WO2022166482A1 - 一种苯并咪唑类enl蛋白抑制剂及其制备方法和用途 - Google Patents

一种苯并咪唑类enl蛋白抑制剂及其制备方法和用途 Download PDF

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WO2022166482A1
WO2022166482A1 PCT/CN2021/142675 CN2021142675W WO2022166482A1 WO 2022166482 A1 WO2022166482 A1 WO 2022166482A1 CN 2021142675 W CN2021142675 W CN 2021142675W WO 2022166482 A1 WO2022166482 A1 WO 2022166482A1
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formula
compound
pharmaceutically acceptable
metabolites
acid
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French (fr)
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李海涛
林木
张士猛
李小林
吴亦钦
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清药同创(北京)药物研发中心有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/20—Two benzimidazolyl-2 radicals linked together directly or via a hydrocarbon or substituted hydrocarbon radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the invention belongs to the field of pharmaceutical compounds, in particular to a benzimidazole ENL protein inhibitor and a preparation method and application thereof.
  • Epigenetic modification plays an important role in the occurrence and development of tumors, and a variety of epigenetic regulation mechanisms have been found, including DNA methylation, histone modification, and non-coding RNA regulation. Covalent modification of histones plays an important role in gene regulation. Common histone modifications include methylation, acetylation, phosphorylation, ubiquitination, and small ubiquitination (SUMO). Different types of histone-modifying proteins or domains are called “readers" in cells. The “reader” is one of the main ways of epigenetic regulation. The “readers” of histone acetylation that have been discovered so far mainly include the bromodomain, the plant zinc finger homology domain and the YEATS domain. Abnormal expression of these domains or proteins containing these domains can lead to the occurrence and development of a series of diseases, such as cancer, inflammatory diseases, cardiovascular diseases and neurological diseases.
  • diseases such as cancer, inflammatory diseases, cardiovascular diseases and neurological diseases.
  • AF9 protein is an important class of transcriptional regulators, which can form complexes with histone H3K79 methyltransferase DOT1L and superelongation complex (SEC), respectively, and play an important regulatory role in the transcription initiation-elongation transition.
  • SEC superelongation complex
  • MLL-AF9 MLL gene
  • ENL proteins are a class of important histone acetylation "reader" epigenetic modification proteins, which play an important role in the progression of leukemia.
  • AML has a variety of cell molecular genetics and epigenetic abnormalities including abnormal expression of cell surface molecules, gene mutation and abnormal gene methylation in the process of occurrence and development, while ENL is involved in the process of leukemia. It plays an important role in maintaining the protein necessary for the occurrence and development of AML, so targeting ENL protein is a good drug target for the treatment of AML.
  • the ENL YEATS domain is important for the transcriptional control of leukemia-causing gene expression (Wan L et al, Nature, 2017, 543(7644):265.). Disrupting the interaction of the ENL YEATS domain with histone acetylation renders histone acetylation unrecognized and inhibits the growth of many types of leukemia cell lines, including MLL-r and non-MLL-r leukemia cell lines ( Wilkinson A W et al, Nature, 2017, 543(7644):186-188.). These studies all show that ENL protein is a good drug target.
  • AML Acute myeloid leukemia
  • CR complete remission
  • the present invention provides a compound represented by formula I and its racemate, stereoisomer, tautomer, isotopic label, nitrogen oxide, solvate, polyamide, etc. Crystal forms, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof:
  • Ar 1 and Ar 2 may be the same or different, and are each independently selected from the following groups optionally substituted by one, two or more R a :
  • the L 1 and L 2 can be the same or different, each independently selected from the bond, or optionally substituted by one, two or more R L (*, ** represent the connection site with other group parts of the general formula, and * represents the connection with the corresponding left group of the general formula, then ** represents the connection with the corresponding right group of the general formula);
  • the R c is selected from halogen, OH, CN, SH, NH 2 , COOH;
  • R is selected from the following groups optionally substituted by one, two or more R e : C 6-20 aryl, 5-14 membered heteroaryl or 3-12 membered heterocyclyl;
  • the Ar 1 and Ar 2 may be the same or different, and are each independently selected from the following groups (*, ** represent the attachment site to other group parts of the general formula, and * represents the The general formula corresponds to the left group part of the connection, then ** represents the connection with the corresponding right group of the general formula):
  • the W is selected from the following groups: -( CH2 )n-, -O-( CH2 )nO-, -O-( CH2 )n-, - ( OCH2CH2 ) 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 -CH2CH2-NRs-( CH2 ) s- , -( CH2 ) s -NRs-( CH2 ) n-NRs-( CH2 ) s- ;
  • the Rs is selected from H, C 1 -C 12 aliphatic hydrocarbon group
  • R 1 and R 2 are independently selected from (C 1 -C 12 ) aliphatic hydrocarbon groups optionally containing one, two or more heteroatoms, further is selected from -(CH 2 ) q N(CH 3 ) 2 , the q is selected from 0, 1, 2, 3;
  • the R 3 is selected from the following groups optionally substituted by one, two or more R e : phenyl, indazolyl, pyrrolidinyl.
  • the R 1 and R 2 may be the same or different, and each is independently selected from the following groups:
  • the "halogen" is selected from F, Cl, Br, I;
  • the (C 1 -C 12 ) aliphatic hydrocarbon group, (C 1 -C 20 ) aliphatic hydrocarbon group may be selected from (C 1 -C 20 ) aliphatic hydrocarbon group C 12 ) alkyl, (C 2 -C 12 ) alkenyl, (C 2 -C 12 ) alkynyl;
  • formula I is selected from the following formula Ia or formula Ib:
  • R 1 , R 2 , W, L 1 , and L 2 are as defined in formula I above.
  • the structure of formula I may be selected from the following formulae II-VII:
  • R 1 , R 2 , R S , s, n, m are as defined in formula I above.
  • the compounds represented by Formula I (including Formula II to Formula VII) and their racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, and solvates , polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, illustrative, non-limiting specific examples of compounds of formula I are shown below:
  • the compound of formula I may further be selected from, for example, the following structures:
  • the present invention also provides the compounds represented by the formula I (including formula II to VII) and their racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs
  • the compounds of the present invention can be synthesized using the methods described below in combination with synthetic methods known in the art of synthetic organic chemistry, or with relevant modifications recognized by those skilled in the art. Those skilled in the art know that, according to a specific target structure, one or more of the following schemes can be optionally combined, or any steps in one or more of the schemes can be combined to obtain a synthesis scheme.
  • the preparation method of the compound of the present invention comprises: under suitable conditions, reacting a raw material containing a benzimidazole structure with a raw material containing a R 1 or R 2 group in a suitable reagent; or connecting a material containing -W- The starting material of the moiety is reacted with the starting material containing the benzimidazole structure in a suitable reagent, or the two reaction steps described above are involved.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula I described in the present invention and its racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs Forms, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof.
  • the pharmaceutical composition of the present invention further comprises a therapeutically effective amount of the compound of formula I of the present invention and its racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides compounds, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers.
  • the compounds of the present invention may be used in combination with additional therapeutic agents.
  • the pharmaceutical compositions of the present invention further comprise a second therapeutic agent.
  • a carrier in the pharmaceutical composition is "acceptable" which is compatible with (and preferably, is capable of stabilizing) the active ingredient of the composition and which is not deleterious to the subject being treated.
  • One or more solubilizers can be used as pharmaceutical excipients for delivery of the active compounds.
  • the present invention further provides the compounds of formula I and their racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or Use of a pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of an ENL inhibitor.
  • the present invention further provides the compounds of formula I and their racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or Use of a pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of a medicament for preventing, regulating or treating diseases or conditions mediated by ENL.
  • the present invention also provides a method of inhibiting ENL activity in a subject, the method comprising administering a compound of the present invention as a therapeutic agent.
  • the ENL-mediated related disease or disorder is selected from cancer, in particular leukemia.
  • the leukemia is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML); and some less common types.
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • CML chronic myeloid leukemia
  • the leukemia is AML.
  • the present invention further provides a method for treating the ENL-mediated disease or condition, the 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 the compound of the present invention.
  • the present invention provides a combined formulation of a compound of the present invention and an additional therapeutic agent for simultaneous, separate or sequential use in therapy.
  • ** represent the connection site of the group and other group parts of the general formula
  • * represents the connection with the group on the left side corresponding to the general formula
  • ** represents the corresponding group of the general formula.
  • the right group is attached.
  • halogen refers to F, Cl, Br and I.
  • F, Cl, Br and I may be described as “halogens" in this specification.
  • Optionally substituted with substituents described herein encompasses both unsubstituted as well as substituted with one or more substituents, eg "optionally substituted with one, two or more R" means that there may be no substitution Substituted with R (unsubstituted) or substituted with one, two or more Rs.
  • aliphatic hydrocarbon group includes saturated or unsaturated, straight or branched chain or cyclic hydrocarbon groups, the type of the aliphatic hydrocarbon group can be selected from alkyl, alkenyl, alkynyl, etc., the carbon atoms of the aliphatic hydrocarbon group
  • the number is preferably 1-20 (specifically selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 ), the further preferred range can be 1-12, the more preferred range can be 1-6, specifically can include but not limited to the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, vinyl, 1- propenyl,
  • the "aliphatic hydrocarbon group” may optionally contain one, two or more heteroatoms (or be interpreted as optionally inserted into the aliphatic hydrocarbon group optionally with CC bonds and CH bonds). Suitable heteroatoms will be apparent to those skilled in the art and include, for example, sulfur, nitrogen, oxygen, phosphorous 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, (C 1 -C 6 ) aliphatic hydrocarbyloxy base, (C 1 -C 6 ) aliphatic hydrocarbyl mercapto, (C 1 -C 6 ) aliphatic hydrocarbyloxy (C 1 -C 6 ) aliphatic hydrocarbyl, (C 1 -C 6 ) aliphatic hydrocarbyl mercapto (C 1 -C 6 ) ) aliphatic hydrocarbyl, (C 1 -C 6 ) aliphatic hydrocarbyloxy (C 1 -C 6 ) aliphatic hydrocarbyloxy, (C 1 -C 6 ) aliphatic hydrocarbyl mercapto (C 1 -C 6 ) ) alipha
  • 3-12 membered heterocyclyl means a saturated or unsaturated monovalent monocyclic or bicyclic ring containing 1-5 heteroatoms independently selected from N, O and S, and the heteroatom-containing group does not have For aromaticity, the 3-12-membered heterocyclic group is preferably a 3-10-membered heterocyclic group.
  • 3-12 membered heterocyclyl means a saturated monovalent monocyclic or bicyclic ring containing 1-5, preferably 1-3 heteroatoms selected from N, O and S.
  • the heterocyclyl group can be attached to the remainder of the molecule through any of the carbon atoms or a nitrogen atom, if present.
  • the heterocyclic group may include, but is not limited to: 4-membered ring, such as azetidinyl, oxetanyl; 5-membered ring, such as tetrahydrofuranyl, tetrahydrothienyl, dioxane Pentenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholine group, piperazinyl, or trithianyl; or a 7-membered ring such as diazepanyl.
