Compound, pharmaceutical composition comprising same, and use thereof

Abstract

Provided are a compound, a pharmaceutical composition comprising same, and a use thereof. The compound has a structure as shown in formula I, wherein substituents are as described in the description. The compound can interfere with the interaction between a Menin protein and an MLL1 or MLL2 or MLL-fusion oncoprotein, and is expected to become a drug for treating tumors, diabetes and other diseases depending on the activity of MLL1, MLL2, and MLL fusion proteins and / or Menin proteins.

Description

A compound, pharmaceutical composition and application thereof 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 a crucial role in gene transcription regulation. In most acute leukemias, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and mixed-lineage leukemia, the MLL gene, located on chromosome 11, q23, frequently undergoes translocation, forming MLL fusion (MLL-r) proteins with one of approximately 80 proteins (e.g., AF4, AF9, ENL, AF10, ELL, AF6, AF1p, GAS7, etc.). MLL-r proteins retain approximately the N-terminal 1400 amino acid sequence of MLL but lack the C-terminal methyltransferase domain. They can dysregulate the transcription of various oncogenes, including HOX and MEIS1, promoting cell proliferation and ultimately leading to 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, encoded by the Multiple Endocrine Neoplasia (MEN) gene, is a ubiquitously expressed nuclear protein that interacts with DNA replication and repair proteins, chromatin modifiers, and multiple transcription factors. Menin binds to the N-terminus of MLL proteins, including MLL1, MLL2, and MLL-r, and this binding is essential for the oncogenic activity of MLL proteins. Interference with the interaction between menin and MLL-r proteins can selectively inhibit the proliferation of MLL-r leukemia cells in vitro and in vivo.

[0004] Certain genetic abnormalities or mutations, such as nucleoporin 98 (NUP98) gene fusions, nucleophosmin (NPM1) gene mutations, DNA methyltransferase 3A (DNMT3A) mutations, and MLL gene amplification, are often associated with elevated HOX gene expression. In Ewing sarcoma, HOXD genes, particularly HOXD13, are abnormally overexpressed, accompanied by elevated levels of meinin and MLL1 proteins. HOXD13 is a downstream gene regulated by both menin and MLL1.

[0005] In addition, hERG potassium channels are crucial for the normal electrical activity of the heart. Inhibition of hERG can lead to QT interval prolongation, a fatal arrhythmia. This side effect is a common cause of drug failure in preclinical safety trials, and compounds that reduce the binding of targeted hERG 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. 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 pyrimidopyridazine nuclei that interfere with the interaction between menin and MLL proteins, such as the compound in Example 3. However, this compound has poor in vivo metabolic properties, poor in vitro and in vivo activity, and has a strong inhibitory effect on hERG ion channels.

[0007] After two cycles of treatment with the clinically investigated drug SNDX5613, nearly 40% of patients developed point mutation resistance, and the activity of most menin inhibitors against mutant strains was significantly reduced (Perner et al., Nature, 03 / 2023).

[0008] Therefore, there is an urgent need to develop small molecule compounds that can interfere with the interaction between menin and MLL proteins, have stronger in vitro and in vivo activity, are equally effective against mutant strains, and do not inhibit 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.

[0009] Summary of the Invention

[0010] The purpose of the present invention is to provide compounds that can interfere with the interaction between menin and MLL protein.

[0011] 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 form, or combination thereof, wherein the compound has a structure as shown in Formula I:

[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 b are each 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 nitrogen atoms to which they are attached together form an optionally substituted 4-8 membered heterocyclic ring; wherein, in addition to the nitrogen atom to which they are attached, 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, halo-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, halo-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 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 1and X 2 Each independently selected from N or CR X ; Among them, R X Selected from the group consisting of 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 refers to the replacement of H in the group 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 to which they are attached 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 Y1Selected from the group consisting of: H, C1-C4 alkyl; wherein the alkyl is optionally further substituted with one or more substituents selected from the group consisting of: halogen, hydroxy, C1-C4 alkoxy, and cyano;

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

[0027] or R Y1 With R Y2 and the nitrogen atoms connected thereto together form an optionally substituted 4-10 membered nitrogen-containing heterocyclic ring; the nitrogen-containing heterocyclic ring includes at least one nitrogen 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, methanyl, 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 membered aryl-O-, 5-10 membered heteroaryl-O-, -OC1-C6 alkylphenyl, -C1-C6 alkyl-OH, -C1-C6 alkyl-SH, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 haloalkyl, -NH2, -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 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 each hydrogen in the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, aryl, heterocyclyl and heteroaryl groups 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 5-6 membered heteroaryl; wherein said heteroaryl is optionally replaced by R 1a replace;

[0031] R a and R b Each is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and 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 5-6 membered heteroaryl; wherein said heteroaryl is optionally replaced by R 1a replace;

[0034] R a and R b Each is independently selected from the group consisting of 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 Selected from the group consisting of H, halogen, methyl and trifluoromethyl, preferably, R 2 Selected from the following group: 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] wherein the B ring is optionally replaced by R B Replace; each R B are independently deuterium, halogen, oxo, C1-C3 alkyl, halo-C1-C3 alkyl or cyano.

[0046] 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.

[0047] In another preferred embodiment, the B ring is selected from the following group: wherein the B ring is optionally replaced by R B Replace; each R B are independently deuterium, halogen, oxo, C1-C3 alkyl, halo-C1-C3 alkyl or cyano.

[0048] 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, and C1-C3 alkyl.

[0049] 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, and C1-C3 alkyl.

[0050] In another preferred embodiment, Ring B is unsubstituted.

[0051] In another preferred embodiment, ring B is selected from

[0052] In another preferred embodiment, L 1Selected 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.

[0053] In another preferred embodiment, L 1 Does not exist.

[0054] In another preferred embodiment, R 5 Selected from the group consisting of C1-C4 alkyl.

[0055] In another preferred embodiment, R 5 Selected from isopropyl.

[0056] 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.

[0057] In another preferred embodiment, X 1 and X 2 are each independently selected from N.

[0058] In another preferred embodiment, X 1 N; X 2 is N or CH.

