Pyrimido [5, 4-c] quinoline compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a pyrimido [5, 4-c] quinoline compound, a pharmaceutical composition and application of the pyrimido [5, 4-c] quinoline compound. The compound is a compound having a formula I or a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate, an isotope compound or a prodrug thereof. The compound provided by the invention can be used for preventing and / or treating cancers. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to a pyrimido[5,4-c]quinoline compound, a preparation method thereof, a pharmaceutical composition and use thereof. Background Art

[0003] At present, the main means of clinical tumor treatment are surgical treatment, radiotherapy, chemotherapy, targeted therapy and immunotherapy. Among them, radiotherapy and chemotherapy have obvious toxic side effects. Relatively speaking, targeted drugs can effectively reduce the systemic toxic side effects of patients and have become a hot spot in tumor treatment in the past 20 years. However, targeted drugs also have shortcomings such as drug resistance. Immunotherapy is to mobilize the body's immune system through active or passive methods to enhance anti-tumor immunity, thereby inhibiting and killing tumor cells, such as the currently popular antibody drug PD-1 inhibitor. However, antibody drugs also have shortcomings such as poor permeability in solid tumor tissues, which limits their widespread application in tumors. Therefore, the discovery of anti-tumor drugs with completely new structures is still of great significance. Summary of the invention

[0004] In order to improve the above technical problems, the present invention provides a pyrimido[5,4-c]quinoline compound and a preparation method, a pharmaceutical composition and use thereof.

[0005] Specifically, the present invention provides a compound having a structure shown in Formula I or a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate, an isotope compound or a prodrug thereof:

[0006]

[0007] wherein Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0008] X is selected from -O-, -S- and -NR 8 -;

[0009] Each R 1 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an oxo group (═O), a thio group (═S), unsubstituted or optionally substituted with 1, 2 or more R a Substituted groups: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, cycloalkynyloxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, cycloalkenylthio, cycloalkynylthio, -NR 17 R 18 ;

[0010] Each R 2are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, unsubstituted or optionally substituted with 1, 2 or more R b Substituted alkyl;

[0011] Each R 3 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, a nitro group, an oxo group (═O), a thio group (═S), unsubstituted or optionally substituted with 1, 2 or more R c Substituted groups: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, cycloalkynyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, cycloalkenylthio, cycloalkynylthio, heterocyclylthio, arylthio, heteroarylthio, -NR 17 R 18 ;

[0012] R 4 , R 5 , R 5 and R 6 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, unsubstituted or optionally substituted with 1, 2 or more R d Substituted groups: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, cycloalkynyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, cycloalkenylthio, cycloalkynylthio, heterocyclylthio, arylthio, heteroarylthio, -NR 17 R 18 、-C(O)R 9 、-C(O)OR 10 、-OC(O)R 11 、-S(O)2R 12 、-S(O)2OR 13 、-OS(O)2R 14 、-P(O)(OR 15 )(OR 16 );

[0013] Or, R 4 , R 5 , R 5 and R 6 The adjacent substituents in the d Substituted from the following groups: cycloalkenyl, heterocyclyl, aryl or heteroaryl;

[0014] R 8 is selected from a hydrogen atom, a deuterium atom, unsubstituted or optionally substituted with 1, 2 or more R e Substituted: alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0015] Each R a , R b , R c , R d and R e are the same or different and are each independently selected from a deuterium atom, a halogen, a cyano group, a hydroxyl group, a nitro group, an oxo group (═O), a thio group (═S), unsubstituted or optionally substituted with 1, 2 or more R f Substituted groups: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, cycloalkynyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, cycloalkenylthio, cycloalkynylthio, heterocyclylthio, arylthio, heteroarylthio, -NR 17 R 18 、-C(O)R 9 、-C(O)OR 10 、-OC(O)R 11 、-S(O)2R 12 、-S(O)2OR 13 、-OS(O)2R 14 、-P(O)(OR 15 )(OR 16 );

[0016] R 9 , R 11 , R 12 , R 14 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, an aryl group, a heteroaryl group, a heterocyclic group, -NR 17 R 18 ;

[0017] R 10 , R 13 , R 14 , R 15 and R 16 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, an aryl group, a heteroaryl group, and a heterocyclic group;

[0018] R 17 and R 18are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

[0019] Each R f are the same or different and are each independently selected from the group consisting of a deuterium atom, a halogen, a cyano group, a hydroxyl group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, a heterocyclyl group, an aryl group, a heteroaryl group, an alkyloxy group, an alkenyloxy group, an alkynyloxy group, a cycloalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxy group, a heterocyclyloxy group, an aryloxy group, a heteroaryloxy group, an alkylthio group, an alkenylthio group, an alkynylthio group, a cycloalkylthio group, a cycloalkenylthio group, a cycloalkynylthio group, a heterocyclylthio group, an arylthio group, a heteroarylthio group, 17 R 18 ;

[0020] m and n are the same or different and are each independently selected from 0, 1, 2, 3, 4 or 5.

