WO2023131179A1 - 苯并咪唑衍生物或其盐在治疗白血病中的用途 - Google Patents

苯并咪唑衍生物或其盐在治疗白血病中的用途 Download PDF

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WO2023131179A1
WO2023131179A1 PCT/CN2023/070411 CN2023070411W WO2023131179A1 WO 2023131179 A1 WO2023131179 A1 WO 2023131179A1 CN 2023070411 W CN2023070411 W CN 2023070411W WO 2023131179 A1 WO2023131179 A1 WO 2023131179A1
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alkyl
heterocyclyl
aryl
leukemia
heteroaryl
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PCT/CN2023/070411
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English (en)
French (fr)
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陈虹
张慧娟
王义乾
丁列明
王家炳
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贝达药业股份有限公司
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Publication of WO2023131179A1 publication Critical patent/WO2023131179A1/zh

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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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

Definitions

  • the present invention relates to the technical field of drug use, in particular to the use of a benzimidazole derivative or a salt thereof in the treatment of leukemia.
  • Leukemia is a kind of malignant clonal disease of hematopoietic stem cells. Its common causes include viral infection, exposure to chemical substances, radiation of radioactive substances, and genetics. wait. Leukemia can be divided into acute leukemia (AL) and chronic leukemia (CL) according to the degree of cell differentiation and maturity and natural course; according to the main cell series involved, it can be divided into lymphocytic leukemia and non-lymphocyte (myeloid) Two types of leukemia.
  • AL acute leukemia
  • CL chronic leukemia
  • lymphocytic leukemia and non-lymphocyte (myeloid) Two types of leukemia.
  • AL can be divided into acute lymphoblastic leukemia (acutelymphoblasticleukemia, ALL) and acute myeloid leukemia (acutemyeloidleukemia, AML);
  • CL chronic leukemia
  • CML chronic myeloid leukemia
  • CLL chronic lymphocytic leukemia Leukemia
  • rare types of leukemia such as hairy cell leukemia, prolymphocytic leukemia, etc.
  • the treatment methods for leukemia mainly include chemotherapy, radiotherapy, targeted therapy, immunotherapy and stem cell transplantation.
  • the inventors unexpectedly found that the compound shown in formula I, its stereoisomers, its tautomers, its polymorphs, its solvates and pharmaceutically acceptable salts thereof have the effect of treating leukemia. Effect, complete the present invention based on this.
  • the first aspect of the present invention provides a compound represented by formula I, at least one of its stereoisomers, tautomers, polymorphs, solvates and pharmaceutically acceptable salts thereof species, or a composition comprising at least one of a compound represented by formula I, its stereoisomer, its tautomer, its polymorph, its solvate, and a pharmaceutically acceptable salt thereof Use in the treatment of leukemia;
  • Ring A is aryl or heteroaryl
  • Z is selected from CH2 , NH, O or S;
  • R are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, aryl, heteroaryl , Heterocyclyl, Heterocyclyl-(CH 2 ) m -, Aryl-C 1-6 Alkyl-, Heteroaryl-C 1-6 Alkyl-, NR 12 R 13 , NR 12 -C 1- 6 alkylene-NR 12 R 13 or heterocyclyl-C(O)-; where C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, aryl, heteroaryl , heterocyclyl, heterocyclyl-(CH 2 ) m -, aryl-C 1-6 alkyl-, heteroaryl-C 1-6 alkyl- or heterocyclyl-C(O)- are each Unsubstituted or substituted by at least one substituent selected from halogen, C 1
  • R 2 and R 3 are each independently selected from hydrogen, hydroxyl, cyano, nitro, amino, halogen, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, aryl, Heteroaryl or heterocyclic; wherein C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, aryl, heteroaryl or heterocyclic are each unsubstituted or replaced by at least one Substituents selected from halogen, hydroxyl, C 1-8 alkyl, C 3-8 cycloalkyl or heterocyclyl;
  • R 12 and R 13 are each independently selected from hydrogen, C 1-8 alkyl, aryl, heteroaryl, heterocyclyl or C 3-8 cycloalkyl; wherein C 1-8 alkyl, aryl, hetero Aryl, heterocyclyl or C 3-8 cycloalkyl are each unsubstituted or substituted by at least one substituent selected from halogen, hydroxyl, C 1-8 alkyl, C 3-8 cycloalkyl or heterocyclyl ;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, 2, 3 or 4;
  • t 0, 1, 2, 3 or 4;
  • the aryl group is a 6- to 10-membered monocyclic or bicyclic aromatic ring group
  • the heteroaryl is a 5-membered or 6-membered monocyclic aromatic ring system consisting of carbon atoms and 1-4 heteroatoms selected from N, O or S;
  • the heterocyclic group is a 3-8 membered stable saturated monocyclic ring system composed of carbon atoms and 1-3 heteroatoms selected from N, O or S.
  • the second aspect of the present invention provides at least one of a compound represented by formula I, its stereoisomer, its tautomer, its polymorph, its solvate and its pharmaceutically acceptable salt species, or a composition comprising at least one of a compound represented by formula I, its stereoisomer, its tautomer, its polymorph, its solvate, and a pharmaceutically acceptable salt thereof Use in the preparation of medicaments for the treatment of leukemia;
  • Ring A is aryl or heteroaryl
  • Z is selected from CH2 , NH, O or S;
  • R are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, aryl, heteroaryl , Heterocyclyl, Heterocyclyl-(CH 2 ) m -, Aryl-C 1-6 Alkyl-, Heteroaryl-C 1-6 Alkyl-, NR 12 R 13 , NR 12 -C 1- 6 alkylene-NR 12 R 13 or heterocyclyl-C(O)-; where C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, aryl, heteroaryl , heterocyclyl, heterocyclyl-(CH 2 ) m -, aryl-C 1-6 alkyl-, heteroaryl-C 1-6 alkyl- or heterocyclyl-C(O)- are each Unsubstituted or substituted by at least one substituent selected from halogen, C 1
  • R 2 and R 3 are each independently selected from hydrogen, hydroxyl, cyano, nitro, amino, halogen, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, aryl, Heteroaryl or heterocyclic; wherein C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, aryl, heteroaryl or heterocyclic are each unsubstituted or replaced by at least one Substituents selected from halogen, hydroxyl, C 1-8 alkyl, C 3-8 cycloalkyl or heterocyclyl;
  • R 12 and R 13 are each independently selected from hydrogen, C 1-8 alkyl, aryl, heteroaryl, heterocyclyl or C 3-8 cycloalkyl; wherein C 1-8 alkyl, aryl, hetero Aryl, heterocyclyl or C 3-8 cycloalkyl are each unsubstituted or substituted by at least one substituent selected from halogen, hydroxyl, C 1-8 alkyl, C 3-8 cycloalkyl or heterocyclyl ;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, 2, 3 or 4;
  • t 0, 1, 2, 3 or 4;
  • the aryl group is a 6- to 10-membered monocyclic or bicyclic aromatic ring group
  • the heteroaryl is a 5-membered or 6-membered monocyclic aromatic ring system consisting of carbon atoms and 1-4 heteroatoms selected from N, O or S;
  • the heterocyclic group is a 3-8 membered stable saturated monocyclic ring system composed of carbon atoms and 1-3 heteroatoms selected from N, O or S.
  • the compound represented by formula I is specifically the compound represented by formula II,
  • the salt is selected from hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, nitrate, phosphate, acetate, propionate, glycolate , Lactate, Succinate, Maleate, Fumarate, Malate, Tartrate, Citrate, Benzoate, Mandelate, Methanesulfonate, Isethionate , benzenesulfonate, oxalate, pamoate, 2-naphthalenesulfonate, p-toluenesulfonate, cyclamate, salicylate, saccharinate, trifluoroacetate, aluminum Salt, calcium salt, chloroprocaine salt, choline, diethanolamine salt, ethylenediamine, lithium salt, magnesium salt, potassium salt, sodium salt and zinc salt at least one.
  • the salt is selected from at least one of tartrate and methanesulfonate; the tartrate is preferably hemitartrate shown in formula III;
  • the leukemia comprises acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, and prolymphocytic leukemia.
  • the acute myeloid leukemia comprises minimally differentiated acute myeloid leukemia, undifferentiated acute myeloid leukemia, partially differentiated acute myeloid leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia Leukemia, acute monocytic leukemia, acute erythroleukemia, and acute megakaryoblastic leukemia.
