Kinase inhibitor compound as well as preparation method and application thereof

Abstract

The invention provides a kinase inhibitor compound as well as a preparation method and application thereof, and particularly relates to a compound with a formula (I) or pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compound and application thereof in medicines for treating tumors, and substituents in the formula (I) are as defined in the specification. # imgabs0 #

Description

Technical Field

[0001] This application belongs to the field of biomedicine, and particularly relates to a reversible tyrosine kinase inhibitor compound, its preparation method and uses. Background Art

[0002] Fumatinib is a second-generation tyrosine kinase inhibitor and is widely used in the treatment of chronic myeloid leukemia (CML). CML is a myeloid tumor, which due to the well-known Philadelphia chromosome abnormality (Ph chromosome), leads to the generation of the BCR-ABL fusion gene. The BCR-ABL protein produced by this abnormal gene activates multiple signaling pathways, promoting the proliferation and survival of leukemia cells. The mechanism of action of fumatinib is to inhibit the BCR-ABL kinase activity, reduce protein activation, thereby inhibiting the growth of leukemia cells. Research shows that fumatinib can significantly improve the survival of CML patients and increase the chance of patients entering a sustained remission state. In addition, fumatinib is also used to treat the progression of chronic myeloid leukemia and acute lymphoblastic leukemia.

[0003] Although compared with other tyrosine kinase inhibitors (TKIs), the side effects of fumatinib are relatively low, some adverse reactions may still occur, such as skin damage, gastrointestinal discomfort, blood and lymphatic system abnormalities, cardiovascular system abnormalities, liver and kidney function damage, etc. Therefore, it is necessary to improve the pharmacokinetic and pharmacodynamic parameters of fumatinib to favorably change the dosage and dosing regimen of fumatinib and reduce side effects. Summary of the Invention

[0004] The object of the present invention is to provide a compound of formula (I) and its pharmaceutically acceptable salts,

[0005]

[0006] wherein,

[0007] X, X1 or X2 are each independently selected from pharmaceutically acceptable anions or bonds, provided that when A is a bond, X is simultaneously a bond, or when B is a bond, X1 is simultaneously a bond, or when C is a bond, X2 is simultaneously a bond;

[0008] A, B or C are selected from a bond, hydrogen or M, provided that at least one of A, B and C is M;

[0009] M is selected from indicating the connection position of A, B or C to the nitrogen atom of the general formula (I).

[0010] R is selected from -NH2, -R3, -OR3, -NHR3 and -NR3R4;

[0011] R1 and R2 are each independently selected from hydrogen, deuterium, halogen, hydroxy, amino, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic group, and the hydroxy, amino, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic group are optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group;

[0012] Alternatively, R1 and R2 together with the atoms to which they are attached form a 3- to 8-membered cycloalkyl or a 4- to 8-membered heterocyclic group, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group;

[0013] R3 are each independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic group, and are optionally further substituted by one or more R5;

[0014] R4 are each independently selected from hydrogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic group, and the hydroxy, amino, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic group are optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group;

[0015] Alternatively, R3 and R4 together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclic group, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group;

[0016] Each R5 is independently selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group, and the hydroxy, amino, mercapto, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic group are optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl;

[0017] Each of R6 and R7 is independently selected from lithium, sodium, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group, and the alkyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic group are optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group

[0018] In certain embodiments of the present invention, since the anion is not covalently attached to the molecule, it should be understood that X, X1 or X2 are not necessarily located near the atoms bearing A, B or C, and when all three are present, they should be considered interchangeable within any given molecule.

[0019] In certain embodiments of the present invention, each of X, X1 or X2 is independently selected from halide ions or sulfonate

[0020] In certain embodiments of the present invention, each of X, X1 or X2 is independently selected from chloride ion, bromide ion, iodide ion, methanesulfonate, tosylate or p-toluenesulfonate.

[0021] In certain embodiments of the present invention, each of R1 and R2 is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 1-6 alkoxy, C 1-6 halogenated alkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 5- to 14-membered heteroaryl and 4- to 14-membered heterocyclic group, and the hydroxy, amino, mercapto, C 1-6 alkyl, C 1-6Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 6-12 Aryl, 5-14 membered heteroaryl and 4-14 membered heterocyclic group, optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, C 6-12 Aryl, 5-7 membered heteroaryl, 4-7 membered heterocyclic group.

[0022] In certain embodiments of the present invention, R1 and R2 are each independently selected from hydrogen, deuterium, halogen, hydroxy, amino, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 6-12 Aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S, SO or SO2 and 4-7 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, S, SO or SO2, said hydroxy, amino, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 6-12Aryl, 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2, and 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2, optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 6-12 aryl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclic group. <x

[0023] In certain embodiments of the present invention, R1 and R2 are each independently selected from hydrogen, deuterium, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl or C 1-3 alkoxy.

[0024] In certain embodiments of the present invention, R1 and R2 are hydrogen.

[0025] In certain embodiments of the present invention, R1 and R2 together with the atoms to which they are attached form a 3- to 8-membered cycloalkyl or a 4- to 8-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2, optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 6-12 aryl, 5- to 7-membered heteroaryl, 4- to 7-membered heterocyclic group.

[0026] In certain embodiments of the present invention, R1 and R2 together with the atoms to which they are attached form a 3- to 6-membered cycloalkyl or a 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2, optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, CDeuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 6-12 Substituted by substituents of aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclic group.