[0059] In another preferred embodiment, Y is selected from: -C1-C6 alkylene-NR Y1 R Y2 、-3-6 membered cycloalkylene-NR Y1 R Y2 ;

[0060] R Y1 Selected from the group consisting of: H, C1-C4 alkyl; wherein the alkyl is optionally further substituted with one or more substituents selected from the group consisting of: halogen, hydroxy, C1-C4 alkoxy, and cyano;

[0061] R Y2 -L 2 -R Y3 ; where L 2 Selected from: absent and C1-C6 alkylene; R Y3Selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, optionally substituted saturated or unsaturated 3-6 membered carbocyclyl, or optionally substituted saturated or unsaturated 4-6 membered heterocyclyl; wherein the substitution refers to substitution by one or more R;

[0062] 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.

[0063] In another preferred embodiment, Y is selected from: -C1-C4 alkylene-NR Y1 R Y2 、-3-6 membered cycloalkylene-NR Y1 R Y2 ;

[0064] R Y1 Selected from the group consisting of: H, C1-C4 alkyl; wherein the alkyl is optionally further substituted with one or more substituents selected from the group consisting of: halogen, hydroxy, C1-C4 alkoxy, and cyano;

[0065] R Y2 -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;

[0066] 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.

[0067] In another preferred embodiment, the nitrogen-containing heterocycle is a monocyclic, fused, bridged or spirocyclic ring.

[0068] In another preferred embodiment, the nitrogen-containing heterocycle is unsubstituted.

[0069] In another preferred embodiment, R Y1 Selected from methyl.

[0070] In another preferred embodiment, L 2 is selected from: absent and C1-C6 alkylene; preferably absent or ethylene.

[0071] 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, and methoxy.

[0072] In another preferred embodiment, L 1 Does not exist; R 5 for

[0073] Y is Wherein, n is selected from: 0, 1, 2; m is selected from: 1, 2;

[0074] R Y1 and R Y2 As defined in the first aspect of the present invention.

[0075] In another preferred embodiment,

[0076] When R Y1 With R Y2 and the nitrogen atoms to which they are connected together form an optionally substituted 4-10 membered nitrogen-containing heterocyclic ring, wherein the 4-10 membered heterocyclic ring is selected from the following group:

[0077] 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.

[0078] In another preferred embodiment, the compound is selected from Table A:

[0079] Table A

[0080] In another preferred embodiment, the compound is selected from Table B:

[0081] Table B

[0082] 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.

[0083] In another preferred embodiment, in the composition, the compound accounts for 0.001-99.999 wt% of the total weight of the composition; preferably 0.01-99.99 wt%; more preferably 0.1-90 wt%.

[0084] In another preferred embodiment, the pharmaceutical composition is in the form of an injection, tablet, capsule, pill, suspension or emulsion.

[0085] 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):

[0086] (a) preparing a medicament for preventing or treating a disease associated with the activity of MLL1, MLL2, MLL fusion protein, and / or menin protein;

[0087] (b) preparing inhibitors related to the activity of MLL1, MLL2, MLL fusion protein, and / or menin protein for non-therapeutic use in vitro;

[0088] (c) Preparation of proliferation inhibitors for non-therapeutic tumor cells in vitro.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] In another preferred embodiment, the pharmaceutical composition further comprises other therapeutic agents.

[0093] In another preferred embodiment, the other therapeutic agent is other anti-tumor drugs.

[0094] 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.

[0095] 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 described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0096] The inventors of the present invention have obtained a new class of compounds that interfere with the interaction between menin and MLL proteins through rational design and comprehensive consideration of the target-related activity of the compounds, the inhibitory activity on the hERG channel, and the pharmacokinetic properties. This type of compound shows good MV-411 cell proliferation inhibitory activity, a significant decrease in hERG inhibitory activity, and 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.

[0097] the term

[0098] 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.

[0099] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0100] 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 invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0101] It should be understood that when a group is present at multiple different positions in a compound, its definition at each position is independent of each other and may be the same or different. That is, the term "selected from the group:" has the same meaning as the term "independently selected from the group:".

[0102] Unless otherwise specified, the structural formulas described herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformers)): for example, R and S configurations containing asymmetric centers, (Z) and (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 conformers) are all within the scope of the present invention.

[0103] The compounds of the present application can be prepared by a variety of synthetic 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 replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0104] Group Definition

[0105] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy and pharmacological methods, are used. Unless otherwise specified, the terms used herein in the descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceuticals and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for use of the kit can be utilized, or reactions and purifications can be carried out in accordance with methods well known in the art or the description of the present invention. The above techniques and methods can generally be implemented according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0106] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0107] The section headings used herein are for organizational purposes only and should not be construed 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, manuals, and papers, are incorporated herein by reference in their entirety.

[0108] Certain chemical groups defined herein are preceded by a simplified notation 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 notation does not include carbons that may be present in substituents of the group.

[0109] In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0110] Unless otherwise indicated, 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 hydroxy (-OH) group; "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 of the amino group are replaced by an alkyl group as defined below (e.g., -NH(CH3) or -N(CH3)2); "alkylsulfonyl" refers to an -SO2-alkyl group; "alkylsulfoxide" refers to an -SO-alkyl group; and "carboxyl" refers to -COOH.

[0111] "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, alkylamido, arylalkylamino, heteroarylalkylamino.

[0112] In the present application, the term "alkyl" as a separate group or as part of another group (for example, as used in a group such as a halogen-substituted alkyl group) refers to a fully saturated straight or branched hydrocarbon chain radical consisting solely 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, including, 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. For the purposes of the present invention, the term "alkyl" preferably refers to an alkyl group containing 1 to 6 carbon atoms.

[0113] In this application, the term "alkenyl" as a separate group or as part of another group 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.

[0114] As used herein, the term "alkynyl" as a separate group or as part of another group 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.

[0115] In the present application, the term "carbocycle" as a separate group or as part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group 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 specified in this specification, the carbon atoms in the carbocycle group 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, 5,6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl, 1,2,3,4-tetrahydro-naphthyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, 1H-indenyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocyclohepten-5, 1,2,3,4-tetrahydro-naphthyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, 1H-indenyl, 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.

[0116] In the present application, as a separate group or as part of another group, the term "heterocycle" 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 to the rest of the molecule is a non-aromatic ring atom. For the purposes 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, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimido, and the like.

[0117] In this 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, an aryl group can be a monocyclic, bicyclic, tricyclic or higher ring system, and can also be fused to a carbocyclic or heterocyclic group as defined above, provided that the aryl group is connected to the rest of the molecule through one or more single bonds via atoms on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like.

[0118] In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted by an aryl group as defined above.

[0119] In this application, the term "heteroaryl" as a separate group or as part of another group means a 5- to 16-membered conjugated ring system 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, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or higher 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 in 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 purposes 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.

