1H),7.19(dd,J=8 .4,2.8Hz,1H),7.04-7.12(m,1H),5.43-5.58(m,1H),3.68-3.85(m,3H),3.46-3.60(m,5H),3.23(br dd,J=14.0,7.2Hz,1H),3.08-3.19(m,1H),2.92-3.03(m,1H),2.73-2.85(m,2H),2.49-2.64(m,3H),2.39-2.48(m,2H),2.28(s, 3H),2.07-2.23(m,2H),1.80-2.01(m,2H),1.50-1.69(m,2H),1.37-1.48(m,2H),1.20-1.32(m,2H),1.11-1.19(m,5H),1.05(br t,J=7.2Hz,1H),0.94(br t,J=7.6Hz,9H).

[0213] Test example

[0214] Determination of the antiproliferative effect of compounds on MV-4-11 cells (CTG method):

[0215] 1. Experimental principle: MV-4-11 is a human leukemia cell line with MLL translocation and expressing MLL fusion protein MLL-AF4. The compounds involved in the present invention inhibit the proliferation of MV-4-11 by interfering with menin / MLL protein / protein interaction.

[0216] 2. Experimental materials: CellTiter-Glo was purchased from Promega (catalog number #G7571); IMDM medium was purchased from Gibco (catalog number #12440061); fetal bovine serum was purchased from Excell (catalog number #FND500); dimethyl sulfoxide (DMSO) was purchased from Sigma (catalog number #D2650); 384-well cell culture plates were purchased from Corning (catalog number #3756); automatic cell counter was purchased from Life technologies (model Countess II); microplate reader was purchased from PerkinElmer (model EnVision Multilabel Reader).

[0217] 3. Experimental method: Resuspend cells in logarithmic growth phase in growth medium (IMDM + 10% FBS) and dilute to target density (50000 / mL). Inoculate 50 μL of the cell suspension into 384-well plates per well; incubate overnight in a 37°C, 5% CO2 incubator.

[0218] Dissolve the compound to be tested in DMSO and prepare a stock solution with a concentration of 10mM. First dilute the stock solution to 2mmol / L with DMSO, then dilute it 3 times in a gradient, for a total of 10 concentrations. Take 5.5μL of the above solution of each concentration and dilute it with 94.5μL of growth medium. Then add 5μL / well to the 384-well plate inoculated with cells.

[0219] The cells with the test compound were placed in a 37°C, 5% CO2 incubator for 72 hours. The 384-well plate was balanced at room temperature, 15 μL CellTiter-Glo reagent was added to each well, mixed on a vortex for 2 minutes, incubated at room temperature for 60 minutes, and the luminescence value was read by EnVision Multilabel Reader. The IC value of the compound was calculated using GraphPad Prism 5.0 software. 50 .

[0220] 4. Experimental data:

[0221] The specific test results are shown in Table 1:

[0222] Table 1

[0223] Test compound <![CDATA[MV4-11IC 50 (nM)]]> Example 1 61.42

[0224] It can be seen from the test data in Table 1 that the compound of formula I of the present invention has a good inhibitory effect on the growth of human myelomonocytic leukemia MV-4-11 cells and has the potential to be used in the preparation of drugs for the treatment and prevention of leukemia.

[0225] The applicant declares that the present invention illustrates the compounds, pharmaceutical compositions containing the compounds and their applications through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