[0027] In certain embodiments of the present invention, each R3 is independently selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 6-12 Aryl, 5-14 membered heteroaryl and 4-14 membered heterocyclic group, optionally further substituted by one or more R5;

[0028] Each R5 is independently selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, C 6-12 Substituted by substituents of aryl, 5-7 membered heteroaryl, 4-7 membered heterocyclic group, optionally, the C 3-8 Cycloalkyl, C 6-12 Aryl, 5-7 membered heteroaryl, 4-7 membered heterocyclic group, optionally further substituted by one or more selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Substituted by substituents of hydroxyalkyl.

[0029] In certain embodiments of the present invention, each R3 is independently selected from C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 6-12 Aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S, SO or SO2, and 4-7 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, S, SO or SO2, optionally further substituted by one or more R5;

[0030] R5 are each independently selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 6-12 Aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S, SO or SO2, 4-7 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, S, SO or SO2, said C 3-6 Cycloalkyl, C 6-12 Aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S, SO or SO2, 4-7 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, S, SO or SO2, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Substituted by substituents of hydroxyalkyl.

[0031] In certain embodiments of the present invention, R4 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C6-12 Aryl, 5- to 14-membered heteroaryl, and 4- to 14-membered heterocyclic group, said hydroxyl, amino, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-12 Aryl, 5- to 14-membered heteroaryl, and 4- to 14-membered heterocyclic group, optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C[[ID=,40]] 6-12 aryl, 5- to 7-membered heteroaryl, 4- to 7-membered heterocyclic group.

[0032] In certain embodiments of the present invention, R4 is selected from hydrogen, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 6-12 aryl, 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2, and 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2, said hydroxyl, amino, mercapto, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 6-12Aryl, 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2, and 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2, optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 6-12 aryl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclic group.

[0033] In certain embodiments of the present invention, R3 and R4 are each independently selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 6-12 aryl-C 1-3 alkyl.

[0034] In certain embodiments of the present invention, R3 and R4 are each independently selected from methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, 3-methylbutan-2-yl, cyclopropyl, cyclobutyl, morpholinyl, benzyl or phenethyl.

[0035] In certain embodiments of the present invention, R3 and R4 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2, optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 6-12 aryl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclic group.

[0036] In certain embodiments of the present invention, R6 and R7 are each independently selected from lithium, sodium, C 1-6 alkyl, C 2-6 alkenyl, C2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, C 6-12 Aryl, 5 - 14 - membered heteroaryl, 4 - 14 - membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, C 6-12 Aryl, 5 - 14 - membered heteroaryl, 4 - 14 - membered heterocyclic group, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, C 6-12 Aryl, 5 - 7 - membered heteroaryl, 4 - 7 - membered heterocyclic group

[0037] In certain embodiments of the present invention, R6 and R7 are each independently selected from lithium, sodium, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 6-12 Aryl, 5 - 6 - membered heteroaryl containing 1 - 3 atoms selected from N, O or S, 4 - 7 - membered heterocyclic group containing 1 - 3 atoms selected from N, O or S, the C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 6-12 Aryl, 5- or 6-membered heteroaryl containing 1 to 3 atoms selected from N, O or S, 4- to 7-membered heterocyclic group containing 1 to 3 atoms selected from N, O or S, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, C 6-12 Aryl, 5- or 6-membered heteroaryl containing 1 to 3 atoms selected from N, O or S, 4- to 7-membered heterocyclic group containing 1 to 3 atoms selected from N, O or S, substituted by substituents.

[0038] In certain embodiments of the present invention, A is

[0039] X is a pharmaceutically acceptable anion; B or C is a bond; X1 or X2 is a bond.

[0040] In certain embodiments of the present invention, the general formula (I) is further a compound represented by the general formula (II-a), (II-b), (II-c) or (II-d) or a pharmaceutically acceptable salt thereof:

[0041]

[0042]

[0043] X, X1 or X2 are each independently selected from halogen ions or sulfonate;

[0044] A, B or C is

[0045] R is selected from -R3, -OR3, -NHR3 and -NR3R4.

[0046] In certain embodiments of the present invention, R1 and R2 are each independently selected from hydrogen, deuterium, halogen, hydroxy, amino, mercapto, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl; R3 and R4 are each independently selected from C 1-6alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 6-12 aryl-C 1-3 alkyl.

[0047] In certain embodiments of the present invention, R1 and R2 are hydrogen; R3 and R4 are each independently selected from methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, morpholinyl, benzyl or phenethyl.

[0048] In certain embodiments of the present invention, R6 and R7 are each independently selected from lithium, sodium, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl containing 1-3 atoms selected from N, O or S, said C 3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine or bromine.

[0049] In certain embodiments of the present invention, A, B or C are each independently selected from:

[0050]

[0051]

[0052]

[0053] In certain embodiments of the present invention, A, B or C are each independently selected from:

[0054]

[0055] In certain embodiments of the present invention, A, B or C is

[0056] On the other hand, the present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any of the shown general formula compounds or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0057] In certain embodiments of the present invention, in the pharmaceutical composition, calculated as the free base, the weight percentage of the compound or its pharmaceutically acceptable salt is 0.1% to 95%, preferably 5% - 70%, such as 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% or 5%.

[0058] In certain embodiments of the present invention, the pharmaceutical composition is selected from tablets, capsules, liquid preparations or injections. Preferably, it further comprises a filler, optionally further comprises a disintegrant, or further comprises one or more of a glidant or a lubricant.

