N-macrocyclic amide compounds, preparation methods thereof and use thereof as medicines

Abstract

The present invention relates to N-macrocyclic amide compounds having structures shown in general formula (I) and general formula (II) or isomers, diastereomers, enantiomers, prodrugs, and pharmaceutically acceptable salts thereof, wherein L, X, Y, Z, R 1 , A, B, C are each as defined in the specification of this application. The present invention also relates to the use of N-macrocyclic amide compounds having the structures shown in the general structural formula (I) and the general structural formula (II) or their isomers, diastereomers, enantiomers, prodrugs, and pharmaceutically acceptable salts in medicine,

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to N-macrocyclic amide compounds, preparation methods thereof and applications thereof in medicine. Background Art

[0002] Human proliferative diseases typically involve abnormal control of cell growth and / or division in the body, resulting in uncontrolled growth of cells in the body, leading to tumor formation and eventual death (Jessica L. Counihan, Elizabeth A. Grossman, and Daniel K. Nomura. Cancer Metabolism: Current Understanding and Therapies. Chem. Rev. 2018, 118, 6893-6923).

[0003] With the improvement of human living standards, higher and higher requirements are put forward for the treatment of cancer clinically. On the one hand, the efficacy needs to be further improved, and on the other hand, it is also necessary to continue to reduce related side effects and improve the quality of life after prognosis. Targeted tumor therapeutic drugs came into being. Among the many targeted anti-tumor drugs, protein kinase ("kinase") inhibitors have achieved great success as anti-tumor drugs and have become an important class of targeted anti-tumor drugs (Kinase inhibitors: the road ahead. Fleur M. Ferguson, and Nathanael S. Gray. Nature Review Drug Discovery, 2018. Volume 17, 353–377).

[0004] Cell growth, division and apoptosis are controlled by signaling cascades or cell-signaling pathways. Kinase-mediated protein phosphorylation plays an important role in the above signal transduction. Studies have found that the occurrence and growth of cancer are closely related to cell signal transduction, cell cycle regulation, induction of apoptosis and tumor blood vessel growth. Kinases are mainly responsible for the control of intracellular signal transduction processes. Abnormal expression of kinases is closely related to the occurrence and development of many diseases, especially tumors (Evolution of Small Molecule Kinase Drugs. Helen Louise Lightfoot, Frederick Woolf Goldberg, and Joerg Sedelmeier. ACS Med. Chem. Lett. 2019, 10, 153-160. Kinase Inhibitors for the Treatment of Immunological Disorders: Recent Advances. Marian C. Bryan and Naomi S. Rajapaksa. J. Med. Chem. 2018, 61, 9030-9058).

[0005] Janus kinases (JAKs), including JAK1, JAK2, JAK3, and TYK2, are cytoplasmic protein kinases that interact with type I and type II cytokine receptors to regulate cytokine signal transduction (Advantages of targeting the tumor immune microenvironment over blocking immune checkpoint in cancer immunotherapy. Signal Transduction and Targeted Therapy (2021) 6: 72-85). Downstream substrates of the JAK family include signal transducers and activators of transcription (STATs). JAK / STAT signal transduction is involved in many abnormal immune responses, such as allergies, asthma, autoimmune diseases such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, as well as solid and hematological malignancies such as leukemia and lymphoma (Kinase Inhibitors for the Treatment of Immunological Disorders: Recent Advances. Marian C. Bryan and Naomi S. Rajapaksa. J. Med. Chem. 2018, 61, 9030-9058).

[0006] Compounds that modulate JAK kinases and combinations containing these compounds appear to provide substantial therapeutic benefits for a variety of patients. Therefore, there is an urgent need to develop inhibitors that can be used for more related protein kinases, and more specifically, more JAK family kinase inhibitors (Christoph Rummelt, Sivahari P. Gorantla, Manja Meggendorfer, Anne Charlet, Cornelia Endres, Konstanze Florian H.Heidel,Thomas Fischer,Torsten Haferlach,Justus Duyster,Nikolas vonBubnoff.Activating JAK-mutations confer resistance to FLT3 kinase inhibitorsin FLT3-ITD positive AML in vitro and in vivo. Leukemia, 2020:1–13. https: / / doi.org / 10.1038 / s41375-020-01077-1).

[0007] Novel macrocyclic structures can be used as important structural units of kinase inhibitors. US20170022202A1 reports the synthesis method of Compound_1 and its analogs and their application as kinase inhibitors. Compound_2 of Central South University is a kinase and HDAC inhibitor, which may have potential medical applications (CN101365703A; WO2007058628A1). Incyte has reported a large number of macrocyclic compounds with multiple kinase inhibitory activities (WO2009132202A2), and its representative compounds are shown in compound_3. Polyphor uses the synthesis of macrocyclic compounds as an important platform, and has successively synthesized and screened various types of compounds. Compound_4 is one of its representative compounds. Polyphor's macrocyclic compounds have the potential to have various medical applications (WO2013139697A1).

[0008]

[0009] Currently, macrocyclic kinase inhibitors have entered various stages of clinical trials as candidate drugs, especially anti-tumor drugs, and have shown good application prospects. How to expand the indications of such compounds and further reduce related potential side effects requires the development of clinical research on the one hand, and more and more powerful new kinase inhibitor drugs on the other hand. Summary of the invention

[0010] In view of the shortcomings of existing drugs, the present invention provides an N-macrocyclic amide compound or its isomers, diastereomers, enantiomers, prodrugs, and pharmaceutically acceptable salts, the chemical structure of which is shown in the general structural formula (I) or the general structural formula (II):

[0011]

[0012] In the general structural formula (I) or the general structural formula (II),

[0013] L is a group represented by the following formula:

[0014] -L 1 -L 2 -,

[0015] Where L 1 One end of L is connected to the A group. 2 One end of is connected to the X group;