  • 4-membered ring such as azetidinyl, oxetanyl
  • 5-membered ring such as tetrahydrofuranyl, tetrahydrothienyl, dioxane Pentenyl,
  • the heterocyclyl group can be benzo-fused.
  • the heterocyclyl group may be bicyclic, such as, but not limited to, a 5,5 membered ring, such as a hexahydrocyclopento[c]pyrrole-2(1H)-yl ring, or a 5,6 membered bicyclic ring, such as a hexahydropyrrole
  • the [1,2-a]pyrazin-2(1H)-yl ring may be partially unsaturated, i.e.
  • the 3-12 membered heterocyclic group can also be selected from, for example, the following groups:
  • C 6-20 aryl is to be understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6-20 carbon atoms, preferably a "C 6-10 aryl” .
  • the term C 6-20 aryl is understood to preferably mean a monovalent aromaticity having 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon rings, especially those having 6 carbon atoms ("C 6 aryl”), such as phenyl; or biphenyl, or those having 9 carbon atoms a ring (“C 9 aryl”) such as indanyl or indenyl, or a ring having 10 carbon atoms (“C 10 aryl”) such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, Either a ring with 13 carbon atoms (" C13 aryl”), such as fluoren
  • 5-14 membered heteroaryl is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 5 or 6 or 9 or 10 carbon atoms, and which contain 1-5, preferably 1-3 heteroatoms independently selected from N, O and S, and, in addition, in each may be benzo-fused.
  • heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl oxazolyl, thi-4H-pyrazolyl, etc.
  • a heterocyclyl or heteroaryl group includes all possible isomeric forms thereof, such as positional isomers thereof.
  • pyridyl or pyridylene includes pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl and pyridin-4-yl;
  • thienyl or thienylene includes thien-2-yl, thien-2-yl, thien-3-yl and thien-3-yl.
  • the compounds of the present invention may be chiral and thus may exist in various enantiomeric forms. Thus these compounds may exist in racemic or optically active forms.
  • the compounds of the present invention or their intermediates can 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 the mixture by reaction with an optically active resolving agent.
  • suitable resolving agents are optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids such as N- Benzoylproline or N-benzenesulfonylproline) or various optically active camphorsulfonic acids. It is also possible to use optically active resolving agents such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel. Chromatographic enantiomeric resolution is advantageously performed. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, eg hexane/isopropanol/acetonitrile.
  • N-oxides can form N-oxides since nitrogen needs to have available lone pairs of electrons for oxidation to nitrogen oxides; those skilled in the art will recognize that N-oxides can be formed - Nitrogen-containing heterocycles of oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
  • N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), peroxyacids Hydrogen oxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane oxidize heterocycles and tertiary amines.
  • MCPBA m-chloroperoxybenzoic acid
  • Hydrogen oxide alkyl hydroperoxides such as t-butyl hydroperoxide
  • sodium perborate sodium perborate
  • dioxiranes such as dimethyldioxirane oxidize heterocycles and tertiary amines.
  • Pharmaceutically acceptable salts may be, for example, acid addition salts of sufficiently basic compounds of the invention having nitrogen atoms in the chain or ring, such as acid addition salts with inorganic acids such as hydrochloric acid, hydrofluoric acid acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or hydrogen sulfate, or acid addition salts with organic acids 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, cyclopentane Propionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, niacin, pamoic
  • alkali metal salts eg sodium or potassium salts
  • alkaline earth metal salts eg calcium or magnesium salts
  • ammonium salts or salts with organic bases that provide physiologically acceptable cations, such as salts with sodium ions, potassium ions, N-methylglucamine, dimethylglucamine, ethylglucamine, Lysine, Dicyclohexylamine, 1,6-Hexanediamine, Ethanolamine, Glucosamine, Meglumine, Sarcosine, Serinol, Trishydroxymethylaminomethane, Aminopropanediol, 1-Amino-2 , 3,4-Butanetriol.
  • such pharmaceutically acceptable salts include salts of the group -COOH with sodium ions, potassium ions, calcium ions, magnesium ions, N-methylglucamine, dimethylglucamine, Ethylglucosamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trihydroxymethylaminomethane, aminopropylene glycol , 1-amino-2,3,4-butanetriol.
  • basic nitrogen-containing groups can be quaternized with the following reagents: lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as sulfuric acid Dimethyl, diethyl, dibutyl, and dipentyl sulfates; long-chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl groups Halides such as benzyl and phenethyl bromide etc.
  • lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates such as sulfuric acid Dimethyl, diethyl, dibutyl, and dipentyl sulfates
  • long-chain halides such as decyl,
  • pharmaceutically acceptable salts include hydrochloride, sulfate, nitrate, bisulfate, hydrobromide, acetate, oxalate, citrate, mesylate, formate or Meglumine salts, etc.
  • the pharmaceutically acceptable salts include not only the salts formed on one of the salt-forming sites of the compounds of the present invention, but also 2, 3 or all of them. salts formed at the site.
  • the molar ratio of the compound of formula (I) to the acid ion (anion) or base cation required for salt formation in the pharmaceutically acceptable salt can vary within a wide range, for example, it can be 4:1 ⁇ 1:4, such as 3:1, 2:1, 1:1, 1:2, 1:3, etc.
  • the compounds of the present invention may also contain one or more asymmetric centers.
  • Asymmetric carbon atoms can exist in (R) or (S) configuration. When there is only one asymmetric center, a racemic mixture is produced, and when multiple asymmetric centers are contained, a diastereomeric mixture is obtained. In some cases, asymmetry may also exist due to hindered rotation about a particular bond, such as the central bond connecting two substituted aromatic rings of a particular compound.
  • the substituents may also exist in the form of cis or trans isomers.
  • the compounds of the present invention also include all possible stereoisomers of each, either a single stereoisomer or said stereoisomer (eg, R-isomer or S-isomer, or E-isomer or Z-isomers) in any ratio in the form of any mixture.
  • Single stereoisomers eg single enantiomers or single diastereomers
  • of the compounds of the invention can be achieved by any suitable prior art method (eg chromatography, particularly eg chiral chromatography) separation.
  • 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 present invention may exhibit tautomerism.
  • Tautomeric compounds can exist as two or more interconvertible species.
  • Proton tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms.
  • Tautomers generally exist in equilibrium, and attempts to separate individual tautomers usually result in a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the ketone form predominates; in phenols, the enol form predominates.
  • the present invention encompasses all tautomeric forms of the compounds.
  • referenced compounds also include isotopically-labeled compounds that are the same as those shown in formula I, but in which one or more atoms are assigned an atomic mass or mass number different from the usual Atomic substitution for naturally occurring atomic mass or mass number.
  • isotopes that may be incorporated into the compounds of the present 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, respectively , 17 O, 32 P, 35 S, 18 F and 36 Cl.
  • Compounds of the invention, prodrugs thereof, or pharmaceutically acceptable salts of said compounds or said prodrugs containing the above isotopes and/or other isotopes of other atoms are within the scope of the invention.
  • Certain isotopically-labeled compounds of the invention, eg, compounds incorporating radioactive isotopes such as3H and14C are useful in drug and/or substrate tissue distribution assays. Tritium (ie 3 H) and carbon 14 (ie 14 C) isotopes are particularly preferred for ease of preparation and detectability.
  • substitution with heavier isotopes may provide certain therapeutic advantages (eg, increased in vivo half - life or reduced dosage requirements) derived from greater metabolic stability, and may therefore be is preferred in some cases.
  • the compounds of the invention as claimed in the claims may in particular be substituted with deuterium or tritium.
  • the presence of hydrogen in a substituent group is not listed individually.
  • deuterium or tritium does not imply the exclusion of deuterium or tritium, but may equally well include deuterium or tritium.
  • an effective amount refers to an amount of a compound of the present invention sufficient to achieve the intended application, including but not limited to disease treatment as defined below.
  • a therapeutically effective amount may vary depending on 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., which It can be easily determined by one of ordinary skill in the art.
  • the specific dose will vary depending on the particular compound chosen, the dosing regimen followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system on which it is carried.
  • solvates are those forms of the compounds of the present invention which, in solid or liquid state, form complexes by coordination with solvent molecules. Hydrates are a specific form of solvates in which the coordination is with water. In the present invention, preferred solvates are hydrates. Further, the pharmaceutically acceptable solvates (hydrates) of the compounds of the general formula I of the present invention refer to co-crystals and clathrates formed by the compound I with stoichiometric one or more molecules of water or other solvents.
  • Useful solvents for solvates include, but are not limited to, water, methanol, ethanol, ethylene glycol, and acetic acid.
  • prodrug refers to the in vivo conversion of a compound to a compound of the aforementioned general formula or specific compound. Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue.
  • the prodrugs of the present invention can be esters.
  • esters can be used as prodrugs including phenyl esters, aliphatic esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters.
  • a compound of the present invention contains a hydroxyl/carboxyl group, which can be acylated to give the compound in the form of a prodrug.
  • Other prodrug forms include phosphates, such as these phosphates are phosphorylated by the hydroxyl group on the parent.
  • the present invention provides a compound of general formula I with novel structure, which has a good inhibitory effect on ENL.
  • LC-MS adopts Agilent 1260-6120 system equipped with Waters Cortecs C18, 2.7 ⁇ m, 4.6 ⁇ 30 mm column; HPLC adopts Waters Acquity UPLC H-class instrument equipped with Acquity BEH C18, 1.7 ⁇ m, 50 ⁇ 2.1 mm column.
  • T 3 P 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphoric acid-2,4,6-trioxide or tripropylphosphoric anhydride
  • BV021 is the abbreviation of PI1701-BV021-1, both of which point to the same compound structure.
  • the rest of the compound numbers can be understood with reference to this example.
  • N,N-Dimethyl-1-(5-nitro-1H-benzo[d]imidazol-2-yl)dimethylamine (4.5 g, 0.02 mol) was dissolved in methanol (50 mL) and palladium was added Carbon (0.87 g, 80 mmol). The system was stirred at 25°C for 14 hours. The mixture was filtered, and the organic phase was concentrated to give the title compound (3.5 g, 90%) as a yellow oily liquid.
  • Step 3 tert-Butyl 4-((2-((dimethylamino)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)benzoate
  • Step 4 4-((2-((Dimethylamino)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)benzoic acid
  • Step 5 N1,N1 ' -(ethane-1,2-diyl)bis(N4-( 2 -((dimethylamino)methyl)-1H-benzo[d]imidazole-5 - base) terephthalamide)
  • Example 2 The following compounds were further synthesized with reference to the synthetic method of Example 1:
  • Step 1 Di-tert-butyl O,O'-(pentane-1,5-diyl)diterephthalate
  • Step 2 4,4'-((pentane-1,5-diylbis(oxy))bis(carbonyl))dibenzoic acid
  • Example 4 The following compounds were synthesized with reference to the synthetic method of Example 3:
  • Step 1 N1, N7 -dibenzyl-N1,N7 - dimethylheptane- 1,7 -diamine
  • 1,7-Dibromoheptane (5.0 g, 19 mmol), N-methylbenzylamine (5.2 g, 42 mmol) and cesium carbonate (13 g, 39 mmol) were dissolved in DMF (50 mL). After the system was stirred at 80°C for 16 hours, the mixture was dissolved in ethyl acetate (50 mL) and washed with 20 mL of water 3 times. The organic phase was dried over anhydrous sodium sulfate and concentrated, followed by column chromatography (40 g silica gel, 10% methanol in dichloromethane) to give the title compound (2.3 g, 35% yield) as a yellow oily liquid.