[0021] According to an embodiment of the present invention, when a substituent such as R 1 , R 3 When the specific substitution position of the like is not particularly specified, each of them can be substituted at any substitution position as long as it does not violate the valence bond rules. For example, each R 1 can be substituted independently at any position of the piperazinyl group (such as a C atom or a N atom), and each R 3 The substitution may be independently carried out at any position of the ring A (eg, a C atom or a N atom).

[0022] According to an embodiment of the present invention, ring A is selected from C 3-40 Cycloalkyl, 5-20 membered heterocyclic group, C 6-20 Aryl and 5-20 membered heteroaryl.

[0023] According to an embodiment of the present invention, ring A is selected from C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl.

[0024] According to an embodiment of the present invention, ring A is selected from C 3-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl and 5-8 membered heteroaryl.

[0025] According to an embodiment of the present invention, when ring A is selected from a 5-20 membered heterocyclic group, it may have 1-5 heteroatoms selected from N, O, S, for example, 1, 2 or 3 heteroatoms selected from N, O, S. As an example, ring A may be a 5-10 membered heterocyclic group having only 1, 2 or 3 heteroatoms N, for example, a 5-8 membered heterocyclic group having only 1 or 2 heteroatoms N. As an example, ring A may be selected from a tetrahydropyrrolyl group (such as a tetrahydropyrrol-1-yl, a tetrahydropyrrol-2-yl, a tetrahydropyrrol-3-yl, such as ), morpholinyl (e.g., morpholin-1-yl, morpholin-2-yl, morpholin-3-yl), piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl), piperazinyl (e.g., piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, piperazin-4-yl), hexahydro-1H-pyrrolazinyl (e.g., hexahydro-1H-pyrrolazin-1-yl, hexahydro-1H-pyrrolazin-2-yl, hexahydro-1H-pyrrolazin-3-yl, hexahydro-1H-pyrrolazin-7a-yl), examples of which may be ).

[0026] According to an embodiment of the present invention, X is selected from -O- and -NR 8 -.

[0027] According to an embodiment of the present invention, R 8 is selected from a hydrogen atom, a deuterium atom, unsubstituted or optionally substituted with 1, 2 or more R e Substituted with the following groups: C 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, 5-20 membered heterocyclic group, C 6-20 Aryl and 5-20 membered heteroaryl.

[0028] According to an embodiment of the present invention, R 8 is selected from a hydrogen atom, a deuterium atom, unsubstituted or optionally substituted with 1, 2 or more R e Substituted with the following groups: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl.

[0029] According to an embodiment of the present invention, R 8 is selected from a hydrogen atom, a deuterium atom, unsubstituted or optionally substituted with 1, 2 or more R e Substituted with the following groups: C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl and 5-8 membered heteroaryl.

[0030] According to an embodiment of the present invention, each R 1 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an oxo group (═O), a thio group (═S), unsubstituted or optionally substituted with 1, 2 or more R a Substituted with the following groups: C 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkynyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 1-40 Alkylthio, C 2-40 Alkenylthio, C 2-40 Alkynylthio, C 3-40 Cycloalkylthio, C 3-40 Cycloalkenylthio, C 3-40 Cycloalkynylthio, -NR 17 R 18 .

[0031] According to an embodiment of the present invention, each R 1 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an oxo group (═O), a thio group (═S), unsubstituted or optionally substituted with 1, 2 or more R a Substituted with the following groups: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 3-10 Cycloalkynyl, C 1-10 Alkyloxy, C 2-10 Alkenyloxy, C 2-10 Alkynyloxy, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkenyloxy, C 3-10 Cycloalkynyloxy, C 1-10 Alkylthio, C 2-10 Alkenylthio, C 2-10 Alkynylthio, C 3-10 Cycloalkylthio, C 3-10 Cycloalkenylthio, C3-10 Cycloalkynylthio, -NR 17 R 18 .