[0059] In certain embodiments of the present invention, the pharmaceutical composition is an immediate-release preparation or a sustained-release preparation.

[0060] In certain embodiments of the present invention, in the pharmaceutical composition, calculated as the free base, the unit dose of the compound or its pharmaceutically acceptable salt is 1 - 1000 mg, preferably 1 - 500 mg, or preferably 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg.

[0061] On the other hand, the present invention further relates to the use of any of the general formula compounds shown or their pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of a medicament for treating a disease related to tyrosine kinase.

[0062] In certain embodiments of the present invention, the present invention further relates to the use of any of the general formula compounds shown or their pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of a medicament for treating a disease related to Bcr - ABL.

[0063] In certain embodiments of the present invention, the present invention further relates to the use of any of the general formula compounds shown or their pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of a medicament for treating tumors.

[0064] In certain embodiments of the present invention, the tumor is a hematological tumor.

[0065] In certain embodiments of the present invention, the hematological tumor is selected from leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome or myeloproliferative neoplasm.

[0066] In certain embodiments of the present invention, leukemia is selected from chronic myeloid leukemia, chronic lymphocytic leukemia, acute myeloid leukemia or acute lymphocytic leukemia.

[0067] By developing the flumatinib prodrug, it is aimed to improve the oral absorption of flumatinib, reduce the accumulation of the prototype drug in the gastrointestinal tract, reduce gastrointestinal side effects, increase the in vivo exposure to reduce the dosing dose and improve the food effect. Detailed implementation manners

[0068] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0069] The term "alkyl" refers to a saturated aliphatic group, including straight-chain alkyl and branched-chain alkyl. In a preferred embodiment, the straight-chain or branched-chain alkyl has 30 or fewer carbon atoms in its main chain (e.g., a straight-chain of C1-C3 and a branched-chain of C3-C3), more preferably 20 or fewer. An alkyl containing 1 to 8 carbon atoms is preferred, more preferably an alkyl containing 1 to 6 carbon atoms, and most preferably an alkyl containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof, etc. The alkyl can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available connection point, and the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate group. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred in the present invention.

[0070] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused and bridged cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.

[0071] The term "spiroalkyl" refers to a polycyclic group having 5 to 20 members, wherein a single carbon atom (called a spiro atom) is shared between monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π-electron system. Preferably it has 6 to 14 members, more preferably 7 to 10 members. Spiroalkyls are classified into monospiroalkyls, bisspiroalkyls or polysiroalkyls according to the number of spiro atoms shared between rings, preferably monospiroalkyls and bisspiroalkyls. More preferably, they are 3 / 6, 3 / 5, 4 / 4, 4 / 5, 4 / 6, 5 / 5 or 5 / 6 monospiroalkyls. Non-limiting examples of spiroalkyls include:

[0072]

[0073] Spiroalkyls also include those in which a monospiroalkyl shares a spiro atom with a heterocycloalkyl. Non-limiting examples include:

[0074]

[0075] The term "fused cycloalkyl" refers to a completely carbonaceous polycyclic group having 5 to 20 members, wherein each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, and one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron system. Preferably it has 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyls, preferably bicyclic or tricyclic, more preferably 5 / 5 or 5 / 6 bicyclic alkyls. Non-limiting examples of fused cycloalkyls include:

[0076]

[0077] The term "bridged cycloalkyl" refers to a completely carbonaceous polycyclic group having 5 to 20 members, wherein any two rings share two non-directly connected carbon atoms, which may contain one or more double bonds, but no ring has a completely conjugated π-electron system. Preferably it has 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyls include:

[0078]

[0079] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring linked to the parent structure is a cycloalkyl group. Non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate group.

[0080] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but does not include the ring moiety of -O-O-, -O-S- or -S-S-. The remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, wherein 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 4 to 7 ring atoms; further preferably, a 4- to 7-membered heterocyclic group containing 1-3 nitrogen atoms, optionally substituted by 1-2 oxygen atoms, sulfur atoms, oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiro heterocyclic groups or nitrogen-containing fused heterocyclic groups.

[0081] Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, azetidine, pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazepanyl, pyranyl, etc. Preferably, pyrrolidinyl, morpholinyl, piperidinyl, azepanyl, 1,4-diazepanyl and piperazinyl. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; the spiro, fused and bridged heterocyclic groups involved are optionally linked to other groups by a single bond, or further fused to other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups through any two or more atoms on the ring.

[0082] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group with 5 to 20 members sharing a single atom (called a spiro atom) between monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) ma heteroatom (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. It is preferably 6 to 14 membered, more preferably 7 to 10 membered. The spiroheterocyclic group is classified into a monospiroheterocyclic group, a bisspiroheterocyclic group or a polyspiroheterocyclic group according to the number of spiro atoms shared between rings, and is preferably a monospiroheterocyclic group and a bisspiroheterocyclic group. More preferably, it is a 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclic group. Non-limiting examples of the spiroheterocyclic group include:

[0083]

[0084] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group having 5 to 20 members, in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, and one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system, and one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 membered, more preferably 7 to 10 membered. It can be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group according to the number of constituent rings, and is preferably a bicyclic or tricyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of the fused heterocyclic group include:

[0085]

[0086] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group having 5 to 14 members, in which any two rings share two non-directly connected atoms, and it may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system, and one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 membered, more preferably 7 to 10 membered. It can be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group according to the number of constituent rings, and is preferably a bicyclic, tricyclic or tetracyclic group, and more preferably a bicyclic or tricyclic group. Non-limiting examples of the bridged heterocyclic group include:

[0087]

[0088] The heterocyclic group ring may be fused to an aryl, heteroaryl or cycloalkyl ring, and the ring connected to the parent structure is a heterocyclic group, and non-limiting examples thereof include:

[0089]

[0090] The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate group.

