CN114853679A

CN114853679A - Benzimidazole ENL protein inhibitor and preparation method and application thereof

Info

Publication number: CN114853679A
Application number: CN202111642897.4A
Authority: CN
Inventors: 李海涛; 林木; 张士猛; 李小林; 吴奕钦
Original assignee: Qingyao Tongchuang Beijing Drug Research And Development Center Co ltd
Current assignee: Qingyao Tongchuang Beijing Drug Research And Development Center Co ltd
Priority date: 2021-02-04
Filing date: 2021-12-29
Publication date: 2022-08-05
Also published as: WO2022166482A1

Abstract

The invention relates to a benzimidazole ENL inhibitor compound shown in a formula I, and racemate, stereoisomer, tautomer, isotope label, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound, a preparation method thereof and medical application thereof, wherein the structure of the formula I is as follows:

Description

Benzimidazole ENL protein inhibitor and preparation method and application thereof

the present application claims priority to a prior application entitled "an imidazole-based ENL protein inhibitor and methods of making and using the same" filed on 8/2021 by the applicant at the national intellectual property office of china, patent application No. 202110166935.7. The entire content of this prior application is incorporated by reference into this application.

Technical Field

The invention belongs to the field of pharmaceutical compounds, and particularly relates to a benzimidazole ENL protein inhibitor, and a preparation method and application thereof.

Background

Epigenetic modifications play an important role in the development of tumors, and a variety of epigenetic regulatory mechanisms have been discovered, including DNA methylation, histone modification, non-coding RNA regulation, and the like. Covalent modification of histones plays an important role in gene regulation. Common histone modification modes include methylation, acetylation, phosphorylation, ubiquitination, SUMO, and the like. The specific recognition of various different types of histone-modifying proteins or domains within a cell is called a "reader". The "reader" is one of the major modes of epigenetic regulation, and the histone acetylation "reader" that has been found so far mainly comprises a bromodomain, a plant zinc finger homeodomain, and a YEATS domain. Abnormal expression of these domains or proteins containing such domains can lead to the development of a range of diseases, such as cancer, inflammatory diseases, cardiovascular diseases and neurological diseases.

The AF9 protein is an important transcription regulation factor, can form a complex with histone H3K79 methyltransferase DOT1L and a Super Extension Complex (SEC) respectively, and plays an important regulation role in the transcription initiation-extension conversion process. Meanwhile, clinical genetics research shows that the fusion of the AF9 gene and the MLL gene (MLL-AF9) is a driving factor of diseases such as human Acute Myeloid Leukemia (AML) and Acute Lymphatic Leukemia (ALL) and the like as the most common MLL rearrangement type. Further cell biology and functional genomics research shows that human AF 9and H3K9ac are strongly co-localized at the whole genome level and regulate the expression of cell proliferation and differentiation genes including MYC, BMP2 and HOXA gene clusters; research shows that AF9 promotes co-deposition and gene activation of histone H3K79 methylation by recognizing histone H3K9 acetylation modification and recruiting DOTL1 to a specific chromatin segment, and discloses a novel histone modification cross-conversation mechanism which embodies the complexity and precision of eukaryotic epigenetic regulation. The YEATS domain-containing proteins identified in nature are hundreds of and spread over 70 different species, conserved from yeast to humans. Protein factors containing the YEATS structural domain, such as AF9, ENL, GAS41 and the like, are closely related to transcriptional regulation, and the abnormal regulation of the protein factors can cause human diseases such as leukemia, cancer and the like.

Among them, the ENL protein is an important histone acetylation 'reader' epigenetic modification protein, and plays an important role in the process of leukemia. Researches show that various cytomolecular genetics and epigenetic abnormalities including cell surface molecular abnormal expression, gene mutation, gene abnormal methylation and the like exist in the process of the occurrence and development of AML, and ENL plays an important role in the process of leukemia and is a necessary protein in the process of maintaining the occurrence and development of AML, so that the targeted ENL protein is a good drug target for treating AML. In 2017, Nature published the results of two research groups on the ENL protein simultaneously. The ENL protein is proved to be a key factor influencing the survival ability of MLL-r cells of leukemia. The ENL YEATS domain is important for transcriptional control of gene expression causing leukemia (Wan L et al, Nature,2017,543(7644): 265.). Disruption of the interaction of the ENL YEATS domain with histone acetylation, which renders histone acetylation unrecognizable, inhibits the growth of various leukemia cell lines, including MLL-r cell lines and non-MLL-r leukemia cell lines (Wilkinson A W et al, Nature,2017,543(7644): 186-188.). These studies all indicate that the ENL protein is a good drug target. Acute Myeloid Leukemia (AML) is a complex hematological disease characterized by an increase in leukemic blasts in the blood or bone marrow. Is the most common acute leukemia type in adult leukemia, and accounts for about 70 percent of the incidence rate of the adult leukemia. In recent years, the cure rate of AML has been improved with the continuous development of combined chemotherapy, but about 40% of patients do not achieve Complete Remission (CR), and the prognosis of AML is poor, even if CR is achieved, 40-50% of young patients have a 5-year survival, while the average survival of older patients is less than 1 year, and the overall 5-year survival of patients is only 26.9%. Recurrent episodes of AML and chemotherapy resistance remain therapeutic challenges in this field.

Currently, only the inhibitor of bromodomain, namely BET inhibitor, of 3 histone acetylation 'readers' is in an active development state, and no ENL inhibitor enters a clinical stage. Therefore, the development of a novel, active, safer and more effective ENL inhibitor is needed.

Disclosure of Invention

In order to solve the problems in the prior art, the invention provides a compound shown as formula I, and racemate, stereoisomer, tautomer, isotopic marker, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof:

wherein, Ar is ₁ ，Ar ₂ May be the same or different, each being independently selected optionally substituted by one, two or more R _a Substituted with the following groups:

the R is _a Is selected fromH, ═ O, halogen, OH, CN, SH, NH ₂ COOH, or optionally substituted by one, two or more R _b Substituted with the following groups: c ₁ -C ₁₂ An aliphatic hydrocarbon group; the R is _b Selected from halogen, OH, CN, SH, NH ₂ ，COOH；

Said L ₁ 、L ₂ May be the same or different, each independently selected from a bond, or optionally substituted with one, two or more R _L Substituted by

(in:, the attachment site to the moiety of the other group of the general formula is represented by:, and the attachment site to the moiety of the left group of the general formula is represented by:, then the attachment site is represented by:; the R is _L Selected from H, ═ O, halogen, OH, CN, SH, NH ₂ COOH, or optionally substituted by one, two or more R _c Substituted with the following groups: c ₁ -C ₁₂ An aliphatic hydrocarbon group; the R is _c Selected from halogen, OH, CN, SH, NH ₂ ，COOH；

W is selected from (C) ₁ -C ₂₀ ) Aliphatic hydrocarbon radical, optionally containing one, two or more heteroatoms (C) ₁ -C ₂₀ ) An aliphatic hydrocarbon group; said W is optionally substituted with one, two or more R _W Substitution; the R is _W Selected from H, ═ O, halogen, OH, CN, SH, NH ₂ COOH, or optionally substituted by one, two or more R _d Substituted with the following groups: c ₁ -C ₁₂ An aliphatic hydrocarbon group; the R is _d Selected from halogen, OH, CN, SH, NH ₂ ，COOH；

Said R is ₁ 、R ₂ May be the same or different and are each independently selected from-NH-C (═ O) R ₃ ，-(CH ₂ ) _p R ₃ ，(C ₁ -C ₁₂ ) Aliphatic hydrocarbon radical, optionally containing one, two or more heteroatoms (C) ₁ -C ₁₂ ) An aliphatic hydrocarbon group;

said R is ₃ Selected from the group optionally substituted by one, two or more R _e Substituted with the following groups: c _6-20 Aryl, 5-14 membered heteroaryl or3-12 membered heterocyclyl;

said R is _e Selected from H, -C (═ O) O-C ₁ -C ₁₂ Aliphatic hydrocarbon radical, -O-C ₁ -C ₁₂ Aliphatic hydrocarbon radical, C ₁ -C ₁₂ Aliphatic hydrocarbon group, ═ O, halogen, OH, CN, SH, NH ₂ COOH; p is selected from 0, 1,2, 3,4, 5;

according to an embodiment of the present invention, said Ar ₁ ，Ar ₂ May be the same or different and is each independently selected from the following groups (representing the attachment site to the moiety of the other group of formula (la), representing the attachment to the moiety of the left group of formula (lb), then representing the attachment to the right group of formula (lb)):

according to an embodiment of the invention, W is selected from the group consisting of: - (CH) ₂ )n-，-O-(CH ₂ )n-O-，-O-(CH ₂ )n-，-(OCH ₂ CH ₂ ) _m -O-，-(OCH ₂ CH ₂ )m-，-(CH ₂ CH ₂ O)m-CH ₂ CH ₂ -，-(CH ₂ )s-NR _s -(CH ₂ CH ₂ O)m-CH ₂ CH ₂ -NR _s -(CH ₂ )s-，-(CH ₂ )s-NR _s -(CH ₂ )n-NR _s -(CH ₂ )s-；

The Rs is selected from H and C ₁ -C ₁₂ An aliphatic hydrocarbon group;

s is selected from 0, 1, 2; said n is selected from 1 to 16, for example from 1,2, 3,4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16; said m is selected from 1 to 8, for example from 1,2, 3,4, 5,6, 7, 8;

according to an embodiment of the invention, it is preferred when R is ₁ 、R ₂ Independently selected from (C) optionally containing one, two or more heteroatoms ₁ -C ₁₂ ) When the aliphatic hydrocarbon group is a group selected from- (CH) ₂ ) _q N(CH ₃ ) ₂ Q is selected from 0, 1,2, 3;

according to an embodiment of the present invention, preferably, R is ₃ Selected from the group consisting of optionally substituted by one, two or more R _e Substituted with the following groups: phenyl, indazolyl, pyrrolidinyl.