  • At least one of the compound represented by the formula I, its stereoisomer, its tautomer, its polymorph, its solvate and its pharmaceutically acceptable salt or a composition comprising at least one of the compound shown in formula I, its stereoisomers, its tautomers, its polymorphs, its solvates and pharmaceutically acceptable salts thereof orally , rectal, topical or parenteral administration to subjects in need.
  • the medicine also includes a pharmaceutically acceptable carrier and/or adjuvant
  • the carrier is selected from lactose, terra alba, sucrose, talcum powder, gelatin, agar, pectin, acacia, stearic acid At least one of magnesium, stearic acid, syrup, peanut oil, olive oil, water, carbon dioxide and nitrogen;
  • the auxiliary material is selected from dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, fragrance at least one of sweeteners, sweeteners and dyes.
  • the dosage form of the drug is selected from granules, suspensions, elixirs, solutions, capsules, cachets, tablets, powders, injections, aerosols, emulsions, ointments, lotions, One of dusting powder and suppository.
  • the third aspect of the present invention provides a method for treating leukemia, which includes administering an effective dose of the compound represented by formula I, its stereoisomer, its tautomer, and its polymorphic form to a subject in need at least one of compound, its solvate and its pharmaceutically acceptable salt, or the compound represented by formula I, its stereoisomer, its tautomer, its polymorph, its solvate Compositions of at least one of pharmaceutically acceptable salts thereof:
  • Ring A is aryl or heteroaryl
  • Z is selected from CH2 , NH, O or S;
  • R are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, aryl, heteroaryl , Heterocyclyl, Heterocyclyl-(CH 2 ) m -, Aryl-C 1-6 Alkyl-, Heteroaryl-C 1-6 Alkyl-, NR 12 R 13 , NR 12 -C 1- 6 alkylene-NR 12 R 13 or heterocyclyl-C(O)-; where C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, aryl, heteroaryl , heterocyclyl, heterocyclyl-(CH 2 ) m -, aryl-C 1-6 alkyl-, heteroaryl-C 1-6 alkyl- or heterocyclyl-C(O)- are each Unsubstituted or substituted by at least one substituent selected from halogen, C 1
  • R 2 and R 3 are each independently selected from hydrogen, hydroxyl, cyano, nitro, amino, halogen, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, aryl, Heteroaryl or heterocyclic; wherein C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, aryl, heteroaryl or heterocyclic are each unsubstituted or replaced by at least one Substituents selected from halogen, hydroxyl, C 1-8 alkyl, C 3-8 cycloalkyl or heterocyclyl;
  • R 12 and R 13 are each independently selected from hydrogen, C 1-8 alkyl, aryl, heteroaryl, heterocyclyl or C 3-8 cycloalkyl; wherein C 1-8 alkyl, aryl, hetero Aryl, heterocyclyl or C 3-8 cycloalkyl are each unsubstituted or substituted by at least one substituent selected from halogen, hydroxyl, C 1-8 alkyl, C 3-8 cycloalkyl or heterocyclyl ;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, 2, 3 or 4;
  • t 0, 1, 2, 3 or 4;
  • the aryl group is a 6- to 10-membered monocyclic or bicyclic aromatic ring group
  • the heteroaryl is a 5-membered or 6-membered monocyclic aromatic ring system consisting of carbon atoms and 1-4 heteroatoms selected from N, O or S;
  • the heterocyclic group is a 3-8 membered stable saturated monocyclic ring system composed of carbon atoms and 1-3 heteroatoms selected from N, O or S.
  • the compound represented by formula I is specifically the compound represented by formula II,
  • the salt is selected from hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, nitrate, phosphate, acetate, propionate, glycolate , Lactate, Succinate, Maleate, Fumarate, Malate, Tartrate, Citrate, Benzoate, Mandelate, Methanesulfonate, Isethionate , benzenesulfonate, oxalate, pamoate, 2-naphthalenesulfonate, p-toluenesulfonate, cyclamate, salicylate, saccharinate, trifluoroacetate, aluminum Salt, calcium salt, chloroprocaine salt, choline, diethanolamine salt, ethylenediamine, lithium salt, magnesium salt, potassium salt, sodium salt and zinc salt at least one.
  • the salt is selected from at least one of tartrate and methanesulfonate; the tartrate is preferably hemitartrate shown in formula III;
  • the leukemia comprises acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, and prolymphocytic leukemia.
  • the acute myeloid leukemia comprises minimally differentiated acute myeloid leukemia, undifferentiated acute myeloid leukemia, partially differentiated acute myeloid leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia Leukemia, acute monocytic leukemia, acute erythroleukemia, and acute megakaryoblastic leukemia.
  • an effective dose of the compound represented by the formula I, its stereoisomers, and its tautomers is administered to the subject in need through oral, rectal, topical or parenteral administration.
  • at least one of its polymorphs, its solvates, and pharmaceutically acceptable salts thereof, or the compound represented by formula I, its stereoisomers, its tautomers, and its polymorphs A composition of at least one of compounds, solvates and pharmaceutically acceptable salts thereof.
  • halogen refers to fluorine, chlorine, bromine or iodine, unless otherwise specified.
  • Preferred halo groups include fluorine, chlorine and bromine.
  • alkyl includes linear or branched monovalent saturated hydrocarbon groups.
  • alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and the like.
  • C 1-8 in “C 1-8 alkyl” refers to a straight chain or branched chain arrangement containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms group.
  • Alkoxy refers to the oxygen ether form of the aforementioned linear or branched alkyl, ie -O-alkyl.
  • compositions comprising "a” pharmaceutically acceptable excipient may be interpreted to mean that the composition includes “one or more” pharmaceutically acceptable excipients.
  • aryl in the present invention, unless otherwise stated, refers to an unsubstituted or substituted monocyclic or condensed ring aromatic group including carbocyclic atoms.
  • the aryl group is a 6- to 10-membered monocyclic or bicyclic aromatic ring group, more preferably phenyl, naphthyl, most preferably phenyl.
  • heterocyclyl in the present invention, unless otherwise specified, refers to an unsubstituted or substituted 3-8 membered stable saturated Monocyclic systems in which the nitrogen or sulfur heteroatoms can be selectively oxidized and the nitrogen heteroatoms can be selectively quaternized.
  • the heterocyclyl group can be attached to any heteroatom or carbon atom to form a stable structure.
  • heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, Tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydro Oxadiazolyl.
  • heteroaryl in the present invention, unless otherwise stated, refers to an unsubstituted or substituted stable five- or six-membered monocyclic aromatic ring system or an unsubstituted or substituted nine- or ten-membered benzo
  • Heteroaryl groups can be attached to any heteroatom or carbon atom to form a stable structure.
  • heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl, Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuryl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzene Thiadiazolyl, benzotriazolyladenine, quinolinyl or isoquinolinyl.
  • cycloalkyl refers to a cyclic saturated alkyl chain having 3-8 carbon atoms, eg, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • substituted means that one or more hydrogen atoms in the group are respectively replaced by the same or different substituents.
  • the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy Butyl, isobutoxy, tert-butoxy, -SCH 3 , -SC 2 H 5 , formaldehyde, -C(OCH 3 ), cyano, nitro, -CF 3 , -OCF 3 , amino, dimethyl Amino, methylthio, sulfonyl and acetyl groups.
  • Substituted alkyl groups include, but are not limited to, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl, and piperazinylmethyl.
  • Substituted alkoxy groups include, but are not limited to, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, and 3-hydroxypropoxy.
  • the medicine of the present invention comprises pharmaceutically acceptable carrier and/or adjuvant and the compound shown in formula I, its stereoisomer, its tautomer, its polymorph, its solvate and At least one of its pharmaceutically acceptable salts may also include one or more therapeutically active compounds that can be used in combination.
  • administration and “treatment” refer to the combination of exogenous drugs, therapeutic agents, diagnostic agents or compositions when applied to animals, humans, experimental subjects, cells, tissues, organs or biological fluids. Contact with animals, humans, subjects, cells, tissues, organs or biological fluids.
  • treating means administering a compound represented by formula I, its stereoisomer, its tautomer, its polymorph, its solvate to a subject having leukemia or diagnosed with leukemia and at least one of its pharmaceutically acceptable salts, or compounds represented by formula I, its stereoisomers, its tautomers, its polymorphs, its solvates and its pharmaceutically acceptable Compositions of at least one of the accepted salts to achieve at least one positive therapeutic effect, such as reducing tumor cell number, reducing tumor size, reducing the rate of tumor cell infiltration into peripheral organs, or reducing tumor metastasis or tumor growth s speed.