[0016] L 1 Selected from: covalent bond, alkyl, -O-, -S-, -N(R 2)-, alkyl-O-, -O-alkyl, alkyl-O-alkyl, alkyl-S-, -S-alkyl, alkyl-S-alkyl, alkyl-N(R 2 )-、-N(R 2 )-alkyl or alkyl-N(R 2 )-alkyl;

[0017] L 2 Selected from: a covalent bond, an alkyl group, an alkyl group-CH=CH-, or a -CH=CH-alkyl group;

[0018] X is selected from: covalent bond, -O-, -S- or -N(R 2 )-;

[0019] Y is selected from: -O-, -S-, -N(R 2 )-、-N(R 2 )-CO-, -O-alkyl, -S-alkyl, -N(R 2 )-alkyl or -N(R 2 )-CO-alkyl;

[0020] Z is selected from: a covalent bond or an alkyl group, wherein one or more carbon atoms in the carbon chain of the alkyl group may be replaced by heteroatoms;

[0021] R 1 A group is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, amino, alkylamino, aminoalkyl, carboxyl, alkylcarboxyl, acylamino, alkylacylamino, alkylsulfonyl or alkylacyl, each of which may be optionally substituted;

[0022] or R 1 The group is selected from one of the following groups:

[0023]

[0024]

[0025] Where m represents 0 to 3;

[0026] R 2 , R 3 and R 4each independently selected from the group consisting of H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, amino, alkylamino, aminoalkyl, carboxyl, alkylcarboxyl, acylamino, alkylacylamino, alkylsulfonyl or acyl, each of which may be optionally substituted;

[0027] The A group is selected from:

[0028]

[0029] R 5 A group is selected from the group consisting of: H, halogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, amino, alkylamino, aminoalkyl, acylamino, alkylsulfonyl or acyl, each of which may be optionally substituted;

[0030] The B group is selected from one of the following groups:

[0031]

[0032] R 5 and R 6 The groups are each independently selected from: H, halogen, alkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, amino, alkylamino, aminoalkyl, carboxyl, alkylcarboxyl, acylamino, alkylacylamino, alkylsulfonyl or acyl, each of which may be optionally substituted;

[0033] The C group is selected from:

[0034]

[0035] In the formula, any one end is connected to the Y group.

[0036] The compounds of the general structural formula (I) and the general structural formula (II) of the present invention, wherein:

[0037] L 1 Selected from alkyl groups, wherein one or more carbon atoms in the carbon chain of the alkyl group may be substituted by heteroatoms;

[0038] L 2 Preferably selected from: -C1-C5 alkyl or -CH=CH-(C1-C5 alkyl);

[0039] Y is preferably selected from: -O-, -O-alkyl, -N(R 2 )-alkyl or -N(R 2 )-CO-alkyl;

[0040] Z is preferably selected from: C1-C2 alkyl;

[0041] R 1 Preferably one selected from the following groups:

[0042]

[0043] More preferably, it is selected from one of the following groups:

[0044]

[0045] Where m represents 0 to 3;

[0046] The B group is preferably selected from one of the following groups:

[0047]

[0048] More preferably selected from:

[0049] The compounds of the general structural formula (I) and the general structural formula (II) of the present invention include the following compounds:

[0050]

[0051]

[0052]

[0053]

[0054]

[0055] The term "unsubstituted" as used herein means that there are no substituents present or the only substituents are hydrogen.

[0056] As used herein, the term "optionally substituted" means that the group may be further substituted or fused with one or more non-hydrogen substituents. These substituents are independently selected from one or more of the following groups: halogen, =O, =S, -CN, -NO2, -CF3, -OCF3, alkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, alkoxy, hydroxyalkyl, amino, alkylamino, aminoalkyl, acylamino, alkylsulfonyl and acyl.

[0057] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0058] As a group or part of a group, "alkyl" is a C1-C14 straight or branched chain aliphatic hydrocarbon group, unless otherwise specified.

[0059] "Heteroatom" refers to S, O and N atoms.

[0060] "Heteroalkyl" refers to a C1-C14 straight or branched chain alkyl group in which one or more carbon atoms are replaced by a heteroatom, and the heteroatom is defined as above.

[0061] "Cycloalkyl" refers to a saturated or partially saturated monocyclic, condensed or spirocyclic carbon ring. Rings consisting of 3 to 9 carbon atoms are preferred. The group can be a terminal group or a bridging group.

[0062] "Cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic ring system, which contains at least one carbon-carbon double bond and preferably has 5 to 10 carbon atoms per ring. The group can be a terminal group or a bridging group.

[0063] "Heterocycloalkyl" refers to a cycloalkyl group containing at least one heteroatom. Preferably, it contains 1-3 heteroatoms. Preferred rings are 3-14 membered rings, and more preferably, 4-7 membered rings. The definitions of cycloalkyl and heteroatom are as described above. The group may be a terminal group or a bridging group.

[0064] As a group or part of a group, "aryl" means an optionally substituted monocyclic or fused polycyclic, aromatic carbocyclic ring, preferably containing 5 to 12 atoms per ring. The group may be a terminal group or a bridging group.

[0065] As a group or part of a group, "heteroaryl" refers to a group containing an aromatic ring having one or more heteroatoms among the ring atoms of the aromatic ring. The heteroatom is defined as above. The group can be a terminal group or a bridging group.

[0066] "Cycloalkylalkyl" means a cycloalkyl-alkyl group in which the cycloalkyl and alkyl portions are as previously described, which group may be a terminal group or a bridging group.

[0067] "Arylalkyl" refers to a group of: (aryl-alkyl)-, wherein aryl and alkyl are as defined herein. The group may be a terminal group or a bridging group.

[0068] "Heteroarylalkyl" refers to a (heteroaryl-alkyl)- group, wherein the aryl and alkyl portions are as defined herein. The group may be a terminal group or a bridging group.