[0120] As used herein, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above.

[0121] In this 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".

[0122] 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.

[0123] In this application, in Indicates the attachment position of the group R.

[0124] In this application, unless otherwise indicated, "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted aryl" means that hydrogen atoms on the aryl group may or may not be substituted, and the description includes both substituted and unsubstituted aryl groups. 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, for example 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 aryl -C1-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)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 heteroaryl, 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 "moiety," "structural moiety," "chemical moiety," "group," and "chemical group" refer to a specific fragment or functional group in a molecule. A chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule.

[0125] In the present invention, (C1-C4 alkyl)2amino represents two identical or different C1-C4 alkyl-substituted amines, for example, wait.

[0126] Unless otherwise specified, "a plurality" herein means 2, 3 or 4.

[0127] Active ingredient

[0128] As used herein, "compound of the present invention" or "active ingredient" refers to the compound represented by Formula I, and also includes pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, cis-trans isomers, solvates, polymorphs, deuterated forms, or combinations thereof.

[0129] "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.

[0130] 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.

[0131] "Tautomers" refer to isomers 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.

[0132] The compounds of the present invention, or pharmaceutically acceptable salts thereof, 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.

[0133] 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.

[0134] In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0135] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without the side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, and naphthalene disulfonate. These salts can be prepared by methods known in the art.

[0136] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. The salt derived from organic base includes but is not limited to following salt: primary amines, secondary amines and tertiary amines, substituted amines, comprise natural substituted amines, cyclic amines and basic ion exchange resins, for example ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidines, N-ethylpiperidine, polyamine resins etc.Preferred organic base comprises isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.These salts can be prepared by methods known to the profession.

[0137] 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 combinations can be easily performed by those skilled in the art to which the present invention belongs.

[0138] 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.

[0139] Pharmaceutical compositions and methods of administration

[0140] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of one or more compounds of the present invention or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof.

[0141] 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.

[0142] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0143] As used herein, a "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, thereby facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0144] As used herein, the term "pharmaceutically acceptable" 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 an adverse biological response or interacting in an adverse manner with any components contained in the composition.

[0145] In this application, "pharmaceutically acceptable carrier" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.

[0146] 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 rhabdomyoma, 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.

[0147] 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.

[0148] As used herein, the terms "prophylactic," "prevention," and "preventing" include reducing the likelihood of a disease or condition occurring or worsening in a patient.

[0149] As used herein, the term "treat," "treat," and other similar synonyms include the following meanings:

[0150] (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;

[0151] (ii) inhibiting the disease or condition, i.e., curbing its development;

[0152] (iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

[0153] (iv) Alleviate the symptoms of the disease or condition.

[0154] As used herein, the terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to an amount of at least one agent or compound that, when administered, is sufficient to provide some relief to one or more symptoms of the disease or condition being treated. The result can be a reduction and / or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system. For example, a therapeutically effective amount is the amount of a composition comprising a compound disclosed herein that provides a clinically significant relief of symptoms. Techniques such as dose escalation studies can be used to determine the effective amount appropriate for any individual case.

[0155] As used herein, the terms "administer," "administer," "dosing," and the like refer to methods by which a compound or composition can be delivered to the 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.

[0156] As used herein, the terms "pharmaceutical combination," "drug combination," "combination therapy," "administration of another therapy," "administration of another therapeutic agent," and the like refer to a pharmaceutical therapy obtained by mixing or combining more than one active ingredient, and include both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that at least one compound described herein and at least one synergistic agent are administered to a patient simultaneously as a single entity or single dosage form. The term "non-fixed combination" means that at least one compound described herein and at least one synergistic agent are administered to a patient simultaneously, in combination, or sequentially at variable intervals as separate entities. This also applies to cocktail therapies, e.g., administration of three or more active ingredients.

[0157] 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 that act on the chemical structure of DNA, such as cisplatin, 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, gefitinib, erlotinib, lapatinib, etc.

[0158] "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 Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0159] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0160] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0161] 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 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.

[0162] Solid dosage forms such as tablets, dragees, 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 opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0163] 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, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0164] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0165] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0166] Compositions for parenteral injection may comprise 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.

[0167] Dosage forms for topical administration of the compounds of this 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.

[0168] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0169] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0170] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0171] Compared with the prior art, the main advantages of the present invention include:

[0172] (1) The present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof;

[0173] (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.

[0174] 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, for which specific conditions are not specified, were 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 according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0175] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0176] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.

[0177] In each embodiment, 1 H NMR was recorded on a BRUKER AVANCE NEO 400 MHz nuclear magnetic resonance instrument, and chemical shifts are expressed in δ (ppm). Liquid chromatography-mass spectrometry (LCMS) was recorded on Shimadzu LC-20AD, SIL-20A, CTO-20AC, SPD-M20A, CBM-20A, or LCMS-2020 mass spectrometers. Preparative HPLC separations were performed using a Gilson 281 liquid chromatograph.

[0178] Example 1

[0179] The synthetic route of compound 1 is as follows:

[0180] (1) To a solution of compound 1-1 (5.00 g, 23.0 mmol) in dichloromethane (80.0 mL) were added ethyldiisopropylamine (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). 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. Aqueous citric acid solution (50.0 mL) was added for washing, and the organic phase was washed with aqueous sodium bicarbonate solution (50.0 mL) and water (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-2.

[0181] MS-ESI[M+H] + , calculated value 261, measured value 261.

[0182] 1 H 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).

[0183] (2) To a solution of compound 1-2 (2.00 g, 7.68 mmol) in tetrahydrofuran (60.0 mL) was added isopropenylmagnesium bromide (1 mol / L, 19.2 mL) at 0°C. The reaction mixture was stirred at 0°C under nitrogen for 1 hour. The mixture was brought to room temperature and the reaction continued for 12 hours. An aqueous ammonium chloride solution (50.0 mL) was added to quench the reaction. The organic phase was extracted with ethyl acetate (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-3.

[0184] MS-ESI[M- t Bu+H] + , calculated value 186, measured value 186.

[0185] 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).

[0186] (3) Palladium on carbon (10%, 200 mg) was added to a solution of compound 1-3 (2.00 g, 8.29 mmol) in methanol (20.0 mL). The reaction mixture was stirred at 25°C for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 0:1) to obtain compound 1-4.

[0187] MS-ESI[M-Boc+H] + , calculated value 144, measured value 144.

[0188] 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).