  • Treatment may include: suspending or delaying progression of leukemia, stabilization of leukemia, amelioration or removal of clinical manifestations of leukemia, reduction in severity or duration of clinical symptoms of leukemia, relative to expected survival of untreated similar patients prolonging a patient's survival, and inducing a complete or partial remission of leukemia; for example, “treatment” may include one or more of the following: reducing the amount of one or more tumor markers, halting or delaying tumor growth, Inhibiting the growth or survival of tumor cells, eliminating or reducing the size of one or more tumors, reducing the level of one or more tumor markers, inducing complete or partial remission of the condition.
  • subject is defined herein to include animals such as mammals, including but not limited to primates (e.g. humans), cows, sheep, goats, horses, dogs, Cats, rabbits, rats, mice, etc.
  • mammals including but not limited to primates (e.g. humans), cows, sheep, goats, horses, dogs, Cats, rabbits, rats, mice, etc.
  • effective dose refers to an amount sufficient to reduce or ameliorate the severity, duration or progression of the leukemia to be treated, prevent the leukemia to be treated when administered in a suitable dosage regimen progression, causing regression of the leukemia being treated, or enhancing or improving the prophylactic or therapeutic effect of another therapy.
  • the effective dose of the present invention can be changed as needed, as understood by those skilled in the art, depending on the disease to be treated, the severity of the disease, the route of administration, the patient's sex, age and general health, excipient Dosage usage, possibility of co-administration with other treatments (e.g., use of other agents), and the judgment of the treating physician.
  • the benzimidazole derivatives represented by formula II provided by the present invention can effectively block the cell cycle progression of human myelomonocytic leukemia cells MV-4-11 and inhibit the proliferation of MV-4-11 cells; and the derivatives represented by formula III Benzimidazole derivatives hemitartrate shows good antitumor activity to the mouse model inoculated with MV-4-11 cells in vivo; Compound shown in formula I provided by the invention, its stereoisomer, its mutual The variants, their polymorphs, their solvates and their pharmaceutically acceptable salts can be used in the treatment of leukemia and in the preparation of medicines for treating leukemia.
  • Fig. 1 is the growth curve figure of tumor in BALB/c nude mouse among the embodiment 3;
  • Fig. 2 is a curve diagram of body weight changes of BALB/c nude mice in Example 3.
  • FBS fetal bovine serum
  • DMSO dimethyl sulfoxide
  • IC 50 half inhibitory concentration
  • SPF animals Specific pathogen-free animals
  • TGI tumor growth inhibition rate
  • benzimidazole derivatives shown in Formula II used in Example 1 and Example 2 of the present invention are prepared as shown in paragraph 0188-paragraph 0209 of the compound patent CN112424202B specification owned by the applicant, wherein step 11 (Paragraph 0209)
  • step 11 The obtained pale yellow solid 1-03 is a benzimidazole derivative represented by formula II.
  • the benzimidazole derivative hemitartrate shown in formula III used in Example 3 of the present invention is prepared as shown in paragraph 0188-paragraph 0211 of the compound patent CN112424202B specification owned by the applicant, wherein step 12 ( Paragraph 0211) obtained compound II is the benzimidazole derivative hemitartrate represented by formula III.
  • CellTiter-Glo cell proliferation detection kit was used to evaluate the growth inhibitory effect of benzimidazole derivatives represented by formula II on human myelomonocytic leukemia cells MV-4-11 cells (Rb genotype is Rb+).
  • the above cultured MV-4-11 cells were resuspended with the above medium to obtain a cell suspension with a cell density of 40 cells/ ⁇ L. Add 100 ⁇ L of the cell suspension to the 96-well plate, so that the seeding volume of the cells is 4000/well.
  • the cells in the 96-well plate were cultured overnight at 37°C, 5% CO 2 .
  • the benzimidazole derivative solution shown in formula II to each well (the solution of benzimidazole derivatives shown in formula II (DMSO is dissolved and then diluted with the above-mentioned medium), so that the formula II in the wells
  • concentrations of the benzimidazole derivatives were 30000nM, 10000nM, 3333nM, 1111nM, 370nM, 123nM, 41.1nM, 13.7nM, 4.6nM respectively; the mixture of DMSO and the above-mentioned medium was used as the solvent control group (the formula II shown in the hole
  • the concentration of benzimidazole derivatives is 0 nM); and the final concentration of DMSO in each well is 0.5v/v%, and three replicate wells are set for each concentration of benzimidazole derivatives shown in formula II.
  • the cells in the 96-well plate after adding the drug were placed at 37° C. and 5% CO 2 to continue culturing for 96 hours.
  • the chemiluminescent signal value of each well was collected.
  • GraphPad Prism 7.0 software was used to analyze the data, and the following nonlinear fitting formula was used to fit the dose-response curve, and the IC50 value was calculated accordingly.
  • the IC of the benzimidazole derivatives shown in the formula II of the present invention is 87nM ;
  • the above results show that the benzimidazole derivatives shown in the formula II have the effect on human myelomonocytic leukemia cells MV-4-11 cells Has a strong inhibitory effect.
  • Human myelomonocytic leukemia cells MV-4-11 cells (Rb genotype is Rb+) were cultured at 37°C and 5% CO 2 in IMDM medium containing 10v/v% FBS.
  • the above cultured MV-4-11 cells were resuspended with the above medium to obtain a cell suspension with a cell density of 500 cells/ ⁇ L. Add 2 mL of cell suspension to the 6-well plate, so that the seeding amount of cells is 1 ⁇ 10 6 cells/well.
  • the cells in the 6-well plate were cultured overnight at 37°C, 5% CO 2 .
  • the concentration of the benzimidazole derivative shown in the formula II in the well is 20000nM, 6667nM, 2222nM respectively , 740.7nM, 246.9nM, 82.3nM, 27.4nM, 9.14nM, 3.0nM; DMSO was used as the solvent control group (the concentration of the benzimidazole derivative shown in the formula II in the hole was 0nM); each concentration was set up three times hole.
  • the cells in the 6-well plate after adding the drug were placed at 37° C. and 5% CO 2 to continue culturing for 24 hours.
  • the cells in each well were collected, fixed, and stained with PI. Then, the CytoFLEX flow cytometer was used for cell cycle detection, and the cell cycle was analyzed with Modfit software.
  • the G1 phase arrest coefficient ie, inhibition rate
  • G1 phase arrest coefficient ((%G1/G0 test drug- %G1/G0 DMSO )/(1-%G1/G0 DMSO )) ⁇ 100; among them, G1/G0 test drug means that the drug-dosed group is in G1 G1/G0 DMSO represents the ratio of G1 phase cells to G0 phase cells in the solvent control group.
  • XL-Fit software was used to analyze the data, and the following formula was used to fit the percentage inhibition curve to obtain IC 50 .
  • Y minimum inhibition rate+(maximum inhibition rate-minimum inhibition rate)/(1+(IC 50 /X) ⁇ slope); wherein, Y represents the inhibition percentage (%), and X represents the molar concentration of the drug to be tested.
  • the IC of the benzimidazole derivatives shown in the formula II of the present invention is 59.7nM ;
  • the above results show that the benzimidazole derivatives shown in the formula II have the effect on human myelomonocytic leukemia cells MV-4-11 The cell cycle of cells has a strong arresting effect.
  • Example 3 Determination of anti-tumor activity in vivo
  • mice SPF grade animals, 6-8 weeks old, weighing 18-22 grams; sex: female; quantity: 40 mice enrolled in the group; provided by Shanghai Sipro-Bikay Experimental Animal Co., Ltd. supply.
  • Human myelomonocytic leukemia cells MV-4-11 were cultured in IMDM medium containing 10v/v% FBS and 1v/v% double antibodies (penicillin and streptomycin) at 37°C and 5% CO 2 Cells (Rb genotype is Rb+), until the number of cells reaches the requirement, the cells are harvested. The cultured MV-4-11 cells were resuspended with the above medium to obtain a cell suspension with a cell density of 5 ⁇ 10 7 cells/mL.
  • the experiment was divided into a solvent control group, a positive drug (ribociclib) control group and three benzimidazole derivative hemitartrate groups represented by formula III, with 8 experimental animals in each group.
  • the dose of the positive drug is 25 mg/kg body weight, dissolved in water, and the pH of the solution is adjusted to 6 with concentrated hydrochloric acid.
  • the benzimidazole derivative hemitartrate shown in the formula III in the three benzimidazole derivative hemitartrate groups is given The doses were 25 mg/kg body weight, 50 mg/kg body weight and 100 mg/kg body weight respectively.