According to an embodiment of the present invention, preferably, R is ₁ 、R ₂ Can be the same or different and are each independently selected from the following groups:

according to an embodiment of the invention, said "halogen" is selected from F, Cl, Br, I; said (C) ₁ -C ₁₂ ) Aliphatic hydrocarbon group (C) ₁ -C ₂₀ ) The aliphatic hydrocarbon group may be selected from (C) ₁ -C ₁₂ ) Alkyl, (C) ₂ -C ₁₂ ) Alkenyl, (C) ₂ -C ₁₂ ) An alkynyl group;

according to an embodiment of the invention, the structure of formula I is selected from formula Ia or formula Ib as follows:

in the structure of the formula Ia, R ₁ 、R ₂ 、W、L ₁ 、L ₂ As defined above for formula I.

According to an embodiment of the invention, the structure of formula I may be selected from the following formulae II to VII:

in the structure of the formula II-VII, R ₁ 、R ₂ 、R _S S, n, m are as defined above for formula I.

According to embodiments of the present invention, in the compounds represented by formula I (including formula II to formula VII) and racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, illustrative, non-limiting specific examples of the compounds of formula I are as follows:

according to an embodiment of the invention, the compound of formula I may also be further selected from, for example, the following structures:

the invention also provides a preparation method of the compound shown in the formula I (including the formula II to the formula VII) and racemate, stereoisomer, tautomer, isotopic marker, nitrogen oxide, solvate, polymorphic substance, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, but not limited to the method described below. All starting materials are prepared or purchased directly according to the general rules of the target molecule and by protocols in these routes, methods well known to those of ordinary skill in the art of organic chemistry. The compounds of the invention can be synthesized by combining the methods described below with synthetic methods known in the art of synthetic organic chemistry or variations thereon as recognized by those skilled in the art. One skilled in the art will recognize that depending on the particular target structure, one or more of the following schemes may optionally be combined, or any of one or more of the schemes may be combined to provide a synthetic scheme.

The preparation method of the compound comprises the following steps: under appropriate conditions, raw materials containing benzimidazole structures are mixed with a solvent containing R ₁ Or R ₂ Reacting the starting materials of the group in a suitable reagent; or reacting a starting material comprising a-W-linking moiety with a starting material comprising a benzimidazole structure in a suitable reagent, or comprising both reaction steps.

The present invention further provides a pharmaceutical composition comprising a compound of formula I as described herein and racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof.

In some embodiments, the pharmaceutical compositions of the present invention further comprise a therapeutically effective amount of a compound of formula I of the present invention and racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs thereof, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

According to an embodiment of the invention, the compounds of the invention may be used in combination with additional therapeutic agents. The pharmaceutical compositions of the present invention further comprise a second therapeutic agent.

The carrier in the pharmaceutical composition is "acceptable" in that it is compatible with (and preferably capable of stabilizing) the active ingredient of the composition and is not deleterious to the subject being treated. One or more solubilizing agents may be used as pharmaceutical excipients for the delivery of the active compound.

The invention further provides the use of the compound of formula I, and racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, or the pharmaceutical composition thereof, for the preparation of an ENL inhibitor.

The invention further provides the use of the compound of formula I, and racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, or the pharmaceutical composition thereof, for the manufacture of a medicament for the prevention, modulation or treatment of diseases or disorders related to ENL-mediated disorders.

The present invention also provides a method of inhibiting ENL activity in a subject comprising administering a compound of the present invention as a therapeutic agent.

According to an embodiment of the invention, the ENL-mediated disease or condition of interest is selected from cancer, in particular leukemia. The leukemia is selected from Acute Lymphoblastic Leukemia (ALL), Acute Myelogenous Leukemia (AML), Chronic Lymphocytic Leukemia (CLL) and Chronic Myelogenous Leukemia (CML); and some less common types. Preferably, the leukemia is AML.

The present invention further provides a method for treating said ENL-mediated diseases or conditions of interest, said method comprising administering to a patient in need thereof a therapeutically effective amount of a first and a second therapeutic agent, wherein the first therapeutic agent is a compound of the present invention. In some embodiments, the invention provides a combined preparation of a compound of the invention and an additional therapeutic agent for simultaneous, separate or sequential use in therapy.

Interpretation of terms:

unless otherwise indicated, the definitions of groups and terms described in the specification and claims of the present application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. The definitions of the groups and the structures of the compounds in such combinations and after the combination should fall within the scope of the present specification.

Where a range of numerical values is recited in the specification and claims of this application, and where the range is defined as an "integer" or is commonly understood as an "integer" as is conventional in the art, it is understood that the two endpoints of the range and each integer within the range are recited. For example, "0 to 6" represents a carbon number, and is understood to describe each integer of 0, 1,2, 3,4, 5 and 6. "more" means three or more.

In the definition of groups described herein, the attachment site of a group to the moiety of another group of the general formula is indicated by a symbol which is attached to the moiety of the left group of the general formula, and then to the moiety of the right group of the general formula.

The term "halogen" refers to F, Cl, Br and I. In other words, F, Cl, Br, and I may be described as "halogen" in the present specification.

The optional substitution with a substituent described herein covers the absence of substitution as well as substitution with one or more substituents, e.g., "optionally substituted with one, two or more R" means that it may be unsubstituted (unsubstituted) or substituted with one, two or more R.

The term "aliphatic hydrocarbon group" includes a saturated or unsaturated, straight-chain or branched chain or cyclic hydrocarbon group, the type of the aliphatic hydrocarbon group may be selected from alkyl, alkenyl, alkynyl and the like, the number of carbon atoms of the aliphatic hydrocarbon group is preferably 1 to 20 (specifically selected from 1,2, 3,4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20), a further preferred range may be 1 to 12, a more preferred range may be 1 to 6, and specifically, the following groups may be included but not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 1-ethylethenyl, 1-methyl-2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 1-hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1-pentynyl, 1-hexynyl, Cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

the "aliphatic hydrocarbon group" may optionally comprise one, two or more heteroatoms (or be construed as an optional insertion of heteroatoms into the aliphatic hydrocarbon group, optionally a C-C bond and a C-H bond). Suitable heteroatoms will be apparent to those skilled in the art and include, for example, sulfur, nitrogen, oxygen, phosphorus and silicon. The heteroatom containing aliphatic hydrocarbyl group may be selected from the following groups: (C) ₁ -C ₁₂ ) Aliphatic hydrocarbyloxy, (C) ₁ -C ₁₂ ) Aliphatic hydrocarbyl mercapto group, (C) ₁ -C ₆ ) Aliphatic hydrocarbyloxy group (C) ₁ -C ₆ ) Aliphatic hydrocarbyl mercapto group, (C) ₁ -C ₆ ) Aliphatic hydrocarbyloxy (C) ₁ -C ₆ ) Aliphatic hydrocarbon group, (C) ₁ -C ₆ ) Aliphatic hydrocarbyl mercapto group (C) ₁ -C ₆ ) Aliphatic hydrocarbon group, (C) ₁ -C ₆ ) Aliphatic hydrocarbyloxy (C) ₁ -C ₆ ) Aliphatic hydrocarbyloxy, (C) ₁ -C ₆ ) Aliphatic hydrocarbyl mercapto group (C) ₁ -C ₆ ) Aliphatic hydrocarbyl mercapto group, N- (C) ₁ -C ₃ ) Aliphatic hydrocarbyl amino group (C) ₁ -C ₆ ) Aliphatic hydrocarbon group, N-di- (C) ₁ -C ₃ ) Aliphatic hydrocarbyl amino group (C) ₁ -C ₆ ) An aliphatic hydrocarbon group; for example, methoxy, ethoxy, propoxy, butoxy, pentoxy, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, methoxypropyl, ethoxypropyl, propoxypropyl, N-methylaminomethyl, N-methylaminoethyl, N-ethylaminoethyl, N-dimethylaminomethyl, N-dimethylaminoethyl, N-diethylaminoethyl; the "aliphatic hydrocarbon group" moiety contained in the other groups is as explained above.