  • Step 2 N1,N7 - dimethylheptane-1,7-diamine
  • N1, N7 -dibenzyl - N1,N7 - dimethylheptane- 1,7 -diamine (2.3 g, 0.01 mol) was dissolved in 100 mL methanol and palladium on carbon (0.30 g) was added. After the system was stirred at 25°C for 14 hours under a hydrogen atmosphere, the mixture was filtered through celite to obtain 1.2 g of the crude title compound as a brown gummy solid.
  • Step 3 N1,N7-Dimethyl-N1, N7 -bis(( 5 -nitro-1H-benzo[d]imidazol- 2 -yl)methyl)heptane-1,7- Diamine
  • Step 4 N1,N7-bis(( 5 -amino-1H-benzo[d]imidazol-2-yl)methyl) -N1 ,N7-dimethylheptane - 1,7-di amine
  • N 1 ,N 7 -dimethyl-N 1 ,N 7 -bis((5-nitro-1H-benzo[d]imidazol-2-yl)methyl)heptane-1,7-diamine (0.62 g, 1.2 mmol) was dissolved in 10 mL of methanol and palladium on carbon (78 mg, 0.73 mmol) was added. Under a hydrogen atmosphere, the system was stirred at 25°C for 16 hours. The mixture was filtered through celite and concentrated to give the title compound (0.40 g, 73%) as a red liquid.
  • Step 5 4,4'-((((((heptane-1,7-diylbis(methylazacyclobi))bis(methylene))bis(1H-benzo[d]imidazole- Dimethyl 2,5-diyl))bis(azadienyl))bis(carbonyl)dibenzoate
  • 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'-tetramethylurea Hexafluorophosphate (0.23 g, 0.60 mmol), N,N-diisopropylethylamine (0.10 g, 0.80 mmol) were dissolved in DMF (5 mL), and the reaction system was stirred at 25°C for 14 hours.
  • Example 6 The following compounds were synthesized with reference to the synthetic method of Example 5:
  • His-tagged human ENL protein was purchased from ACTIVE MOTIF (Cat#81098). Proteins were dissolved in sterile water and stored at -80°C after aliquoting. Biotin-labeled peptides were synthesized by GenScript, dissolved in DMSO and stored in aliquots at -20°C. Hisdidine Detection Kit (Nickel Chelate) (6760619M) was purchased from PerkinElmer. The Source plate (PP-0200) was purchased from Labcyte, and the Proxiplate-384plus target plate was purchased from Perkin Elmer (Cat#6008280). The reaction buffer was prepared in-house: 50 mM HEPES, 0.005% Brij35, 1 mM TCEP, pH 7.4.
  • the candidate compound was dissolved in DMSO, added to the source plate according to a certain concentration gradient, and then the compound was transferred to the target plate with ECHO550 to form 11 concentrations.
  • Proteins and peptides were diluted with reaction buffer, mixed gently, and 10 ⁇ l per well was added to the target plate with Multidrop (the working concentration of protein was 5nM, and the working concentration of peptide was 30nM), and incubated at room temperature for 1 hour. Add 10 ⁇ l Donor/Acceptor beads (working concentration 15 ⁇ g/mL) to each well and incubate at room temperature for one hour. Finally read with Envision Plate Reader. The IC50 for each compound was obtained after fitting with XLfit.
  • His-tagged human ENL protein was purchased from ACTIVE MOTIF (Cat#81098). Proteins were dissolved in sterile water and stored at -80°C after aliquoting. Biotin-labeled peptides were synthesized by GenScript, dissolved in DMSO and stored in aliquots at -20°C. Streptavidin-XL665 (Cat#610SAXLA) and Tb3+cryptate labeled anti-6His antibody (Cat#61HI2TLA) were purchased from Cisbio. Source plate (PP-0200) was purchased from Labcyte Company, Proxiplate-384plus target plate was purchased from Perkin Elmer Company. The reaction buffer was prepared by itself: PBS, 0.1% BSA, pH 7.2.
  • the candidate compound was dissolved in DMSO, added to the source plate according to a certain concentration gradient, and then the compound was transferred to the target plate with ECHO550 to form 11 concentrations.
  • Proteins and peptides were diluted with reaction buffer, mixed gently, and 10 ⁇ l per well was added to the target plate with Multidrop (the working concentration of protein was 5nM and the working concentration of peptide was 100nM), and incubated at room temperature for 1 hour.
  • Add 10 ⁇ l of the diluted mixture of Streptavidin-XL665 and Tb3+cryptate labeled anti-6His antibody to each well and incubate for one hour at room temperature. Finally read with Envision Plate Reader. The IC50 for each compound was obtained after fitting with XLfit.
  • A-Linker-A The structure of the dimer form of the compound of the present invention (shown as A-Linker-A) is composed of the corresponding monomer structure part (shown as A) (refer to Table 2 below), the inventors found that the dimer structure is directed to The activity of ENL is further improved compared to the monomer.
  • the Monomer/Dimer (AS) ratio is more than 10 times, such as BV013, BV018; some dimers are relative to The activity of the monomer has been particularly improved, and the Monomer/Dimer(AS) ratio has reached more than 100 times; for example, BV008, BV012, BV024, BV025, BV026, BV028; some dimers have a great degree of activity relative to the monomer. Improvement, the Monomer/Dimer(AS) ratio can even reach more than 500 times, such as BV009, BV023, BV027, BV031.
  • PI1701-BV002-1 ⁇ OCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 O ⁇ PI1701-BV008-1
  • PI1701-BV003-1 ⁇ NH(CH 2 ) 5 NH ⁇ PI1701-BV009-1
  • PI1701-BV003-1 ⁇ NHCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 NH ⁇ PI1701-BV012-1
  • PI1701-LY160-1 ⁇ (CH 2 ) 5 ⁇ PI1701-BV023-1
  • PI1701-LY160-1 ⁇ (CH 2 ) 4 ⁇ PI1701-BV024-1
  • PI1701-LY160-1 ⁇ (CH 2 ) 3 ⁇ PI1701-BV025-1
  • PI1701-LY160-1 ⁇ (CH 2 ) 2 ⁇ PI1701-BV026-1
  • PI1701-LY160-1 ⁇ CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2
  • ENL protein was purchased from ACTIVE MOTIF Company. Proteins were dissolved in sterile water and stored at -80°C after aliquoting.
  • CM5 chip was purchased from GE Company, and DMSO was purchased from Sigma Company.
  • Source plate PP-0200 was purchased from Labcyte Company, Proxiplate-384plus target plate was purchased from Perkin Elmer Company.
  • the candidate compound was dissolved in DMSO, added to the source plate according to a certain concentration gradient, and then the compound was transferred to the target plate with ECHO550 to form 11 concentrations.
  • the above-mentioned ENL recombinant protein was coupled to the CM5 chip by the method of amino coupling, and the coupling level was 5000RU.
  • Each compound was tested by Biacore T200 of the State Key Laboratory of Bei Medicine.

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Abstract

一种式I所示的苯并咪唑类ENL抑制剂化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐，以及包含其的药物组合物，其制备方法，及其医药用途，所述式I结构如下。