[0189] (4) To a solution of the hydrochloride of compound 1-5 (100 mg, 242 μmol, synthesis reference patent WO2023078426) in methanol (20.0 mL) was added triethylamine to adjust the pH to 8. 1-4 (53.0 mg, 218 μmol) and zinc chloride (132 mg, 969 μmol) were then added, and the reaction mixture was stirred at 80°C under nitrogen for 12 hours. Sodium cyanoborohydride (121 mg, 1.94 mmol) was added and stirring continued for 72 hours. Water (5.0 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30.0 mL × 1). The combined organic phases were washed with water (75.0 mL × 2) and saturated brine (75.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 10:1) to obtain compound 1-6.

[0190] MS-ESI[M+H] + , calculated value 640, measured value 640.

[0191] 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).

[0192] (5) To a solution of compound 1-6 (60.0 mg, 93.7 μmol) in dichloromethane (6.0 mL) was added dioxane hydrochloride (4 mol / L, 1.50 mL). The reaction mixture was stirred at 25°C under nitrogen for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to obtain the crude hydrochloride salt of compound 1-7.

[0193] MS-ESI[M+H] + , calculated value 540, measured value 540.

[0194] 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).

[0195] (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 mixture was stirred at 50°C under nitrogen for 5 hours. The reaction mixture 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 min) to obtain compound 1.

[0196] MS-ESI[M+H] + , calculated value 598, measured value 598.

[0197] 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).

[0198] Examples 2 and 3

[0199] The synthetic routes of compounds 2 and 3 are as follows:

[0200] (1) Compound 2-1 (21.0 g, synthesis reference patent WO2023078426) was resolved by chiral supercritical fluid chromatography to obtain compound 2-2. Separation conditions: Column model: Chiralpak AD; Column size: 50×4.6 mm ID, 3 μm; Injection volume: 10 μL; Mobile phase: A: carbon dioxide, B: isopropanol (0.05% diethylamine), B%: 5%-40% gradient elution over 1.5 minutes, 40% fixed concentration elution over 1 minute, 5% fixed concentration elution over 0.5 minutes; Detection wavelength: 254 nm; Column temperature: 35°C. Retention time: 1.185 minutes, ee value: 98.56%. MS-ESI [M+H] + , calculated value 513, measured value 513.

[0201] (2) A solution of hydrochloric acid in dioxane (30.0 mL) was added to a solution of compound 2-2 (10.0 g, 19.5 mmol) in dichloromethane (100 mL), and the reaction mixture was stirred at 25°C for 24 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude hydrochloride of compound 2-3. MS-ESI [M+H] + , calculated value 413, measured value 413.

[0202] (3) To a solution of the hydrochloride salt of compound 2-3 (4.30 g, 9.58 mmol) in methanol (80.0 mL) was added triethylamine to adjust the pH to 8. 1-4 (2.80 g, 11.4 mmol) and zinc chloride (5.22 g, 38.3 mmol, 1.80 mL) were then added, and the reaction mixture was stirred at 80°C under nitrogen for 2 hours. Sodium cyanoborohydride (2.41 g, 38.31 mmol) was added, and stirring was continued for 72 hours. Water (50.0 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (300 mL × 1). The organic phases were combined, washed with water (150 mL × 2) and saturated brine (150 mL × 2), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 10:1) to obtain compound 2-4.

[0203] MS-ESI[M+H] + , calculated value 640, measured value 640.

[0204] (4) To a solution of compound 2-4 (2.00 g, 3.13 mmol) in dichloromethane (20.0 mL) was added dioxane hydrochloride (4 mol / L, 10.0 mL). The reaction mixture was stirred at 25°C under nitrogen for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to obtain the crude hydrochloride salt of compound 2-5.

[0205] MS-ESI[M+H] + , calculated value 540, measured value 540.

[0206] (5) Potassium carbonate (3.07 g, 22.2 mmol) was added to a solution of compound 2-5 (2.40 g, 4.45 mmol) in N,N-dimethylformamide (10.0 mL) at 0°C. Compound 1-8 (1.82 g, 9.78 mmol) was then added, and the reaction mixture was stirred at 50°C under nitrogen for 5 hours. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was separated by HPLC (Xtimate C18, 150 mm × 40 mm 10 μm, A: water (ammonium bicarbonate); B: acetonitrile, 44%-84%: 25 min) to obtain compound 2-6.

[0207] MS-ESI[M+H] + , calculated value 598, measured value 598.

[0208] (6) Compound 2-6 (0.45 g) was separated by chiral supercritical fluid chromatography to give compounds 2 and 3. Separation conditions: Column model: Chiralpak IG; Column size: 50 × 4.6 mm ID, 3 μm; Injection volume: 10 μL; Mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 20%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 20% fixed concentration elution for 0.5 minutes; Detection wavelength: 254 nm; Column temperature: 35°C.

[0209] Compound 2: retention time 1.547 minutes, ee value 99.58%. MS-ESI [M+H] + , calculated value 598, measured value 598. 1 H NMR (400MHz, MeOD) δ8.14(s,1H),7.48-7.57(m,1H),7.35(td,J=8.4,2.8Hz,1H),7.12-7.25(m,2H),3.77-4.01(m,5H),3.75(t,J=4.8Hz,3H),3.67(br d,J=13.2Hz,2H),3.46-3.51(m,1H),3.42(s,3H),3.38(br s,2H),3.25-3.29(m,2H),3.08-3.21(m,1H),2.93(s,3H),2.40-2.85(m,2H),2.1 7-2.38(m,2H),1.91-2.10(m,2H),1.76-1.90(m,3H),1.18-1.38(m,3H),1.17(br s,3H),1.00-1.15(m,9H),0.98(br s,1H).

[0210] Compound 3: retention time 1.708 minutes, ee value 98.44%. MS-ESI [M+H] + , calculated value 598, measured value 598. 1H NMR(400MHz,MeOD)δ7.99(s,1H),7.48-7.57(m,1H),7.30-7.35(m,1H),7.10-7.22(m,2H),3.62-3.89(m,3H),3.59(br t,J=5.2Hz,2H),3.40-3.56(m,2H),3.36(s,3H),3.10-3.28(m,2H),2.92-3.02(m,1H),2.88(br s,2H),2.59-2.80(m,3H),2.50(br s,3H),2.27(br d,J=3.9Hz,2H),1.97-2.12(m,3H),1.85-1.95(m,1H),1.57-1.76(m,2H),1.42-1.57(m,2H),1.28-1.35(m,1H),1.10-1.27(m,6H),1.06(br t,J=6.8Hz,1H),0.85-1.02(m,8H).