The term "3-12 membered heterocyclic group" means a saturated or unsaturated monovalent monocyclic or bicyclic ring containing 1 to 5 heteroatoms independently selected from N, O and S, the heteroatom-containing group having no aromaticity, said 3-12 membered heterocyclic group, preferably 3-10 membered heterocyclic group. The term 3-12 membered heterocyclyl means a saturated monovalent monocyclic or bicyclic ring comprising 1-5, preferably 1-3 heteroatoms selected from N, O and S. The heterocyclic group may be attached to the rest of the molecule through any of the carbon atoms or nitrogen atom (if present). In particular, the heterocyclic group may include, but is not limited to: 4-membered rings such as azetidinyl, oxetanyl; 5-membered rings such as tetrahydrofuranyl, tetrahydrothienyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclyl group may be bicyclic, for example but not limited to a 5,5 membered ring, such as a hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl ring, or a 5,6 membered bicyclic ring, such as a hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl ring. The nitrogen atom containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, 2, 5-dihydro-1H-pyrrolyl, 4H- [1,3,4] thiadiazinyl, 4, 5-dihydrooxazolyl, or 4H- [1,4] thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolyl, 2, 3-dihydrobenzofuranyl, 3, 4-dihydro-2H-1-benzopyranyl (chromanyl), 2, 3-dihydrobenzo [ b ] [1,4] dioxanyl. The 3-12 membered heterocyclyl may also be selected from, for example, the following groups:

the term "C _6-20 Aryl "is to be understood as preferably meaning a mono-, bi-or tricyclic hydrocarbon ring of monovalent or partially aromatic character having 6 to 20 carbon atoms, preferably" C _6-10 Aryl ". Term C _6-20 Aryl is understood as preferably meaning a mono-, bi-or tricyclic hydrocarbon ring having a monovalent or partial aromaticity of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms, in particular a ring having 6 carbon atoms ("C) ₆ Aryl "), such as phenyl; or biphenyl, or of 9Ring of carbon atoms (' C) ₉ Aryl), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C ₁₀ Aryl radicals), such as tetralinyl, dihydronaphthyl or naphthyl, or rings having 13 carbon atoms ("C ₁₃ Aryl radicals), such as the fluorenyl radical, or a ring having 14 carbon atoms ("C) ₁₄ Aryl), such as anthracenyl.

The term "5-14 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: which has 5,6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and which contains 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S and, in addition, can be benzo-fused in each case. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and their benzo derivatives, such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, and the like; or azocinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.

Unless otherwise indicated, heterocyclyl or heteroaryl includes all possible isomeric forms thereof, e.g. positional isomers thereof. Thus, for some illustrative, non-limiting examples, pyridyl or pyridinylene includes pyridin-2-yl, pyridinylene-2-yl, pyridin-3-yl, pyridinylene-3-yl, pyridin-4-yl, and pyridinylene-4-yl; thienyl or thienylene includes thien-2-yl, thien-3-yl and thien-3-yl.

Depending on their molecular structure, the compounds of the invention may be chiral and may therefore exist in various enantiomeric forms. These compounds may thus be present in racemic or optically active form. The compounds of the invention or intermediates thereof may be separated into enantiomeric compounds by chemical or physical methods well known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from mixtures by reaction with optically active resolving agents. Examples of suitable resolving agents are optically active acids such as tartaric acid in the R and S forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g. N-benzoylproline or N-benzenesulfonylproline) or various optically active camphorsulfonic acids. The chromatographic enantiomeric resolution can also advantageously be carried out with the aid of optically active resolving agents, such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chirally derivatized methacrylate polymers, which are immobilized on silica gel. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane/isopropanol/acetonitrile.

Those skilled in the art will appreciate that not all nitrogen-containing heterocycles can form N-oxides, as the nitrogen needs to have available lone pairs of electrons for oxidation to an oxynitride; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes (dioxiranes) such as dimethyldioxirane. These methods for preparing N-oxides have been widely described and reviewed in the literature.

Pharmaceutically acceptable salts may be acid addition salts of the compounds of the invention having sufficient basicity, for example having a nitrogen atom in the chain or ring, for example with the following inorganic acids: for example hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or hydrogen sulfates, or acid addition salts with organic acids such as: such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, and mixtures thereof, Mandelic acid, ascorbic acid, glucoheptylic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid.

In addition, another suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt (e.g., sodium or potassium salt), an alkaline earth metal salt (e.g., calcium or magnesium salt), an ammonium salt, or a salt with an organic base which affords a physiologically acceptable cation, such as a salt with: sodium ions, potassium ions, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1, 6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trihydroxymethylaminomethane, aminopropanediol, 1-amino-2, 3, 4-butanetriol. By way of example, the pharmaceutically acceptable salts include salts of the group-COOH with: sodium ion, potassium ion, calcium ion, magnesium ion, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1, 6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trihydroxymethylaminomethane, aminopropanediol, 1-amino-2, 3, 4-butanetriol.

In addition, the basic nitrogen-containing groups may be quaternized with the following agents: lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromide, and the like. By way of example, pharmaceutically acceptable salts include hydrochloride, sulfate, nitrate, bisulfate, hydrobromide, acetate, oxalate, citrate, methanesulfonate, formate, or meglumine salts and the like.

Since the compound of the present invention may exist at a plurality of salt-forming sites, the pharmaceutically acceptable salts include not only salts formed at 1 of the salt-forming sites of the compound of the present invention but also salts formed at 2,3 or all of the salt-forming sites thereof. For this purpose, the molar ratio of the cation of the compound of formula (I) to the acid (anion) or base required for salt formation in the pharmaceutically acceptable salt may vary within a wide range, and may be, for example, 4:1 to 1:4, such as 3:1, 2:1, 1:2, 1:3, etc.

Depending on the position and nature of the various substituents, the compounds of the present invention may also contain one or more asymmetric centers. Asymmetric carbon atoms may exist in either the (R) or (S) configuration, with only one asymmetric center yielding a racemic mixture and multiple asymmetric centers yielding a diastereomeric mixture. In some cases, asymmetry may also exist due to hindered rotation about a particular bond, for example, the central bond connects two substituted aromatic rings of a particular compound. Also, the substituents may exist in cis or trans isomeric forms.

The compounds of the invention also include all possible stereoisomers of each, either in the form of a single stereoisomer or in the form of any mixture of said stereoisomers (e.g. R-or S-isomers, or E-or Z-isomers) in any proportion. Separation of individual stereoisomers (e.g. individual enantiomers or individual diastereomers) of the compounds of the invention may be achieved by any suitable prior art method (e.g. chromatography, particularly, for example, chiral chromatography).

The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule. The compounds of the invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; whereas in phenol the enol type predominates. The present invention encompasses all tautomeric forms of the compounds.

In the present invention, reference to compounds also includes isotopically-labeled compounds, which are identical to those shown in formula I, but wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of H, C, N, O, S, F and Cl, such as ² H、 ³ H、 ¹³ C、 ¹¹ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ O、 ¹⁷ O、 ³² P、 ³⁵ S、 ¹⁸ F and ³⁶ and (4) Cl. Compounds of the present invention, prodrugs thereof, or pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example, by incorporation of a radioactive isotope (such as ³ H and ¹⁴ C) the compounds of (a) are useful in drug and/or substrate tissue distribution assays. Tritium (i.e. tritium ³ H) And carbon 14 (i.e. ¹⁴ C) Isotopes are particularly preferred for their ease of preparation and detectability. Again, with heavier isotopes such as deuterium (i.e. deuterium) ² H) Substitutions may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances. The invention as claimedThe compounds may be specifically defined as replacement with deuterium or tritium. Furthermore, the absence of hydrogen in the substituents indicating the term deuterium or tritium alone is not meant to exclude deuterium or tritium, but may equally well comprise deuterium or tritium.

The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound of the present invention sufficient to effect the intended use, including but not limited to the treatment of a disease as defined below. The therapeutically effective amount may vary depending on the following factors: the intended application (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition and the mode of administration, etc., can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending on the following factors: the particular compound selected, the dosage regimen to be followed, whether to administer in combination with other compounds, the timing of administration, the tissue to be administered and the physical delivery system carried.

The term "solvate" is those forms of the compounds of the present invention which form complexes in the solid or liquid state by coordination with solvent molecules. Hydrates are a particular form of solvates in which the coordination is with water. In the present invention, the preferred solvate is a hydrate. Further, pharmaceutically acceptable solvates (hydrates) of the compounds of general formula I according to the invention refer to co-crystals and clathrates of compound I with one or more molecules of water or other solvents in stoichiometric amounts. Solvents that may be used for the solvate include, but are not limited to: water, methanol, ethanol, ethylene glycol and acetic acid.

The term "prodrug", or "prodrug" refers to a compound that is converted in vivo to a compound of the general formula or a particular compound. Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrugs of the present invention may be esters, and esters useful as prodrugs in the present invention are esters of benzene, aliphatic, acyloxymethyl, carbonate, carbamate and amino acids. For example, a compound of the present invention comprises a hydroxy/carboxy group, i.e., it may be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent.

Advantageous effects

The invention provides a compound with a novel structure and a general formula I, which has a good inhibition effect on ENL.

Detailed Description

The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.

Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.

Instrument and meter and general method

Using deuterated reagent (DMSO-d) ₆ 、CDCl ₃ 、CD ₃ OD) were recorded on a Bruker Ascend 400 spectrometer ¹ H and ¹⁹ f NMR. Deuterated solvents or TMS as internal standard. Chemical shifts are expressed in ppm, coupling constants (J) are expressed in Hz, and splitting patterns are s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad). LC-MS was performed using an Agilent 1260-; HPLC was performed using a Waters Acquity UPLC H-class instrument equipped with an Acquity BEH C18,1.7 μm, 50X 2.1mm column. The final compound was purified or resolved by preparative HPLC (Kromasil-C18 (100X 21.2mm, 5 μm) column, Xtimate-C18 (250X 30mm) column or Xbridge-C18 (150X 19mm, 5 μm) column), chiral preparative SFC (Daicel ChiralPak IG (250mm X30 mm,10 μm) column, (S, S) Whelk-O1 (100X 4.6mm) column, Daicel Chiralpak IC-3 (50X 4.6mm) column, Daicel Chiralpak AD-H (250X 4.6mm) column and Chirex S-VAL R-NEA column (250X 4.6 mm)).