Description

一种苯并咪唑类ENL蛋白抑制剂及其制备方法和用途
本申请要求享有申请人于2021年2月4日向中国国家知识产权局提交的，专利申请号为202110166935.7，发明名称为“一种苯并咪唑类ENL蛋白抑制剂及其制备方法和用途”的在先申请的优先权。该在先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明属于药物化合物领域，具体涉及一种苯并咪唑类ENL蛋白抑制剂及其制备方法和用途。
背景技术
表观遗传学修饰在肿瘤的发生发展过程中起到重要作用，现已发现有多种表观遗传学调控机制，包括DNA甲基化、组蛋白修饰、非编码RNA调控等。组蛋白的共价修饰在基因调控中发挥着重要的作用。常见的组蛋白修饰方式包括甲基化、乙酰化、磷酸化、泛素化和小类泛素化(SUMO)等。细胞内可以特异性识别各种不同类型的组蛋白修饰蛋白或结构域称为“阅读器”。“阅读器”是表观遗传调控的主要方式之一，目前已发现的组蛋白乙酰化“阅读器”主要包括溴结构域、植物锌指同源结构域和YEATS结构域。这些结构域或含此结构域的蛋白异常表达会导致一系列疾病的发生发展，如癌症、炎性疾病、心血管疾病及神经***疾病。
AF9蛋白是一类重要的转录调控因子，可以分别与组蛋白H3K79甲基化转移酶DOT1L和超级延伸复合物(SEC)形成复合物，在转录起始-延伸转换过程中发挥着重要调控作用。同时，临床遗传学研究表明AF9基因和MLL基因的融合(MLL-AF9)作为最常见的MLL重排类型，是导致人类急性髓细胞白血病(AML)以及急性淋巴性白血病(ALL)等疾病的驱动性因素。进一步的细胞生物学和功能基因组学研究发现，人AF9与H3K9ac修饰在全基因组水平有强烈的共定位，并且调控了包括MYC、BMP2、HOXA基因簇在内的细胞增殖分化基因的表达；研究表明AF9通过识别组蛋白H3K9乙酰化修饰，招募DOTL1到特定染色质区段，促进了组蛋白H3K79甲基化的共沉积和基因活化，揭示出一种新型组蛋白修饰交叉会话机制，体现了真核生物表观遗传调控的复杂和精密性。目前自然界中鉴定出的含YEATS结构域的蛋白已达数百个，遍布于70多个不同物种，从酵母到人类都保守存在。含有YEATS结构域的蛋白因子，如AF9、ENL、GAS41等，不仅与转录调控密切相关，它们的调控异常通常会导致白血病、癌症等人类疾病的发生。
其中，ENL蛋白是一类重要的组蛋白乙酰化“阅读器”表观遗传修饰蛋白，在白血病进程中发挥重要作用。研究表明，发现AML在发生、发展的过程中存在包括细胞表面分子异常表达、基因突变和基因异常甲基化等多种细胞分子遗传学及表观遗传学方面的异常，而ENL在白血病进程中发挥重要作用，是维持AML的发生和发展过程中所必需的蛋白，因此靶向ENL蛋白是治疗AML的一个良好的药物靶点。2017年，Nature同时发表两个研究团队关于ENL蛋白的研究成果。证实ENL蛋白是影响白血病MLL-r细胞存活能力的关键因子。ENL YEATS结 构域对引起白血病的基因表达的转录控制很重要(Wan L et al,Nature,2017,543(7644):265.)。扰乱ENL YEATS结构域与组蛋白乙酰化的相互作用可使之无法识别到组蛋白乙酰化，会抑制多种类型白血病细胞系的生长，包括MLL-r细胞系和非MLL-r白血病细胞系(Wilkinson A W et al,Nature,2017,543(7644):186-188.)。这些研究均表明ENL蛋白是一个良好的药物靶点。急性髓性白血病(AML)是一种复杂的血液疾病，以血液或骨髓中白血病原始细胞的增加为特征。是成人白血病中最常见的急性白血病类型，约占成人白血病发病率的70％。近几年，随着联合化疗手段的不断发展，AML的治愈率有所提高，但仍有40％左右的患者不能达到完全缓解(CR)，且AML的预后较差，即使达到CR，年轻患者仅有40％-50％有5年生存期，而老年患者的平均生存期不足1年，患者总体的5年生存率仅为26.9％。AML的反复发作和化疗耐药仍是该领域的治疗难题。
目前，3种组蛋白乙酰化“阅读器”只有溴结构域的抑制剂-BET抑制剂处于活跃的研发状态，尚无ENL抑制剂进入临床阶段。因此，亟需开发一类结构新颖的，活性好且更加安全有效的ENL抑制剂。
发明内容
为解决现有技术中存在的问题，本发明提供一种式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐：
Figure PCTCN2021142675-appb-000001
其中，所述Ar 1，Ar 2可以相同或不同，各自独立地选自任选被一个、两个或更多个R a取代的如下基团：
Figure PCTCN2021142675-appb-000002
所述R a选自H，＝O，卤素，OH，CN，SH，NH 2，COOH，或任选被一个、两个或更多个R b取代的如下基团：C 1-C 12脂肪烃基；所述R b选自卤素，OH，CN，SH，NH 2，COOH；
所述L 1、L 2可以相同或不同，各自独立的选自键，或任选被一个、两个或更多个R L取代的
Figure PCTCN2021142675-appb-000003
(以*，**表示与通式其他基团部分的连接位点，以*代表与通式对应左侧基团部分连接，则**表示与通式对应右侧基团连接)；所述R L选自H，＝O，卤素，OH，CN，SH，NH 2，COOH，或任选被一个、两个或更多个R c取代的如下基团：C 1-C 12脂肪烃基；所述R c选自卤素，OH，CN，SH，NH 2，COOH；
所述W选自(C 1-C 20)脂肪烃基，任选地包含一个、两个或更多个杂原子的(C 1-C 20)脂肪烃基；所述W任选被一个、两个或更多个R W取代；所述R W选自H，＝O，卤素，OH，CN，SH，NH 2，COOH，或任选被一个、两个或更多个R d取代的如下基团：C 1-C 12脂肪烃基； 所述R d选自卤素，OH，CN，SH，NH 2，COOH；
所述R 1、R 2可以相同或不同，各自独立的选自-NH-C(＝O)R 3，-(CH 2) pR 3，(C 1-C 12)脂肪烃基，任选地包含一个、两个或更多个杂原子的(C 1-C 12)脂肪烃基；
所述R 3选自任选被一个、两个或更多个R e取代的如下基团：C 6-20芳基，5-14元杂芳基或3-12元杂环基；
所述R e选自H，-C(＝O)O-C 1-C 12脂肪烃基，-O-C 1-C 12脂肪烃基，C 1-C 12脂肪烃基，＝O，卤素，OH，CN，SH，NH 2，COOH；p选自0，1，2，3，4，5；
根据本发明的实施方案，所述Ar 1，Ar 2可以相同或不同，各自独立地选自如下基团(以*，**表示与通式其他基团部分的连接位点，以*代表与通式对应左侧基团部分连接，则**表示与通式对应右侧基团连接)：
Figure PCTCN2021142675-appb-000004
根据本发明的实施方案，所述W选自如下基团：-(CH 2)n-，-O-(CH 2)n-O-，-O-(CH 2)n-，-(OCH 2CH 2) m-O-，-(OCH 2CH 2)m-，-(CH 2CH 2O)m-CH 2CH 2-，-(CH 2)s-NR s-(CH 2CH 2O)m-CH 2CH 2-NR s-(CH 2)s-，-(CH 2)s-NR s-(CH 2)n-NR s-(CH 2)s-；
所述Rs选自H，C 1-C 12脂肪烃基；
所述s选自0，1，2；所述n选自1-16，例如选自1，2，3，4，5，6，7，8，9，10，11，12，13，14，15，16；所述m选自1-8，例如选自1，2，3，4，5，6，7，8；
根据本发明的实施方案，优选的，当所述R 1、R 2独立的选自任选地包含一个、两个或更多个杂原子的(C 1-C 12)脂肪烃基时，可以进一步选自-(CH 2) qN(CH 3) 2，所述q选自0，1，2，3；
根据本发明的实施方案，优选的，所述R 3选自任选被一个、两个或更多个R e取代的如下基团：苯基，吲唑基，吡咯烷基。
根据本发明的实施方案，优选的，所述R 1、R 2可以相同或不同，各自独立的选自如下基团：
Figure PCTCN2021142675-appb-000005
根据本发明的实施方案，所述“卤素”选自F、Cl、Br、I；所述(C 1-C 12)脂肪烃基，(C 1-C 20)脂肪烃基可以选自(C 1-C 12)烷基、(C 2-C 12)烯基、(C 2-C 12)炔基；
根据本发明的实施方案，所述式I结构选自如下式Ia或式Ib：
Figure PCTCN2021142675-appb-000006
Figure PCTCN2021142675-appb-000007
所述式Ia结构中，R 1、R 2、W、L 1、L 2如前述式I所定义。
根据本发明的实施方案，所述式I结构可以选自如下式II-VII：
Figure PCTCN2021142675-appb-000008
Figure PCTCN2021142675-appb-000009
所述式II-VII结构中，R 1、R 2、R S、s，n，m如上前述式I所定义。
根据本发明的实施方案，所述式I(包括式II至式VII)所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐中，式I化合物的举例性的、非限制性的具体实例如下所示：
Figure PCTCN2021142675-appb-000010
Figure PCTCN2021142675-appb-000011
Figure PCTCN2021142675-appb-000012
Figure PCTCN2021142675-appb-000013
根据本发明的实施方案，所述式I化合物还可以进一步选自例如如下结构：
Figure PCTCN2021142675-appb-000014
本发明还提供所述式I所示的化合物(包括式II至式VII)及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐的制备方法，但不仅限于以下描述的方法。所有的原料都是根据符合通式规律的目标分子的基团特征，并通过这些路线中的方案、有机化学领域普通技术人员熟知的方法制备或者直接购买的。可将用下述方法和合成有机化学领域中已知的合成方法或本领域技术人 员意识到的有关改变方法结合在一起，合成本发明化合物。本领域技术人员可知，根据特定的目标结构，可以任选采用下述一种或几种方案进行结合，或者一种或几种方案中的任意步骤进行组合得到合成方案。
本发明所述化合物的制备方法包括：在合适的条件下，将含苯并咪唑结构的原料与含有R 1或R 2基团的原料在合适的试剂中进行反应；或者将含有-W-连接结构部分的原料与含有苯并咪唑结构的原料在合适的试剂中进行反应，或者包含前述两个反应步骤。
本发明进一步提供一种药物组合物，其包含本发明所述的式I化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐。
在一些实施方案中，本发明所述的药物组合物进一步包含治疗有效量的本发明所述式I化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐和药学上可接受的载体。
根据本发明的实施方案，本发明的化合物可以与另外的治疗剂组合使用。本发明所述的药物组合物进一步包含第二种治疗剂。
所述药物组合物中的载体为“可接受的”，其可与组合物的活性成分相容(并且优选地，能够稳定活性成分)并且对被治疗的受试者不是有害的。可以使用一种或多种增溶剂作为药物赋形剂用于递送活性化合物。
本发明进一步提供所述式I化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐或所述药物组合物在制备ENL抑制剂中的应用。
本发明进一步提供所述式I化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐或所述药物组合物在制备预防，调节或治疗与ENL介导的有关疾病或病症的药物中的用途。
本发明还提供了一种在受试者中抑制ENL活性的方法，该方法包括给予本发明所述化合物作为治疗剂。
根据本发明的实施方案，所述ENL介导的有关疾病或病症选自癌症，具体的为白血病。所述白血病选自急性淋巴母细胞性白血病(ALL)、急性髓细胞性白血病(AML)、慢性淋巴细胞性白血病(CLL)和慢性髓细胞性白血病(CML)；以及一些不太常见的类型。优选的，所述白血病为AML。
本发明进一步提供了一种用于治疗所述ENL介导的有关疾病或病症的方法，所述方法包括向有需要的患者施用治疗有效量的第一和第二治疗剂，其中第一治疗剂是本发明的化合物。在一些实施方案中，本发明提供了本发明所述化合物与另外的治疗剂的组合制剂，用于在治疗中同时，分开或依次使用。
术语解释：
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围。
本申请说明书和权利要求书记载的数值范围，当该数值范围被定义为“整数”时或按照本领域常规理解通常为“整数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如，“0～6”表示碳数时，应当理解为记载了0、1、2、3、4、5和6的每一个整数。“更多个”表示三个或三个以上。
本文所述基团定义中，以*，**表示基团与通式其他基团部分的连接位点，以*代表与通式对应左侧基团部分连接，则**表示与通式对应右侧基团连接。
术语“卤素”指F、Cl、Br和I。换言之，F、Cl、Br和I在本说明书中可描述为“卤素”。
本文所述任选的被取代基所取代的情形涵盖了无取代以及被一个或多个取代基所取代的情形，例如“任选被一个、两个或更多个R取代”意味着可以不被R取代(无取代)或被一个、两个或更多个R取代。
术语“脂肪烃基”包括饱和或不饱和，直链或支链的链状或环状烃基，所述脂肪烃基的类型可选自烷基、烯基、炔基等，所述脂肪烃基的碳原子数优选为1-20(具体的选自1，2，3，4，5，6，7，8，9，10，11，12，13，14，15，16，17，18，19，20)，进一步优选的范围可以为1-12，更优选的范围可以为1-6，具体可包括但不限于如下基团：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基、乙烯基、1-丙烯基、2-丙烯基、1-甲基乙烯基、1-丁烯基、1-乙基乙烯基、1-甲基-2-丙烯基、2-丁烯基、3-丁烯基、2-甲基-1-丙烯基、2-甲基-2-丙烯基、1-戊烯基、1-己烯基、乙炔基，1-丙炔基，2-丙炔基，1-丁炔基，1-甲基-2-丙炔基，3-丁炔基，1-戊炔基、1-己炔基、环丙基、环丁基、环戊基和环己基；