[0091] The term "aryl" refers to a 6- to 14-membered fully carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6 to 12 members, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, including benzo 5- to 10-membered heteroaryl, benzo 3- to 8-membered cycloalkyl and benzo 3- to 8-membered heteroalkyl, preferably benzo 5- to 6-membered heteroaryl, benzo 3- to 6-membered cycloalkyl and benzo 3- to 6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1 to 3 nitrogen atoms, oxygen atoms or sulfur atoms; or further includes a three-membered nitrogen-containing fused ring containing a benzene ring.

[0092] Wherein the ring linked to the parent structure is an aryl ring, and non-limiting examples thereof include:

[0093]

[0094] The aryl may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate group.

[0095] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl is preferably 5 to 12 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, quinolinyl, pyridazinyl, triazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl, pyrrolyl and oxazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:

[0096]

[0097] The heteroaryl can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate group.

[0098] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl is defined as above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate group.

[0099] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is defined as above.

[0100] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is defined as above.

[0101] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, where alkyl is defined as above.

[0102] The term "alkenyl" refers to an aliphatic group containing at least one double bond, including "unsubstituted alkenyl" and "substituted alkenyl", the latter referring to an alkenyl moiety in which one or more hydrogens on one or more carbons of the alkenyl are replaced by substituents. These substituents can be on one or more carbons, with or without inclusion in one or more double bonds. Additionally, as described below, these substituents include all substituents of alkyl, unless stability is restricted. For example, consider substituting the alkenyl with one or more alkyl, carbocyclic, aryl, heterocyclic or heteroaryl groups. In a preferred embodiment, the straight-chain or branched alkenyl has 1-12 carbons in its backbone, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms. Exemplary alkenyls include allyl, propenyl, butenyl, 2-methyl-2-butenyl, etc.

[0103] The term "alkynyl" refers to an aliphatic group containing at least one triple bond, and is intended to include "unsubstituted alkynyl" and "substituted alkynyl", the latter referring to an alkynyl moiety having substituents that replace hydrogen on one or more carbons of the alkynyl group. Such substituents can occur on one or more carbons, which may or may not be included in one or more triple bonds. Additionally, as described above, these substituents include all substituents of an alkyl group, except where stability is restricted. For example, consider an alkynyl group substituted with one or more alkyl groups, carbocyclic groups, aryl groups, heterocyclic groups, or heteroaryl groups. In a preferred embodiment, the alkynyl group has 1-12 carbons in its backbone, preferably 1-8 carbons in its backbone, and more preferably 1-6 carbons in its backbone. Exemplary alkynyl groups include propargyl, butynyl, 3-methylpent-1-ynyl, and the like.

[0104] The term "aralkyl" refers to an alkyl group substituted with one or more aryl groups.

[0105] The terms "halogen", "halide", and "halo" refer to halogens, including fluorine, chlorine, bromine, and iodine.

[0106] The term "alkylene" includes straight-chain and branched-chain, saturated and unsaturated (i.e., containing one double bond) divalent alkylene groups and monovalent alkyl groups.

[0107] The term "alkanol" likewise includes straight-chain and branched-chain, saturated and unsaturated alkyl moieties of an alkanol group, where the hydroxyl group can be located at any position of the alkyl moiety. The term "cycloalkanol" includes unsubstituted or substituted (e.g., methyl or ethyl) cycloalcohols.

[0108] The term "heteroatom" refers to an atom of any element other than carbon or hydrogen, and preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0109] The compounds disclosed in the present invention, such as the compounds of formula (I), (II-a), (II-b), (II-c), (II-d), are intended to include one or more of the following: the free base of the compound or its pharmaceutically acceptable salt, stereoisomers, or a mixture of two or more stereoisomers. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereoisomeric and enantiomeric forms of the compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereoisomers are stereoisomers having two or more chiral centers that are not identical and are not mirror images of each other.

[0110] The compounds disclosed in the present invention include all pharmaceutically acceptable isotopically labeled compounds, wherein one or more atoms of the compounds disclosed in the present invention are replaced by atoms having the same atomic number but different atomic mass or mass number from the atomic mass or mass number usually found. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine. Examples of isotopes include deuterium, tritium, and the like.

[0111] "Optional" or "optionally" means that the subsequent described event or circumstance may or may not occur, and this description includes the cases where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted by an alkyl group" means that the alkyl group may or may not be present, and this description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.

[0112] "Pharmaceutical composition" refers to a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to an organism, promote the absorption of the active ingredient and thus exert its biological activity.

[0113] "Pharmaceutically acceptable salt", "medicinally acceptable salt" refers to the salts of the compounds of the present invention, which are safe and effective when used in mammals and have the due biological activity.