Compound abbreviations:

T ₃ p: 2,4, 6-tripropyl-1, 3,5,2,4, 6-trioxatriphosphoric acid-2, 4, 6-trioxides or tripropyl phosphoric anhydride

BOP: benzotriazole-1-oxytris (dimethylamino) phosphonium hexafluorophosphate

For the series of compounds of the invention, there are two forms, full numbered and abbreviated numbered, where, for example, BV021 is the abbreviation for PI1701-BV021-1, both pointing to the same compound structure. The remaining compound numbers can be understood with reference to this example.

Synthetic examples

EXAMPLE 1 Synthesis of Compound BV021

Step 1: n, N-dimethyl-1- (5-nitro-1H-benzo [ d ] imidazol-2-yl) dimethylamine

2- (chloromethyl) -5-nitro-1H-1, 3-benzodiazole (10g,47mmol) was dissolved in a solution of dimethylamine in THF (1M in volume of 0.10L) and the system was stirred at 70 ℃ for 14H. Concentration and slurrying with acetonitrile gave the title compound (9.9g, 95%) as a red solid.

¹ H NMR(400MHz,DMSO-d ₆ )δ13.04(brs,1H),8.40(s,1H),8.09(dd,J＝8.8and 2.0Hz,1H),7.67(s,1H),3.75(s,2H),2.27(s,6H).LC-MS:ESI m/z 221.2[M+H] ⁺ ；C ₁₀ H ₁₂ N ₄ O ₂ Calculated 220.23.

And 2, step: 2- ((dimethylamino) methyl) -1H-benzo [ d ] imidazol-5-amine

N, N-dimethyl-1- (5-nitro-1H-benzo [ d ] imidazol-2-yl) dimethylamine (4.5g,0.02mol) was dissolved in methanol (50mL), and palladium on carbon (0.87g,80mmol) was added. The system was stirred at 25 ℃ for 14 hours. The mixture was filtered and the organic phase was concentrated to give the title compound (3.5g, 90%) as a yellow oily liquid.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.14(d,J＝8.4Hz,1H),6.60(d,J＝1.6Hz,1H),6.44(dd,J＝8.4and 2.0Hz,1H),3.53(s,2H),2.20(s,6H).LC-MS:ESI m/z 191.1[M+H] ⁺ ；C ₁₀ H ₁₄ N ₄ Calculated 190.25.

And step 3: 4- ((2- ((dimethylamino) methyl) -1H-benzo [ d ] imidazol-5-yl) carbamoyl) benzoic acid tert-butyl ester

Reacting 2- ((dimethylamino) methyl) -1H-benzo [ d]Imidazol-5-amine (0.95g,5.0mmol) was dissolved in dichloromethane (20mL) and 4- ((tert-butoxy) carbonyl) benzoic acid (1.1g,5.0mmol), T ₃ P (2.4g,7.5mmol) and triethylamine (1.5g,15 mmol). The system was stirred for 3 hours at 25 ℃, dissolved in dichloromethane (30mL) and washed with saturated brine (30mL × 3 times). The organic phase was dried over anhydrous sodium sulfate and concentrated to give the title compound (2.5g, crude) as a red solid.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.43(brs,1H),8.11–7.99(m,7H),7.47(s,1H),3.71(s,2H),2.28(s,6H),1.58(s,9H).LC-MS:ESI m/z 395.2[M+H] ⁺ ；C ₂₂ H ₂₆ N ₄ O ₃ Calculate value 394.48.

And 4, step 4: 4- ((2- ((dimethylamino) methyl) -1H-benzo [ d ] imidazol-5-yl) carbamoyl) benzoic acid

Tert-butyl 4- ((2- ((dimethylamino) methyl) -1H-benzo [ d ] imidazol-5-yl) carbamoyl) benzoate (2.5g,60mmol) was dissolved in dichloromethane (30mL) and trifluoroacetic acid (30mL) was added. After stirring the reaction at 25 ℃ for 14 h, concentration gave the title compound (5g, crude) as a red oily liquid.

LC-MS:ESI m/z 339.1[M+H] ⁺ ；C ₁₈ H ₁₈ N ₄ O ₃ Calculated 338.37.

And 5: n is a radical of ¹ ，N ^1' - (ethane-1, 2-diyl) bis (N) ⁴ - (2- ((dimethylamino) methyl) -1H-benzo [ d)]Imidazol-5-yl) terephthalamide)

4- ((2- ((dimethylamino) methyl) -1H-benzo [ d ] imidazol-5-yl) carbamoyl) benzoic acid was dissolved in DMF (5mL), and decane-1, 10-diamine (51mg,0.29mmol), BOP (0.52g,1.2mmol) and triethylamine (0.23g,1.8mmol) were added in that order. After the reaction was stirred for 14 hours at 25 ℃, the system was concentrated and purified by preparative HPLC under the following conditions [ column: Kromasil-C18100X 21.2mm 5 um; mobile phase: aqueous acetonitrile (containing 0.1% trifluoroacetic acid); gradient: 25-35% acetonitrile; flow rate 20mL/min time: 14 min ], to give the title compound (2.6mg, 1.0%) as a white solid.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.30(brs,2H),8.60(brs,2H),8.29(brs,2H),8.03(d,J＝7.2Hz,6H),7.98-7.88(m,4H),7.44(s,4H),3.66–3.60(m,4H),3.30–3.23(m,4H),2.22(s,12H),1.63–1.50(m,4H),1.30–1.22(m,12H).LC-MS:(ESI)m/z 813.5[M+H] ⁺ ；C ₄₆ H ₅₆ N ₁₀ O ₄ Calculated value 812.45 HPLC purity 98.82% (214nm), 98.83% (254nm).

Example 2: the following compounds were further synthesized according to the synthesis method of example 1:

BV022：

¹ H NMR(400MHz,DMSO-d ₆ )δ10.41(brs,2H),8.62(brs,2H),8.24(brs,2H),8.12–7.94(m,10H),7.64–7.54(m,4H),4.47(s,4H),3.28–3.25(m,4H),2.85(s,12H),1.63–1.50(s,4H),1.44–1.28(s,8H).LC-MS:(ESI)m/z 813.5[M+H] ⁺ ；C ₄₄ H ₅₂ N ₁₀ O ₄ calculated value 784.42 HPLC purity 98.73% (214nm), 96.69% (254nm).

BV023：

¹ H NMR(400MHz,DMSO)δ10.33(brs,2H),8.64(brs,2H),8.26(brs,2H),8.10–8.02(m,6H),8.01–7.96(m,4H),7.46(s,4H),3.70–3.64(m,4H),3.31(d,J＝5.6Hz,4H),2.25(s,12H),1.66–1.57(m,4H),1.44–1.39(m,2H).LC-MS:ESI m/z 743.3[M+H] ⁺ ；C ₄₁ H ₄₆ N ₁₀ O ₄ Calculated value 742.37 HPLC purity 98.44% (214nm), 98.45% (254nm).

BV024：

¹ H NMR(400MHz,DMSO-d ₆ )δ12.32(brs,2H),10.31(brs,2H),8.24(brs,2H),8.08–8.02(m,6H),7.99–7.94(m,4H),7.55–7.25(m,4H),3.63(s,4H),3.23–3.20(m,4H),2.23(s,12H),1.65–1.56(m,4H).LC-MS:(ESI)m/z 729.3[M+H] ⁺ ；C ₄₀ H ₄₄ N ₁₀ O ₄ Calculated value 728.35 HPLC purity 97.39% (214nm), 95.74% (254nm).

BV025：

¹ H NMR(400MHz,MeOD-d ₄ )δ8.27(s,2H),8.05(d,J＝8.4Hz,4H),7.99(d,J＝8.4Hz,4H),7.66(d,J＝8.8Hz,2H),7.55(dd,J＝8.8and 1.6Hz,2H),4.60(s,4H),3.54(t,J＝6.8Hz,4H),3.01(s,12H),2.00–1.94(m,2H).LC-MS:ESI m/z 715.3[M+H] ⁺ ；C ₃₉ H ₄₂ N ₁₀ O ₄ Calculated value 714.34 HPLC purity 98.22% (214nm), 98.34% (2)54nm).

BV026：

¹ H NMR(400MHz,DMSO-d ₆ )δ12.32(brs,2H),10.33(brs,2H),8.81(brs,2H),8.07(d,J＝8.4Hz,4H),8.00(d,J＝8.4Hz,4H),7.52–7.44(m,4H),3.65(s,4H),3.51(s,4H),2.25(s,12H).LC-MS:ESI m/z 701.3[M+H] ⁺ ；C ₃₈ H ₄₀ N ₁₀ O ₄ Calculated value 700.32 HPLC purity 91.04% (214nm), 92.14% (254nm).

BV027：

¹ H NMR(400MHz,DMSO)δ12.32(brs,2H),10.33(brs,2H),8.71(brs,2H),8.05(d,J＝8.4Hz,6H),7.98(d,J＝8.4Hz,4H),7.52-741(m,4H),3.64(s,4H),3.58(d,J＝4.4Hz,8H),3.46(s,4H),2.23(s,12H).LC-MS:ESI m/z 789.3[M+H] ⁺ ；C ₄₂ H ₄₈ N ₁₀ O ₆ Calculated value 788.38 HPLC purity 90.45% (214nm), 93.00% (254nm).

BV028：

¹ H NMR(400MHz,DMSO-d ₆ )δ12.30(brs,2H),10.33(brs,2H),8.71(brs,2H),8.05(d,J＝8.4Hz,6H),7.98(d,J＝8.4Hz,4H),7.46(s,4H),3.66(s,4H),3.62(d,J＝5.6Hz,4H),3.49(s,4H),2.25(s,12H).LC-MS:ESI m/z 745.7[M+H] ⁺ ；C ₄₀ H ₄₄ N ₁₀ O ₅ Calculated 744.35 HPLC purity 96.54% (214nm), 96.49% (254nm).