所述“脂肪烃基”可以任选地包含一个、两个或更多个杂原子(或解释为任选地杂原子***至脂肪烃基中任选地C-C键和C-H键)。适宜的杂原子对于本领域技术人员而言是显而易见的，并且包括例如硫、氮、氧、磷和硅。所述包含杂原子的脂肪烃基基团可选自以下基团：(C 1-C 12)脂肪烃基氧基、(C 1-C 12)脂肪烃基巯基，(C 1-C 6)脂肪烃基氧基，(C 1-C 6)脂肪烃基巯基，(C 1-C 6)脂肪烃基氧基(C 1-C 6)脂肪烃基、(C 1-C 6)脂肪烃基巯基(C 1-C 6)脂肪烃基、(C 1-C 6)脂肪烃基氧基(C 1-C 6)脂肪烃基氧基、(C 1-C 6)脂肪烃基巯基(C 1-C 6)脂肪烃基巯基、N-(C 1-C 3)脂肪烃基胺基(C 1-C 6)脂肪烃基、N,N-二-(C 1-C 3)脂肪烃基胺基(C 1-C 6)脂肪烃基；例如可以为甲氧基，乙氧基，丙氧基，丁氧基，戊氧基，甲氧基甲基，乙氧基甲基、丙氧基甲基、甲氧基乙基、乙氧基乙基、丙氧基乙基、甲氧基丙基、乙氧基丙基、丙氧基丙基、N-甲基胺甲基、N-甲基胺乙基、N-乙基胺乙基、N,N-二甲基胺甲基、N,N-二甲基胺乙基、N,N-二乙基胺乙基；其他基团中所含“脂肪烃基”部分同上述解释。
术语“3-12元杂环基”意指饱和或不饱和的一价单环或双环，其包含1-5个独立选自N、O和S的杂原子，含杂原子的基团不具有芳香性，所述3-12元杂环基，优选3-10元杂环基。术语3-12元杂环基意指饱和的一价单环或双环，其包含1-5个，优选1-3个选自N、O和S的杂原子。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地，所述杂环基可以包括但不限于：4元环，如氮杂环丁烷基、氧杂环丁烷基；5元环，如四氢呋喃基、四氢噻吩基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基；或6元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基；或7元环，如二氮杂环庚烷基。任选地，所述杂环基可以是苯并稠合的。 所述杂环基可以是双环的，例如但不限于5,5元环，如六氢环戊并[c]吡咯-2(1H)-基环，或者5,6元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的，即它可以包含一个或多个双键，例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4]噻嗪基，或者，它可以是苯并稠合的，例如但不限于二氢异喹啉基，2,3-二氢苯并呋喃基，3,4-二氢-2H-1-苯并吡喃基(色烷基)，2,3-二氢苯并[b][1,4]二噁烷基。所述3-12元杂环基还可以选自例如如下基团：
Figure PCTCN2021142675-appb-000015
术语“C 6-20芳基”应理解为优选表示具有6-20个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环，优选“C 6-10芳基”。术语C 6-20芳基应理解为优选表示具有6、7、8、9、10、11、12、13、14、15、16、17、18、19、20个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环，特别是具有6个碳原子的环(“C 6芳基”)，例如苯基；或联苯基，或者是具有9个碳原子的环(“C 9芳基”)，例如茚满基或茚基，或者是具有10个碳原子的环(“C 10芳基”)，例如四氢化萘基、二氢萘基或萘基，或者是具有13个碳原子的环(“C 13芳基”)，例如芴基，或者是具有14个碳原子的环(“C 14芳基”)，例如蒽基。
术语“5-14元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系：其具有5、6、7、8、9、10、11、12、13或14个环原子，特别是5或6或9或10个碳原子，且其包含1-5个，优选1-3个独立选自N、O和S的杂原子，并且，另外在每一种情况下可为苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、***基、噻二唑基、噻-4H-吡唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并***基、吲唑基、吲哚基、异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物，例如喹啉基、喹唑啉基、异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。
除非另有说明，杂环基或杂芳基包括其所有可能的异构形式，例如其位置异构体。因此，对于一些说明性的非限制性实例，吡啶基或亚吡啶基包括吡啶-2-基、亚吡啶-2-基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基；噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基。
根据其分子结构，本发明的化合物可以是手性的，因此可能存在各种对映异构体形式。因而这些化合物可以以消旋体形式或光学活性形式存在。本发明的化合物或其中间体可以通过本领域技术人员公知的化学或物理方法分离为对映异构体化合物，或者以此形式用于合成。在外消旋的胺的情况中，通过与光学活性的拆分试剂反应，从混合物制得非对映异构体。适当的拆分试剂的示例是光学活性的酸，例如R和S形式的酒石酸、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸、乳酸、适当的N-保护的氨基酸(例如N-苯甲酰脯氨酸或N-苯磺酰基脯氨酸)或各种光学活性的樟脑磺酸。借助光学活性的拆分试剂(例如固定在硅胶上的二硝 基苯甲酰基苯基甘氨酸、三乙酸纤维素或其它碳水化合物的衍生物或手性衍生化的异丁烯酸酯聚合物)，也可有利地进行色谱对映体拆分。用于此目的的适当的洗脱剂是含水或含醇的溶剂混合物，例如，己烷/异丙醇/乙腈。
本领域技术人员将理解，由于氮需要具有可用的孤对电子用于被氧化为氮氧化物，因此并非所有的含氮杂环都可以形成N-氧化物；本领域技术人员将识别能够形成N-氧化物的含氮杂环。本领域技术人员还将认识到叔胺能够形成N-氧化物。制备杂环和叔胺的N-氧化物的合成方法对于本领域技术人员而言是熟知的，所述合成方法包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(MCPBA)、过氧化氢、烷基氢过氧化物如叔丁基氢过氧化物、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷氧化杂环和叔胺。这些制备N-氧化物的方法已在文献中广泛地描述和综述。
药学上可接受的盐可以是例如在链或环中具有氮原子的具有足够碱性的本发明的化合物的酸加成盐，例如与如下无机酸形成的酸加成盐：例如盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸或硝酸，或硫酸氢盐、或者与如下有机酸形成的酸加成盐：例如甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸、3-羟基-2-萘甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸。
另外，具有足够酸性的本发明的化合物的另一种适合的药学上可接受的盐是碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如钙盐或镁盐)、铵盐，或与提供生理学可接受的阳离子的有机碱形成的盐，例如与如下物质形成的盐：钠离子、钾离子、N-甲基葡糖胺、二甲基葡糖胺、乙基葡糖胺、赖氨酸、二环己基胺、1,6-己二胺、乙醇胺、葡糖胺、葡甲胺、肌氨酸、丝氨醇、三羟基甲基氨基甲烷、氨基丙二醇、1-氨基-2,3,4-丁三醇。作为实例，所述药学上可接受的盐包括基团-COOH与如下物质形成的盐：钠离子、钾离子、钙离子、镁离子、N-甲基葡糖胺、二甲基葡糖胺、乙基葡糖胺、赖氨酸、二环己基胺、1,6-己二胺、乙醇胺、葡糖胺、葡甲胺、肌氨酸、丝氨醇、三羟基甲基氨基甲烷、氨基丙二醇、1-氨基-2,3,4-丁三醇。
另外，碱性含氮基团可用如下试剂季铵化：低级烷基卤化物，例如甲基、乙基、丙基和丁基氯化物、溴化物和碘化物；硫酸二烷基酯，例如硫酸二甲酯、硫酸二乙酯、硫酸二丁酯和硫酸二戊酯；长链卤化物，例如癸基、月桂基、肉豆蔻基和硬脂基氯化物、溴化物和碘化物；芳烷基卤化物如苄基和苯乙基溴化物等。作为实例，药学上可接受的盐包括盐酸盐、硫酸盐、硝酸盐、硫酸氢盐、氢溴酸盐、醋酸盐、草酸盐、柠檬酸盐、甲磺酸盐、甲酸盐或葡甲胺盐等。
由于本发明的化合物可存在多个成盐位点，所述药学上可接受的盐不仅包括本发明化合物其中1个成盐位点上形成的盐，而且还包括其中2、3或全部成盐位点上形成的盐。为此，所述药学上可接受的盐中式(I)化合物与成盐所需的酸的根离子(阴离子)或碱的阳离子摩尔比可以在较大的范围内变化，例如可以是4:1～1:4，如3:1、2:1、1:1、1:2、1:3等。
根据不同取代基的位置和性质，本发明的化合物还可以包含一个或多个不对称中心。不 对称碳原子可以(R)或(S)构型存在，仅有一个不对称中心时，产生外消旋混合物，含有多个不对称中心时，得到非对映异构体混合物。在某些情况下，由于围绕特定键的旋转受阻还可能存在不对称性，例如该中心键连接特定化合物的两个被取代的芳族环。并且，取代基还可以顺式或反式异构的形式存在。
本发明化合物还包括其各自所有可能的立体异构体，其是单一立体异构体或所述立体异构体(例如R-异构体或S-异构体，或者E-异构体或Z-异构体)的任意比例的任意混合物的形式。可通过任意适合的现有技术方法(例如色谱法，特别是例如手性色谱法)实现本发明的化合物的单一立体异构体(例如单一对映异构体或单一非对映异构体)的分离。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。
在本发明中，所涉及的化合物亦包括经同位素标记的化合物，所述经同位素标记的化合物与式I中所示的那些相同，但是其中一或多个原子被原子质量或质量数不同于通常天然存在的原子质量或质量数的原子替代。可掺入本发明的化合物的同位素的实例包括H、C、N、O、S、F及Cl的同位素，分别诸如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 32P、 35S、 18F及 36Cl。含有上述同位素和/或其他原子的其他同位素的本发明的化合物、其前药、或者所述化合物或所述前药的药学上可接受的盐在本发明的范围内。本发明的某些经同位素标记的化合物，例如掺入放射性同位素(诸如 3H和 14C)的化合物可用于药物和/或底物组织分布测定。氚(即 3H)和碳14(即 14C)同位素因易于制备和可检测性而成为特别优选的。再者，以较重的同位素(诸如氘，即 2H)替代可提供源自更高的代谢稳定性的某些治疗优势(例如增加的体内半衰期或减少的剂量需求)，并因此可在某些情况下是优选的。如权利要求所请求保护的本发明化合物可特别地限定以氘或氚替代。此外，取代基中出现的氢未单独列明术语氘或氚并不表示排除氘或氚，而是同样也可以包含氘或氚。
术语“有效量”或者“治疗有效量”是指足以实现预期应用(包括但不限于如下定义的疾病治疗)的本发明所述化合物的量。治疗有效量可以取决于以下因素而改变：预期应用(体外或者体内)，或者所治疗的受试者和疾病病症如受试者的重量和年龄、疾病病症的严重性和给药方式等，其可以由本领域普通技术人员容易地确定。具体剂量将取决于以下因素而改变：所选择的特定化合物、所依据的给药方案、是否与其它化合物组合给药、给药的时间安排、所给药的组织和所承载的物理递送***。
术语“溶剂化物”是本发明的化合物的那些形式，其以固体或液体的状态通过与溶剂分子的配位作用形成配合物。水合物是溶剂化物的特定形式，其中配位作用是与水进行。在本发明中，优选的溶剂化物是水合物。进一步的，本发明通式I化合物的药学上可接受的溶剂化物(水合物)是指化合物I与化学计量学的一个或多个分子的水或其他溶剂形成的共晶和包合物。可用于溶剂化物的溶剂包括但不限于：水、甲醇、乙醇、乙二醇和醋酸。
术语“前药”或称为“药物前体”，代表化合物在体内转化为前述通式或具体化合物所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。 本发明前药可以是酯，在本发明中酯可以作为前药的有苯酯类，脂肪族酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基/羧基，即可以将其酰化得到前体药物形式的化合物。其他的前药形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。
有益效果
本发明提供了结构新颖的通式I化合物，具有对ENL的良好抑制作用。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
仪器仪表和一般方法
采用氘代试剂(DMSO-d 6、CDCl 3、CD 3OD)在Bruker Ascend 400光谱仪上记录 1H和 19F NMR。氘代溶剂或TMS作为内标。化学位移以ppm表示，耦合常数(J)以Hz表示，裂分方式有s(单峰)，d(双峰)，t(三重峰)，q(四重峰)，m(多重峰)，br(宽峰)。LC-MS采用安捷伦1260-6120***配备Waters Cortecs C18，2.7μm,4.6×30mm柱子；HPLC采用Waters Acquity UPLC H-class仪器配备Acquity BEH C18,1.7μm,50×2.1mm柱子。采用制备型HPLC(Kromasil-C18(100×21.2mm，5μm)柱子、Xtimate-C18(250×30mm)柱子或者Xbridge-C18(150×19mm，5μm)柱子)、手性制备型SFC(Daicel ChiralPak IG(250mm×30mm,10μm)柱子、(S,S)Whelk-O1(100×4.6mm)柱子、Daicel Chiralpak IC-3(50×4.6mm)柱子、Daicel Chiralpak AD-H(250×4.6mm)柱子和Chirex S-VAL R-NEA柱子(250×4.6mm))纯化或者拆分最终化合物。
化合物缩写：
T 3P：2,4,6-三丙基-1,3,5,2,4,6-三氧三磷酸-2,4,6-三氧化物或称三丙基磷酸酐
BOP：六氟磷酸苯并***-1-氧基三(二甲氨基)磷
针对本发明的系列化合物，存在完整编号与缩写编号两种形式，其中，例如BV021即为PI1701-BV021-1的缩写，两者指向相同的化合物结构。其余化合物编号可参照此例理解。
合成实施例
实施例1化合物BV021的合成
Figure PCTCN2021142675-appb-000016
步骤1：N，N-二甲基-1-(5-硝基-1H-苯并[d]咪唑-2-基)二甲胺
Figure PCTCN2021142675-appb-000017
将2-(氯甲基)-5-硝基-1H-1,3-苯并二唑(10g,47mmol)溶于二甲胺的THF溶液中(浓度为1M，体积为0.10L)，体系在70℃搅拌14小时。浓缩并用乙腈打浆后得到标题化合物(9.9g,95％)，红色固体。
1H 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 10H 12N 4O 2计算值220.23.