[0032] According to an embodiment of the present invention, each R 1 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an oxo group (═O), a thio group (═S), unsubstituted or optionally substituted with 1, 2 or more R a Substituted with the following groups: C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy, C 2-8 Alkynyloxy, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, C 1-8 Alkylthio, C 2-8 Alkenylthio, C 2-8 Alkynylthio, C 3-8 Cycloalkylthio, C 3-8 Cycloalkenylthio, C 3-8 Cycloalkynylthio, -NR 17 R 18 .

[0033] As an example, each R 1 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkyloxy, halogenated C 1-8 Alkyl, halogenated C 1-8 Alkyloxy, cyano, amino, -CH-NR 17 R 18 , hydroxyl and hydroxyl C 1-8 alkyl;

[0034] According to an embodiment of the present invention, m and n are the same or different and are each independently selected from 0, 1, 2, 3 or 4.

[0035] According to an embodiment of the present invention, each R 2 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, unsubstituted or optionally substituted with 1, 2 or more R b Substituted C 1-40 alkyl.

[0036] According to an embodiment of the present invention, each R 2 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, unsubstituted or optionally substituted with 1, 2 or more R b Substituted C 1-10 alkyl.

[0037] According to an embodiment of the present invention, each R 2 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, unsubstituted or optionally substituted with 1, 2 or more R b Substituted C 1-8 alkyl.

[0038] As an example, each R 2 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a C 1-8 Alkyl, halogenated C 1-8 Alkyl and hydroxyl C 1-8 Alkyl. For example, R 2 A hydrogen atom.

[0039] According to an embodiment of the present invention, each R 3 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, a nitro group, unsubstituted or optionally substituted with 1, 2 or more R c Substituted with the following groups: C 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkynyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 1-40 Alkylthio, C 2-40 Alkenylthio, C 2-40 Alkynylthio, C 3-40 Cycloalkylthio, C 3-40 Cycloalkenylthio, C 3-40 Cycloalkynylthio, -NR 17 R 18 .

[0040] According to an embodiment of the present invention, each R 3 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, a nitro group, unsubstituted or optionally substituted with 1, 2 or more R c Substituted with the following groups: C1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 3-10 Cycloalkynyl, 5-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-10 Alkyloxy, C 2-10 Alkenyloxy, C 2-10 Alkynyloxy, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkenyloxy, C 3-10 Cycloalkynyloxy, 5-10 membered heterocyclyloxy, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 1-10 Alkylthio, C 2-10 Alkenylthio, C 2-10 Alkynylthio, C 3-10 Cycloalkylthio, C 3-10 Cycloalkenylthio, C 3-10 Cycloalkynylthio, 5-10 membered heterocyclylthio, C 6-10 Arylthio, 5-10 membered heteroarylthio, -NR 17 R 18 .

[0041] According to an embodiment of the present invention, each R 3 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, a nitro group, unsubstituted or optionally substituted with 1, 2 or more R c Substituted with the following groups: C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, 5-8 membered heterocyclic group, C 6-10 Aryl, 5-8 membered heteroaryl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy, C 2-8 Alkynyloxy, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, 5-8 membered heterocyclyloxy, C 6-20 Aryloxy, 5-8 membered heteroaryloxy, C 1-8 Alkylthio, C 2-8 Alkenylthio, C 2-8 Alkynylthio, C 3-8 Cycloalkylthio, C 3-8 Cycloalkenylthio, C3-8 Cycloalkynylthio, 5-8 membered heterocyclylthio, C 6-10 Arylthio, 5-8 membered heteroarylthio, -NR 17 R 18 .

[0042] According to an embodiment of the present invention, each R 3 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkyloxy, halogenated C 1-8 Alkyl, halogenated C 1-8 Alkyloxy, cyano, amino, nitro, hydroxy, hydroxy C 1-8 Alkyl, C 3-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl and 5-8 membered heteroaryl.

[0043] As an example, each R 3 The same or different, and each independently selected from hydrogen atom, hydroxyl group, halogen.