BV032：

¹ H NMR(400MHz,DMSO-d ₆ )δ12.40(brs,2H),10.31(brs,2H),8.62(brs,2H),8.47–8.39(m,4H),8.04(d,J＝8.4Hz,4H),7.96(d,J＝8.4Hz,2H),7.45(s,2H),3.64(s,4H),3.30–3.26(m,4H),2.54(m,6H),2.24(s,6H),2.03–1.96(m,2H),1.60–1.52(m,2H),1.39–1.32(m,4H),1.26–1.22(m,4H).LC-MS:(ESI)m/z 771.3[M+H] ⁺ ；C ₄₃ H ₅₀ N ₁₀ O ₄ Calculated value 770.40 HPLC purity 97.21% (214nm), 98.03% (254nm).

BV033：

¹ H NMR(400MHz,DMSO-d ₆ )δ12.33(brs,2H),10.31(brs,2H),8.63(brs,2H),8.26(brs,1H),8.12–7.90(m,10H),7.46(s,4H),3.64(s,4H),3.30(d,J＝6.0Hz,4H),2.24(s,12H),1.57(s,4H),1.38(s,4H).LC-MS:(ESI)m/z 757.3[M+H] ⁺ ；C ₄₂ H ₄₈ N ₁₀ O ₄ Calculated value 756.39 HPLC purity 100% (214nm), 99.27% (254nm).

EXAMPLE 3 Synthesis of Compound BV005

Step 1: o, O' - (Pentane-1, 5-diyl) di-tert-butyl di-p-phthalate

4- (tert-Butoxycarbonyl) benzoic acid (1.2g,5.2mmol) and 4-dimethylaminopyridine (0.64g,5.2mmol) were dissolved in dichloromethane (10mL) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.99g,5.2mmol) was added. The system was stirred at 0 ℃ for 30 minutes and 1, 5-pentanediol (0.27g,2.6mmo) was added. After stirring the system at 25 ℃ for 4 hours, it was poured into 20mL of water, extracted 3 times with dichloromethane (15mL) and the organic phase was dried over anhydrous sodium sulfate. After concentration, column chromatography (petroleum ether/ethyl acetate 100% to 95%) was performed to obtain the title compound (0.53g, 20%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ -d ₃ )δ8.05(q,J＝8.8Hz,8H),4.38(t,J＝6.8Hz,4H),1.93–1.83(m,4H),1.66–1.58(m,20H).

Step 2: 4,4' - ((pentane-1, 5-diylbis (oxy)) bis (carbonyl)) dibenzoic acid

Di-tert-butyl O, O' - (pentane-1, 5-diyl) di-p-phthalate (0.53g,0.91mmol) and trifluoroacetic acid (1mL) were dissolved in dichloromethane (3mL), and after stirring at 25 ℃ for 30 minutes, the system was concentrated to give the title compound (0.44g, crude) which was used directly in the next step.

LC-MS:ESI m/z 401.1[M+H] ⁺ ；C ₂₁ H ₂₀ O ₈ Calculated 400.12.

And step 3: pentane-1, 5-diylbis (4- ((2- (((S) -2-methylpyrrolidin-1-yl) methyl) -1H-benzo [ d ] imidazol-5-yl) carbamoyl) benzoate)

4,4' - ((pentane-1, 5-diylbis (oxy)) bis (carbonyl)) dibenzoic acid (0.12g,0.30mmol), (S) -2- ((2-methylpyrrolidin-1-yl) methyl) -1H-benzo [ d ] imidazol-5-amine (0.15g,0.66mmol) (Angew. chem. int. Ed.2018,57,16302) and 2- (7-azabenzotriazole) -N, N, N ', N ' -tetramethyluronium hexafluorophosphate (0.29g,0.75mmol), N, N-diisopropylethylamine (0.16g,1.2mmol) were dissolved in DMF (6mL) and the reaction stirred at 25 ℃ for 14H. The mixture was poured into 10mL of water and extracted 3 times with 10mL of ethyl acetate. The organic phase was washed with saturated ammonium chloride solution (20mL), then dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC under the following conditions [ column: Kromasil-C18100X 21.2mm 5 um; mobile phase: aqueous acetonitrile (containing 0.1% trifluoroacetic acid); gradient: 25-35% acetonitrile; flow rate 20mL/min time: 14 min ], to give the title compound (37mg, 13%) as a white solid.

¹ H NMR(400MHz,DMSO-d ₆ )δ12.74(brs,2H),10.50(brs,2H),8.24(s,2H),8.17–8.05(m,8H),7.66-7.50(m,4H),4.81-4.69(m,2H),4.54-4.43(m,2H),4.37(t,J＝6.4Hz,4H),3.71-3.53(m,4H),3.39-3.36(m,2H),2.27-2.17(m,2H),2.02-1.90(m,4H),1.89-1.79(m,4H),1.69–1.56(m,4H),1.38(d,J＝5.6Hz,6H).LC-MS:ESI m/z 825.3[M+H] ⁺ ；C ₄₇ H ₅₂ N ₈ O ₆ Calculated value 824.40 HPLC purity 98.5% (214nm), 98.1% (254nm).

Example 4 the following compounds were synthesized according to the synthesis method of example 3:

BV006：

¹ H NMR(400MHz,DMSO-d ₆ )δ12.23(brs,2H),10.39(brs,2H),8.29(s,2H),8.12-8.02(m,8H),7.45(s,4H),4.32(t,J＝6.4Hz,4H),4.05(d,J＝14.4Hz,2H),3.52(s,2H),2.95-2.89(m,2H),2.47–2.41(m,2H),2.31–2.23(m,2H),1.97–1.88(m,2H),1.82–1.57(m,8H),1.40(s,10H),1.08(d,J＝6.0Hz,6H).LC-MS:ESI m/z 867.4[M+H] ⁺ ；C ₅₀ H ₅₈ N ₈ O ₆ calculated value 866.45 HPLC purity 98.0% (214nm), 98.1% (254nm).

BV007：

¹ H NMR(400MHz,DMSO-d ₆ )δ10.51(brs,2H),8.24(brs,2H),8.10(s,8H),7.63(d,J＝8.8Hz,2H),7.56(d,J＝8.8Hz,2H),4.78(d,J＝13.2Hz,2H),4.51(d,J＝14.4Hz,2H),4.31(t,J＝6.4Hz,4H),3.71-3.58(m,4H),3.38-3.28(m,2H),2.26-2.19(m,2H),2.02-1.89(m,4H),1.78-1.61(m,6H),1.49–1.27(m,18H).LC-MS:ESI m/z 895.4[M+H] ⁺ ；C ₅₂ H ₆₂ N ₈ O ₆ Calculated value 894.48 HPLC purity 98.4% (214nm), 97.3% (254nm).

BV008：

¹ H NMR(400MHz,DMSO-d ₆ )δ12.24(brs,2H),10.39(brs,2H),8.15(s,2H),8.09(s,6H),8.05(s,2H),7.46(s,4H),4.47–4.39(m,4H),4.08(d,J＝14.2Hz,2H),3.81–3.78(m,4H),3.65(s,2H),3.61-3.54(m,2H),3.17(s,2H),2.95(dd,J＝12.0and 4.8Hz,2H),2.57-2.53(m,2H),2.33(t,J＝8.8Hz,2H),1.94(dd,J＝10.0and 4.0Hz,2H),1.74–1.59(m,4H),1.38(d,J＝8.8Hz,2H),1.09(d,J＝6.0Hz,6H).LC-MS:ESI m/z 436.3[M/2+H] ⁺ ；C ₄₈ H ₅₄ N ₈ O ₈ Calculated 870.41 HPLC purity 99.2% (214nm), 99.4% (254nm).

BV009：

¹ H NMR(400MHz,DMSO-d ₆ )δ12.15(brs,2H),10.31(brs,2H),8.63(t,J＝5.6Hz,2H),8.32(s,4H),8.07–8.03(m,6H),7.97(d,J＝8.4Hz,4H),7.45(s,4H),4.05(d,J＝14.0Hz,2H),3.56–3.50(m,2H),3.33–3.29(m,2H),2.98–2.88(m,2H),2.49–2.41(m,4H),2.32–2.26(m,2H),1.99–1.89(m,2H),1.68–1.56(m,8H),1.46–1.30(m,4H),1.09(d,J＝6.0Hz,4H).LC-MS:ESI m/z 412.2[M/2+H] ⁺ ；C ₄₇ H ₅₄ N ₁₀ O ₄ Calorie 823.43 HPLC purity 99.74% (214nm), 99.41% (254nm).

BV010：

¹ H NMR(400MHz,DMSO)δ12.20(brs,2H),10.30(s,2H),8.60(t,J＝5.6Hz,2H),8.16(s,2H),8.04(d,J＝8.1Hz,6H),7.97(d,J＝8.3Hz,4H),7.45(s,4H),4.05(d,J＝14.1Hz,2H),3.54(d,J＝14.2Hz,2H),3.27(s,2H),2.95–2.89(m,2H),2.54(s,4H),2.31–2.24(m,2H),1.93(dd,J＝12.0and 6.5Hz,2H),1.69–1.51(m,8H),1.33(s,10H),1.09(d,J＝6.0Hz,6H).LC-MS:ESI m/z433.2[M/2+H] ⁺ ；C ₅₀ H ₆₀ N ₁₀ O ₄ Calculated value 433.24 HPLC 98.70% (254nm), 98.39% (214nm).