  • the benzimidazole derivative hemitartrate represented by formula III was dissolved in water and administered in the form of solution.
  • the administration volume of all groups was the same;
  • the solvent control group was given an equal volume of water. From the day of grouping, intragastric administration was started, once a day, for a total of 22 days.
  • the tumor diameter was measured with a vernier caliper twice a week, and the body weight of BALB/c nude mice was weighed with a weighing scale.
  • Tumor Growth Inhibition Rate [(1-(average tumor volume at the end of administration of a treatment group-average tumor volume at the beginning of administration of this treatment group))/(average tumor volume at the end of treatment of solvent control group-solvent control The average tumor volume at the beginning of treatment)] ⁇ 100%.
  • the mean values of tumor volumes at different time points in each group are shown in Table 1, and the growth curve of tumors in BALB/c nude mice is shown in FIG. 1 .
  • Table 1 The average tumor volume of each group at different time points
  • Table 2 shows the TGI of each group after administration for 22 days.
  • the average weight of BALB/c nude mice at different time points in each group is shown in Table 3, and the curve of body weight change of BALB/c nude mice is shown in FIG. 2 .
  • Table 3 The average body weight of each group at different time points
  • the benzimidazole derivatives represented by formula II provided by the present invention can effectively block the cell cycle progression of human myelomonocytic leukemia cells MV-4-11, inhibit the proliferation of MV-4-11 cells, and
  • the benzimidazole derivative hemitartrate shown in formula III shows good antitumor activity to the mouse model that is inoculated with MV-4-11 cells in vivo; Therefore, above-mentioned benzimidazole derivative or its salt can be used for For treating leukemia and for preparing medicines for treating leukemia.

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Abstract

本发明提供了式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐中的至少一种，或包含式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐中的至少一种的组合物在治疗白血病中的用途。

Description

苯并咪唑衍生物或其盐在治疗白血病中的用途
本发明要求于2022年01月05日提交的国际申请号为PCT/CN2022/070298、发明名称为“苯并咪唑衍生物或其盐在治疗白血病中的用途”的在先申请的优先权，其全部内容通过引用结合在本发明中。
技术领域
本发明涉及药物用途技术领域，特别是涉及一种苯并咪唑衍生物或其盐在治疗白血病中的用途。
背景技术
白血病是一类造血干细胞恶性克隆性疾病，其常见病因包括病毒感染、化学物质接触、放射线物质辐射和遗传等，症状包括不同程度的贫血、出血、感染发热以及肝、脾、淋巴结肿大和骨骼疼痛等。白血病按细胞分化成熟程度和自然病程可分为急性白血病(acuteleukemia，AL)和慢性白血病(chronicleukemia，CL)两类；按照主要受累的细胞系列可分为淋巴细胞白血病和非淋巴细胞(髓细胞)白血病两类。因此，可将AL分为急性淋巴细胞白血病(acutelymphoblasticleukemia，ALL)和急性髓系白血病(acutemyeloidleukemia，AML)；可将CL(慢性白血病)可分为慢性髓系白血病(chronicmyeloidleukemia，CML)、慢性淋巴细胞白血病(chroniclymphocyticleukemia，CLL)及少见类型的白血病如毛细胞白血病、幼淋巴细胞白血病等。
目前白血病的治疗手段主要包括化学治疗﹑放射治疗﹑靶向治疗、免疫治疗和干细胞移植等，但治疗效果还有待提高，尚需开发更多能够针对白血病的药物。
发明内容
发明人在研究中意外地发现，式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐具有治疗白血病的作用，基于此完成本发明。
本发明第一方面提供了一种式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐中的至少一种，或包含式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐中的至少一种的组合物在治疗白血病中的用途；
Figure PCTCN2023070411-appb-000001
其中，
环A为芳基或杂芳基；
Z选自CH 2、NH、O或S；
R 1分别独立地选自氢、卤素、氰基、硝基、羟基、氨基、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、芳基、杂芳基、杂环基、杂环基-(CH 2) m-、芳基-C 1-6烷基-、杂芳基-C 1-6烷基-、NR 12R 13、NR 12-C 1-6亚烷基-NR 12R 13或杂环基-C(O)-；其中C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、芳基、杂芳基、杂环基、杂环基-(CH 2) m-、芳基-C 1-6烷基-、杂芳基-C 1-6烷基-或杂环基-C(O)-是各自未取代或者被至少一个选自卤素、C 1-8烷基、C 3-8环烷基、杂环基、NR 12R 13、(CH 2) t-OH的取代基取代；
R 2和R 3各自独立地选自氢、羟基、氰基、硝基、氨基、卤素、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、芳基、杂芳基或杂环基；其中C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、芳基、杂芳基或杂环基是各自未取代或者被至少一个选自卤素、羟基、C 1-8烷基、C 3-8环烷基或杂环基的取代基取代；
R 12和R 13各自独立地选自氢、C 1-8烷基、芳基、杂芳基、杂环基或C 3-8环烷基；其中C 1-8烷基、芳基、杂芳基、杂环基或C 3-8环烷基是各自未取代或者被至少一个选自卤素、羟基、C 1-8烷基、C 3-8环烷基或杂环基的取代基取代；
m为0、1、2、3或4；
n为0、1、2、3或4；
t为0、1、2、3或4；
所述芳基为6到10元的单环或双环的芳香环基团；
所述杂芳基为5元或6元单环芳香族环系统，其由碳原子和1-4个选自N、O或S的杂原子组成；
所述杂环基为由碳原子和1-3个选自N、O或S的杂原子组成的3-8元稳定饱和单环系统。