步骤2：2-((二甲基氨基)甲基)-1H-苯并[d]咪唑-5-胺
Figure PCTCN2021142675-appb-000018
将N，N-二甲基-1-(5-硝基-1H-苯并[d]咪唑-2-基)二甲胺(4.5g,0.02mol)溶于甲醇(50mL)中，加入钯碳(0.87g,80mmol)。体系在25℃下搅拌14小时。将混合物过滤，有机相浓缩得标题化合物(3.5g,90％)，黄色油状液体。
1H 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 10H 14N 4计算值190.25.
步骤3：4-((2-((二甲基氨基)甲基)-1H-苯并[d]咪唑-5-基)氨基甲酰基)苯甲酸叔丁酯
Figure PCTCN2021142675-appb-000019
将2-((二甲基氨基)甲基)-1H-苯并[d]咪唑-5-胺(0.95g,5.0mmol)溶于二氯甲烷(20mL)中，依次加入4-((叔丁氧基)羰基)苯甲酸(1.1g,5.0mmol),T 3P(2.4g,7.5mmol)和三乙胺(1.5g,15mmol)。体系在25℃下反应搅拌3小时后，溶于二氯甲烷(30mL)，并用饱和食盐水洗(30mL*3次)。有机相用无水硫酸钠干燥后浓缩，得到标题化合物(2.5g,粗品)，为红色固体。
1H 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 22H 26N 4O 3计算值394.48.
步骤4：4-((2-((二甲基氨基)甲基)-1H-苯并[d]咪唑-5-基)氨基甲酰基)苯甲酸
Figure PCTCN2021142675-appb-000020
将4-((2-((二甲基氨基)甲基)-1H-苯并[d]咪唑-5-基)氨基甲酰基)苯甲酸叔丁酯(2.5g,60mmol)溶于二氯甲烷(30mL)中，加入三氟乙酸(30mL)。体系在25℃下反应搅拌14小时后，浓缩后得到标题化合物(5g，粗品)，红色油状液体。
LC-MS:ESI m/z 339.1[M+H] +；C 18H 18N 4O 3计算值338.37.
步骤5：N 1，N 1'-(乙烷-1,2-二基)双(N 4-(2-((二甲基氨基)甲基)-1H-苯并[d]咪唑-5-基)对苯二甲酰胺)
Figure PCTCN2021142675-appb-000021
将4-((2-((二甲基氨基)甲基)-1H-苯并[d]咪唑-5-基)氨基甲酰基)苯甲酸溶于DMF(5mL)，依次加入癸烷-1,10-二胺(51mg,0.29mmol)，BOP(0.52g,1.2mmol)和三乙胺(0.23g,1.8mmol)。体系在25℃下反应搅拌14小时后，浓缩后通过制备HPLC在以下条件下纯化[柱：Kromasil-C18 100×21.2mm 5um；流动相：乙腈的水溶液(含0.1％三氟乙酸)；梯 度：25-35％乙腈；流速为20mL/min时间：14分钟]，得到标题化合物(2.6mg,1.0％)，白色固体。
1H 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 46H 56N 10O 4计算值812.45.HPLC纯度:98.82％(214nm),98.83％(254nm).
实施例2：参照实施例1的合成方法进一步合成得到如下化合物：
BV022：
Figure PCTCN2021142675-appb-000022
1H 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 44H 52N 10O 4计算值784.42.HPLC纯度:98.73％(214nm),96.69％(254nm).
BV023：
Figure PCTCN2021142675-appb-000023
1H 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 41H 46N 10O 4计算值742.37.HPLC纯度:98.44％(214nm),98.45％(254nm).
BV024：
Figure PCTCN2021142675-appb-000024
1H 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 40H 44N 10O 4计算值728.35.HPLC纯度:97.39％(214nm),95.74％(254nm).
BV025：
Figure PCTCN2021142675-appb-000025
1H 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 39H 42N 10O 4计算值714.34.HPLC纯度:98.22％(214nm),98.34％(254nm).
BV026：
Figure PCTCN2021142675-appb-000026
1H 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 38H 40N 10O 4计算值700.32.HPLC纯度:91.04％(214nm),92.14％(254nm).
BV027：
Figure PCTCN2021142675-appb-000027
1H 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 42H 48N 10O 6计算值788.38.HPLC纯度:90.45％(214nm),93.00％(254nm).
BV028：
Figure PCTCN2021142675-appb-000028
1H 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 40H 44N 10O 5计算值744.35.HPLC纯度:96.54％(214nm),96.49％(254nm).
BV032：
Figure PCTCN2021142675-appb-000029
1H 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 43H 50N 10O 4计算值770.40.HPLC纯度:97.21％(214nm),98.03％(254nm).
BV033：
Figure PCTCN2021142675-appb-000030
1H 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 42H 48N 10O 4计算值756.39.HPLC纯度:100％(214nm),99.27％(254nm).
实施例3化合物BV005的合成
Figure PCTCN2021142675-appb-000031
步骤1：O，O'-(戊烷-1,5-二基)二对苯二甲酸二叔丁酯
Figure PCTCN2021142675-appb-000032
将4-(叔丁氧羰基)苯甲酸(1.2g,5.2mmol)和4-二甲氨基吡啶(0.64g,5.2mmol)溶于二氯甲烷(10mL)，再加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.99g,5.2mmol)。体系在0℃下搅拌30分钟后加入1,5-戊二醇(0.27g,2.6mmo)。体系在25℃下搅拌4小时后，倒入20mL水中，用二氯甲烷(15mL)萃取3次，有机相用无水硫酸钠干燥。浓缩后经过柱层析(石油醚/乙酸乙酯＝100％～95％)得到标题化合物(0.53g,20％)，白色固体。
1H 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).
步骤2：4,4'-((戊烷-1,5-二基双(氧基))双(羰基))二苯甲酸
Figure PCTCN2021142675-appb-000033
将O，O'-(戊烷-1,5-二基)二对苯二甲酸二叔丁酯(0.53g,0.91mmol)与三氟乙酸(1mL)溶于二氯甲烷(3mL)，在25℃搅拌30分钟后，体系浓缩得到标题化合物(0.44g,粗品)直接用于下一步。
LC-MS:ESI m/z 401.1[M+H] +；C 21H 20O 8计算值400.12.
步骤3：戊烷-1,5-二基双(4-((2-(((S)-2-甲基吡咯烷-1-基)甲基)-1H-苯并[d]咪唑-5-基)氨基甲酰基)苯甲酸酯))
Figure PCTCN2021142675-appb-000034
将4,4'-((戊烷-1,5-二基双(氧基))双(羰基))二苯甲酸(0.12g,0.30mmol),(S)-2-((2-甲基吡咯烷-1-基)甲基)-1H-苯并[d]咪唑-5-胺(0.15g,0.66mmol)(Angew.Chem.Int.Ed.2018,57,16302)与2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.29g,0.75mmol)，N,N-二异丙基乙胺(0.16g,1.2mmol)溶于DMF(6mL)，反应体系在25℃搅拌14小时。体系混合物倒入10mL水中，用乙酸乙酯10mL萃取3次。有机相用饱和氯化铵溶液(20mL)洗涤，然后用无水硫酸钠干燥，浓缩后通过制备HPLC在以下条件下纯化[柱：Kromasil-C18 100×21.2mm 5um；流动相：乙腈的水溶液(含0.1％三氟乙酸)；梯度：25-35％乙腈；流速为20mL/min时间：14分钟]，得到标题化合物(37mg,13％)，白色固体。
1H 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 47H 52N 8O 6计算值824.40.HPLC纯度:98.5％(214nm),98.1％(254nm).
实施例4参照实施例3的合成方法合成以下化合物：
BV006：
Figure PCTCN2021142675-appb-000035
1H 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 50H 58N 8O 6计算值866.45.HPLC纯度:98.0％(214nm),98.1％(254nm).
BV007：
Figure PCTCN2021142675-appb-000036
1H 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 52H 62N 8O 6计算值894.48. HPLC纯度:98.4％(214nm),97.3％(254nm).