BV011：

¹ H NMR(400MHz,DMSO-d ₆ )δ12.18(brs,2H),10.30(s,2H),8.60(t,J＝5.2Hz,2H),8.18(s,2H),8.06–8.00(m,6H),7.98–7.94(m,4H),7.45(s,4H),4.05(d,J＝14.0Hz,2H),3.54(d,J＝14.0Hz,2H),3.30–3.24(m,2H),2.95–2.87(m,2H),2.56–2.52(m,4H),2.31–2.26(m,2H),1.97–1.89(m,2H),1.70–1.61(m,4H),1.58–1.50(m,4H),1.41–1.28(m,14H),1.08(d,J＝6.0Hz,6H).LC-MS:ESI m/z 893.4[M+H] ⁺ ；C ₅₂ H ₆₄ N ₁₀ O ₄ Calculated value 892.15.HPLC purity of 99.17% (214nm), 98.49% (254nm).

BV012：

¹ H NMR(400MHz,DMSO-d ₆ )δ10.31(s,2H),8.71(t,J＝5.2Hz,2H),8.34(brs,4H),8.06–7.97(m,8H),7.45(s,2H),4.04(d,J＝14.2Hz,2H),3.60–3.51(m,10H),3.47–3.43(m,4H),2.95–2.89(m,2H),2.54(s,2H),2.31–2.24(m,2H),1.97–1.90(m,2H),1.70–1.58(m,4H),1.40–1.32(m,2H),1.08(d,J＝6.0Hz,6H).LC-MS:ESI m/z 869.4[M+H] ⁺ ；C ₄₈ H ₅₆ N ₁₀ O ₆ Calcd 868.44.HPLC purity 99.30% (214nm), 99.50% (254nm).

BV031：

¹ H NMR(400MHz,DMSO-d ₆ )δ12.15(brs,2H),10.43(brs,2H),8.09(s,10H),7.49(s,4H),4.47–4.40(m,4H),3.87(s,4H),3.81–3.78(m,4H),3.65(s,4H),2.40(s,12H).LC-MS:(ESI)m/z396.3[M/2+H] ⁺ ；C ₄₂ H ₄₆ N ₈ O ₈ Calculated 790.34 HPLC purity, 97.9% (214nm), 97.7% (254nm).

Example 5: synthesis of compound BV 013:

step 1: n is a radical of ¹ ，N ⁷ -dibenzyl-N ¹ ，N ⁷ 1, 7-Dimethylenebistetramethylene-diamine

1, 7-dibromoheptane (5.0g,19mmol), N-methylbenzylamine (5.2g,42mmol) and cesium carbonate (13g,39mmol) were dissolved in DMF (50 mL). After the system was stirred at 80 ℃ for 16 hours, the mixture was dissolved in ethyl acetate (50mL) and washed 3 times with 20mL of water. After the organic phase was dried over anhydrous sodium sulfate and concentrated, column chromatography (40g of silica gel, 10% methanol in dichloromethane) gave the title compound (2.3g, 35% yield) as a yellow oily liquid.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.33–7.19(m,10H),3.41(s,4H),2.31–2.24(m,4H),2.08(s,6H),1.49–1.37(m,4H),1.29–1.19(m,6H).LC-MS:ESI m/z 339.4[M+H] ⁺ ；C ₂₃ H ₃₄ N ₂ Calculated 338.27.

And 2, step: n is a radical of ¹ ，N ⁷ 1, 7-Dimethylenebistetramethylene-diamine

Will N ¹ ，N ⁷ -dibenzyl-N ¹ ，N ⁷ -Dimethylheptane-1, 7-diamine (2.3g,0.01mol) was dissolved in 100mL of methanol and palladium on carbon (0.30g) was added. After stirring the system under hydrogen at 25 ℃ for 14 h, the mixture was filtered through celite to give the crude title compound as a brown gummy solid (1.2 g).

¹ H NMR(400MHz,CDCl ₃ )δ2.60–2.53(m,4H),2.43(s,6H),1.55–1.43(m,4H),1.35-1.28(m,6H).LC-MS:ESI m/z 159.3[M+H] ⁺ ；C ₉ H ₂₂ N ₂ Calculated 158.18.

And step 3: n is a radical of ¹ ，N ⁷ -dimethyl-N ¹ ，N ⁷ -bis ((5-nitro-1H-benzo [ d ]]Imidazol-2-yl) methyl) heptane-1, 7-diamine

Reacting 2- (chloromethyl) -5-nitro-1H-benzo [ d]Imidazole (5.3g,25mmol) was dissolved in 15mL acetonitrile and N was added ¹ ，N ⁷ -Dimethylheptane-1, 7-diamine and sodium carbonate (1.2g,10mmol) were dissolved in a solution of 5mL DMF. After the system was stirred at 40 ℃ for 14 hours, the solvent was evaporated to dryness, 15mL of water was added, and extraction was performed 3 times with 10mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to give the title compound (0.40g, 79%) as a brown gum.

¹ H NMR(400MHz,DMSO-d ₆ )δ12.80(brs,2H),8.39(s,2H),8.14(s,2H),8.08(dd,J＝8.8,2.0Hz,2H),7.66(d,J＝8.8Hz,2H),3.77(s,4H),2.40–2.32(m,4H),2.22(s,6H),1.47–1.38(m,4H),1.26–1.16(m,6H).LC-MS:ESI m/z 509.3[M+H] ⁺ ；C ₂₅ H ₃₂ N ₈ O ₄ Calculated 508.25.

And 4, step 4: n is a radical of hydrogen ¹ ，N ⁷ -bis ((5-amino-1H-benzo [ d ]]Imidazol-2-yl) methyl) -N ¹ ，N ⁷ 1, 7-Dimethylenebistetramethylene-diamine

Will N ¹ ，N ⁷ -dimethyl-N ¹ ，N ⁷ -bis ((5-nitro-1H-benzo [ d ]]Imidazol-2-yl) methyl) heptane-1, 7-diamine (0.62g,1.2mmol) was dissolved in 10mL of methanol and palladium on carbon (78mg,0.73mmol) was added. The system was stirred at 25 ℃ for 16 hours under a hydrogen atmosphere. The mixture was filtered through celite and concentrated to give the title compound (0.40g, 73%) as a red liquid.

LC-MS:ESI m/z 449.3[M+H] ⁺ ；C ₂₅ H ₃₆ N ₈ Calculated 448.31.

And 5: dimethyl 4,4' - ((((((heptane-1, 7-diylbis (methylazacyclodi)) bis (methylene)) bis (1H-benzo [ d ] imidazole-2, 5-diyl)) bis (azeadienyl)) bis (carbonyl) dibenzoate

Will N ¹ ，N ⁷ -bis ((5-amino-1H-benzo [ d ]]Imidazol-2-yl) methyl) -N ¹ ，N ⁷ Dimethylheptane-1, 7-diamine (0.10g,0.20mmol), monomethyl terephthalate (0.11g,0.60mmol), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (0.23g,0.60mmol), N, N-diisopropylethylamine (0.10g,0.80mmol) was dissolved in DMF (5mL) and the reaction stirred at 25 ℃ for 14 h. The mixture was poured into 10mL of water, and extracted 3 times with 10mL of ethyl acetate. The organic phase was washed with saturated ammonium chloride solution (20mL), then dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC under the following conditions [ column: Kromasil-C18100X 21.2mm 5 um; mobile phase: aqueous acetonitrile (containing 0.1% trifluoroacetic acid); gradient: 25-35% acetonitrile; flow rate 20mL/min time: 14 minutes]To give the title compound (5mg, 5%) as a white solid.

¹ H NMR(400MHz,DMSO-d ₆ )δ12.17(brs,2H),10.41(s,2H),8.26(s,2H),8.10-8.06(m,8H),7.45(s,4H),3.90(s,6H),3.68(s,4H),2.38–2.33(m,4H),2.20(s,6H),1.49–1.30(m,4H),1.28–1.21(m,6H).LC-MS:ESI m/z 773.5[M+H] ⁺ ；C ₄₃ H ₄₈ N ₈ O ₆ Calculated 772.37 HPLC purity 95.03% (214nm), 95.51% (254nm).

Example 6 the following compounds were synthesized according to the synthesis method of example 5:

BV014：

¹ H NMR(400MHz,DMSO-d ₆ )δ12.18(brs,2H),10.42(brs,2H),8.20-7.95(m,10H),7.52-7.37(m,4H),3.90(s,6H),3.67(s,4H),2.39-2.32(m,4H),2.20(s,6H),1.49-1.39(m,4H),1.30-1.13(m,12H).LC-MS:ESI m/z 815.4[M+H] ⁺ ；C ₄₆ H ₅₄ N ₈ O ₆ calculated 814.42 HPLC purity 99.65% (214nm), 99.66% (254nm).

BV015：

¹ H NMR(400MHz,DMSO-d ₆ )δ12.20(brs,2H),10.42(brs,2H),8.09(s,10H),7.50–7.41(m,4H),3.90(s,6H),3.67(s,4H),2.38–2.31(m,4H),2.20(s,6H),1.48–1.41(m,4H),1.24–1.05(m,16H).LC-MS:ESI m/z 422.3[M/2+H] ⁺ ；C ₄₈ H ₅₈ N ₈ O ₆ Calculated 843.45 HPLC purity 95.16% (214nm) 92.24% (254nm).