[0044] According to an embodiment of the present invention, R 4 , R 5 , R 5 and R 6 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, unsubstituted or optionally substituted with 1, 2 or more R d Substituted with the following groups: C 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl, 5-20 membered heterocyclic group, C 6-20 Aryl, 5-20 membered heteroaryl, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkynyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, 5-20 membered heterocyclyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, C 1-40 Alkylthio, C 2-40 Alkenylthio, C 2-40 Alkynylthio, C 3-40 Cycloalkylthio, C 3-40 Cycloalkenylthio, C 3-40Cycloalkynylthio, 5-20 membered heterocyclylthio, C 6-20 Arylthio, 5-20 membered heteroarylthio, -NR 17 R 18 、-C(O)R 9 、-C(O)OR 10 、-OC(O)R 11 、-S(O)2R 12 、-S(O)2OR 13 、-OS(O)2R 14 、-P(O)(OR 15 )(OR 16 ).

[0045] According to an embodiment of the present invention, R 4 , R 5 , R 5 and R 6 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, unsubstituted or optionally substituted with 1, 2 or more R d Substituted with the following groups: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 3-10 Cycloalkynyl, 5-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-10 Alkyloxy, C 2-10 Alkenyloxy, C 2-10 Alkynyloxy, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkenyloxy, C 3-10 Cycloalkynyloxy, 5-10 membered heterocyclyloxy, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 1-10 Alkylthio, C 2-10 Alkenylthio, C 2-10 Alkynylthio, C 3-10 Cycloalkylthio, C 3-10 Cycloalkenylthio, C 3-10 Cycloalkynylthio, 5-10 membered heterocyclylthio, C 6-10 Arylthio, 5-10 membered heteroarylthio, -NR 17 R 18 、-C(O)R 9 、-C(O)OR 10 、-OC(O)R 11 、-S(O)2R 12 、-S(O)2OR 13、-OS(O)2R 14 、-P(O)(OR 15 )(OR 16 ).

[0046] According to an embodiment of the present invention, R 4 , R 5 , R 5 and R 6 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, unsubstituted or optionally substituted with 1, 2 or more R d Substituted with the following groups: C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, 5-8 membered heterocyclic group, C 6-10 Aryl, 5-8 membered heteroaryl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy, C 2-8 Alkynyloxy, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, 5-8 membered heterocyclyloxy, C 6-20 Aryloxy, 5-8 membered heteroaryloxy, C 1-8 Alkylthio, C 2-8 Alkenylthio, C 2-8 Alkynylthio, C 3-8 Cycloalkylthio, C 3-8 Cycloalkenylthio, C 3-8 Cycloalkynylthio, 5-8 membered heterocyclylthio, C 6-10 Arylthio, 5-8 membered heteroarylthio, -NR 17 R 18 、-C(O)R 9 、-C(O)OR 10 、-OC(O)R 11 、-S(O)2R 12 、-S(O)2OR 13 、-OS(O)2R 14 、-P(O)(OR 15 )(OR 16 ).

[0047] As an example, R 4 , R 5 , R 5 and R 6are the same or different and are each independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, methoxy, dimethylamino, trifluoromethyl, methylsulfonyl, dimethylaminocarbonyl, pyrrolidin-1-yl;

[0048] Or, R 4 and R 5 The atoms to which it is attached together form an unsubstituted or optionally substituted group consisting of 1, 2 or more R d Substituted with the following groups: or,

[0049] R 5 and R 6 The atoms to which it is attached together form an unsubstituted or optionally substituted group consisting of 1, 2 or more R d Substituted with the following groups: or,

[0050] R 6 and R 7 The atoms to which it is attached together form an unsubstituted or optionally substituted group consisting of 1, 2 or more R d Substituted with the following groups:

[0051] in, represents the chemical bond inside the phenyl group connected to the above ring structure.

[0052] According to an embodiment of the present invention, each R a , R b , R c , R d and R e are the same or different and are each independently selected from a deuterium atom, a halogen, a cyano group, a hydroxyl group, a nitro group, an unsubstituted group or an optionally substituted group with 1, 2 or more R f Substituted with the following groups: C 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl, 5-20 membered heterocyclic group, C 6-20 Aryl, 5-20 membered heteroaryl, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkynyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, 5-20 membered heterocyclyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, C 1-40 Alkylthio, C 2-40 Alkenylthio, C2-40 Alkynylthio, C 3-40 Cycloalkylthio, C 3-40 Cycloalkenylthio, C 3-40 Cycloalkynylthio, 5-20 membered heterocyclylthio, C 6-20 Arylthio, 5-20 membered heteroarylthio, -NR 17 R 18 、-C(O)R 9 、-C(O)OR 10 、-OC(O)R 11 、-S(O)2R 12 、-S(O)2OR 13 、-OS(O)2R 14 、-P(O)(OR 15 )(OR 16 ).