BV008：
Figure PCTCN2021142675-appb-000037
1H 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 48H 54N 8O 8计算值870.41.HPLC纯度:99.2％(214nm),99.4％(254nm).
BV009：
Figure PCTCN2021142675-appb-000038
1H 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 47H 54N 10O 4计算值823.43.HPLC纯度:99.74％(214nm),99.41％(254nm)。
BV010：
Figure PCTCN2021142675-appb-000039
1H 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/z 433.2[M/2+H] +；C 50H 60N 10O 4计算值433.24.HPLC:98.70％(254nm),98.39％(214nm).
BV011：
Figure PCTCN2021142675-appb-000040
1H 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 52H 64N 10O 4计算值892.15.HPLC纯度:99.17％(214nm),98.49％(254nm).
BV012：
Figure PCTCN2021142675-appb-000041
1H 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 48H 56N 10O 6计算值868.44.HPLC纯度:99.30％(214nm),99.50％(254nm).
BV031：
Figure PCTCN2021142675-appb-000042
1H 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/z 396.3[M/2+H] +；C 42H 46N 8O 8计算值790.34.HPLC纯度:97.9％(214nm),97.7％(254nm).
实施例5：化合物BV013的合成:
Figure PCTCN2021142675-appb-000043
步骤1：N 1，N 7-二苄基-N 1，N 7-二甲基庚烷-1,7-二胺
Figure PCTCN2021142675-appb-000044
将1,7-二溴庚烷(5.0g,19mmol)、N-甲基苄胺(5.2g,42mmol)与碳酸铯(13g,39mmol)溶于DMF(50mL)中。体系在80℃下搅拌16小时后，将混合物溶于乙酸乙酯(50mL)，用20mL水洗3次。有机相用无水硫酸钠干燥并浓缩后，柱层析(40g硅胶，10％甲醇溶于二氯甲烷)得到标题化合物(2.3g,35％yield)，黄色油状液体。
1H 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 23H 34N 2计算值338.27.
步骤2：N 1，N 7-二甲基庚烷-1,7-二胺
Figure PCTCN2021142675-appb-000045
将N 1，N 7-二苄基-N 1，N 7-二甲基庚烷-1,7-二胺(2.3g,0.01mol)溶于100mL甲醇中，加入钯碳(0.30g)。在氢气氛围下，体系在25℃下搅拌14小时后，混合物用硅藻土过滤后得到标题化合物粗品1.2g，棕色胶状固体。
1H 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 9H 22N 2计算值158.18.
步骤3：N 1，N 7-二甲基-N 1，N 7-双((5-硝基-1H-苯并[d]咪唑-2-基)甲基)庚烷-1,7-二胺
Figure PCTCN2021142675-appb-000046
将2-(氯甲基)-5-硝基-1H-苯并[d]咪唑(5.3g,25mmol)溶于15mL乙腈中，加入N 1，N 7-二甲基庚烷-1,7-二胺与碳酸钠(1.2g,10mmol)溶解在5mL DMF的溶液中。体系在40℃下搅拌14小时后，蒸干溶剂，加入15mL水，用10mL乙酸乙酯萃取3次。有机相用无水硫酸钠干燥、浓缩后，柱层析得到标题化合物(0.40g,79％)，棕色胶状物质。
1H 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 25H 32N 8O 4计算值508.25.
步骤4：N 1，N 7-双((5-氨基-1H-苯并[d]咪唑-2-基)甲基)-N 1，N 7-二甲基庚烷-1,7-二胺
Figure PCTCN2021142675-appb-000047
将N 1，N 7-二甲基-N 1，N 7-双((5-硝基-1H-苯并[d]咪唑-2-基)甲基)庚烷-1,7-二胺(0.62g,1.2mmol)溶于10mL甲醇中，加入钯碳(78mg,0.73mmol)。在氢气氛围下，体系在25℃下搅拌16小时。混合物经过硅藻土过滤并浓缩后得到标题化合物(0.40g,73％)，红色液体。
LC-MS:ESI m/z 449.3[M+H] +；C 25H 36N 8计算值448.31.
步骤5：4,4'-(((((庚烷-1,7-二基双(甲基氮杂环二))双(亚甲基))双(1H-苯并[d]咪唑-2,5-二基))双(氮杂二烯基))双(羰基)二苯甲酸二甲酯
Figure PCTCN2021142675-appb-000048
将N 1，N 7-双((5-氨基-1H-苯并[d]咪唑-2-基)甲基)-N 1，N 7-二甲基庚烷-1,7-二胺(0.10g,0.20mmol)、对苯二甲酸单甲酯(0.11g,0.60mmol)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.23g,0.60mmol)，N,N-二异丙基乙胺(0.10g,0.80mmol)溶于DMF(5mL)，反应体系在25℃搅拌14小时。体系混合物倒入10mL水中，用乙酸乙酯10mL萃取3次。有机相用饱和氯化铵溶液(20mL)洗涤，然后用无水硫酸钠干燥，浓缩后通过制备HPLC在以下条件下纯化[柱：Kromasil-C18 100×21.2mm 5um；流动相：乙腈的水溶液(含0.1％三氟乙酸)；梯度：25-35％乙腈；流速为20mL/min时间：14分钟]，得到标题化合物(5mg,5％)，白色固体。
1H 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 43H 48N 8O 6计算值772.37.HPLC纯度:95.03％(214nm),95.51％(254nm).
实施例6参照实施例5的合成方法合成以下化合物：
BV014：
Figure PCTCN2021142675-appb-000049
1H 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 46H 54N 8O 6计算值814.42.HPLC纯度:99.65％(214nm),99.66％(254nm).
BV015：
Figure PCTCN2021142675-appb-000050
1H 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 48H 58N 8O 6计算值843.45.HPLC纯度:95.16％(214nm)92.24％(254nm)。
BV016：
Figure PCTCN2021142675-appb-000051
1H NMR(400MHz,Me 3OD-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/z 418.3[M/2+H] +；C 44H 50N 8O 9计算值834.37.HPLC纯度:95.03％(214nm),95.43％(254nm).
BV017：
Figure PCTCN2021142675-appb-000052
1H 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 43H 48N 12O 2计算值764.40.HPLC纯度:95.03％(214 nm),95.51％(254nm).
BV018：
Figure PCTCN2021142675-appb-000053
1H 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 46H 54N 12O 2计算值806.45.HPLC纯度:97.69％(214nm),98.49％(254nm).
BV019：
Figure PCTCN2021142675-appb-000054
1H 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 48H 58N 12O 2计算值835.48.HPLC纯度:93.43％(214nm),95.68％(254nm).
BV020：
Figure PCTCN2021142675-appb-000055
1H 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 44H 50N 12O 5计算值826.40.HPLC纯度:92.25％(214nm),93.74％(254nm).
BV037：
Figure PCTCN2021142675-appb-000056
1H 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 42H 46N 12O 4计算值782.38.HPLC纯度:98.50％(214nm),97.23％(254nm).
实施例6：单体合成
LY120：4-((2-((二甲基氨基)甲基)-1H-苯并[d]咪唑-5-基)氨基甲酰基)苯甲酸甲酯
Figure PCTCN2021142675-appb-000057
将2-((二甲氨基)甲基)-1H-苯并[d]咪唑-5-胺(200mg,1.05mmol)、对苯二甲酸单甲酯(189mg,1.05mmol)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.23g,0.60mmol)，N,N-二异丙基乙胺(0.10g,0.80mmol)溶于DMF(5mL)，反应体系在25℃搅拌16小时。体系混合物倒入10mL水中，用乙酸乙酯10mL萃取3次。有机相用饱和氯化铵溶液(20mL)洗涤，然后用无水硫酸钠干燥，浓缩后通过制备HPLC在以下条件下纯化[柱：Kromasil-C18 100×21.2mm 5um；流动相：乙腈的水溶液(含0.1％三氟乙酸)；梯度：25-35％乙腈；流速为20mL/min时间：14分钟]，得到标题化合物(98.8mg,26％)，白色固体。
1H 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] +；计算值352.15.HPLC纯度:97.44％(214nm),98.55％(254nm).
参照4-((2-((二甲基氨基)甲基)-1H-苯并[d]咪唑-5-基)氨基甲酰基)苯甲酸甲酯的合成方法合成以下化合物：
LY108：
Figure PCTCN2021142675-appb-000058
1H NMR(400MHz,DMSO):δ12.49-12.12(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(M+H),349.2.计算值348.17.HPLC纯度:98.78％(214nm),99.46％(254nm).
BV002：
Figure PCTCN2021142675-appb-000059
1H 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 22H 24N 4O 3计算值392.18.
BV003：
Figure PCTCN2021142675-appb-000060
1H 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 22H 25N 5O 2计算值391.20.
LY160：
Figure PCTCN2021142675-appb-000061
1H 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 19H 21N 5O 2计算值351.41.HPLC纯度:100％(214nm),98.66％(254nm).