BV016：

¹ H NMR(400MHz,Me ₃ OD-d ₄ )δ8.30(d,J＝1.6Hz,2H),8.14(s,2H),8.11(s,2H),8.01(s,2H),7.98(s,2H),7.63(s,1H),7.61(s,1H),7.50(d,J＝2.0Hz,1H),7.48(d,J＝2.0Hz,1H),4.51(s,4H),3.94(s,6H),3.83–3.80(m,4H),3.68(d,J＝2.0Hz,12H),2.87(s,6H).LC-MS:ESI m/z418.3[M/2+H] ⁺ ；C ₄₄ H ₅₀ N ₈ O ₉ Calculated value 834.37 HPLC purity 95.03% (214nm), 95.43% (254nm).

BV017：

¹ H NMR(400MHz,DMSO-d ₆ )δ12.12(brs,2H),10.24(s,2H),8.47(d,J＝0.8Hz,2H),8.23(d,J＝0.8Hz,2H),8.18(s,2H),8.08(s,2H),8.01(dd,J＝8.8and 1.6Hz,2H),7.75(d,J＝8.8Hz,2H),7.46(s,4H),4.10(s,6H),3.69(s,4H),2.39–2.34(m,4H),2.21(s,6H),1.47–1.43(m,4H),1.23(s,6H).LC-MS:ESI m/z 765.4[M+H] ⁺ ；C ₄₃ H ₄₈ N ₁₂ O ₂ Calculated value 764.40 HPLC purity 95.03% (214nm), 95.51% (254nm).

BV018：

¹ H NMR(400MHz,DMSO-d ₆ )δ12.17(brs,2H),10.24(brs,2H),8.48(s,2H),8.24(d,J＝0.8Hz,2H),8.09(s,2H),8.02(dd,J＝8.8and 1.6Hz,2H),7.75(d,J＝8.8Hz,2H),7.46(s,4H),4.10(s,6H),3.67(s,4H),2.39–2.33(m,4H),2.20(s,6H),1.49–1.39(m,4H),1.31–1.13(m,12H).LC-MS:ESI m/z 807.5[M+H] ⁺ ；C ₄₆ H ₅₄ N ₁₂ O ₂ Calculations 806.45 HPLC purity 97.69% (214nm), 98.49% (254nm).

BV019：

¹ H NMR(400MHz,DMSO-d ₆ )δ12.16(brs,2H),10.23(brs,2H),8.48(s,2H),8.24(s,2H),8.10(d,J＝10.0Hz,2H),8.02(d,J＝7.2Hz,2H),7.75(d,J＝8.8Hz,2H),7.50–7.39(m,4H),4.10(s,6H),3.67(s,4H),2.35–2.24(m,4H),2.23–2.20(m,6H),1.45–1.41(m,4H),1.24–1.17(m,16H).LC-MS:ESI m/z 836.3[M+H] ⁺ ；C ₄₈ H ₅₈ N ₁₂ O ₂ Calculated value 835.48 HPLC purity 93.43% (214nm), 95.68% (254nm).

BV020：

¹ H NMR(400MHz,DMSO-d ₆ )δ12.19(brs,2H),10.26(brs,2H),8.47(s,2H),8.24(s,2H),8.11(s,2H),8.04–7.99(m,2H),7.75(d,J＝8.8Hz,2H),7.52–7.41(m,4H),4.10(s,6H),3.75(s,4H),3.55–3.48(m,12H),2.61–2.58(m,4H),2.25(s,6H).LC-MS:(ESI)m/z 849.3[M+Na] ⁺ ；C ₄₄ H ₅₀ N ₁₂ O ₅ Calculated value 826.40 HPLC purity 92.25% (214nm), 93.74% (254nm).

BV037：

¹ H NMR(400MHz,DMSO-d ₆ )δ10.21(brs,2H),8.44(brs,2H),8.20(s,2H),8.10(brs,1H),8.06(s,2H),7.98(d,J＝8.8Hz,2H),7.71(d,J＝8.8Hz,2H),7.42(d,J＝9.2Hz,4H),4.07(s,6H),3.75(s,4H),3.54(t,J＝5.6Hz,4H),3.47(s,4H),2.60(t,J＝5.6Hz,4H),2.25(s,6H).LC-MS:(ESI)m/z 783.7[M+H] ⁺ ；C ₄₂ H ₄₆ N ₁₂ O ₄ Calculated value 782.38 HPLC purity 98.50% (214nm), 97.23% (254nm).

Example 6: monomer synthesis

LY 120: 4- ((2- ((dimethylamino) methyl) -1H-benzo [ d ] imidazol-5-yl) carbamoyl) benzoic acid methyl ester

2- ((dimethylamino) methyl) -1H-benzo [ d ] imidazol-5-amine (200mg,1.05mmol), monomethyl terephthalate (189mg,1.05mmol), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (0.23g,0.60mmol), N, N-diisopropylethylamine (0.10g,0.80mmol) were dissolved in DMF (5mL) and the reaction was stirred at 25 ℃ for 16H. The mixture was poured into 10mL of water, and extracted 3 times with 10mL of ethyl acetate. The organic phase was washed with saturated ammonium chloride solution (20mL), then dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC under the following conditions [ column: Kromasil-C18100X 21.2mm 5 um; mobile phase: aqueous acetonitrile (containing 0.1% trifluoroacetic acid); gradient: 25-35% acetonitrile; flow rate 20mL/min time: 14 min ], to give the title compound (98.8mg, 26%) as a white solid.

¹ H NMR(400MHz,DMSO)δ10.53(s,1H),8.25(s,1H),8.11(s,4H),7.64(d,J＝8.7Hz,1H),7.58(d,J＝8.7Hz,1H),4.60(s,2H),3.91(s,3H),2.91(d,J＝12.6Hz,6H).LC-MS:ESI m/z353.2[M+H] ⁺ (ii) a Calculated value 352.15 HPLC purity 97.44% (214nm), 98.55% (254nm).

Referring to the synthesis of methyl 4- ((2- ((dimethylamino) methyl) -1H-benzo [ d ] imidazol-5-yl) carbamoyl) benzoate the following compounds were synthesized:

LY108：

¹ h NMR (400MHz, DMSO): δ 12.49-12.12(brs,1H),10.28-10.20(brs,1H),8.48(d, J ═ 0.7Hz,1H),8.24(d, J ═ 0.8Hz,1H),8.20-8.15(brs,1H),8.07(s,1H),8.02(dd, J ═ 8.9and 1.5Hz,1H),7.76(d, J ═ 8.9Hz,1H),7.53-7.38(M,2H),4.10(s,3H),3.65(s,2H),2.24(s, 6H): LC-MS (ESI) M/z (calculated value M + H),349.2. HPLC purity: 98.78% (214nm), 99.46% (254nm).

BV002：

¹ H NMR(400MHz,DMSO-d ₆ )δ12.18(brs,1H),10.41(brs,1H),8.28(s,1H),8.12–8.02(m,4H),7.45(s,2H),4.05(d,J＝14.2Hz,1H),3.90(s,3H),3.53(d,J＝14.2Hz,1H),2.95–2.88(m,1H),2.51–2.43(m,1H),2.31–2.22(m,1H),1.97–1.90(m,1H),1.71–1.59(m,2H),1.40–1.33(m,1H),1.08(d,J＝6.0Hz,3H).LC-MS:ESI m/z 393.2[M+H] ⁺ ；C ₂₂ H ₂₄ N ₄ O ₃ Calculated 392.18.

BV003：

¹ H NMR(400MHz,DMSO-d ₆ )δ12.18(brs,1H),10.32(brs,1H),8.60(d,J＝4.6Hz,1H),8.05–7.84(m,5H),7.50–7.38(m,2H),4.04(d,J＝13.6Hz,1H),3.53(d,J＝14.2Hz,1H),3.30(s,1H),2.93–2.86(m,1H),2.81(t,J＝4.8Hz,3H),2.29–2.24(m,1H),1.95–1.89(m,1H),1.72–1.63(m,2H),1.39–1.32(m,1H),1.08(d,J＝6.0Hz,3H).LC-MS:ESI m/z 392.1[M+H] ⁺ ；C ₂₂ H ₂₅ N ₅ O ₂ Calculated 391.20.

LY160：

¹ H NMR(400MHz,DMSO-d ₆ )δ12.53(brs,1H),10.33(brs,1H),8.62(brs,1H),8.04(s,2H),7.97(s,2H),7.47(s,2H),6.56(s,1H),3.43(s,2H),2.82(s,3H),2.30(s,6H).LC-MS:ESI m/z352.2[M+H]+；C ₁₉ H ₂₁ N ₅ O ₂ Calculated value 351.41 HPLC purity 100% (214nm), 98.66% (254nm).

Evaluation test of biological Activity

Biological experimental example 1: two biochemical test compounds were tested for their ability to inhibit ENL: AlphaScreen, homogeneous time-resolved fluorescence technology (HTRF)

1.1AlphaScreen

Experimental materials: his-tagged human ENL protein was purchased from ACTIVE MOTIF (Cat #81098). Dissolving protein with sterile water, packaging, and storing at-80 deg.C. Biotin-labeled polypeptides were synthesized by GenScript, dissolved in DMSO and stored at-20 ℃.