[0069] "Arylheteroalkyl" refers to a group of (aryl-heteroalkyl)-, wherein aryl and heteroalkyl are as defined herein, and the group can be a terminal group or a bridging group.

[0070] "Cycloalkylheteroalkyl" refers to a group of (cycloalkyl-heteroalkyl)-, wherein cycloalkyl and heteroalkyl are as defined herein. The group may be a terminal group or a bridging group.

[0071] "Heterocycloalkylheteroalkyl" refers to a group of (heterocycloalkyl-heteroalkyl)-, wherein heterocycloalkyl and heteroalkyl are as defined herein. The group may be a terminal group or a bridging group.

[0072] "Heteroarylheteroalkyl" refers to a group of (heteroaryl-heteroalkyl)-, wherein heteroaryl and heteroalkyl are as defined herein. The group may be a terminal group or a bridging group.

[0073] "Aminoalkyl" refers to a group of (amino-alkyl)-, wherein alkyl is as defined herein. The group may be a terminal group or a bridging group.

[0074] "Alkoxy" refers to -O-alkyl, wherein alkyl is as defined herein. The alkoxy is preferably C1-C6 alkoxy. The group may be a terminal group or a bridging group.

[0075] Unless otherwise indicated, "alkylamino" refers to monoalkylamino and dialkylamino. "Monoalkylamino" refers to -NH-alkyl, where alkyl is as defined above. "Dialkylamino" refers to -N(alkyl)2, where each alkyl group may be the same or different and conforms to the definition of alkyl herein. The group may be a terminal group or a bridging group.

[0076] Unless otherwise specified, "arylamino" includes monoarylamino and diarylamino. "Monoarylamino" means the formula aryl-NH-, wherein aryl is as defined above. Diarylamino means the formula (aryl)2N-, wherein each aryl may be the same or different and conforms to the definition of aryl herein. The group may be a terminal group or a bridging group.

[0077] "Acyl" means an alkyl-CO- group, wherein alkyl is as defined herein. The group may be a terminal group or a bridging group.

[0078] "Acylamino" means a group of (acyl-amino)-, wherein acyl and alkyl are as defined herein. This group may be a terminal group or a bridging group.

[0079] "Alkylsulfonyl" refers to a -S(O)2-alkyl group, wherein alkyl is as defined herein. This group can be a terminal group or a bridging group.

[0080] "Hydroxyalkyl" refers to the radical -alkyl-hydroxy wherein alkyl is as defined herein.

[0081] The term "pharmaceutical salt" or "pharmaceutically acceptable salt" refers to salts of the above identified compounds that retain the desired biological activity, including pharmaceutically acceptable acid addition salts and base addition salts. Acid addition salts of compounds shown in general structural formula (I) and general structural formula (II) can be prepared from inorganic acids or organic acids. Inorganic acids can be, but are not limited to, hydrochloric acid, phosphoric acid and sulfuric acid. Suitable organic acids can be, but are not limited to, formic acid, acetic acid, propionic acid, succinic acid, alkylsulfonic acid, glycolic acid, gluconic acid, lactic acid, malic acid, citric acid, tartaric acid, fumaric acid, maleic acid, arylsulfonic acid. Base addition salts of compounds shown in general structural formula (I) include, but are not limited to, metal salts prepared from lithium, sodium, potassium, calcium, magnesium, aluminum and zinc, and organic salts prepared from organic bases such as choline, morpholine, diethanolamine, etc.

[0082] The compounds shown in the general structural formula (I) and the general structural formula (II) include isomeric forms, including diastereomers, enantiomers, tautomers and geometric isomers in "E" or "Z" configuration isomers or mixtures of E and Z isomers. Some of the compounds in the embodiments may exist as single stereoisomers, racemates and / or mixtures of enantiomers and / or diastereomers.

[0083] Furthermore, the general formula (I) and the general formula (II) are intended to include both solvated and unsolvated forms of the compounds.

[0084] In the general structural formula (I) and the general structural formula (II), when the A group is The B group is The C group is X is -O-, Y is -NH-CO-, L 1 is alkyl-O-, L 2 When it is an alkyl group -CH=CH-, when Z is an alkyl group, the corresponding compound can be synthesized by the method shown in the first synthetic route:

[0085] Synthetic route 1

[0086]

[0087]

[0088] Specifically, as shown in the first synthetic route, a suitable boron compound I is selected to react with a pyrimidine derivative II having a suitable substituent under Suzuki coupling conditions to obtain a biaryl compound compound III. In the presence of a suitable base, compound III undergoes a condensation reaction with an alkenyl bromide IV to obtain compound V. On the other hand, a suitable compound VI is selected as a raw material and condensed with a pyrimidine derivative VII having a corresponding substituent to obtain an intermediate VIII. After reduction and monoprotection, X is obtained. The intermediate V obtained above is condensed with compound X under alkaline conditions to obtain a compound intermediate XI. The intermediate XI is catalyzed by a Grubbs II catalyst to undergo a ring-closing metathesis reaction to obtain a macrocyclic intermediate XII. The protecting group is removed under acidic conditions to obtain compound XIII. Under the action of suitable reagents and solvents, compound XIII reacts with XIV and XV to obtain target compounds XVI and XVII, respectively.

[0089] Where R 1 , R 5 and R 6 As defined above, r, s, t, and u each independently represent 0 to 5.

[0090] The present invention also provides the use of the N-macrocyclic amide compound or its isomers, diastereomers, enantiomers, prodrugs, and pharmaceutically acceptable salts described in any one of the above technical solutions in medicine.

[0091] The present invention also provides a pharmaceutical composition, which comprises the N-macrocyclic amide compound or its isomers, diastereomers, enantiomers, prodrugs, pharmaceutically acceptable salts described in any one of the above technical schemes, and one or more of pharmaceutically acceptable diluents, excipients, and carriers.