生物活性评价实验
生物实验例1：两种生物化学测试化合物对ENL的抑制能力：AlphaScreen、均相时间分辨荧光技术(HTRF)
1.1AlphaScreen
实验材料：带有His标签的人ENL蛋白购自ACTIVE MOTIF公司(Cat#81098)。蛋白用无菌水溶解，分装后储存于-80℃。生物素标记的多肽由GenScript合成，DMSO溶解后分装存于-20℃。
Figure PCTCN2021142675-appb-000062
Hisdidine Detection Kit(Nickel Chelate)(6760619M)购自PerkinElmer公司。Source板(PP-0200)购自Labcyte公司，Proxiplate-384plus目标板购自Perkin Elmer公司(Cat#6008280)。反应缓冲液自行配制：50mM HEPES,0.005％Brij35,1mM TCEP,pH 7.4。
实验方法：将备选化合物用DMSO溶解，按一定浓度梯度加到Source板上，然后用ECHO550将化合物转移到目标板，使之形成11个浓度。蛋白和多肽用反应缓冲液稀释，轻柔混匀，并用Multidrop以每孔10μl加到目标板中(蛋白的工作浓度为5nM，多肽的工作浓度为30nM)，室温孵育1个小时。每孔加入10μl Donor/Acceptor beads(工作浓度15μg/mL)，室温孵育一个小时。最后用Envision Plate Reader读数。每个化合物的IC 50用XLfit拟合后获得。
1.2均相时间分辨荧光技术(HTRF)
实验材料：带有His标签的人ENL蛋白购自ACTIVE MOTIF公司(Cat#81098)。蛋白用无菌水溶解，分装后储存于-80℃。生物素标记的多肽由GenScript合成，DMSO溶解后分装存于-20℃。Streptavidin-XL665(Cat#610SAXLA)和Tb3+cryptate labeled anti-6His antibody(Cat#61HI2TLA)购自Cisbio公司。Source板(PP-0200)购自Labcyte公司，Proxiplate-384plus目标板购自Perkin Elmer公司。反应缓冲液自行配制：PBS,0.1％BSA,pH 7.2。
实验方法：将备选化合物用DMSO溶解，按一定浓度梯度加到Source板上，然后用ECHO550将化合物转移到目标板，使之形成11个浓度。蛋白和多肽用反应缓冲液稀释，轻柔混匀，并用Multidrop以每孔10μl加到目标板中(蛋白的工作浓度为5nM，多肽的工作浓度为100nM)，室温孵育1个小时。每孔加入10μl稀释后的Streptavidin-XL665和Tb3+cryptate labeled anti-6His antibody混合液，室温孵育一个小时。最后用Envision Plate Reader读数。每个化合物的IC 50用XLfit拟合后获得。
1.3实验结果
(1)本发明化合物对ENL均具有良好抑制作用，具体测试结果如下表所示：
表1本发明化合物的HTRF和AS测试结果
  AlfaScreen HTRF
BV013 A B
BV014 B C
BV015 B B
BV016 A C
BV017 A B
BV018 A B
BV020 B C
BV037 B C
BV005 A B
BV006 A B
BV007 A B
BV008 A A
BV009 A A
BV011 C B
BV012 A B
BV031 A B
BV023 A -
BV024 A -
BV025 A -
BV026 A -
BV027 A -
BV028 A -
注：A：<100nM；B：100-1000nM；C：>1000nM
(2)本发明化合物的二聚体形式结构(示意为A-Linker-A)由相应单体结构部分(示意为A)构成(参见下表2示意)，发明人发现，二聚体结构针对ENL的活性相较于单体进一步改善。根据AS IC 50(nM)测试结果显示，一些二聚体相对于单体的活性具有较好的改善，Monomer/Dimer(AS)比值达到10倍以上，例如BV013、BV018；一些二聚体相对于单体的活性有特别好的改善，Monomer/Dimer(AS)比值达到100倍以上；例如BV008，BV012，BV024，BV025，BV026，BV028；一些二聚体相对于单体的活性有极大程度的改善，Monomer/Dimer(AS)比值甚至可以达到500倍以上，例如BV009，BV023，BV027，BV031。
表2本发明二聚体化合物与相应单体结构
A(Monomer) Linker A-Linker-A(Dimer)
PI1701-LY120-1 ─(CH 2) 7─ PI1701-BV013-1
PI1701-LY120-1 ─(CH 2) 10─ PI1701-BV014-1
PI1701-LY120-1 ─(CH 2) 12─ PI1701-BV015-1
PI1701-LY120-1 ─CH 2(CH 2OCH 2) 3CH 2─ PI1701-BV016-1
PI1701-LY108-1 ─(CH 2) 7─ PI1701-BV017-1
PI1701-LY108-1 ─(CH 2) 10─ PI1701-BV018-1
PI1701-LY108-1 ─(CH 2) 12─ PI1701-BV019-1
PI1701-LY108-1 ─CH 2(CH 2OCH 2) 3CH 2─ PI1701-BV020-1
PI1701-BV002-1 ─O(CH 2) 5O─ PI1701-BV005-1
PI1701-BV002-1 ─O(CH 2) 8O─ PI1701-BV006-1
PI1701-BV002-1 ─O(CH 2) 10O─ PI1701-BV007-1
PI1701-BV002-1 ─OCH 2CH 2OCH 2CH 2OCH 2CH 2O─ PI1701-BV008-1
PI1701-BV003-1 ─NH(CH 2) 5NH─ PI1701-BV009-1
PI1701-BV003-1 ─NHCH 2CH 2OCH 2CH 2OCH 2CH 2NH─ PI1701-BV012-1
PI1701-LY160-1 ─(CH 2) 5─ PI1701-BV023-1
PI1701-LY160-1 ─(CH 2) 4─ PI1701-BV024-1
PI1701-LY160-1 ─(CH 2) 3─ PI1701-BV025-1
PI1701-LY160-1 ─(CH 2) 2─ PI1701-BV026-1
PI1701-LY160-1 ─CH 2CH 2OCH 2CH 2OCH 2CH 2─ PI1701-BV027-1
PI1701-LY160-1 ─CH 2CH 2OCH 2CH 2─ PI1701-BV028-1
PI1701-LY120-1 ─OCH 2CH 2OCH 2CH 2OCH 2CH 2O─ PI1701-BV031-1
生物实施例2：表面等离子共振技术(SPR)实验材料：ENL蛋白购自ACTIVE MOTIF公司。蛋白用无菌水溶解，分装后储存于-80℃。CM5芯片购自GE公司，DMSO购自Sigma公司。Source板(PP-0200)购自Labcyte公司，Proxiplate-384plus目标板购自Perkin Elmer公司。
实验方法：将备选化合物用DMSO溶解，按一定浓度梯度加到Source板上，然后用ECHO550将化合物转移到目标板，使之形成11个浓度。采用氨基偶联的方法将上述ENL重组蛋白偶联的CM5芯片上，偶联水平为5000RU。采用北医国家重点实验室Biacore T200测试各个化合物。
表3本发明化合物的SPR测试结果。
  SPR
BV002 B
BV003 B
BV008 A
BV009 A
注：A：<100nM；B：100-1000nM；C：>1000nM
以上对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (13)

  1. 一种式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐：
    Figure PCTCN2021142675-appb-100001
    其中，所述Ar 1，Ar 2可以相同或不同，各自独立地选自任选被一个、两个或更多个R a取代的如下基团：
    Figure PCTCN2021142675-appb-100002
    所述R a选自H，＝O，卤素，OH，CN，SH，NH 2，COOH，或任选被一个、两个或更多个R b取代的如下基团：C 1-C 12脂肪烃基；所述R b选自卤素，OH，CN，SH，NH 2，COOH；
    所述L 1、L 2可以相同或不同，各自独立的选自键，或任选被一个、两个或更多个R L取代的
    Figure PCTCN2021142675-appb-100003
    (以*，**表示与通式其他基团部分的连接位点，以*代表与通式对应左侧基团部分连接，则**表示与通式对应右侧基团连接)；所述R L选自H，＝O，卤素，OH，CN，SH，NH 2，COOH，或任选被一个、两个或更多个R c取代的如下基团：C 1-C 12脂肪烃基；所述R c选自卤素，OH，CN，SH，NH 2，COOH；
    所述W选自(C 1-C 20)脂肪烃基，任选地包含一个、两个或更多个杂原子的(C 1-C 20)脂肪烃基；所述W任选被一个、两个或更多个R W取代；所述R W选自H，＝O，卤素，OH，CN，SH，NH 2，COOH，或任选被一个、两个或更多个R d取代的如下基团：C 1-C 12脂肪烃基；所述R d选自卤素，OH，CN，SH，NH 2，COOH；
    所述R 1、R 2可以相同或不同，各自独立的选自-NH-C(＝O)R 3，-(CH 2) pR 3，(C 1-C 12)脂肪烃基，任选地包含一个、两个或更多个杂原子的(C 1-C 12)脂肪烃基；
    所述R 3选自任选被一个、两个或更多个R e取代的如下基团：C 6-20芳基，5-14元杂芳基或3-12元杂环基；
    所述R e选自H，-C(＝O)O-C 1-C 12脂肪烃基，-O-C 1-C 12脂肪烃基，C 1-C 12脂肪烃基，＝O，卤素，OH，CN，SH，NH 2，COOH；p选自0，1，2，3，4，5。
  2. 根据权利要求1所述的一种式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐，其特征在于：
    所述W选自如下基团：-(CH 2)n-，-O-(CH 2)n-O-，-O-(CH 2)n-，-(OCH 2CH 2) m-O-，-(OCH 2CH 2)m-，-(CH 2CH 2O)m-CH 2CH 2-，-(CH 2)s-NR s-(CH 2CH 2O)m-CH 2CH 2-NR s-(CH 2)s-，-(CH 2)s-NR s-(CH 2)n-NR s-(CH 2)s-；
    所述Rs选自H，C 1-C 12脂肪烃基；
    所述s选自0，1，2；所述n选自1-16，例如选自1，2，3，4，5，6，7，8，9，10，11，12，13，14，15，16；所述m选自1-8，例如选自1，2，3，4，5，6，7，8。
  3. 根据权利要求1-2任一项所述的一种式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐，其特征在于：
    所述R 1、R 2独立的选自任选地包含一个、两个或更多个杂原子的(C 1-C 12)脂肪烃基时，可以进一步选自-(CH 2) qN(CH 3) 2，所述q选自0，1，2，3。
  4. 根据权利要求1-3任一项所述的一种式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐，其特征在于，所述R 3选自任选被一个、两个或更多个R e取代的如下基团：苯基，吲唑，吡咯烷。
  5. 根据权利要求1-4任一项所述的一种式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐，其特征在于，所述R 1、R 2可以相同或不同，各自独立的选自如下基团：
    Figure PCTCN2021142675-appb-100004
  6. 根据权利要求1-5任一项所述的一种式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐，其特征在于，所述式I结构选自如下式Ia或式Ib：
    Figure PCTCN2021142675-appb-100005
    所述式Ia结构中，R 1、R 2、W、L 1、L 2如前述式I所定义。
  7. 根据权利要求1-6任一项所述的一种式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐，其特征在于，所述式I结构可以选自如下式II-VII：
    Figure PCTCN2021142675-appb-100006
    所述式II-VII结构中，R 1、R 2、R S、s，n，m如上前述式I所定义。
  8. 根据权利要求1-7任一项所述的一种式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐，其特征在于，式I选自如下具体化合物：
    Figure PCTCN2021142675-appb-100007
    Figure PCTCN2021142675-appb-100008
    Figure PCTCN2021142675-appb-100009
  9. 根据权利要求1-7任一项所述的一种式I所示的化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐，其特征在于，式I选自如下具体化合物：
    Figure PCTCN2021142675-appb-100010
  10. 根据权利要求1-9任一项所述化合物的制备方法，其特征在于，包括如下步骤：在合适的条件下，将含苯并咪唑结构的原料与含有R 1或R 2基团的原料在合适的试剂中进行反应；或者将含有-W-连接结构部分的原料与含有苯并咪唑结构的原料在合适的试剂中进行反应，或者包含前述两个反应步骤。
  11. 一种药物组合物，其包含权利要求1-9任一项所述的式I化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐；优选的，所述药物组合物包含治疗有效量的式I化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐和药学上可接受的载体。
  12. 根据权利要求1-9任一项所述的式I化合物及其消旋体、立体异构体、互变异构体、同位素标记物、氮氧化物、溶剂化物、多晶型物、代谢产物、酯、前药或其药学上可接受的盐或所述药物组合物制备预防，调节或治疗与ENL介导的有关疾病或病症的药物中的用途。
  13. 根据权利要求12所述的用途，所述ENL介导的有关疾病或病症选自癌症，具体的为白血病。所述白血病选自急性淋巴母细胞性白血病(ALL)、急性髓细胞性白血病(AML)、慢性淋巴细胞性白血病(CLL)和慢性髓细胞性白血病(CML)；以及一些不太常见的类型。优选的，所述白血病为AML。
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