本发明第二方面提供了一种式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐中的至少一种，或包含式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐中的至少一种的组合物在制备用于治疗白血病的药物中的用途；
Figure PCTCN2023070411-appb-000002
其中，
环A为芳基或杂芳基；
Z选自CH 2、NH、O或S；
R 1分别独立地选自氢、卤素、氰基、硝基、羟基、氨基、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、芳基、杂芳基、杂环基、杂环基-(CH 2) m-、芳基-C 1-6烷基-、杂芳基-C 1-6烷基-、NR 12R 13、NR 12-C 1-6亚烷基-NR 12R 13或杂环基-C(O)-；其中C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、芳基、杂芳基、杂环基、杂环基-(CH 2) m-、芳基-C 1-6烷基-、杂芳基-C 1-6烷基-或杂环基-C(O)-是各自未取代或者被至少一个选自卤素、C 1-8烷基、C 3-8环烷基、杂环基、NR 12R 13、(CH 2) t-OH的取代基取代；
R 2和R 3各自独立地选自氢、羟基、氰基、硝基、氨基、卤素、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、芳基、杂芳基或杂环基；其中C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、芳基、杂芳基或杂环基是各自未取代或者被至少一个选自卤素、羟基、C 1-8烷基、C 3-8环烷基或杂环基的取代基取代；
R 12和R 13各自独立地选自氢、C 1-8烷基、芳基、杂芳基、杂环基或C 3-8环烷基；其中C 1-8烷基、芳基、杂芳基、杂环基或C 3-8环烷基是各自未取代或者被至少一个选自卤素、羟基、C 1-8烷基、C 3-8环烷基或杂环基的取代基取代；
m为0、1、2、3或4；
n为0、1、2、3或4；
t为0、1、2、3或4；
所述芳基为6到10元的单环或双环的芳香环基团；
所述杂芳基为5元或6元单环芳香族环系统，其由碳原子和1-4个选自N、O或S的杂原子组成；
所述杂环基为由碳原子和1-3个选自N、O或S的杂原子组成的3-8元稳定饱和单环系统。
在一些实施方式中，式I所示的化合物具体为式Ⅱ所示的化合物，
Figure PCTCN2023070411-appb-000003
在一些实施方式中，所述盐选自盐酸盐、氢溴酸盐、氢碘酸盐、高氯酸盐、硫酸盐、硝酸盐、磷酸盐、乙酸盐、丙酸盐、乙醇酸盐、乳酸盐、琥珀酸盐、马来酸盐、富马酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐、扁桃酸盐、甲磺酸盐、羟乙基磺酸盐、苯磺酸盐、草酸盐、扑酸盐、2-萘磺酸盐、对甲苯磺酸盐、环己胺磺酸盐、水杨酸盐、糖精酸盐、三氟乙酸盐、铝盐、钙盐、氯普鲁卡因盐、胆碱、二乙醇胺盐、乙二胺、锂盐、镁盐、钾盐、钠盐和锌盐中的至少一种。
在一些实施方式中，所述盐选自酒石酸盐和甲磺酸盐中的至少一种；所述酒石酸盐优选为式Ⅲ所示的半酒石酸盐；
Figure PCTCN2023070411-appb-000004
在一些实施方式中，所述白血病包含急性淋巴细胞白血病、急性髓系白血病、慢性髓系白血病、慢性淋巴细胞白血病、毛细胞白血病和幼淋巴细胞白血病。
在一些实施方式中，所述急性髓系白血病包含急性髓细胞白血病微小分化型、急性粒细胞白血病未分化型、急性粒细胞白血病部分分化型、急性早幼粒细胞白血病、急性粒-单核细胞白血病、急性单核细胞白血病、急性红白血病和急性巨核细胞白血病。
在一些实施方式中，所述式I所示的化合物、其立体异构体、其互变异构体、其多晶 型物、其溶剂化物及其药学上可接受的盐中的至少一种，或包含式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐中的至少一种的组合物通过口服、直肠、局部或胃肠外给药的方式施用于有需要的对象。
在一些实施方式中，所述药物还包括药学上可接受的载体和/或辅料，所述载体选自乳糖、石膏粉、蔗糖、滑石粉、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁、硬脂酸、糖浆、花生油、橄榄油、水、二氧化碳和氮气中的至少一种；所述辅料选自分散剂、稳定剂、增稠剂、络合剂、缓冲剂、渗透促进剂、芳香剂、甜味剂和染料中的至少一种。
在一些实施方式中，所述药物的剂型选自颗粒剂、悬浮剂、酏剂、溶液剂、胶囊剂、扁囊剂、片剂、散剂、注射剂、气溶胶、乳剂、软膏剂、洗剂、撒粉和栓剂中的一种。
本发明第三方面提供了一种治疗白血病的方法，其包括向有需要的对象施以有效剂量的式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐中的至少一种，或包含式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐中的至少一种的组合物：
Figure PCTCN2023070411-appb-000005
其中，
环A为芳基或杂芳基；
Z选自CH 2、NH、O或S；
R 1分别独立地选自氢、卤素、氰基、硝基、羟基、氨基、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、芳基、杂芳基、杂环基、杂环基-(CH 2) m-、芳基-C 1-6烷基-、杂芳基-C 1-6烷基-、NR 12R 13、NR 12-C 1-6亚烷基-NR 12R 13或杂环基-C(O)-；其中C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、芳基、杂芳基、杂环基、杂环基-(CH 2) m-、芳基-C 1-6烷基-、杂芳基-C 1-6烷基-或杂环基-C(O)-是各自未取代或者被至少一个选自卤素、C 1-8烷基、C 3-8环烷基、杂环基、NR 12R 13、(CH 2) t-OH的取代基取代；
R 2和R 3各自独立地选自氢、羟基、氰基、硝基、氨基、卤素、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、芳基、杂芳基或杂环基；其中C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、芳基、杂芳基或杂环基是各自未取代或者被至少一个选自卤素、羟基、C 1-8烷基、C 3-8环烷基或杂环基的取代基取代；
R 12和R 13各自独立地选自氢、C 1-8烷基、芳基、杂芳基、杂环基或C 3-8环烷基；其中C 1-8烷基、芳基、杂芳基、杂环基或C 3-8环烷基是各自未取代或者被至少一个选自卤素、羟基、C 1-8烷基、C 3-8环烷基或杂环基的取代基取代；
m为0、1、2、3或4；
n为0、1、2、3或4；
t为0、1、2、3或4；
所述芳基为6到10元的单环或双环的芳香环基团；
所述杂芳基为5元或6元单环芳香族环系统，其由碳原子和1-4个选自N、O或S的杂原子组成；
所述杂环基为由碳原子和1-3个选自N、O或S的杂原子组成的3-8元稳定饱和单环系统。
在一些实施方式中，式I所示的化合物具体为式Ⅱ所示的化合物，
Figure PCTCN2023070411-appb-000006
在一些实施方式中，所述盐选自盐酸盐、氢溴酸盐、氢碘酸盐、高氯酸盐、硫酸盐、硝酸盐、磷酸盐、乙酸盐、丙酸盐、乙醇酸盐、乳酸盐、琥珀酸盐、马来酸盐、富马酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐、扁桃酸盐、甲磺酸盐、羟乙基磺酸盐、苯磺酸盐、草酸盐、扑酸盐、2-萘磺酸盐、对甲苯磺酸盐、环己胺磺酸盐、水杨酸盐、糖精酸盐、三氟乙酸盐、铝盐、钙盐、氯普鲁卡因盐、胆碱、二乙醇胺盐、乙二胺、锂盐、镁盐、钾盐、钠盐和锌盐中的至少一种。
在一些实施方式中，所述盐选自酒石酸盐和甲磺酸盐中的至少一种；所述酒石酸盐优选为式Ⅲ所示的半酒石酸盐；
Figure PCTCN2023070411-appb-000007
在一些实施方式中，所述白血病包含急性淋巴细胞白血病、急性髓系白血病、慢性髓系白血病、慢性淋巴细胞白血病、毛细胞白血病和幼淋巴细胞白血病。
在一些实施方式中，所述急性髓系白血病包含急性髓细胞白血病微小分化型、急性粒细胞白血病未分化型、急性粒细胞白血病部分分化型、急性早幼粒细胞白血病、急性粒-单核细胞白血病、急性单核细胞白血病、急性红白血病和急性巨核细胞白血病。
在一些实施方式中，通过口服、直肠、局部或胃肠外给药，向有需要的对象施以有效剂量的所述式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐中的至少一种，或包含式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐中的至少一种的组合物。
本发明中，式I结构通式中使用的一般化学术语具有通常的含义。例如，除非另有说明，本发明所用的术语“卤素”是指氟、氯、溴或碘。优选的卤素基团包括氟、氯和溴。
在本发明中，除非另有说明，“烷基”包括直链或支链的一价饱和烃基。例如，烷基包括甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、正己基、2-己基、2-甲基戊基等。类似的，“C 1-8烷基”中的“C 1-8”是指包含有1、2、3、4、5、6、7或8个碳原子的直链或支链形式排列的基团。