[0092] The present invention also provides the use of the N-macrocyclic amide compound or its isomer, diastereomer, enantiomer, prodrug, pharmaceutically acceptable salt or the pharmaceutical composition described in any one of the above technical schemes, optionally in combination with one or more other drugs, for the preparation of drugs for inhibiting one or more kinases.

[0093] In the use described in the present invention, the kinase is selected from: CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIREK, PCTAIRE2, PCTAIRE3, CAK / MO15, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRKK, PfC2R, EhC2R, CfCdc2R, cdc2+, CDC28, PHO85, KIN28, FpCdc2, MsCdc2B, OsC2R, PDGFR-b, PDGFR-a, CSF1R, c-kit, Flk2, FLT1, FLT2, FLT3, FLT4, TYK2, JAK1, JAK2, HOP or their functional equivalents.

[0094] The present invention also provides the use of the N-macrocyclic amide compound or its isomer, diastereomer, enantiomer, prodrug, pharmaceutically acceptable salt or the pharmaceutical composition described in any one of the above technical schemes, which is used to prepare a drug for treating diseases caused by, associated with or accompanied by the destruction of cell proliferation and / or angiogenesis.

[0095] In the use of the present invention, the disease may be a proliferative disease.

[0096] In the use described in the present invention, the proliferative disease may be cancer.

[0097] In the use of the present invention, the proliferative disease can be selected from: myeloproliferative diseases (chronic idiopathic myelofibrosis, polycythemia vera, idiopathic thrombocythemia, chronic myelocytic leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute myelocytic leukemia, juvenile myelomonocytic leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, acute B-cell leukemia, leukocytosis, Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, breast cancer, ovarian cancer, colon cancer, prostate cancer, melanoma, myelodysplastic syndrome, keloid, retinoblastoma, breast malignancy, colon malignancy, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma, hepatocellular carcinoma, pancreatic malignancy, myeloid leukemia, cervical cancer, fibroma, colon adenocarcinoma, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma, bladder tumor or musculoskeletal tumor.

[0098] In the use described in the present invention, the proliferative disease can be selected from: prostate cancer, retinoblastoma, breast malignancy, colon malignancy, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma, hepatocellular carcinoma, pancreatic malignancy, myeloid leukemia, cervical cancer, fibroma, colon adenocarcinoma, T-cell leukemia, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, restenosis, astrocytoma, bladder tumor, musculoskeletal tumor or Alzheimer's disease.

[0099] In the use described in the present invention, the proliferative disease can be selected from: acute myeloid leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, leukocytosis, juvenile myelomonocytic leukemia, acute B-cell leukemia, chronic myeloid leukemia, acute T-cell leukemia, myeloproliferative disease or chronic myelomonocytic leukemia. DETAILED DESCRIPTION

[0100] In the following examples, all temperatures are in degrees Celsius unless otherwise indicated.

[0101] All starting materials and reagents were obtained from commercial suppliers, including but not limited to Aldrich Chemical Company, Lancaster Synthesis Ltd, etc. Unless otherwise specified, commercially available materials and reagents were used directly without further purification.

[0102] The glassware was oven dried and / or heat dried. The reaction was followed on a glass silica gel-60F254 plate (0.25 mm) (TLC). Analytical thin layer chromatography was developed with an appropriate solvent ratio (v / v). The reaction endpoint was when the starting material of the reaction was exhausted on TLC.

[0103] 1 H-NMR spectra were measured using a Bruker instrument (300 MHz or 400 MHz), and chemical shifts were expressed in ppm. Chloroform was used as a reference standard (7.25 ppm) or tetramethylsilane as an internal standard (0.00 ppm). Other solvents commonly used in NMR may also be used as needed. 1 H-NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0104] The mass spectrum is obtained by using a MS instrument, and the ionization method can be ESI or APCI.

[0105] The following examples are only used to illustrate the synthesis methods of the specific compounds invented. However, there is no limitation on the synthesis methods. Compounds not listed in the examples can also be prepared by the same synthesis routes and methods as below, by selecting appropriate starting materials and slightly adjusting the reaction conditions according to common sense where necessary.

[0106] Example 1

[0107] Synthetic route 1

[0108] (1) 3-(2-Chloro-pyrimidin-4-yl)-benzyl alcohol (III-1)

[0109]

[0110] Add the compound 3-hydroxymethylphenylboronic acid (II-1, 35.2g, 231.5mmol), 2,4-dichloropyrimidine (I-1, 30.0g, 201.3mmol), a saturated solution of sodium carbonate (32.0g, 302.0mmol), tetrakistriphenylphosphine palladium (11.6g, 10.1mmol), ethylene glycol dimethyl ether (300mL) to the reaction bottle, and then replace with nitrogen three times, and protect with nitrogen. Heat to 80℃ and react for 3 hours. The reaction system is detected by TLC spot plate (PE / EA=2:1), and the raw material disappears at 254nm of the ultraviolet analyzer, and the product no longer increases, and the reaction is judged to be terminated. Add saturated ammonium chloride solution to quench the reaction, add 100mL of dichloromethane, stir for 10 minutes, let stand and separate, and collect the organic phase. The aqueous phase is extracted with 50mL×2 of dichloromethane, the organic phases are combined, and the aqueous phase is discarded. The organic phase was washed with 50 mL of saturated brine, and after standing for stratification, the aqueous phase was discarded, and the organic phase was dried with an appropriate amount of anhydrous sodium sulfate. After drying, the desiccant was filtered out, and the filtrate was concentrated to dryness under reduced pressure to obtain a residue. The residue was passed through a fast column (the elution system was ethyl acetate / petroleum ether, and the ratio was gradually increased from 1:20 to 1:3), and the eluate of the corresponding product was collected, and the eluate was concentrated to dryness under reduced pressure to obtain compound III-1 (39 g, 88.2%). 1 H NMR (400MHz, DMSO-d6): δ8.67(d,J=5.2Hz,1H),8.09(s,1H),7.97(dd,J=1.4and 6.8Hz, 1H), 7.65 (d, J = 5.2Hz, 1H), 7.55-7.47 (m, 2H), 4.79 (d, J = 6.0Hz, 2H), 2.36 (t, J = 6.0Hz, 1H). MS(m / z):243(M Na) + .