[0114] The term "substituted" refers to a moiety having a substituent that replaces hydrogen on one or more carbons of the main chain. It should be understood that "substituted" or "being substituted" includes implicit restrictive conditions, that is, such substitution conforms to the allowed valences of the substituted atom and the substituent, and the substitution produces a stable compound, for example, it will not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. The term "substituted" used herein is considered to include all allowed substituents of organic compounds. Broadly speaking, allowed substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For suitable organic compounds, the allowed substituents can be one or more and can be the same or different. In the present invention, heteroatoms such as nitrogen can have hydrogen substituents and / or any allowed substituents of the organic compounds described herein that satisfy the valence of the heteroatom.

[0115] The term "tumor" refers to a hyperproliferative disease, such as cancer.

[0116] The term "co - administration" refers to the administration of two or more drugs to a subject as part of a single treatment regimen. The administration can be simultaneous or sequential, i.e., the second drug (and / or the third drug, etc.) is administered after the administration of one drug. At a later time, as long as the administered agents co - exist in the treated subject, or at least one agent will have the opportunity to act on the same target tissue of the other agent, while the target tissue is still under the influence of the other agent. In one embodiment, the agents to be administered can be included in a single pharmaceutical composition and administered together. In one embodiment, the agents are administered simultaneously, including by different routes. In one embodiment, one or more drugs are administered continuously, while other drugs are administered only at predetermined time intervals (e.g., a single large dose, or two small doses per week, etc.).

[0117] The term "treatment" includes reversing, alleviating or preventing symptoms, clinical signs and the underlying pathology of a disease in a manner that improves or stabilizes the condition of a subject. As used herein and well - known in the art, "treatment" is a method of obtaining a beneficial or desired result, including clinical outcomes. Beneficial or desired clinical outcomes can include, but are not limited to, remission or improvement of one or more symptoms or disorders, reduction in the degree of a disease, stabilization of a disease state (i.e., not worsening), prevention of disease spread, delay or slowing of disease progression, improvement or remission of a disease state (whether partial or complete), whether detectable or not. "Treatment" can also refer to an extension of survival compared to the expected survival time if treatment is not received.

[0118] The present invention also contemplates within its scope the effect of selecting a suitable counterion. The counterion of the compounds of the present invention can be selected by choosing the dissociation constant of a drug that can ionize within the said pH range. By estimating the ionized and non - ionized drug concentrations of any compound (using established equations such as the Henderson - Hasselbach equation), the solubility and absorption of the drug can be altered.

[0119] The present invention also relates to a method for synthesizing the compound, specifically as follows:

[0120] Step 1:

[0121]

[0122] Fumatinib reacts with a suitable halogenating agent 1a (where X is a halogen atom) in a solvent within the temperature range from room temperature to reflux, and then the excess solvent is evaporated to obtain intermediate 1, and this product can be further purified to the target purity by crystallization or solvent washing.

[0123] Step 2: Ion exchange

[0124]

[0125] Quaternary ammonium salts such as 2 can be prepared using a suitable halomethylformyl reagent (such as iodomethylformyl) by the method in Step 1 above. Compound 2 can be treated with a suitable metal salt such as silver methanesulfonate in a suitable solvent (such as acetonitrile) at a desired temperature from room temperature to reflux to produce a precipitate of silver iodide and the desired product 3. The insoluble silver halide is removed by filtration to obtain the target product 3 with a higher purity.

[0126]

[0127] Imatinib mesylate reacts with a suitable halomethyl reagent 1a in a dry solvent at a reaction temperature from room temperature to reflux temperature, and then the excess solvent is evaporated to obtain the final product 4. If necessary, it can be further purified by crystallization or solvent washing with a solvent.

[0128] The above method is applicable to anion exchange of all types of quaternary ammonium salts having any halide such as chloride, bromide or iodide as a counter ion. The silver salts that can be used include, but are not limited to, silver acetate, silver methanesulfonate, silver toluenesulfonate, silver oxalate, silver tartrate, silver trifluoromethanesulfonate, etc.

[0129] General method for preparing formula M: It can be directly prepared from the corresponding acid, amine and alcohol. Activated or unactivated acids can react with the corresponding aldehyde in the presence of a Lewis acid to provide type II reagents; in the presence of a base, an alcohol can react with a halomethyl chloroformate to provide type I reagents; similarly, an amine (primary or secondary) can react with a haloacetic acid halomethyl ester with or without the presence of a base to provide type III reagents.

[0130] General method for synthesizing type II reagents:

[0131] Method 1:

[0132]

[0133] Lewis acids such as anhydrous zinc chloride and aldehydes such as paraformaldehyde and acyl chloride 6 can react under anhydrous conditions and at an appropriate temperature, usually from -10°C to 60°C, and the reaction time can be up to 24 hours. The reaction mixture can be diluted with a solvent (such as dichloromethane), washed with a dilute aqueous base solution (such as sodium bicarbonate solution), and purified by treatment to obtain the target product 7.

[0134] Method 2:

[0135]

[0136] The metal salt 5 of the required acid can be treated with bromoiodomethane in dry THF at an appropriate temperature, usually from 0 °C to room temperature, and can be heated if necessary. The reaction mixture can be diluted with a solvent and washed with a dilute aqueous base (such as sodium carbonate solution), and the target product 8 can be obtained after treatment and purification.

[0137] Method 3:

[0138]

[0139] At room temperature, an aqueous solution of a base (such as sodium bicarbonate) and tetrabutylammonium hydrogensulfate is added to a vigorously stirred solution of the acid [5] in a solvent (such as dichloromethane), and then a solution of chloromethyl chloroformate in a solvent (such as dichloromethane) is added dropwise. After the reaction is complete, the organic layer is washed with 5% aqueous sodium carbonate solution. The target product [9] can be obtained after treatment and purification.