[0211] Examples 4 and 5

[0212] The synthetic routes of compounds 4 and 5 are as follows:

[0213] (1) Compound 2-1 (21.0 g, synthesis reference patent WO2023078426) was resolved by chiral supercritical fluid chromatography to give compound 4-1. Separation conditions: Column model: Chiralpak AD; Column size: 50×4.6 mm ID, 3 μm; Injection volume: 10 μL; Mobile phase: A: carbon dioxide, B: isopropanol (0.05% diethylamine), B%: 5%-40% gradient elution over 1.5 minutes, 40% fixed concentration elution over 1 minute, 5% fixed concentration elution over 0.5 minutes; Detection wavelength: 254 nm; Column temperature: 35°C. Retention time: 1.411 minutes, ee value: 94.16%. MS-ESI [M+H] + , calculated value 513, measured value 513.

[0214] (2) A solution of hydrochloric acid in dioxane (30.0 mL) was added to a solution of compound 4-1 (10.6 g, 20.6 mmol) in dichloromethane (100 mL), and the reaction mixture was stirred at 25°C for 24 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude hydrochloride of compound 4-2. MS-ESI [M+H] + , calculated value 413, measured value 413.

[0215] (3) To a solution of the hydrochloride of compound 4-2 (10.0 g, 22.2 mmol) in methanol (80.0 mL) was added triethylamine to adjust the pH to 8. 1-4 (6.50 g, 26.7 mmol) and zinc chloride (12.1 g, 89.1 mmol) were then added, and the reaction mixture was stirred at 80°C under nitrogen for 2 hours. Sodium cyanoborohydride (5.60 g, 89.1 mmol) was added, and stirring was continued for 72 hours. Water (50.0 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (300 mL × 1). The organic phases were combined, washed with water (150 mL × 2) and saturated brine (150 mL × 2), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 10:1) to obtain compound 4-3. MS-ESI [M+H] + , calculated value 640, measured value 640.

[0216] (4) Compound 4-3 (13.0 g) was separated by chiral supercritical fluid chromatography to give compounds 4-4 and 5-4. Separation conditions: Column model: Chiralpak AD-3; Column size: 50×4.6 mm ID, 3 μm; Injection volume: 10 μL; Mobile phase: A: carbon dioxide, B: isopropanol (0.05% diethylamine), B%: 5%-40% gradient elution over 1.5 minutes, 40% fixed concentration elution over 1 minute, 5% fixed concentration elution over 0.5 minutes; Detection wavelength: 254 nm; Column temperature: 35°C. Compound 4-4: Retention time 1.034 minutes, ee value 95.00%. MS-ESI [M+H] + , calculated value 640, found value 640. Compound 5-4: retention time 1.105 minutes, ee value 87.90%. MS-ESI [M+H] + , calculated value 640, measured value 640.

[0217] (5) To a solution of compound 4-4 (4.50 g, 7.03 mmol) in dichloromethane (20.0 mL) was added dioxane hydrochloride (4 mol / L, 10.0 mL). The reaction mixture was stirred at 25°C under nitrogen for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to obtain the crude hydrochloride of compound 4-5.

[0218] MS-ESI[M+H] + , calculated value 540, measured value 540.

[0219] (6) Potassium carbonate (3.60 g, 26.0 mmol) was added to a solution of compound 4-5 (3.00 g, 5.21 mmol) in N,N-dimethylformamide (35.0 mL) at 0°C. Compound 1-8 (1.94 g, 10.4 mmol) was then added, and the reaction mixture was stirred at 50°C under nitrogen for 5 hours. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was separated by HPLC (Xtimate C18, 200 mm × 40 mm 10 μm, A: water (formic acid); B: acetonitrile, 0%-24%: 20 min) to obtain compound 4.

[0220] MS-ESI[M+H] + , calculated value 598, measured value 598. 1 H NMR(400MHz,MeOD)δ8.45(br d,J=9.2Hz,1H),7.54-7.68(m,1H),7.22-7.47(m,2H),6.93-7.17(m,1H),5.45-5.70(m,1H),3.60-4.09(m,12H),3.40-3.53(m,7H),3. 12-3.24(m,2H),2.94(d,J=4.0Hz,3H),2.47-2.59(m,2H),2.24-2.40(m,1H),1.98-2.15(m,1H),1.78-1.96(m,3H),1.07-1.27(m,15H).

[0221] (7) Compound 5-4 was used as the raw material and compound 5 was obtained by the same experimental method as (5) and (6): MS-ESI [M+H] + , calculated value 598, measured value 598. 1 H NMR(400MHz,MeOD)δ8.45(d,J=14.4Hz,1H),7.52-7.69(m,1H),7.34-7.46(m,1H) ),7.28(dd,J=8.0,2.8Hz,1H),6.85-7.23(m,1H),5.24-5.76(m,1H),3.92-4.25( m,4H),3.55-3.92(m,7H),3.33-3.55(m,8H),3.09-3.28(m,2H),2.90-2.98(m,3 H),2.47-2.66(m,2H),2.28-2.44(m,1H),1.78-2.13(m,4H),1.06-1.31(m,15H).

[0222] Test Example 1

[0223] Determination of the antiproliferative effect of compounds on MV-4-11 cells (CTG method):

[0224] 1. Experimental Principle: MV-4-11 is a human leukemia cell line that carries an MLL translocation and expresses the MLL fusion protein MLL-AF4. The compounds of this invention inhibit MV-4-11 proliferation by interfering with the menin / MLL protein / protein interaction.

[0225] 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); an automated cell counter was purchased from Life technologies (model Countess II); and a microplate reader was purchased from PerkinElmer (model EnVision Multilabel Reader).

[0226] 3. Experimental Methods: Resuspend cells in logarithmic growth phase in growth medium (IMDM + 10% FBS) and dilute to the target density (50,000 / mL). Plate 50 μL of the cell suspension into each well of a 384-well plate and incubate overnight at 37°C in a 5% CO2 incubator.

[0227] Dissolve the test compound in DMSO to prepare a 10 mM stock solution. First, dilute the stock solution to 2 mmol / L with DMSO. Then, serially dilute the solution three-fold to a total of 10 concentrations. Take 5.5 μL of each concentration and dilute it with 94.5 μL of growth medium. Then, add 5 μL / well to a 384-well plate seeded with cells.