[0111] (2) 4-(3-(allyloxymethyl)-phenyl)-2-chloropyrimidine (V-1)

[0112]

[0113] Add compound III-1 (5.0g, 22.7mmol), 3-bromopropylene (IV-1, 25mL), potassium hydroxide (2.5g, 45.4mmol), tetrabutylammonium iodide (0.4g, 1.1mmol) to the reaction flask and stir at room temperature overnight. The reaction system was detected by TLC spot plate (PE / EA=2:1). The raw material disappeared at 254nm of the ultraviolet analyzer, and the product no longer increased. It was judged that the reaction was terminated. Add 30mL of water, stir for 10 minutes, stand and separate, and collect the organic phase. The aqueous phase was extracted with 20mL×2 of dichloromethane, the organic phases were combined, and the aqueous phase was discarded. The organic phase was washed with 20mL of saturated brine, and after standing and separating, the aqueous phase was discarded, and the organic phase was dried with an appropriate amount of anhydrous sodium sulfate. After drying, the desiccant was filtered off, and the filtrate was concentrated to dryness under reduced pressure to obtain a residue. The residue was passed through a flash column (elution system was ethyl acetate / petroleum ether, the ratio was gradually increased from 1:20 to 1:5), the eluate of the corresponding product was collected, and the eluate was concentrated to dryness under reduced pressure to obtain compound V-1 (5 g, 84.7%). 1 H NMR (400MHz, DMSO-d6): δ 8.64-7.47 (m, 6H), 6.07-5.94 (m, 2H), 5.37-5.22 (m, 4H), 4.61 (s, 2H), 4.09 (d, 2H, J = 10.8Hz). MS(m / z):261(MH) + .

[0114] (3) 1-((allyl)methyl)-3,5-dinitrobenzene (VIII-1)

[0115]

[0116]

[0117] Add 3,5-dinitrobenzyl alcohol (VI-1, 20.0 g, 119.1 mmol), 3-bromopropylene (VII-1, 100 mL), potassium hydroxide (16.7 g, 297.8 mmol), tetrabutylammonium iodide (2.2 g, 6 mmol) to the reaction bottle and stir at room temperature overnight. The reaction system was detected by TLC spot plate (PE / EA=5:1). The UV analyzer showed that the raw material disappeared at 254 nm and the product no longer increased, and the reaction was judged to be terminated. Add 200 mL of water, stir for 10 minutes, stand and separate, and collect the organic phase. The aqueous phase was extracted with 50 mL×2 of dichloromethane, the organic phases were combined, and the aqueous phase was discarded. The organic phase was washed with 100 mL of saturated brine, and after standing and separating, the aqueous phase was discarded, and the organic phase was dried with an appropriate amount of anhydrous sodium sulfate. After drying, the desiccant was filtered out, and the filtrate was concentrated to dryness under reduced pressure to obtain a residue. The residue was passed through a flash column (elution system was ethyl acetate / petroleum ether, the ratio was gradually increased from 1:50 to 1:10), the eluate of the corresponding product was collected, and the eluate was concentrated to dryness under reduced pressure to obtain compound VIII-1 (10.4 g, 43.3%).

[0118] (4) 1-((allyl)methyl)-3,5-diaminobenzene (XI-1)

[0119]

[0120] Compound VIII-1 (7.7 g, 32.4 mmol) and anhydrous ethanol (85 mL) were added to the reaction flask, and then the temperature was raised to 50 ° C. Iron powder (10.9 g, 194.1 mmol) and an aqueous solution of ammonium chloride (20.6 g, 388.2 mmol) were added to the reaction flask, and then refluxed for 4 hours. The reaction system was detected by TLC spot plate (PE / EA=2:1), and the raw material disappeared at 254 nm of the ultraviolet analyzer, and the product no longer increased, and the reaction was judged to be terminated. The system was cooled to room temperature, the iron powder was removed by suction filtration, and the filtrate was concentrated to dryness under reduced pressure. The residue was added to water, adjusted to pH=7 with saturated sodium bicarbonate, ethyl acetate 20 mL was added, stirred for 10 minutes, and the organic phase was collected. The aqueous phase was extracted with ethyl acetate 30 mL×2, the organic phases were combined, and the aqueous phase was discarded. The organic phase was washed with 30 mL of saturated brine, and after standing and stratification, the aqueous phase was discarded, and the organic phase was dried with an appropriate amount of anhydrous sodium sulfate. After drying, the desiccant was filtered off, and the filtrate was concentrated to dryness under reduced pressure to obtain a residue. The residue was passed through a flash column (elution system was ethyl acetate / petroleum ether, the ratio was gradually increased from 1:10 to 1:3), the eluate of the corresponding product was collected, and the eluate was concentrated to dryness under reduced pressure to obtain compound XI-1 (5 g, 87.7%).

[0121] (5) 3-allyl-3-tert-butoxycarbonylamino-aniline (X-1)

[0122]

[0123] Add compound IX-1 (5.0 g, 28.1 mmol) and tetrahydrofuran (50 mL) to the reaction bottle, then cool to 0 ° C, dissolve (Boc) 2 O (5.8 g, 26.7 mmol) in tetrahydrofuran (50 mL) and drip into the reaction system, then restore room temperature to react overnight. The reaction system is detected by TLC spot plate (PE / EA=2:1), and the raw material disappears at 254 nm of the ultraviolet analyzer, and the product no longer increases, and the reaction is judged to be terminated. Add 100 mL of water and 30 mL of ethyl acetate, stir for 10 minutes, stand and separate, and collect the organic phase. The aqueous phase is extracted with 30 mL of ethyl acetate × 2, the organic phases are combined, and the aqueous phase is discarded. The organic phase is washed with 30 mL of saturated brine, and after standing and separating, the aqueous phase is discarded, and the organic phase is dried with an appropriate amount of anhydrous sodium sulfate. After drying, the desiccant is filtered out, and the filtrate is concentrated to dryness under reduced pressure to obtain a residue. The residue was passed through a flash column (elution system was ethyl acetate / petroleum ether, the ratio was gradually increased from 1:20 to 1:8), the eluate of the corresponding product was collected, and the eluate was concentrated to dryness under reduced pressure to obtain compound X-1 (4.7 g, 60.3%).