[0140] General method for synthetic reagent type III:

[0141]

[0142] The corresponding primary or secondary amine can react with substituted or unsubstituted chloromethyl chloroformate 10 at 0 °C in a solvent such as hexane or DCM. The reaction mixture can be filtered, and the filtrate can be washed with 1.0 N HCl. The organic matter can be evaporated to obtain the required reagent 11. If necessary, it can be further purified by conventional purification methods such as precipitation or crystallization or preparative purification.

[0143] General method for synthetic reagent type I:

[0144] Method 1:

[0145]

[0146] Under ice-cooling, a pyridine / hexane solution is added dropwise to a solution of chloromethyl chloroformate 12 in a solvent such as hexane, and the corresponding alcohol can be added to the reaction mixture at the same temperature. The reaction mixture can be stirred for up to 24 hours, and the corresponding carbonate reagent 13 can be obtained after treatment and purification.

[0147] Method 3: General synthetic method for halide exchange

[0148]

[0149] When reagent 7 is treated with a suitable bromide reagent such as lithium bromide or sodium bromide at a suitable temperature, usually in the range of 40 - 80 °C, for up to 24 hours, and then treated and purified to obtain bromine reagent 8.

[0150] Method 3:

[0151]

[0152] Reagent 7 is treated with a reagent such as sodium iodide at an appropriate temperature (usually from room temperature to 60 °C) for up to 24 hours, and then processed and purified to obtain iodine reagent 14.

[0153] Method 4:

[0154]

[0155] Reagent 7 is treated with silver methanesulfonate at an appropriate temperature (usually in the range of room temperature to 60 °C to 90 °C) for 24 hours, and then processed and purified to obtain (methanesulfonyloxy) reagent 15.

[0156] Method 5:

[0157]

[0158] Reagent 7 is treated with silver p-toluenesulfonate at an appropriate temperature (usually in the range of room temperature to 60 °C to 90 °C) for 24 hours, and then processed and purified to obtain (p-toluenesulfonyloxy) reagent 16.

[0159] Examples

[0160] The following examples are used to explain the present invention, but should not be considered as limiting the scope of the present invention. If the specific conditions of the experimental methods are not specifically described in the examples of the present invention, they generally follow the conventional conditions or recommended conditions of the raw material and product manufacturers. Reagents without specifying the specific source are commercially available conventional reagents.

[0161] Example 1

[0162]

[0163] Chloromethyl chloroformate (5.00 g, 38.78 mmol) and (R)-(-)-2-butanol (2.87 g, 38.71 mmol) were added to 50 ml of dichloromethane, cooled to 0 °C, and pyridine (3.07 g, 38.81 mmol) was slowly added dropwise. After the addition, the mixture was warmed to room temperature and stirred overnight, diluted with water, washed successively with 1% citric acid, sodium carbonate solution, and sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 4.21 g of (R)-sec-butyl (chloromethyl) carbonate.

[0164]

[0165] (R)-sec-Butyl (chloromethyl) carbonate (4.00 g, 24.01 mmol) was added to 40 ml of ethyl acetate. Sodium iodide (4.31 g, 28.75 mmol) and calcium chloride (1.33 g, 11.98 mmol) were added. The mixture was heated to reflux until the reaction was complete, cooled to 0 °C, washed with 5% sodium thiosulfate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 5.33 g of (R)-sec-butyl (iodomethyl) carbonate.

[0166]

[0167] Fumatinib (5.63 g, 10.01 mmol) was added to 100 ml of dichloromethane, and then added to (R)-sec-butyl (iodomethyl) carbonate (2.58 g, 10.00 mmol). The mixture was stirred for 4 hours, filtered, and dried to obtain 2.72 g of the target product.

[0168] MS m / z(ESI): 693.

[0169] Example 2

[0170]

[0171] Chloromethyl chloroformate (5.00 g, 38.78 mmol) and (S)-(+)-2-butanol (2.87 g, 38.71 mmol) were added to 50 ml of dichloromethane. The temperature was cooled to 0 °C, and pyridine (3.07 g, 38.81 mmol) was slowly added dropwise. After addition, the mixture was stirred at room temperature overnight, diluted with water, washed successively with 1% citric acid, sodium bicarbonate solution, and sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 4.52 g of (S)-sec-butyl (chloromethyl) carbonate.

[0172]

[0173] (S)-sec-Butyl (chloromethyl) carbonate (4.00 g, 24.01 mmol) was added to 40 ml of ethyl acetate. Sodium iodide (4.31 g, 28.75 mmol) and calcium chloride (1.33 g, 11.98 mmol) were added. The mixture was heated to reflux until the reaction was complete, cooled to 0 °C, washed with 5% sodium thiosulfate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 5.24 g of (S)-sec-butyl (iodomethyl) carbonate.

[0174]

[0175] Fumatinib (5.63 g, 10.01 mmol) was added to 80 ml of dichloromethane, and then added to (S)-sec-butyl (iodomethyl) carbonate (2.58 g, 10.00 mmol). The mixture was stirred for 4 hours, filtered, and dried to obtain 3.25 g of the target product.

[0176] MS m / z (ESI): 693.

[0177] Other examples are prepared with reference to the preparation method of Example 1 or 2:

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188] X - or X1 - is I - .