[0226] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form or combination thereof, characterized in that: The compound has a structure as shown in Formula I: in, R 1 Selected from the group consisting of: -C(O)(NR a R b ), phenyl and 5-6 membered heteroaryl; wherein the phenyl or heteroaryl may be optionally replaced by R 1a replace; R a and R b Each is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted 3-8 membered cycloalkyl or optionally substituted 4-8 membered heterocyclyl; or R a With R b and the N atoms connected to them together form an optionally substituted 4-8 membered heterocyclic ring; wherein, in addition to the connected N atoms, the heterocyclic ring further comprises 0-2 heteroatoms selected from N, O, S and P; wherein the substitution means that H in the group is replaced by one or more R; Each R 1a Independently selected from the group consisting of H, cyano, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, halogenated C1-C3 alkoxy, and C3-C5 cycloalkyl; R 2 Selected from the group consisting of H, halogen, methyl and trifluoromethyl; R 3 represents 0, 1, 2 or 3 groups each independently selected from the group consisting of H, halogen, C1-C3 alkyl, and halogenated C1-C3 alkyl; R 4 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, optionally substituted (C1-C4 alkyl)2amino, halogen, -NH2, -NO2, -COOH, -CN, -OH, optionally substituted C1-C6 alkylsulfone, optionally substituted C1-C6 alkylsulfoxide, optionally substituted C1-C6 alkylthio, -NHCOCR 4a =CH2, -NHCOCHR 4a R 4b 、-SO2C(R 4a )=CH2、-NHSO2CR 4a =CH2 or -NHSO2CHR 4a R 4b ; Among them, R 4a are each independently selected from the group consisting of H, methyl and fluoro; R 4b are each independently a chlorine or bromine atom; wherein the substitution means that the H in the group is replaced by one or more (such as 1, 2 or 3) R; X 1 and X 2 Each independently selected from N or CR X ; Among them, R X Selected from the following group: H, halogen, -CN, -OH, -NH2, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 alkylamino, and optionally substituted (C1-C4 alkyl)2amino; wherein the substitution means that H in the group is replaced by one or more R; Ring B is a 4-12 membered saturated or partially saturated nitrogen-containing heterocyclic ring; wherein the nitrogen-containing heterocyclic ring may be optionally replaced by R B Substitution, the nitrogen-containing heterocycle includes at least one N atom and 0-2 heteroatoms selected from N, O and S; Each R B Independently selected from the group consisting of deuterium, halogen, oxo, C1-C3 alkyl, halogenated C1-C3 alkyl or cyano; L 1 Select from: absence (i.e. single bond), -(CR La R Lb )-、-(CR La R Lb )2-; where R La and R Lb are independently selected from the group consisting of H, deuterium, optionally substituted C1-C4 alkyl and halogen, or R La and R Lb and the carbon atoms connected to them together form an optionally substituted 3-8 membered saturated or unsaturated carbon alkyl group, an optionally substituted 4-8 membered saturated or unsaturated heterocyclic group; wherein the heterocyclic ring contains 1-3 heteroatoms selected from N, O, S, and P; R 5 Selected from the following group: optionally substituted C1-C4 alkyl, optionally substituted 3-8 membered saturated or unsaturated carbon alkyl, optionally substituted 4-8 membered saturated or unsaturated heterocyclic group; wherein the heterocyclic ring contains 1-3 heteroatoms selected from N, O, S, and P; wherein the substitution refers to substitution by one or more R; Y is selected from: -C1-C6 alkylene-NR Y1 R Y2 、-3-6 membered cycloalkylene-NR Y1 R Y2 , an optionally substituted 4-8 membered heterocyclic group; wherein the substitution refers to substitution by one or more R; R Y1 Selected from the following group: H, C1-C4 alkyl; wherein the alkyl is optionally further substituted by one or more substituents selected from the following: halogen, hydroxyl, C1-C4 alkoxy and cyano; R Y2 For -L 2 -R Y3 ; where L 2 Selected from: absent and C1-C6 alkylene; R Y3 Selected from the following group: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, optionally substituted saturated or unsaturated 3-8 membered carbocyclic group, or optionally substituted saturated or unsaturated 4-12 membered heterocyclic group; wherein, the substitution refers to substitution by one or more R; or R Y1 With R Y2 and the N atoms connected to them together form an optionally substituted 4-10-membered nitrogen-containing heterocyclic ring; the nitrogen-containing heterocyclic ring includes at least one N atom and 0-2 heteroatoms selected from N, O and S, wherein the substitution refers to the replacement of H in the group by one or more R; Each R is independently selected from the group consisting of deuterium, halogen, -OH, oxo, mercapto, cyano, -CD3, -C1-C6 alkyl, methylene, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 6-10 membered aryl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl, 6-10 membered aryl-C1-C6 alkylene-, 5-10 membered heteroaryl-C1-C6 alkylene-, C3-C8 cycloalkyl-C1-C6 alkylene-, 4-12 membered heterocyclyl-C1-C6 alkylene-, C1-C6 haloalkyl-, -OC1-C6 alkyl, -OC2-C6 alkenyl, C3-C8 cycloalkyl-O-, 4-12 membered heterocyclyl-O-, 6-10 -C1-C6 alkyl-NH2, -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkylphenyl), -NH(C1-C6 alkylphenyl), -N(C1-C6 alkyl)(6-10 membered aryl), -NH(6-10 membered aryl), nitro, -C(O)-OH, -C(O)OC1-C6 alkyl, -CONR i R ii , -NHC(O)(C1-C6 alkyl), -NHC(O)(phenyl), -N(C1-C6 alkyl)C(O)(C1-C6 alkyl), -N(C1-C6 alkyl)C(O)(phenyl), -C(O)C1-C6 alkyl, 5-10 membered heteroaryl C(O)-, -C(O)C1-C6 alkylphenyl, -C(O)C1-C6 haloalkyl, -OC(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl, -S(O)-C1-C6 -S(O)2-phenyl, -S(O)2-C1-C6 haloalkyl, -S(O)2NH2, -S(O)2NH(C1-C6 alkyl), -S(O)2NH(phenyl), -NHS(O)2(C1-C6 alkyl), -NHS(O)2(phenyl) and -NHS(O)2(C1-C6 haloalkyl); wherein each hydrogen in the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, aryl, heterocyclyl and heteroaryl is optionally replaced by one or more selected from the following Substituents further substituted: halogen, -OH, oxo (=O), -NH2, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C1-C4 alkyl, C1-C4 haloalkyl-, -OC1-C4 alkyl, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, cyano, nitro, -C(O)-OH, -C(O)OC1-C6 alkyl, -CON(C1-C6 alkyl)2, -CONH(C1-C6 alkyl) -C6 alkyl), -CONH2, -NHC(O)(C1-C6 alkyl), -NH(C1-C6 alkyl)C(O)(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2(phenyl), -SO2(C1-C6 haloalkyl), -SO2NH2, -SO2NH(C1-C6 alkyl), -SO2NH(phenyl), -NHSO2(C1-C6 alkyl), -NHSO2(phenyl) and -NHSO2(C1-C6 haloalkyl); R i and R ii Each is independently H, deuterium or C1-C6 alkyl.