[0228] The cells with the test compound were incubated in a 37°C, 5% CO2 incubator for 72 hours. A 384-well plate was equilibrated at room temperature, and 15 μL of CellTiter-Glo reagent was added to each well. The cells were mixed on a vortex for 2 minutes and incubated at room temperature for 60 minutes. Luminescence values ​​were read using an EnVision Multilabel Reader, and the IC values ​​of the compounds were calculated using GraphPad Prism 5.0 software. 50 .

[0229] 4. Experimental data:

[0230] The specific test results are shown in Table 1:

[0231] Table 1

[0232] Comparative compound 1 is from Example 3 of patent WO2023078426, and its structure is:

[0233] Comparative compound 2 is from Example 4 in patent WO2023078426, and its structure is:

[0234] Comparative compound 3 is from Example 28 of patent WO2023078426, and its structure is:

[0235] Comparative compound 4 is from Example 29 of patent WO2023078426, and its structure is:

[0236] Comparative compound 5 is from Example 39 in patent WO2023078426, and its structure is:

[0237] Comparative compound 6 is from Example 40 in patent WO2023078426, and its structure is:

[0238] The test data in Table 1 show that the compound of formula I of the present invention has a better inhibitory effect on the growth of human myelomonocytic leukemia MV-4-11 cells, which is better than the reported compounds and has the potential to be used in the preparation of drugs for the treatment and prevention of leukemia.

[0239] Test Example 2

[0240] The compound inhibits the proliferation of MV-4-11, Molm-13, OCI-AML-3, and HL-60 cells:

[0241] 1. Principle: MV-4-11, Molm-13, and OCI-AML-3 cells are all human hematologic malignant cell lines harboring Menin-MLL fusions. HL-60 is a wild-type, non-Menin-MLL fusion human hematologic malignant cell line. The compounds described herein inhibit the proliferation of MV-4-11, Molm-13, and OCI-AML-3 cells by non-covalently binding to Menin, but have minimal inhibitory activity against HL-60 cells.

[0242] 2. Experimental materials: MV-4-11, Molm-13, OCI-AML-3, and HL-60 cells were purchased from Kebai; CellTiter-GloR was purchased from Promega (Cat. No. G7571); RPMI-1640 was purchased from Viva cell (Cat. No. C3010-0500); IMDM was purchased from Viva cell (Cat. No. C3040-0500); fetal bovine serum (FBS) was purchased from Biosera (Cat. No. FB-1058 / 500); penicillin-streptomycin was purchased from BasalMedia (Cat. No. S110JV); 0.25% trypsin-ethylenediaminetetraacetic acid digestion solution (Trypsin-EDTA) was purchased from BasalMedia (Cat. No. S310KJ); dimethyl sulfoxide (DMSO) was purchased from Sinopharm (Cat. No. 30072418); 96-well plates were purchased from Corning (Cat. No. 3610); incubator was purchased from PHCbi (Model MCO-18AC); inverted microscope was purchased from Mingmei (Cat. No. MI52-0); automatic cell counter was purchased from BodBoge (Model JSY-SC-031N); microplate reader was purchased from PerkinElmer (Model Envision); data processing software was GraphPad Prism 8.0.

[0243] 3. Experimental Methods: Cells from each of the four logarithmic growth phases were resuspended in growth medium (MV-4-11: IMDM + 20% FBS, Molm-13: RPMI-1640 + 20% FBS, OCI-AML-3: RPMI-1640 + 20% FBS, HL-60: RPMI-1640 + 10% FBS) and diluted to the target density (12,500, 6,250, 12,500, and 12,500 / mL, respectively). 80 μL of the cell suspension was plated per well in a 96-well plate and incubated overnight at 37°C in a 5% CO2 incubator. Culture medium served as a background control. Test compounds were dissolved in DMSO to prepare a 10 mmol / L stock solution. The stock solution was first diluted to 2 mmol / L with DMSO, followed by a 4-fold serial dilution for a total of 10 concentrations. 2 μL of each concentration was diluted with 78 μL of growth medium. Then, 20 μL / well was added to a 96-well plate seeded with cells. The cells with the test compound were incubated in a 37°C, 5% CO2 incubator for 7 days. The 96-well plate was equilibrated at room temperature, and 25 μL of CellTiter-Glo reagent was added to each well. The cells were incubated at room temperature for 10 minutes. Luminescence values ​​were read on an EnVision microplate reader, and the IC values ​​of the compounds were calculated using GraphPad Prism 8.0 software. 50 .

[0244] 4. Experimental data:

[0245] The specific test results are shown in Table 2:

[0246] Table 2

[0247] From the test data in Table 2, it can be seen that the compound represented by Formula I of the present invention has a good inhibitory effect on the growth of leukemia cells, but has little effect on normal cell lines.

[0248] SNDX5613 structure:

[0249] KO539 structure:

[0250] Test Example 3

[0251] Inhibitory effect of compounds on hERG ion channels:

[0252] 1. Experimental purpose: To test the inhibitory effect of the test compound on hERG current in HEK293 cells stably transfected with hERG potassium channel by manual patch clamp.

[0253] 2. Experimental Materials: The test drug was compound 3 prepared in the examples of the present invention; the positive compound SNDX-5613 was purchased from Chengdu Zhihui Zhongxin Biopharmaceutical Co., Ltd.; HEK293 cells were purchased from Procell (catalog number CL-0001). The manual patch clamp system amplifier was purchased from AXON (model Axon MultiClamp 700B); the manual patch clamp system digital-to-analog converter was purchased from Axon (model Axon Digidata 1550B); the electric micromanipulator was purchased from Sutter Instruments (model MP-225); the peristaltic pump was purchased from Lange Company, Baoding, China (model BT100-2J); and the microelectrode puller was purchased from NARISHIGE (model PC-10).

[0254] 3. Experimental methods:

[0255] Preparation of electrophysiological solution:

[0256] Extracellular fluid: 140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2·6H2O, 2 mM CaCl2·2H2O, 10 mM D-Glucose, 10 mM HEPES, 1.25 mM NaH2PO4·2H2O, pH adjusted to 7.4 with NaOH; osmotic pressure adjusted to 290-310 mOsm; stored at 4°C after filtration.

[0257] Electrode solution (mM): 20 mM KCl, 115 mM K-Aspartic, 1 mM MgCl2·6H2O, 5 mM EGTA, 10 mM HEPES, 2 mM Na2-ATP, pH adjusted to 7.2 with KOH; osmotic pressure adjusted to 290-310 mOsm; filter, aliquot, and store at -20°C.