[0189] Biological test evaluation

[0190] I. Pharmacokinetics determination in SD rats

[0191] 1. Research purpose:

[0192] Using SD rats as test animals, study the pharmacokinetic behavior of the compound example in rat plasma after oral administration at doses of 20 mg / kg and 50 mg / kg.

[0193] 2. Test protocol

[0194] 2.1 Test drug

[0195] The example of the present invention, self-made.

[0196] 2.2 Test animals:

[0197] 3 male SD rats in each group.

[0198] 2.3 Formulation prescription:

[0199] Drug preparation for oral administration: Sterile normal saline.

[0200] Weigh the compound of the example, and add sterile physiological saline according to the proportion of the total administration volume to obtain a wine-red clear and transparent solution.

[0201] Weigh the compound of the example, add sterile physiological saline according to the proportion of the total administration volume, heat in a water bath at 40 °C for 1 min, and sonicate for 30 min to obtain a wine-red clear and transparent solution.

[0202] Weigh the compound of the example, and add sterile physiological saline according to the proportion of the total administration volume to obtain an orange suspension.

[0203] 2.4 Administration

[0204] Three male rats are fasted overnight and then administered p.o. respectively; the dose is 20 mg / kg, and the administration volume is 10 mL / kg.

[0205] Three male rats are fasted overnight and then administered p.o. respectively; the dose is 50 mg / kg, and the administration volume is 10 mL / kg.

[0206] 2.5 Sample collection

[0207] Before and after the rats are administered, 0.2 mL of jugular vein blood is collected at 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours, placed in an EDTA-K2 test tube, centrifuged at 6000 rpm for 6 min at 4 °C to separate the plasma, and stored at -80 °C. The rats are allowed to eat 4 h after administration.

[0208] 2.6 Sample treatment:

[0209] 1) Add 50 μL of plasma sample to 5 μL of methanol:acetonitrile (1:1), add 500 μL of 1&10 ng / mL ITSD solution to it, with the solvent being methanol:acetonitrile (1:1). After precipitation, vortex for one minute and then centrifuge at 4000 rpm for 10 minutes.

[0210] 2) Take 50 μL of the treated supernatant solution, dilute it 5 times with mobile phase A:B (1:1), and perform LC / MS / MS analysis to determine the concentration of the compound to be measured.

[0211] 2.7 Liquid phase analysis

[0212] ● Liquid phase conditions: LC-20AD pump

[0213] ● Mass spectrometry conditions: API 5000 mass spectrometer

[0214] ● Chromatographic column: Luna 5um C18 2.0×30mm

[0215] ● Mobile phase: Solution A is an aqueous solution of ammonium acetate containing 5 mM and 0.1% formic acid, and solution B is acetonitrile containing 0.1% formic acid

[0216] ● Flow rate: 0.5 mL / min

[0217] ● Elution time: 0 - 4.0 minutes, and the eluent is as follows:

[0218]

[0219] 3. Test results and analysis

[0220] The main pharmacokinetic parameters were calculated using WinNonlin 8.2, and the results of the pharmacokinetic experiment in rats are shown in the following table:

[0221] Table 1: Pharmacokinetic parameters of the compound of the present invention after oral administration to rats

[0222]

[0223] Note: * represents insufficient elimination phase

[0224] 4. Experimental conclusion:

[0225] The data in the table show that in the pharmacokinetic evaluation experiment of rats, the compound of the embodiment of the present invention showed a high exposure after oral administration.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: Wherein, X, X1 or X2 are each independently selected from pharmaceutically acceptable anions or bonds, provided that when A is a bond, X is simultaneously a bond, or when B is a bond, X1 is simultaneously a bond, or when C is a bond, X2 is simultaneously a bond; A, B or C are selected from a bond, hydrogen or M, provided that at least one of A, B and C is M; M is selected from R is selected from -NH2, -R3, -OR3, -SR3, -OC(O)R3, -NHR3 and -NR3R4; R1 and R2 are each independently selected from hydrogen, deuterium, halogen, hydroxy, amino, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic group, and the hydroxy, amino, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic group are optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group; Alternatively, R1 and R2 together with the atoms to which they are attached form a 3- to 8-membered cycloalkyl or 4- to 8-membered heterocyclic group, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group; R3 are each independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic group, optionally further substituted by one or more R5; R4 are each independently selected from hydrogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic group, and the hydroxy, amino, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic group are optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group; Alternatively, R3 and R4 together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclic group, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group; Each R5 is independently selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group, and the hydroxy, amino, mercapto, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic group are optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl; Each of R6 and R7 is independently selected from lithium, sodium, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group, and the alkyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic group are optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, Each of X, X1 or X2 is independently selected from halogen ions or sulfonate, preferably chloride ion, bromide ion, iodide ion, methanesulfonate, toluenesulfonate, more preferably p-toluenesulfonate; R1 and R2 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, thiol, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 6-12 Aryl, 5-14 membered heteroaryl and 4-14 membered heterocyclic group, the hydroxyl, amino, thiol, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 6-12 Aryl, 5-14 membered heteroaryl and 4-14 membered heterocyclic radical, optionally further substituted by one or more radicals selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, C 6-12 substituted by aryl, 5-7 membered heteroaryl, or 4-7 membered heterocyclic group; Alternatively, R1 and R2 together with the atoms to which they are attached form a 3- to 8-membered cycloalkyl or a 4- to 8-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2, optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 6-12 aryl, 5- to 7-membered heteroaryl, 4- to 7-membered heterocyclic group; Preferably, R1 and R2 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 6-12 aryl, 5- to 6-membered heteroaryl containing one to three heteroatoms selected from N, O, S, SO or SO2, and 4- to 7-membered heterocyclic group containing one to three heteroatoms selected from N, O, S, SO or SO2, said hydroxyl, amino, mercapto, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 6-12 aryl, 5- to 6-membered heteroaryl containing one to three heteroatoms selected from N, O, S, SO or SO2, and 4- to 7-membered heterocyclic group containing one to three heteroatoms selected from N, O, S, SO or SO2, optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 6-12 aryl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclic group; Alternatively, R1 and R2 together with the atoms to which they are attached form a 3-6 membered cycloalkyl or a 4-7 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, S, SO or SO2, optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 6-12 aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclic group; More preferably, R1 and R2 are each independently selected from hydrogen, deuterium, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, and further preferably hydrogen.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, Each R3 is independently selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 5-14 membered heteroaryl and 4-14 membered heterocyclic group, optionally further substituted by one or more R5; Each R5 is independently selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 6-12 aryl, 5-7-membered heteroaryl, 4-7-membered heterocyclic group which is substituted by substituents, optionally, the C 3-8 cycloalkyl, C 6-12 aryl, 5-7-membered heteroaryl, 4-7-membered heterocyclic group which is optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl; Preferably, Each R3 is independently selected from C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 6-12 aryl, 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2, and 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2, optionally further substituted by one or more R5; each R5 is independently selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 6-12 aryl, 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2, 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2, the C 3-6 cycloalkyl, C 6-12 aryl, 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2, 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl; R4 is selected from hydrogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 5-14 membered heteroaryl and 4-14 membered heterocyclic group, said hydroxy, amino, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 5-14 membered heteroaryl and 4-14 membered heterocyclic group, optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 6-12 aryl, 5-7 membered heteroaryl, 4-7 membered heterocyclic group; Preferably, R4 is selected from hydrogen, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 6-12 aryl, 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2, and 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2, wherein the hydroxy, amino, mercapto, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 6-12 aryl, 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2, and 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, S, SO or SO2, optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 6-12 aryl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclic group; Alternatively, R3 and R4, together with the nitrogen atom to which they are attached, form a 4-7 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, S, SO or SO2, optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 6-12 aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclic group; More preferably, R3 and R4 are each independently selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 6-12 aryl-C 1-3 alkyl, and more preferably methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, 3-methylbutan-2-yl, cyclopropyl, cyclobutyl, morpholinyl, benzyl or phenethyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, R6 and R7 are each independently selected from lithium, sodium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, C 6-12 aryl, 5- to 14-membered heteroaryl, 4- to 14-membered heterocyclic group, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, C 6-12 aryl, 5- to 14-membered heteroaryl, 4- to 14-membered heterocyclic group, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 6-12 aryl, 5- to 7-membered heteroaryl, 4- to 7-membered heterocyclic group; Preferably, R6 and R7 are each independently selected from lithium, sodium, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 6-12 aryl, a 5- or 6-membered heteroaryl containing 1-3 atoms selected from N, O or S, a 4- to 7-membered heterocyclic group containing 1-3 atoms selected from N, O or S, wherein the C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 6-12 aryl, a 5- or 6-membered heteroaryl containing 1-3 atoms selected from N, O or S, a 4- to 7-membered heterocyclic group containing 1-3 atoms selected from N, O or S, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 6-12 aryl, a 5- or 6-membered heteroaryl containing 1-3 atoms selected from N, O or S, a 4- to 7-membered heterocyclic group containing 1-3 atoms selected from N, O or S, and is substituted by substituents of 4-7 heterocyclic groups.

5. The compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof, characterized in that, A is X is a pharmaceutically acceptable anion; B or C is a bond; X1 or X2 is a bond.

6. The compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof, further being a compound shown by general formula (II-a), (II-b), (II-c) or (II-d) or a pharmaceutically acceptable salt thereof: Each of X, X1 or X2 is independently selected from halogen ions or sulfonate; A, B or C is R is selected from -R3, -OR3, -NHR3 and -NR3R4; R1 and R2 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, preferably hydrogen; R3 and R4 are each independently selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 6-12 aryl-C 1-3 alkyl, preferably methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, morpholinyl, benzyl or phenethyl; R6 and R7 are each independently selected from lithium, sodium, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, phenyl, a 5- or 6-membered heteroaryl containing 1 to 3 atoms selected from N, O or S, the C 3-6 cycloalkyl, phenyl, a 5- or 6-membered heteroaryl containing 1 to 3 atoms selected from N, O or S, optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine or bromine; Preferably, A, B or C is 7. The compound or a pharmaceutically acceptable salt thereof as described below: A, B and C are Each of X, X1 or X2 is independently selected from pharmaceutically acceptable anions.

8. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1-7 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

9. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8 in the preparation of a drug for treating a disease related to tyrosine kinase, preferably in the preparation of a drug for treating a disease related to Bcr-ABL.

10. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8, in the preparation of a medicament for treating tumors; preferably, the tumor is a hematological tumor; more preferably, the hematological tumor is selected from leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome or myeloproliferative neoplasm; further preferably, the leukemia is selected from chronic myeloid leukemia, chronic lymphocytic leukemia, acute myeloid leukemia or acute lymphocytic leukemia.

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