[0124] (6) Synthesis of macrocyclic intermediate (XI-1)

[0125]

[0126]

[0127] Compound V-1 (3.3 g, 12.6 mmol), compound X-1 (3.5 g, 12.6 mmol), cesium carbonate (10.3 g, 31.5 mmol), X-PHOS (0.6 g, 1.3 mmol), tris(dibenzylideneacetone)dipalladium (0.6 g, 0.6 mmol), dioxane (55 mL) were added to the reaction bottle, and the temperature was raised to 100 °C for overnight reaction. The reaction system was detected by TLC spot plate (PE / EA=3:1), and the raw material disappeared at 254 nm of the ultraviolet analyzer, and the product no longer increased, and the reaction was judged to be terminated. 30 mL of saturated ammonium chloride was added to quench the reaction, 20 mL of ethyl acetate was added, and after stirring for 10 minutes, the organic phase was allowed to stand for stratification, and the organic phase was collected. The aqueous phase was extracted with 20 mL of ethyl acetate × 2, the organic phases were combined, and the aqueous phase was discarded. The organic phase was washed with 20 mL of saturated brine, and after standing for stratification, the aqueous phase was discarded, and the organic phase was dried with an appropriate amount of anhydrous sodium sulfate. After drying, the desiccant was filtered off, and the filtrate was concentrated to dryness under reduced pressure to obtain a residue. The residue was passed through a flash column (elution system was ethyl acetate / petroleum ether, the ratio was gradually increased from 1:20 to 1:5), the eluate of the corresponding product was collected, and the eluate was concentrated to dryness under reduced pressure to obtain compound XI-1 (4.5 g, 71.4%).

[0128] (7) Synthesis of macrocyclic intermediate (XII-1)

[0129]

[0130] Add compound XI-1 (4.5 g, 9.0 mmol), trifluoroacetic acid (1.6 mL), Zhan Catalyst 1B (0.7 g, 0.9 mmol), and dichloromethane (1350 mL) to the reaction bottle, and heat to 50 ° C for 3 hours. The reaction system was detected by TLC spot plate (PE / EA = 2:1). The UV analyzer showed that the raw material disappeared at 254 nm, and the product no longer increased, and the reaction was judged to be terminated. Cool to room temperature and then concentrate to dryness under reduced pressure to obtain a residue. The residue was passed through a fast column (the elution system was ethyl acetate / petroleum ether, and the ratio was gradually increased from 1:20 to 1:3), and the eluent of the corresponding product was collected. The eluent was concentrated to dryness under reduced pressure to obtain compound XII-1 (2.1 g, 50%).

[0131] (8) Synthesis of macrocyclic intermediate (XIII-1)

[0132]

[0133] Compound XII-1 (2.1 g, 4.4 mmol) and EA / HCl (20 mL) were added to the reaction flask, and then reacted at room temperature for 1 hour. The reaction system was detected by TLC spot plate (PE / EA=2:1), and the raw material disappeared at 254 nm of the ultraviolet analyzer, and the product no longer increased, and the reaction was judged to be terminated. The system was directly concentrated to dryness under reduced pressure to obtain a residue. Then it was added to water, and then the pH was adjusted to 8 with saturated sodium bicarbonate. Solids precipitated, filtered, and the filter cake was washed twice with water, and then the filter cake was dried to obtain a crude product. The crude product was passed through a fast column (the elution system was methanol / dichloromethane, and the ratio was gradually increased from 1:100 to 1:30), and the eluent of the corresponding product was collected. The eluent was concentrated to dryness under reduced pressure to obtain compound XIII-1 (1.6 g, 97%). MS (m / z): 375 (MH) + . 1 H NMR(400MHz,DMSO_d6)δ4.00-4.06(m,4H),4.35(s,2H),4.52(s,2H),5.01(s,2H),5.77-5.81(m,2H),6.30(s,1H),6.35(s ,1H),7.40-7.42(d,1H),7.53-7.54(d,2H),7.84(s,1H),8.02-8.04(d,1H),8.28(s,1H),8.51-8.53(d,1H),9.47(s,1H).

[0134] (9) Synthesis of macrocyclic intermediate (XVI-A)

[0135]

[0136]

[0137] Compound XIII-1 (500.0 mg, 1.3 mmol), compound XIV-1 (248.3 mg, 1.6 mmol), HATU (760.4 mg, 2.0 mmol), and dimethyl sulfoxide (6 mL) were added to the reaction flask, and then the temperature was lowered to 5 ° C. N, N-diisopropylethylamine (335.9 mg, 2.6 mmol) was added dropwise to the system, and then nitrogen was protected and reacted at room temperature overnight. The reaction system was detected by LC-MS, and the raw materials disappeared and the product no longer increased, and it was judged that the reaction was terminated. Ice water was added to the system, and solids precipitated, and then filtered, the filter cake was washed with water twice, and the filter cake was dried to obtain a crude product. The crude product was prepared by preparative liquid phase (Xbridge C18, 5μm 19×150mm / water-acetonitrile / 35-70-8min-300m) to obtain compound XIV-1 (102 mg, purity 98% by HPLC). MS (m / z): 512 (MH) + . 1 H NMR(400MHz,DMSO_d6)δ1.72-1.75(d,4H),2.48(s,4H),3.23-3.24(d,2H),4 .01-4.10(m,4H),4.47-4.54(d,4H),5.74-5.85(m,2H),6.30-6.34(d,1H),6 .75-6.81(m,1H),7.36(s,1H),7.45-7.48(m,2H),7.52-7.57(m,2H),8.04-8 .06(d,1H),8.26-8.32(d,2H),8.56-8.57(d,1H),9.82(s,1H),10.04(s,1H).