“烷氧基”是指前述的直链或支链烷基的氧醚形式，即-O-烷基。
在本发明中，“一”、“一个”、“该”、“至少一个”、“至少一种”和“一个或多个”可互换使用。因此，例如，包含“一种”药学上可接受的赋形剂的组合物可以被解释为表示该组合物包括“一种或多种”药学上可接受的赋形剂。
术语“芳基”，在本发明中，除非另有说明，是指未取代或取代的包括碳环的原子的单环或稠环芳香基团。优选芳基为6到10元的单环或双环的芳香环基团，进一步优选为苯基、萘基，最优选为苯基。
术语“杂环基”，在本发明中，除非另有说明，是指由碳原子和1-3个选自N、O或S的杂原子组成的未取代或取代的3-8元稳定饱和单环系统，其中氮或硫杂原子可以选择性 地被氧化，并且氮杂原子可以选择性地被季铵化。该杂环基可以被连接到任何的杂原子或碳原子上以形成稳定的结构。这些杂环基的实例包括但不限于氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、氧代哌嗪基、氧代哌啶基、四氢呋喃基、二氧戊环基、四氢咪唑基、四氢噻唑基、四氢恶唑基、四氢吡喃基、吗啉基、硫代吗啉基、硫代吗啉基亚砜、硫代吗啉基砜基和四氢恶二唑基。
术语“杂芳基”，在本发明中，除非另有说明，是指未取代或取代的稳定的五元或六元单环芳族环系统或未取代或取代的九元或十元苯并稠合杂芳族环系统或双环杂芳族环系统，其由碳原子和1-4个选自N、O或S的杂原子组成，并且其中所述氮或硫杂原子可以选择性地被氧化，所述氮杂原子可以选择性地被季铵化。杂芳基可以连接在任何杂原子或碳原子上以形成稳定的结构。杂芳基的实例包括但不限于噻吩基、呋喃基、咪唑基、异恶唑基、恶唑基、吡唑基、吡咯基、噻唑基、噻二唑基、三唑基、吡啶基、哒嗪基、吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并异恶唑基、苯并噻唑基、苯并噻唑基、苯并噻二唑基、苯并三唑基腺嘌呤、喹啉基或异喹啉基。
术语“环烷基”是指具有3-8个碳原子的环状饱和烷基链，例如，环丙基、环丁基、环戊基或环己基。
术语“取代的”是指基团中的一个或多个氢原子分别被相同的或者不同的取代基所取代。典型的取代基包括但不限于卤素(F、Cl、Br或I)、C 1-8烷基、C 3-12环烷基、-OR 1、-SR 1、＝O、＝S、-C(O)R 1、-C(S)R 1、＝NR 1、-C(O)OR 1、-C(S)OR 1、-NR 1R 2、-C(O)NR 1R 2、氰基、硝基、-S(O) 2R 1、-O-S(O 2)OR 1、-O-S(O) 2R 1、-OP(O)(OR 1)(OR 2)；其中R 1和R 2独立地选自-H，C 1-6烷基，C 1-6卤代烷基。在一些实施例中，取代基独立地选自包含-F、-Cl、-Br、-I、-OH、三氟甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、-SCH 3、-SC 2H 5、甲醛基、-C(OCH 3)、氰基、硝基、-CF 3、-OCF 3、氨基、二甲基氨基、甲硫基、磺酰基和乙酰基的基团。
取代烷基的基团包括但不限于2-氨基乙基、2-羟乙基、五氯乙基、三氟甲基、甲氧基甲基、五氟乙基和哌嗪基甲基。
取代烷氧基的基团包括但不限于氨基甲氧基、三氟甲氧基、2-二乙基氨基乙氧基、2-乙氧基羰基乙氧基和3-羟基丙氧基。
本发明所述的药物，其包括药学上可接受的载体和/或辅料和式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐中的至少一种， 还可以包括一种或多种具有治疗活性的可联合用药的化合物。
本发明中，“施用”和“治疗”在其应用至动物、人、实验受试者、细胞、组织、器官或生物流体时，是指外源性药物、治疗剂、诊断剂或组合物与动物、人、受试者、细胞、组织、器官或生物流体接触。如本发明所用，“治疗”意指向具有白血病或诊断具有白血病的受试者施用式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐中的至少一种，或包含式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐中的至少一种的组合物，以实现至少一种阳性治疗效果，例如减少肿瘤细胞数量，减小肿瘤大小，降低肿瘤细胞浸润至外周器官中的速率，或降低肿瘤转移或肿瘤生长的速率。“治疗”可以包括：中止或延迟与白血病的进展，白血病的稳定化，改善或去除白血病的临床表现，降低白血病的临床症状的严重程度或持续时间，相对于未治疗的类似患者的预期存活期延长患者的存活期，和诱导白血病的完全或部分缓解；例如，“治疗”可以包括以下中的一项或多项：减少一种或多种肿瘤标志物的数量，中止或延迟肿瘤的生长，抑制肿瘤细胞的生长或存活，消除或减小一个或多个肿瘤的大小，降低一种或多种肿瘤标志物的水平，诱导病况的完全或者部分缓解。
如本发明所用，且除非另有说明，否则术语“对象”在本发明定义为包括动物例如哺乳动物，包括但不限于灵长类动物(例如人)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠等。
如本发明使用的术语“有效剂量”是指这样的量，当以合适的给药方案施用时，该量足够降低或改善要治疗的白血病的严重度、持续时间或发展，防止要治疗的白血病的进展，引起要治疗的白血病的消退，或增强或改善另一种疗法的预防或治疗效果。本发明所述的有效剂量，可以根据需要变化，如本领域技术人员所了解的，取决于所治疗的疾病、疾病的严重度、给药途径、患者的性别、年龄和一般健康状况、赋形剂用法、与其他治疗方法共同使用的可能性(例如使用其他试剂)、以及治疗医师的判断。
本发明提供的式Ⅱ所示的苯并咪唑衍生物能够有效阻滞人髓性单核细胞白血病细胞MV-4-11细胞周期进程，抑制MV-4-11细胞增殖；且式Ⅲ所示的苯并咪唑衍生物半酒石酸盐在体内对接种有MV-4-11细胞的小鼠模型显示出良好的抗肿瘤活性；本发明提供的式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐能够用于治疗白血病，以及用于制备治疗白血病的药物。
附图说明
为了更清楚地说明本发明实施例和现有技术的技术方案，下面对实施例和现有技术中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为实施例3中BALB/c裸小鼠中肿瘤的生长曲线图；
图2为实施例3中BALB/c裸小鼠体重变化曲线图。
具体实施方式
为使本发明的目的、技术方案及优点更加清楚明白，以下参照附图并举实施例，对本发明进一步详细说明。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例中使用了下列缩略语：
FBS：胎牛血清；
DMSO：二甲基亚砜；
IC 50：半数抑制浓度；
PI：碘化丙啶；
SPF级动物：无特定病原体动物；
TGI：肿瘤生长抑制率。
本发明实施例1和实施例2采用的式Ⅱ所示的苯并咪唑衍生物，其制备方法如申请人所拥有的化合物专利CN112424202B说明书中第0188段-第0209段所示，其中步骤十一(第0209段)得到的淡黄色固体1-03为式Ⅱ所示的苯并咪唑衍生物。
本发明实施例3采用的式Ⅲ所示的苯并咪唑衍生物半酒石酸盐，其制备方法如申请人所拥有的化合物专利CN112424202B说明书中第0188段-第0211段所示，其中步骤十二(第0211段)得到的化合物Ⅱ为式Ⅲ所示的苯并咪唑衍生物半酒石酸盐。
实施例1：细胞增殖抑制测定
采用CellTiter-Glo细胞增殖检测试剂盒，评价式Ⅱ所示的苯并咪唑衍生物对人髓性单核细胞白血病细胞MV-4-11细胞(Rb基因型为Rb+)的生长抑制作用。
(1)细胞培养
采用IMDM培养基(含10v/v％FBS和1v/v％双抗(青霉素和链霉素))，在37℃、5％CO 2(体积分数，其余为空气)条件下培养MV-4-11细胞。
(2)细胞接种
用上述培养基对上述培养得到的MV-4-11细胞进行重悬，得到细胞密度为40个/μL的细胞悬液。分别添加100μL细胞悬液至96孔板中，使得细胞接种量为4000个/孔。
将96孔板中的细胞置于37℃、5％CO 2条件下培养过夜。
(3)添加药物
在相应的接种有细胞的96孔板中，每孔加入100μL式Ⅱ所示的苯并咪唑衍生物溶液(DMSO溶解后进行梯度稀释，再用上述培养基稀释得到)，使得孔中式Ⅱ所示的苯并咪唑衍生物的浓度分别为30000nM、10000nM、3333nM、1111nM、370nM、123nM、41.1nM、13.7nM、4.6nM；采用DMSO和上述培养基的混合物作为溶剂对照组(孔中式Ⅱ所示的苯并咪唑衍生物的浓度为0nM)；且各孔DMSO终浓度为0.5v/v％，每个式Ⅱ所示的苯并咪唑衍生物浓度设置三个复孔。
将添加药物后的96孔板中的细胞置于37℃、5％CO 2条件下继续培养96小时。
(4)数据收集和分析
按照CellTiter-Glo细胞增殖检测试剂盒说明书中的方法，收集每孔的化学发光信号值。使用GraphPad Prism 7.0软件分析数据，利用下述非线性拟合公式拟合，得出剂量-响应曲线，并由此计算得到IC 50值。
非线性拟合公式：Y＝最小抑制率+(最大抑制率-最小抑制率)/(1+10^((LogIC 50-X)×斜率))；其中，Y表示抑制百分数(％)，X表示待测药物摩尔浓度的对数；其中，抑制率(％)＝(高读值对照读数-化合物孔读值)/(高读值对照读数-低读值对照读数)×100。