2. The compound as claimed in claim 1, characterized in that R 1 Selected from the group consisting of: -C(O)(NR a R b ) and a 5-6 membered heteroaryl; wherein the heteroaryl is optionally replaced by R 1a replace; R a and R b Each is independently selected from the following group: H, optionally substituted C1-C6 alkyl, optionally substituted 3-8 membered cycloalkyl; Each R 1a Independently selected from the group consisting of H, cyano, halogen, C1-C3 alkyl, halogenated C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy and C3-C5 cycloalkyl.

3. The compound as claimed in claim 1, characterized in that Ring B is selected from the group shown below: Wherein, the B ring is optionally R B Replace; each R B are independently deuterium, halogen, oxo, C1-C3 alkyl, halogenated C1-C3 alkyl or cyano.

4. The compound according to claim 1, characterized in that X 1 N; X 2 It is N or CH.

5. The compound according to claim 1, characterized in that Y is selected from: -C1-C6 alkylene-NR Y1 R Y2 、-3-6 membered cycloalkylene-NR Y1 R Y2 ; R Y1 Selected from the following group: H, C1-C4 alkyl; wherein the alkyl is optionally further substituted by one or more substituents selected from the following: halogen, hydroxyl, C1-C4 alkoxy and cyano; R Y2 For -L 2 -R Y3 ; where L 2 Selected from: absent and C1-C6 alkylene; R Y3 Selected from the following group: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, optionally substituted saturated or unsaturated 3-6-membered carbocyclic group, or optionally substituted saturated or unsaturated 4-6-membered heterocyclic group; wherein the substitution refers to substitution by one or more R; or R Y1 With R Y2 and the N atoms connected to them together form an optionally substituted 4-9 membered nitrogen-containing heterocyclic ring; the nitrogen-containing heterocyclic ring includes at least one N atom and 0-2 heteroatoms selected from N and O, wherein the substitution means that the H in the group is replaced by one or more R; Preferably, Y is selected from: -C1-C4 alkylene-NR Y1 R Y2 、-3-6 membered cycloalkylene-NR Y1 R Y2 ; R Y1 Selected from the following group: H, C1-C4 alkyl; wherein the alkyl is optionally further substituted by one or more substituents selected from the following: halogen, hydroxyl, C1-C4 alkoxy and cyano; R Y2 For -L 2 -R Y3 ; where L 2 Selected from: absent and C1-C4 alkylene; R Y3 Selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy; or R Y1 With R Y2 and the N atoms connected to them together form an optionally substituted 4-10 membered nitrogen-containing heterocycle; the nitrogen-containing heterocycle includes at least one N atom and 0-2 heteroatoms selected from N and O, wherein the substitution means that the H in the group is replaced by one or more R, and R is as described in claim 1.

6. The compound according to claim 1, characterized in that L 1 Does not exist; R 5 for Y is Wherein, n is selected from: 0, 1, 2; m is selected from 1, 2; Among them, R Y1 Selected from the following group: H, C1-C4 alkyl; wherein the alkyl is optionally further substituted by one or more substituents selected from the following: halogen, hydroxyl, C1-C4 alkoxy and cyano; R Y2 For -L 2 -R Y3 ; where L 2 Selected from: absent and C1-C4 alkylene; R Y3 Selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy; or R Y1 With R Y2 When the N atom to which they are connected together forms an optionally substituted 4-10-membered nitrogen-containing heterocycle, the 4-10-membered nitrogen-containing heterocycle is selected from the following group: The substitution refers to that H in the group is replaced by one or more R, and R is as described in claim 1.

7. The compound according to claim 1, characterized in that The compound is selected from Table A: Table A 8. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises a safe and effective amount of one or more compounds according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier.

9. Use of the compound according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8, characterized in that: The use is selected from any one or more of the following (a)-(c): (a) preparing a drug for preventing or treating a disease associated with the activity of MLL1, MLL2, MLL fusion protein, and / or menin protein; (b) preparing inhibitors related to the activity of MLL1, MLL2, MLL fusion protein, and / or menin protein for non-therapeutic use in vitro; (c) Preparation of proliferation inhibitors for non-therapeutic tumor cells in vitro.

10. The use according to claim 9, characterized in that The diseases related to the activity of MLL1, MLL2, MLL fusion protein, and / or menin protein are selected from the following groups: tumors, diabetes and other diseases related to the activity of MLL1, MLL2, MLL fusion protein, and / or menin protein; wherein the tumor is selected from the following group: leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdoid tumor, synovial sarcoma, colorectal cancer, endometrioma, gastric cancer, liver cancer, kidney cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, glioma, bile duct cancer, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer, and other diseases are selected from the following group: autoimmune diseases and non-alcoholic hepatitis.

Images