[0138] (10) Synthesis of macrocyclic intermediate (XVII-1)

[0139]

[0140] Compound XIII-1 (500.0 mg, 1.3 mmol), XV-1 (112.0 mg, 1.6 mmol), HATU (760.4 mg, 2.0 mmol), and dimethyl sulfoxide (6 mL) were added to the reaction flask, and then the temperature was lowered to 5 ° C. N, N-diisopropylethylamine (335.9 mg, 2.6 mmol) was added dropwise to the system, and then nitrogen was protected and reacted at room temperature overnight. The reaction system was detected by LC-MS, and the raw materials disappeared and the product no longer increased, and it was judged that the reaction was terminated. Ice water was added to the system, and solids precipitated, and then filtered, the filter cake was washed twice with water, and the filter cake was dried to obtain a crude product. The crude product was prepared by preparative liquid phase (Xbridge C18, 5μm19×150mm / water+acetonitrile / 30-70-8min-300m) to obtain compound XVII-1 (110 mg). MS (m / z): 427 (MH) + . 1 H NMR(400MHz,DMSO_d6)δ4.01-4.09(m,4H),4.40(s,1H),4.46-4.53(d,4H),5.76-5.81(m,2H),7.25(s,1H),7.43-7.48 (m,2H),7.54-7.56(d,2H),8.04-8.06(d,1H),8.25(s,1H),8.37(s,1H),8.56-8.57(d,1H),9.84(s,1H),10.81(s,1H).

[0141] Other embodiments:

[0142] The compounds in Table 1 were synthesized according to the above-mentioned synthetic route 1 by selecting appropriate starting materials and appropriate reaction reagents.

[0143] Table 1 Compounds with the general structural formula (I) and the general structural formula (II) that can be synthesized by the method of the present invention

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152] Pharmacological tests

[0153] The biological efficacy of the compounds of the present invention can be evaluated by enzyme inhibition activity, cell proliferation inhibition activity, etc. The determination method of the enzyme inhibition activity, cell proliferation inhibition activity, etc. of the compounds can be carried out by using but not limited to the following method.

[0154] Enzyme inhibition activity determination method:

[0155] The activity of a series of compounds on human recombinant protein kinases was detected by radioisotope labeling method, provided by Eurofins. The compounds to be tested were mixed with the corresponding protein kinase buffer (20 mM propanesulfonate (MPOS, pH = 7.0), 1 mM EDTA, 0.1% β-mercaptoethanol, 0.01% Brij-35, 5% glycerol, and 1 mg / mL BSA), and the reaction system (100 μM reaction substrate KKRNRTLTV, 8 mM MOPS at pH 7.0, 10 mM MgAcetate, 0.2 mM EDTA and a certain concentration of γ- 33 P-ATP). The reaction started after adding the MgATP complex solution, and the reaction lasted for 40 minutes at room temperature. The reaction was terminated by adding 5 μl of 3% phosphoric acid solution. Then 10 μl of the reaction solution was dripped onto the filter and washed three times with 75 mM phosphoric acid solution for 5 minutes each time, and then washed once with methanol, dried and flash counted.

[0156] Table 2 shows the inhibitory activity at a single concentration (1 μM). Table 3 shows the IC values ​​of some compounds. 50 .

[0157] Table 2 Inhibitory activity at a single concentration (1 μM)

[0158]

[0159]

[0160] Table 3 IC of some compounds 50

[0161]

[0162] Cell proliferation inhibitory activity:

[0163] Human cancer cell lines were purchased from ATCC. They were cultured in culture medium according to the ATCC workbook. Dose-response curves were plotted using XL-fit to determine the IC of the compounds. 50 Value. IC 50Defined as the concentration of compound required to inhibit 50% cell growth. As shown in the table below, the compounds of the present invention inhibit cell proliferation. The data show that the compounds of the present invention are active in inhibiting the growth of tumor cells. Cell proliferation inhibition detection can be determined by MTT method (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT; 3-(4,5-dimethylthiazol-2)-2,5-diphenyltetrazolium bromide, Thiazolyl blue).

[0164] First, cells were cultured in a culture dish. Cells in the logarithmic growth phase were inoculated in a specific number in a 96-well plate (3000-5000 adherent cells / well, 10000-30000 suspended cells / well), 100 μl per well, and then placed in an incubator at 5% CO2 and 37°C for culture. After overnight, 100 μl of different concentration gradient drugs prepared in the specified culture medium were added. Three replicate wells were set for each concentration gradient to ensure the accuracy of the results, and a blank control group and a solvent control group were set. After adding the drugs, the plates were placed in an incubator for 72 hours. On the day of the MTT experiment, the MTT test solution (5 mg / ml MTT solution dissolved in physiological saline, stored at 4°C in the dark) was prepared in advance, 20 μl of MTT solution was added to each well, and the plates were placed in an incubator for further culture for 2-4 hours. Then, 50 μl of 20% SDS aqueous solution was added to each well and placed overnight. The absorbance value at 570 nm was detected on an ELISA instrument to calculate the in vitro proliferation inhibition rate of the drugs on tumor cells. The absorbance value of the control group should be between 0.8-1.2 as normal. After obtaining the absorbance value data, GraphPad Prism6.03 software was used to fit the inhibition rate change curve and calculate the IC 50 value.