(5)结果分析
本发明所述的式Ⅱ所示的苯并咪唑衍生物的IC 50为87nM；上述结果表明，式Ⅱ所示的苯并咪唑衍生物对人髓性单核细胞白血病细胞MV-4-11细胞具有较强的抑制作用。
实施例2：细胞周期阻滞测定
(1)细胞培养
采用含10v/v％FBS的IMDM培养基，在37℃、5％CO 2条件下培养人髓性单核细胞白血病细胞MV-4-11细胞(Rb基因型为Rb+)。
(2)细胞接种
用上述培养基对上述培养得到的MV-4-11细胞进行重悬，得到细胞密度为500个/μL的细胞悬液。分别添加2mL细胞悬液至6孔板中，使得细胞接种量为1×10 6个/孔。
将6孔板中的细胞置于37℃、5％CO 2条件下培养过夜。
(3)添加药物
在相应的接种有细胞的6孔板中，每孔加入式Ⅱ所示的苯并咪唑衍生物的DMSO溶液，使得孔中式Ⅱ所示的苯并咪唑衍生物的浓度分别为20000nM、6667nM、2222nM、740.7nM、246.9nM、82.3nM、27.4nM、9.14nM、3.0nM；采用DMSO作为溶剂对照组(孔中式Ⅱ所示的苯并咪唑衍生物的浓度为0nM)；每个浓度设置三个复孔。
将添加药物后的6孔板中的细胞置于37℃、5％CO 2条件下继续培养24小时。
(4)数据收集和分析
收集每孔的细胞，固定，PI染色，之后采用CytoFLEX流式细胞仪进行细胞周期检测，并用Modfit软件分析细胞周期，利用下述公式计算得到G1期阻滞系数(即抑制率)：
G1期阻滞系数＝((％G1/G0 待测药-％G1/G0 DMSO)/(1-％G1/G0 DMSO))×100；其中，G1/G0 待测药表示加药组处于G1期细胞与G0期细胞的比值，G1/G0 DMSO表示溶剂对照组G1期细胞与G0期细胞的比值。
使用XL-Fit软件分析数据，利用下述公式拟合获得百分比抑制曲线，得到IC 50。
公式：Y＝最小抑制率+(最大抑制率-最小抑制率)/(1+(IC 50/X)×斜率)；其中，Y表示抑制百分数(％)，X表示待测药物的摩尔浓度。
(5)结果分析
本发明所述的式Ⅱ所示的苯并咪唑衍生物的IC 50为59.7nM；上述结果表明，式Ⅱ所示的苯并咪唑衍生物对人髓性单核细胞白血病细胞MV-4-11细胞的细胞周期具有较强的阻滞作用。
实施例3：体内抗肿瘤活性测定
实验动物：BALB/c裸小鼠：SPF级动物，6-8周龄，体重18-22克；性别：雌性；数量：入组小鼠40只；由上海西普尔-必凯实验动物有限公司提供。
(1)细胞培养
采用含10v/v％FBS和1v/v％双抗(青霉素和链霉素)的IMDM培养基，在37℃、5％CO 2条件下培养人髓性单核细胞白血病细胞MV-4-11细胞(Rb基因型为Rb+)，直至细胞数量达要求时收取细胞。用上述培养基对培养得到的MV-4-11细胞进行重悬，得到细胞密度 为5×10 7个/mL的细胞悬液。
(2)建模和给药
在每只BALB/c祼小鼠右后背皮下接种0.2mL MV-4-11细胞悬液(接种量为1×10 7个/只)，建立MV-4-11异种移植肿瘤动物模型，待肿瘤平均体积达175mm 3时开始分组给药。
实验分为1个溶剂对照组、1个阳性药(瑞博西尼)对照组和3个式Ⅲ所示的苯并咪唑衍生物半酒石酸盐组，每组8只实验动物。阳性药剂量为25mg/kg体重，用水溶解，浓盐酸调节溶液pH至6。3个式Ⅲ所示的苯并咪唑衍生物半酒石酸盐组中式Ⅲ所示的苯并咪唑衍生物半酒石酸盐给药量分别为25mg/kg体重、50mg/kg体重和100mg/kg体重，式Ⅲ所示的苯并咪唑衍生物半酒石酸盐溶解在水中，以溶液形式给药，所有组的给药体积相同；溶剂对照组给予等体积的水。从分组当天开始灌胃给药，每天一次，共给药22天。
(3)数据收集和分析
每周两次用游标卡尺测量肿瘤直径，并用体重秤称量BALB/c裸小鼠体重。
肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。
肿瘤生长抑制率(TGI)＝[(1-(某处理组给药结束时平均肿瘤体积－该处理组开始给药时平均肿瘤体积))/(溶剂对照组治疗结束时平均肿瘤体积－溶剂对照组开始治疗时平均肿瘤体积)]×100％。
(4)结果分析
各组不同时间点的肿瘤体积的平均值如表1所示，BALB/c裸小鼠中肿瘤的生长曲线图如图1所示。
表1各组不同时间点的平均肿瘤体积
Figure PCTCN2023070411-appb-000008
Figure PCTCN2023070411-appb-000009
各组给药22天后的TGI如表2所示。
表2TGI结果
Figure PCTCN2023070411-appb-000010
由上述结果可知，通过对不同组BALB/c裸小鼠给予不同剂量的式Ⅲ所示的苯并咪唑衍生物半酒石酸盐，肿瘤的生长均得到显著的抑制，TGI达到64.7％。给药量为50mg/kg体重时，式Ⅲ所示的苯并咪唑衍生物半酒石酸盐比瑞博西尼对应的肿瘤生长抑制率(TGI)更高，说明本发明所述的式Ⅲ所示的苯并咪唑衍生物半酒石酸盐比瑞博西尼具有更高的抗肿瘤活性。上述结果表明，本发明所述的式Ⅲ所示的苯并咪唑衍生物半酒石酸盐具有明显的体内抗肿瘤活性。
各组不同时间点的BALB/c裸小鼠体重的平均值如表3所示，BALB/c裸小鼠体重变化曲线图如图2所示。
表3各组不同时间点的平均体重
Figure PCTCN2023070411-appb-000011
Figure PCTCN2023070411-appb-000012
由上述结果可知，不同组BALB/c裸小鼠给予不同剂量的式Ⅲ所示的苯并咪唑衍生物半酒石酸盐后，小鼠体重未见大幅下降，且未见明显毒性表现，表明式Ⅲ所示的苯并咪唑衍生物半酒石酸盐在有效抑瘤剂量下，小鼠耐受性较好。
综合上述实施例，本发明提供的式Ⅱ所示的苯并咪唑衍生物能够有效阻滞人髓性单核细胞白血病细胞MV-4-11细胞周期进程，抑制MV-4-11细胞增殖，且式Ⅲ所示的苯并咪唑衍生物半酒石酸盐在体内对接种有MV-4-11细胞的小鼠模型显示出良好的抗肿瘤活性；因此，上述苯并咪唑衍生物或其盐能够用于治疗白血病，以及用于制备治疗白血病的药物。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，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，均应包含在本发明保护的范围之内。

Claims (17)

  1. 式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐中的至少一种，或包含式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐中的至少一种的组合物在治疗白血病中的用途；
    Figure PCTCN2023070411-appb-100001
    其中，
    环A为芳基或杂芳基；
    Z选自CH 2、NH、O或S；
    R 1分别独立地选自氢、卤素、氰基、硝基、羟基、氨基、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、芳基、杂芳基、杂环基、杂环基-(CH 2) m-、芳基-C 1-6烷基-、杂芳基-C 1-6烷基-、NR 12R 13、NR 12-C 1-6亚烷基-NR 12R 13或杂环基-C(O)-；其中C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、芳基、杂芳基、杂环基、杂环基-(CH 2) m-、芳基-C 1-6烷基-、杂芳基-C 1-6烷基-或杂环基-C(O)-是各自未取代或者被至少一个选自卤素、C 1-8烷基、C 3-8环烷基、杂环基、NR 12R 13、(CH 2) t-OH的取代基取代；
    R 2和R 3各自独立地选自氢、羟基、氰基、硝基、氨基、卤素、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、芳基、杂芳基或杂环基；其中C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、芳基、杂芳基或杂环基是各自未取代或者被至少一个选自卤素、羟基、C 1-8烷基、C 3-8环烷基或杂环基的取代基取代；
    R 12和R 13各自独立地选自氢、C 1-8烷基、芳基、杂芳基、杂环基或C 3-8环烷基；其中C 1-8烷基、芳基、杂芳基、杂环基或C 3-8环烷基是各自未取代或者被至少一个选自卤素、羟基、C 1-8烷基、C 3-8环烷基或杂环基的取代基取代；
    m为0、1、2、3或4；
    n为0、1、2、3或4；
    t为0、1、2、3或4；
    所述芳基为6到10元的单环或双环的芳香环基团；
    所述杂芳基为5元或6元单环芳香族环系统，其由碳原子和1-4个选自N、O或S的杂原子组成；
    所述杂环基为由碳原子和1-3个选自N、O或S的杂原子组成的3-8元稳定饱和单环系统。
  2. 式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐中的至少一种，或包含式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐中的至少一种的组合物在制备用于治疗白血病的药物中的用途；
    Figure PCTCN2023070411-appb-100002
    其中，
    环A为芳基或杂芳基；