[0258] Cell preparation:

[0259] After subculturing HEK-293-hERG cells to an appropriate state, rinse with phosphate-buffered saline, dissociate with Tryple solution, resuspend the cells in culture medium, and place in a centrifuge tube. After centrifugation, discard the supernatant and resuspend the cells in extracellular medium until ready for use. Store at 2-8°C. Plate the cell suspension onto a cell slide and culture in a 24-well plate / 6cm cell culture dish. After 18 hours, remove the cell slide for patch clamp analysis. Before patch clamp recording, place the cells dropwise into the culture dish to ensure that the cells are at a certain density and are individually isolated.

[0260] Electrophysiological experiments:

[0261] Whole-cell patch clamp techniques were used to record hERG currents. Cell suspensions were placed in small culture dishes on an inverted microscope stage. After the cells adhered, extracellular solution was perfused at a recommended flow rate of 1–2 mL / min. Glass microelectrodes were pulled in two steps using a microelectrode puller. After filling with solution, the resistance in water was 2–5 MΩ.

[0262] After establishing the whole-cell recording mode, the clamping potential was maintained at -80mV. The clamping voltage was depolarized from -80mV to -50mV for 0.5s (as a leak current detection), then stepped to 30mV for 2.5s, and then quickly restored to -50mV for 4s to stimulate the tail current of the hERG channel. Data were collected repeatedly every 16s to observe the effect of the drug on the hERG tail current. A 0.5s stimulation of -50mV was used as a leak current detection. Fluid exchange was performed by perfusion using a peristaltic pump. When the recorded hERG current stabilized, continuous extracellular perfusion from low to high concentrations (0.3, 1, 3, 10 and 30μmol / L) was used. After each drug concentration was completed, the next concentration was tested after at least 5 minutes of action (or when the current stabilized). At least three cells were used for each concentration and the test was repeated three times independently. All electrophysiological experiments were performed at room temperature.

[0263] Data collection and analysis:

[0264] The experimental data were collected by Clampex software and processed and analyzed by Clampfit software. First, the current after each drug concentration was normalized with the blank control current. Then calculate the inhibition rate corresponding to each drug concentration The mean and standard error were calculated for each concentration, and the half-inhibitory concentration (CI) of each compound was calculated using the following equation:

[0265] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0266] The above equation was used to perform nonlinear fitting of the dose-dependent effect, where IC 50 is the half-inhibitory concentration. Curve fitting and IC 50 The calculation of IC was completed using Graphpad Prism software. If the maximum inhibition rate of all concentrations of the test substance was less than 50%, the IC was not calculated. 50 Numeric value.

[0267] Test results: IC of compound 3 50 >30μM, IC of positive compound SNDX-5613 50 =7.59 μM, indicating that compound 3 has a weak inhibitory effect on hERG channels and is superior to SNDX-5613 in terms of cardiac safety.

[0268] Test Example 4

[0269] In vivo efficacy experiment of MV-4-11

[0270] 1. Purpose: To evaluate the in vivo efficacy of the test substance in a female NOD / SCID mouse model with MV-4-11 tumors implanted subcutaneously.

[0271] 2. Experimental Materials: The test drug was compound 3 of Example 3 of the present invention, which was prepared in-house; the positive compound SNDX-5613 was purchased from Chengdu Zhihui Zhongxin Biotechnology Co., Ltd.; MV-4-11 cells were purchased from Nanjing Kebai; and NOD / SCID mice were purchased from Beijing Weitonglihua Biotechnology Co., Ltd.

[0272] 3. Experimental methods:

[0273] NOD / SCID nude mice, female, 6-8 weeks old, weighing 16-22 g. MV-4-11 cells were cultured in IMDM medium containing 20% ​​fetal bovine serum. MV-4-11 cells were collected in the exponential growth phase and resuspended in phosphate buffered saline to a density of 1×10 7 The cell suspension was subcutaneously inoculated on the right side of the neck of each mouse (1×10 7 / mouse) (+50% Matrigel). When the average tumor volume reached about 50-100 mm 3Around 6:00 am, randomized groups were randomly divided and gavage was administered once a day. Tumor diameter was measured with a vernier caliper twice a week. The tumor volume was calculated as: V = 0.5a × b 2 , a and b represent the long diameter and short diameter of the tumor, respectively.

[0274] The experimental results are shown in FIG1 , which show that compound 3 of the present invention exhibits superior therapeutic effect to that of the positive control drug SNDX-5613 in the MV-4-11 tumor subcutaneous transplantation animal model.

[0275] Test Example 5

[0276] Pharmacokinetic properties of the compounds in rats

[0277] 1. Purpose: This study aimed to determine the pharmacokinetic characteristics of some of the compounds of the present invention in SD rats after single intravenous (IV) and oral administration (PO) by LC-MS / MS.

[0278] 2. Experimental Materials: The experimental drugs were homemade compounds of the examples of the present invention; SD male rats were obtained from the Experimental Animal Management Department of Shanghai Institute of Family Planning Science (License No. (SCXK (Shanghai) 2018-0006)) or Shanghai Jihui Experimental Animal Breeding Co., Ltd. (License No.: SCXK (Shanghai) 2022-0009).

[0279] 3. Test method:

[0280] Preparation of 0.5% methylcellulose: Weigh 5g of methylcellulose and dissolve it in 1000mL of purified water.

[0281] Preparation of 0.5% methylcellulose (pH = 5.03): Weigh 5 g of methylcellulose, dissolve it in 1000 mL of purified water, and adjust the pH to 5.03 with 100 mM citric acid.

[0282] Preparation of oral prescriptions:

[0283] Weigh the required amount of the test compound and dissolve it in 0.5% methylcellulose solution or 0.5% methylcellulose (pH = 5.03) to obtain a 1 or 3 mg / mL suspension or solution.

[0284] Preparation of intravenous prescriptions:

[0285] Weigh the required amount of test compound (EB229, EB300, EB341, EB342) and dissolve in 0.5 mL of dimethyl sulfoxide to prepare a 4 mg / mL solution. Add 0.5 mL of polyethylene glycol 15-hydroxystearate (solutol) and 4.25 mL of saline to 0.25 mL of this solution to obtain a 0.2 mg / mL solution.

[0286] Weigh 6 mg of EB834, dissolve it in 0.1 mL of dimethyl sulfoxide, add 0.2 mL of polyethylene glycol 15-hydroxystearate (solutol) and 1.7 mL of normal saline to obtain a 3 mg / mL solution.