[0165] Calculation of drug inhibition rate: relative cell proliferation inhibition rate = [(control group A570-experimental group A570) / control group A570×100%, where A570 represents the absorbance value at 570 nm.

[0166] Table 4 Summary of the MTT study results of the compounds of the present invention on 8 cell models

[0167]

[0168] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. An N-macrocyclic amide compound or its "E" or "Z" configuration isomer, or a pharmaceutically acceptable salt thereof, wherein the chemical structure is as shown in the general structural formula (I) or the general structural formula (II): In the general structural formula (I) or the general structural formula (II), L is a group represented by the following formula: -L 1 -L 2 -, Where L 1 One end of L is connected to the A group. 2 One end of is connected to the X group; L 1 Selected from: methylene-O-, -O-methylene or methylene-O-methylene; L 2 Selected from: methylene -CH=CH- or -CH=CH-methylene; X is selected from: -O-; Y is selected from: -N(R 2 )-CO-; Z is selected from: a covalent bond or a methylene group; R 1 The group is selected from: hydrogen, methyl or carboxyl; or R 1 The group is selected from one of the following groups: ， Where m represents 0~3; R 2 Selected from: H or methyl, R 3 Selected from: H, methyl, C3~C9 cycloalkyl, 4~7 membered heterocycloalkyl, hydroxyl or amino; When R 1 The group is selected from When R 2 and R 3 Not at the same time H; The A group is selected from: ， The B group is selected from: ， R 5 and R 6 The groups are each independently selected from: H or methyl; The C group is selected from: ， In the formula, any one end is connected to the Y group.

2. The N-macrocyclic amide compound or its "E" or "Z" configuration isomer, or pharmaceutically acceptable salt according to claim 1, characterized in that: L 1 Selected from: methylene-O-methylene; L 2 Selected from: -CH=CH-methylene; X is selected from: -O-; Y is selected from: -N(R 2 )-CO-; Z is selected from: methylene; R 1 The group is selected from one of the following groups: ， Where m represents 0~3; R 2 Selected from: H or methyl, R 3 Selected from: H, methyl, hydroxyl or amino; When R 1 The group is selected from When R 2 and R 3 Not H at the same time.

3. The N-macrocyclic amide compound or its "E" or "Z" configuration isomer, or pharmaceutically acceptable salt according to claim 2, characterized in that: X is selected from: -O-; Y is selected from: -N(R 2 )-CO-; R 2 Selected from: H; R 1 The group is selected from: ， Where m represents 0~3; R 3 Selected from: H.

4. The N-macrocyclic amide compound or its "E" or "Z" configuration isomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: The compound is one of the following compounds: 。 5. A pharmaceutical composition comprising the N-macrocyclic amide compound or its "E" or "Z" configuration isomer, a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable diluents, excipients, and carriers as described in any one of claims 1 to 4.

6. Use of the N-macrocyclic amide compound or its "E" or "Z" configuration isomer, pharmaceutically acceptable salt or pharmaceutical composition as claimed in any one of claims 1 to 4, optionally in combination with one or more other drugs, for the preparation of a drug for inhibiting one or more kinases, wherein: The kinase is selected from: CDK2, CDK3, CDK4, CDK5, CDK6, CDK9, PCTAIREK, PCTAIRE2, PCTAIRE3, CAK / MO15, Dm2, Dm2c, Ddcdc2, DdPRK, LmmCRKK, PfC2R, EhC2R, CfCdc2R, cdc2+, CDC28, PHO85, KIN28, FpCdc2, MsCdc2B, OsC2R, PDGFR-b, PDGFR-a, CSF1R, c-kit, Flk2, FLT1, FLT2, FLT3, FLT4, TYK2, JAK1, JAK2, HOP or their functional equivalents.

7. Use of the N-macrocyclic amide compound or its "E" or "Z" configuration isomer, pharmaceutically acceptable salt or pharmaceutical composition as described in any one of claims 1 to 4, for preparing a medicament for treating a disease caused by, associated with or accompanied by the disruption of cell proliferation and / or angiogenesis.

8. The use according to claim 7, characterized in that The disorder is a proliferative disease.

9. The use according to claim 8, characterized in that The proliferative disease is cancer.

10. The use according to claim 8, characterized in that The proliferative disease is a myeloproliferative disease.

11. The use according to claim 8, characterized in that The proliferative disease is selected from the group consisting of chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia, myeloid metaplasia, chronic myelomonocytic leukemia, acute myeloid leukemia, juvenile myelomonocytic leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, acute B-cell leukemia, leukocytosis, Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, breast cancer. Adenocarcinoma, ovarian cancer, colon cancer, prostate cancer, melanoma, myelodysplastic syndrome, keloid, retinoblastoma, breast malignancy, colon malignancy, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, hepatocellular carcinoma, pancreatic malignancy, myeloid leukemia, cervical cancer, fibroma, colon adenocarcinoma, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, astrocytoma, bladder tumor, or musculoskeletal tumor.

12. The use according to claim 8, characterized in that The proliferative disease is selected from the group consisting of prostate cancer, retinoblastoma, breast malignancy, colon malignancy, endometrial hyperplasia, osteosarcoma, squamous cell carcinoma, non-small cell lung cancer, melanoma, hepatocellular carcinoma, pancreatic malignancy, myeloid leukemia, cervical cancer, fibroids, colon adenocarcinoma, T-cell leukemia, glioma, glioblastoma, oligodendroglioma, lymphoma, ovarian cancer, astrocytoma, bladder tumor or musculoskeletal tumor.

13. The use according to claim 8, characterized in that The proliferative disease is selected from the group consisting of acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, leukocytosis, juvenile myelomonocytic leukemia, acute B-cell leukemia, chronic myeloid leukemia, or acute T-cell leukemia.

14. The use according to claim 8, characterized in that The proliferative disease is selected from the group consisting of acute promyelocytic leukemia or chronic myelomonocytic leukemia.

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