    Z选自CH 2、NH、O或S；
    R 1分别独立地选自氢、卤素、氰基、硝基、羟基、氨基、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、芳基、杂芳基、杂环基、杂环基-(CH 2) m-、芳基-C 1-6烷基-、杂芳基-C 1-6烷基-、NR 12R 13、NR 12-C 1-6亚烷基-NR 12R 13或杂环基-C(O)-；其中C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、芳基、杂芳基、杂环基、杂环基-(CH 2) m-、芳基-C 1-6烷基-、杂芳基-C 1-6烷基-或杂环基-C(O)-是各自未取代或者被至少一个选自卤素、C 1-8烷基、C 3-8环烷基、杂环基、NR 12R 13、(CH 2) t-OH的取代基取代；
    R 2和R 3各自独立地选自氢、羟基、氰基、硝基、氨基、卤素、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、芳基、杂芳基或杂环基；其中C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、芳基、杂芳基或杂环基是各自未取代或者被至少一个选自卤素、羟基、C 1-8烷基、C 3-8环烷基或杂环基的取代基取代；
    R 12和R 13各自独立地选自氢、C 1-8烷基、芳基、杂芳基、杂环基或C 3-8环烷基；其中C 1-8烷基、芳基、杂芳基、杂环基或C 3-8环烷基是各自未取代或者被至少一个选自卤素、羟基、C 1-8烷基、C 3-8环烷基或杂环基的取代基取代；
    m为0、1、2、3或4；
    n为0、1、2、3或4；
    t为0、1、2、3或4；
    所述芳基为6到10元的单环或双环的芳香环基团；
    所述杂芳基为5元或6元单环芳香族环系统，其由碳原子和1-4个选自N、O或S的杂原子组成；
    所述杂环基为由碳原子和1-3个选自N、O或S的杂原子组成的3-8元稳定饱和单环系统。
  3. 根据权利要求1或2所述的用途，其中，所述化合物是式Ⅱ所示的化合物，
    Figure PCTCN2023070411-appb-100003
  4. 根据权利要求1-3中任一项所述的用途，其中，所述盐选自盐酸盐、氢溴酸盐、氢碘酸盐、高氯酸盐、硫酸盐、硝酸盐、磷酸盐、乙酸盐、丙酸盐、乙醇酸盐、乳酸盐、琥珀酸盐、马来酸盐、富马酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐、扁桃酸盐、甲磺酸盐、羟乙基磺酸盐、苯磺酸盐、草酸盐、扑酸盐、2-萘磺酸盐、对甲苯磺酸盐、环己胺磺酸盐、水杨酸盐、糖精酸盐、三氟乙酸盐、铝盐、钙盐、氯普鲁卡因盐、胆碱、二乙醇胺盐、乙二胺、锂盐、镁盐、钾盐、钠盐和锌盐中的至少一种。
  5. 根据权利要求4所述的用途，其中，所述盐选自酒石酸盐和甲磺酸盐中的至少一种；所述酒石酸盐优选为式Ⅲ所示的半酒石酸盐；
    Figure PCTCN2023070411-appb-100004
  6. 根据权利要求1-5中任一项所述的用途，其中，所述白血病包含急性淋巴细胞白血 病、急性髓系白血病、慢性髓系白血病、慢性淋巴细胞白血病、毛细胞白血病和幼淋巴细胞白血病。
  7. 根据权利要求6所述的用途，其中，所述急性髓系白血病包含急性髓细胞白血病微小分化型、急性粒细胞白血病未分化型、急性粒细胞白血病部分分化型、急性早幼粒细胞白血病、急性粒-单核细胞白血病、急性单核细胞白血病、急性红白血病和急性巨核细胞白血病。
  8. 根据权利要求1-7中任一项所述的用途，其中，所述式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐中的至少一种，或包含式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐中的至少一种的组合物通过口服、直肠、局部或胃肠外给药的方式施用于有需要的对象。
  9. 根据权利要求2或3所述的用途，其中，所述药物还包括药学上可接受的载体和/或辅料，所述载体选自乳糖、石膏粉、蔗糖、滑石粉、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁、硬脂酸、糖浆、花生油、橄榄油、水、二氧化碳和氮气中的至少一种；所述辅料选自分散剂、稳定剂、增稠剂、络合剂、缓冲剂、渗透促进剂、芳香剂、甜味剂和染料中的至少一种。
  10. 根据权利要求2或3所述的用途，其中，所述药物的剂型选自颗粒剂、悬浮剂、酏剂、溶液剂、胶囊剂、扁囊剂、片剂、散剂、注射剂、气溶胶、乳剂、软膏剂、洗剂、撒粉和栓剂中的一种。
  11. 一种治疗白血病的方法，其包括向有需要的对象施以有效剂量的式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐中的至少一种，或包含式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐中的至少一种的组合物：
    Figure PCTCN2023070411-appb-100005
    其中，
    环A为芳基或杂芳基；
    Z选自CH 2、NH、O或S；
    R 1分别独立地选自氢、卤素、氰基、硝基、羟基、氨基、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、芳基、杂芳基、杂环基、杂环基-(CH 2) m-、芳基-C 1-6烷基-、杂芳基-C 1-6烷基-、NR 12R 13、NR 12-C 1-6亚烷基-NR 12R 13、或杂环基-C(O)-；其中C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、芳基、杂芳基、杂环基、杂环基-(CH 2) m-、芳基-C 1-6烷基-、杂芳基-C 1-6烷基-或杂环基-C(O)-是各自未取代或者被至少一个选自卤素、C 1-8烷基、C 3-8环烷基、杂环基、NR 12R 13、(CH 2) t-OH的取代基取代；
    R 2和R 3各自独立地选自氢、羟基、氰基、硝基、氨基、卤素、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、芳基、杂芳基或杂环基；其中C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、芳基、杂芳基或杂环基是各自未取代或者被至少一个选自卤素、羟基、C 1-8烷基、C 3-8环烷基或杂环基的取代基取代；
    R 12和R 13各自独立地选自氢、C 1-8烷基、芳基、杂芳基、杂环基或C 3-8环烷基；其中C 1-8烷基、芳基、杂芳基、杂环基或C 3-8环烷基是各自未取代或者被至少一个选自卤素、羟基、C 1-8烷基、C 3-8环烷基或杂环基的取代基取代；
    m为0、1、2、3或4；
    n为0、1、2、3或4；
    t为0、1、2、3或4；
    所述芳基为6到10元的单环或双环的芳香环基团；
    所述杂芳基为5元或6元单环芳香族环系统，其由碳原子和1-4个选自N、O或S的杂原子组成；
    所述杂环基为由碳原子和1-3个选自N、O或S的杂原子组成的3-8元稳定饱和单环系统。
  12. 根据权利要求11所述的方法，其中，所述化合物是式Ⅱ所示的化合物，
    Figure PCTCN2023070411-appb-100006
  13. 根据权利要求11或12所述的方法，其中，所述盐选自盐酸盐、氢溴酸盐、氢碘酸盐、高氯酸盐、硫酸盐、硝酸盐、磷酸盐、乙酸盐、丙酸盐、乙醇酸盐、乳酸盐、琥珀酸盐、马来酸盐、富马酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐、扁桃酸盐、甲磺酸盐、羟乙基磺酸盐、苯磺酸盐、草酸盐、扑酸盐、2-萘磺酸盐、对甲苯磺酸盐、环己胺磺酸盐、水杨酸盐、糖精酸盐、三氟乙酸盐、铝盐、钙盐、氯普鲁卡因盐、胆碱、二乙醇胺盐、乙二胺、锂盐、镁盐、钾盐、钠盐和锌盐中的至少一种。
  14. 根据权利要求13所述的方法，其中，所述盐选自酒石酸盐和甲磺酸盐中的至少一种；所述酒石酸盐优选为式Ⅲ所示的半酒石酸盐；
    Figure PCTCN2023070411-appb-100007
  15. 根据权利要求11或12所述的方法，其中，所述白血病包含急性淋巴细胞白血病、急性髓系白血病、慢性髓系白血病、慢性淋巴细胞白血病、毛细胞白血病和幼淋巴细胞白血病。
  16. 根据权利要求15所述的方法，其中，所述急性髓系白血病包含急性髓细胞白血病微小分化型、急性粒细胞白血病未分化型、急性粒细胞白血病部分分化型、急性早幼粒细胞白血病、急性粒-单核细胞白血病、急性单核细胞白血病、急性红白血病和急性巨核细胞白血病。
  17. 根据权利要求11或12所述的方法，其中，通过口服、直肠、局部或胃肠外给药，向有需要的对象施以有效剂量的所述式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐中的至少一种，或包含式I所示的化合物、其立体异构体、其互变异构体、其多晶型物、其溶剂化物及其药学上可接受的盐中的至少一种的组合物。
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