Hisdidine Detection Kit (Nickel Chemate) (6760619M) was purchased from Perkinelmer. Source plates (PP-0200) were obtained from Labcyte, and Proxiplate-384plus target plates were obtained from Perkin Elmer (Cat # 6008280). Self-preparation of reaction buffer solution: 50mM HEPES, 0.005% Brij35,1mM TCEP, pH 7.4.

The experimental method comprises the following steps: candidate compounds were dissolved in DMSO, applied to Source plates in concentration gradients, and then transferred to target plates using ECHO550 to give 11 concentrations. The protein and polypeptide were diluted in reaction buffer, gently mixed, and added to the target plate at 10. mu.l per well using Multidrop (working concentration of protein 5nM, working concentration of polypeptide 30nM), and incubated for 1 hour at room temperature. Mu.l Donor/Acceptor beads (working concentration 15. mu.g/mL) were added to each well and incubated for one hour at room temperature. Finally read with Envision Plate Reader. IC of each compound ₅₀ Obtained after fitting with XLfit.

1.2 homogeneous phase time-resolved fluorescence technique (HTRF)

Experimental materials: his-tagged human ENL protein was purchased from ACTIVE MOTIF (Cat # 81098). Dissolving protein with sterile water, packaging, and storing at-80 deg.C. Biotin-labeled polypeptides were synthesized by GenScript, dissolved in DMSO and dispensed at-20 ℃. Streptavidin-XL665(Cat #610SAXLA) and Tb3+ cryptate labeled anti-6His antibody (Cat #61HI2TLA) were purchased from Cisbio. Source plates (PP-0200) were obtained from Labcyte, and Proxiplate-384plus target plates were obtained from Perkin Elmer. Self-preparation of reaction buffer solution: PBS, 0.1% BSA, pH 7.2.

The experimental method comprises the following steps: candidate compounds were dissolved in DMSO, applied to Source plates in concentration gradients, and then transferred to target plates using ECHO550 to give 11 concentrations. The protein and polypeptide were diluted in reaction buffer, gently mixed, and added to the target plate using Multidrop at 10. mu.l per well (working concentration of protein 5nM, working concentration of polypeptide 5 nM)100nM) were incubated at room temperature for 1 hour. Mu.l of diluted Streptavidin-XL665 and Tb3+ cryptate labeled anti-6His antibody mixture was added to each well and incubated at room temperature for one hour. Finally read with Envision Plate Reader. IC of each compound ₅₀ Obtained after fitting with XLfit.

1.3 results of the experiment

(1) The compounds of the invention have good inhibitory effect on ENL, and the specific test results are shown in the following table:

TABLE 1 HTRF and AS test results for compounds of the invention

Note: a: <100 nM; b: 100-1000 nM; c: 1000nM

(2) The dimeric form structure (shown as a-Linker-a) of the compounds of the invention is composed of the corresponding monomeric moiety (shown as a) (see table 2 below for an illustration), and the inventors have found that the activity of the dimeric structure towards ENL is further improved compared to the monomer. According to AS IC ₅₀ (nM) results showed some better improvement in dimer activity over Monomer, Monomer/dimer (AS) ratios of more than 10-fold, e.g., BV013, BV 018; some dimers show particularly good improvements in activity over the monomers, with Monomer/dimer (AS) ratios of over 100 times; for example BV008, BV012, BV024, BV025, BV026, BV 028; some dimers have greatly improved activity relative to the monomers, and Monomer/dimer (AS) ratios can even be more than 500-fold, for example BV009, BV023, BV027, BV 031.

TABLE 2 dimer compounds of the invention and corresponding monomer structures

Biological example 2: surface Plasmon Resonance (SPR) experimental materials: the ENL protein was purchased from ACTIVE MOTIF. Dissolving protein with sterile water, packaging, and storing at-80 deg.C. CM5 chips were purchased from GE, DMSO from Sigma. Source plates (PP-0200) were obtained from Labcyte, and Proxiplate-384plus target plates were obtained from Perkin Elmer.

The experimental method comprises the following steps: candidate compounds were dissolved in DMSO, applied to Source plates in concentration gradients, and then transferred to target plates using ECHO550 to give 11 concentrations. The ENL recombinant protein is coupled on a CM5 chip by adopting an amino coupling method, wherein the coupling level is 5000 RU. Each compound was tested using the north medical national focus laboratory Biacore T200.

Table 3 SPR test results for compounds of the present invention.

	SPR
		BV002	B
BV003	B
		BV008	A
BV009	A

Note: a: <100 nM; b: 100-; c: 1000nM

The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A compound of formula I, and racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof:

the R is _a Selected from H, ═ O, halogen, OH, CN, SH, NH ₂ COOH, or optionally substituted by one, two or more R _b Substituted with the following groups: c ₁ -C ₁₂ An aliphatic hydrocarbon group; the R is _b Selected from halogen, OH, CN, SH, NH ₂ ，COOH；

(in the general formula with other groups of the connecting sites, in the general formula with the left side of the group part connection, then the corresponding right side of the general formula withBall bonding); the R is _L Selected from H, ═ O, halogen, OH, CN, SH, NH ₂ COOH, or optionally substituted by one, two or more R _c Substituted with the following groups: c ₁ -C ₁₂ An aliphatic hydrocarbon group; said R is _c Selected from halogen, OH, CN, SH, NH ₂ ，COOH；

The R is ₁ 、R ₂ May be the same or different and are each independently selected from-NH-C (═ O) R ₃ ，-(CH ₂ ) _p R ₃ ，(C ₁ -C ₁₂ ) Aliphatic hydrocarbon radical, optionally containing one, two or more heteroatoms (C) ₁ -C ₁₂ ) An aliphatic hydrocarbon group;

the R is ₃ Selected from the group consisting of optionally substituted by one, two or more R _e Substituted with the following groups: c _6-20 Aryl, 5-14 membered heteroaryl or 3-12 membered heterocyclyl;

the R is _e Selected from H, -C (═ O) O-C ₁ -C ₁₂ Aliphatic hydrocarbon radical, -O-C ₁ -C ₁₂ Aliphatic hydrocarbon radical, C ₁ -C ₁₂ Aliphatic hydrocarbon group, ═ O, halogen, OH, CN, SH, NH ₂ COOH; p is selected from 0, 1,2, 3,4, 5.

2. A compound of formula I as claimed in claim 1, and racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, characterized in that:

the W is selected from the following groups: - (CH) ₂ )n-，-O-(CH ₂ )n-O-，-O-(CH ₂ )n-，-(OCH ₂ CH ₂ ) _m -O-，-(OCH ₂ CH ₂ )m-，-(CH ₂ CH ₂ O)m-CH ₂ CH ₂ -，-(CH ₂ )s-NR _s -(CH ₂ CH ₂ O)m-CH ₂ CH ₂ -NR _s -(CH ₂ )s-，-(CH ₂ )s-NR _s -(CH ₂ )n-NR _s -(CH ₂ )s-；

The Rs is selected from H and C ₁ -C ₁₂ An aliphatic hydrocarbon group;

s is selected from 0, 1, 2; said n is selected from 1 to 16, for example from 1,2, 3,4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16; said m is selected from 1 to 8, for example from 1,2, 3,4, 5,6, 7, 8.

3. A compound of formula I according to any one of claims 1-2, and racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, characterized in that:

the R is ₁ 、R ₂ Independently selected from (C) optionally containing one, two or more heteroatoms ₁ -C ₁₂ ) When the aliphatic hydrocarbon group is a group selected from- (CH) ₂ ) _q N(CH ₃ ) ₂ And q is selected from 0, 1,2 and 3.

4. A compound of formula I and racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs thereof according to any one of claims 1 to 3, wherein R is R ₃ Selected from the group consisting of optionally substituted by one, two or more R _e Substituted with the following groups: phenyl, indazole, pyrrolidine.

5. A compound of formula I according to any one of claims 1 to 4 andwherein R is selected from the group consisting of racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs and pharmaceutically acceptable salts thereof, wherein R is ₁ 、R ₂ Can be the same or different and are each independently selected from the following groups:

6. the compound of formula I and racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs thereof according to any one of claims 1 to 5, wherein the formula I structure is selected from formula Ia or formula Ib as follows:

7. The compound of formula I as claimed in any one of claims 1 to 6, wherein the structure of formula I is selected from the group consisting of following formulae II to VII:

8. A compound of formula I according to any one of claims 1 to 7, wherein formula I is selected from the following specific compounds:

9. a compound of formula I according to any one of claims 1 to 7, wherein formula I is selected from the following specific compounds:

10. a process for the preparation of a compound according to any one of claims 1 to 9, comprising the steps of: under proper conditions, raw materials containing benzimidazole structures and raw materials containing R ₁ Or R ₂ Reacting the starting materials of the group in a suitable reagent; or reacting a starting material comprising a-W-linking moiety with a starting material comprising a benzimidazole structure in a suitable reagent, or comprising both reaction steps。

11. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 9and racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof; preferably, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula I and racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs thereof or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.

12. Use of a compound of formula I according to any one of claims 1 to 9, as well as racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs thereof or pharmaceutically acceptable salts thereof or said pharmaceutical composition for the manufacture of a medicament for the prevention, modulation or treatment of diseases or disorders related to ENL-mediated disorders.

13. Use according to claim 12, wherein the ENL-mediated associated disease or condition is selected from cancer, in particular leukemia. The leukemia is selected from Acute Lymphoblastic Leukemia (ALL), Acute Myelogenous Leukemia (AML), Chronic Lymphocytic Leukemia (CLL) and Chronic Myelogenous Leukemia (CML); and some less common types. Preferably, the leukemia is AML.