[0287] Dosing: Male SD rats were fasted overnight and then administered orally (PO). Fasting was not required for the single intravenous (IV) injection group. The specific experimental design is shown in Table 3 below. Food was consumed 4 hours after dosing.

[0288] Table 3

[0289] Sample Collection: Blood was collected via the jugular vein or other suitable vein, with 0.2 mL collected at each time point. The sample was placed in a tube containing dipotassium ethylenediaminetetraacetic acid and stored on ice until centrifuged. Within 1 hour of collection, the blood sample was centrifuged at 6800 g for 6 minutes at 2-8°C and stored at -80°C. The time points for intravenous and oral administration are shown in the table above. Specific test results are shown in Table 4.

[0290] Table 4

[0291] Comparative compound 7 is from Example 9 in patent WO2023078426, and its structure is:

[0292] Comparative compound 8 is from Example 11 in patent WO2023078426, and its structure is:

[0293] Comparative compound 9 is from Example 12 in patent WO2023078426, and its structure is:

[0294] Comparative compound 10 is from Example 13 in patent WO2023078426, and its structure is:

[0295] The data in Table 4 show that some of the compounds of the present invention have excellent pharmacokinetic properties in rats, which are better than those of reported compounds.

[0296] Test Example 6

[0297] Pharmacokinetic studies in mice

[0298] 1. Purpose: This study aimed to determine the pharmacokinetic characteristics of some of the compounds of the present invention in ICR male mice after single intravenous (IV) and oral administration (PO) by LC-MS / MS.

[0299] 2. Experimental Materials: The experimental drugs were homemade compounds of the examples of the present invention; ICR male mice were obtained from Shanghai Jihui Experimental Animal Breeding Co., Ltd. (License No.: SCXK (Shanghai) 2022-0009).

[0300] 3. Test method:

[0301] Preparation of 0.5% methylcellulose (pH = 4.91): Weigh 5 g of methylcellulose, dissolve it in 1000 mL of purified water, and adjust the pH to 4.91 with 100 mM citric acid.

[0302] Preparation of oral formulations: Weigh the required amount of the compound to be tested and dissolve it in 0.5% methylcellulose (pH = 4.91) solution to obtain a 3 mg / mL suspension or solution.

[0303] Preparation of intravenous injection: Weigh the required amount of the test compound and dissolve it in 0.5 mL of dimethyl sulfoxide to prepare a 12 mg / mL solution. To 0.25 mL of this solution, add 0.5 mL of polyethylene glycol 15-hydroxystearate (solutol) and 4.25 mL of normal saline to obtain a 0.6 mg / mL solution.

[0304] Dosing: ICR male mice were fasted overnight and then administered orally (PO). Fasting was not required for the single intravenous (IV) injection group. Dosage and volume are shown in Table 5 below. Food was consumed 4 hours after administration.

[0305] Table 5

[0306] Sample Collection: Blood samples were collected from the jugular vein or other suitable vein, with 0.03 mL collected at each time point. The sample was placed in a tube containing dipotassium ethylenediaminetetraacetic acid and stored on ice until centrifuged. Within 1 hour of blood collection, the blood sample was centrifuged at 6800 g for 6 minutes at 2-8°C and stored at -80°C. For intravenous administration, blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, and 32 hours post-dose. For oral administration, blood samples were collected at 0.25, 0.5, 1, 2, 4, 8, 24, and 32 hours post-dose.

[0307] The specific test results are shown in Table 6.

[0308] Table 6

[0309] Test Example 7

[0310] Inhibitory effects of compounds on wild-type Menin protein and its mutant proteins

[0311] 1. Purpose of the experiment: To investigate the inhibitory effect of the compound on the activity of Menin wild type protein (Menin-WT) and its mutant proteins (Menin-M327V, Menin-M327I, Menin-T349M, Menin-S160T, Menin-S160C, Menin-G331R and Menin-G331D).

[0312] 2. Experimental Principle: The experiment uses fluorescence polarization (FP) to detect the binding of wild-type Menin and its mutant proteins to the MLL peptide. In the absence of an inhibitor, the binding of wild-type Menin and its mutant proteins to the MLL peptide produces a high FP signal. When an inhibitor is added, the binding of wild-type Menin and its mutant proteins to the MLL peptide is inhibited, resulting in a low FP signal.

[0313] 3. Test materials: Menin wild-type protein and its mutant protein final concentration: 8 nM, MLL peptide final concentration: 4 nM

[0314] Assay buffer: 50 mM Tris-HCl (pH 8.0), 120 mM NaCl, 0.005% CA-630, 2 mM DTT

[0315] 4. Experimental Procedure: Use a 384-well plate and add 10 μL of wild-type menin protein or its mutant protein to each experimental well (except wells A1-H1 and I24-P24). Add 10 μL of assay buffer to wells A1-H1 and I24-P24 as a 100% inhibition control. Centrifuge the plate at 1000 rpm for 60 seconds. Add 10 μL of MLL peptide to each experimental well. Centrifuge the plate at 1000 rpm for 60 seconds and seal the plate with sealing film. Incubate at 23°C for 60 minutes. Read the plate using a Perkin Elmer Envision reader.

[0316] Data Analysis:

[0317] %inhibition=(sampledata-0%inhibition) / (100%inhibition-0%inhibition)*100 Curve fitting: XLFIT software was used for curve fitting, with the logarithm of percent inhibition (complex concentration) as the variable and a four-parameter logistic model was used for fitting. Specific test results are shown in Table 7.

[0318] Table 7

[0319] As shown in the test data in Table 7, the compound of Formula I of the present invention has good inhibitory activity against wild-type and various mutant subtypes of Menin protein. In particular, the inhibitory activity against the major mutant subtypes of Menin protein is superior to that of SNDX5613 and KO539.

[0320] The applicant declares that the present invention illustrates the compounds, pharmaceutical compositions comprising the same, and their uses through the aforementioned examples, but the present invention is not limited to these examples, and does not necessarily rely on these examples for implementation. Those skilled in the art will appreciate that any improvements to the present invention, equivalent substitutions for raw materials in the products of the present invention, addition of auxiliary ingredients, and selection of specific methods, etc., fall within the scope of protection and disclosure of the present invention.

[0321] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

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 Separately is 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 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; 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 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( wherein each hydrogen in the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, aryl, heterocyclyl and heteroaryl radicals is optionally further substituted by one or more substituents selected from the group consisting of 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), -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 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 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; 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.

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