[0053] According to an embodiment of the present invention, each R a , R b , R c , R d and R e are the same or different and are each independently selected from a deuterium atom, a halogen, a cyano group, a hydroxyl group, a nitro group, an unsubstituted group or an optionally substituted group with 1, 2 or more R f Substituted with the following groups: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 3-10 Cycloalkynyl, 5-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-10 Alkyloxy, C 2-10 Alkenyloxy, C 2-10 Alkynyloxy, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkenyloxy, C 3-10 Cycloalkynyloxy, 5-10 membered heterocyclyloxy, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 1-10 Alkylthio, C 2-10 Alkenylthio, C 2-10 Alkynylthio, C 3-10 Cycloalkylthio, C 3-10 Cycloalkenylthio, C 3-10 Cycloalkynylthio, 5-10 membered heterocyclylthio, C 6-10 Arylthio, 5-10 membered heteroarylthio, -NR 17 R 18 、-C(O)R 9、-C(O)OR 10 、-OC(O)R 11 、-S(O)2R 12 、-S(O)2OR 13 、-OS(O)2R 14 、-P(O)(OR 15 )(OR 16 ).

[0054] According to an embodiment of the present invention, each R a , R b , R c , R d and R e are the same or different and are each independently selected from a deuterium atom, a halogen, a cyano group, a hydroxyl group, a nitro group, an unsubstituted group or an optionally substituted group with 1, 2 or more R f Substituted with the following groups: C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, 5-8 membered heterocyclic group, C 6-10 Aryl, 5-8 membered heteroaryl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy, C 2-8 Alkynyloxy, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, 5-8 membered heterocyclyloxy, C 6-10 Aryloxy, 5-8 membered heteroaryloxy, C 1-8 Alkylthio, C 2-8 Alkenylthio, C 2-8 Alkynylthio, C 3-8 Cycloalkylthio, C 3-8 Cycloalkenylthio, C 3-8 Cycloalkynylthio, 5-8 membered heterocyclylthio, C 6-10 Arylthio, 5-8 membered heteroarylthio, -NR 17 R 18 、-C(O)R 9 、-C(O)OR 10 、-OC(O)R 11 、-S(O)2R 12 、-S(O)2OR 13 、-OS(O)2R 14 、-P(O)(OR 15 )(OR 16 ).

[0055] According to an embodiment of the present invention, each R f are the same or different and are each independently selected from a deuterium atom, a halogen, a cyano group, a hydroxyl group, a nitro group, a C 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl, 5-20 membered heterocyclic group, C 6-20 Aryl, 5-20 membered heteroaryl, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkynyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, 5-20 membered heterocyclyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, C 1-40 Alkylthio, C 2-40 Alkenylthio, C 2-40 Alkynylthio, C 3-40 Cycloalkylthio, C 3-40 Cycloalkenylthio, C 3-40 Cycloalkynylthio, 5-20 membered heterocyclylthio, C 6-20 Arylthio, 5-20 membered heteroarylthio, -NR 17 R 18 .

[0056] According to an embodiment of the present invention, each R f are the same or different and are each independently selected from a deuterium atom, a halogen, a cyano group, a hydroxyl group, a nitro group, a C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 3-10 Cycloalkynyl, 5-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-10 Alkyloxy, C 2-10 Alkenyloxy, C 2-10 Alkynyloxy, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkenyloxy, C 3-10 Cycloalkynyloxy, 5-10 membered heterocyclyloxy, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 1-10 Alkylthio, C 2-10 Alkenylthio, C 2-10 Alkynylthio, C 3-10Cycloalkylthio, C 3-10 Cycloalkenylthio, C 3-10 Cycloalkynylthio, 5-10 membered heterocyclylthio, C 6-10 Arylthio, 5-10 membered heteroarylthio, -NR 17 R 18 .

[0057] According to an embodiment of the present invention, each R f are the same or different and are each independently selected from a deuterium atom, a halogen, a cyano group, a hydroxyl group, a nitro group, a C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, 5-8 membered heterocyclic group, C 6-10 Aryl, 5-8 membered heteroaryl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy, C 2-8 Alkynyloxy, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, 5-8 membered heterocyclyloxy, C 6-10 Aryloxy, 5-8 membered heteroaryloxy, C 1-8 Alkylthio, C 2-8 Alkenylthio, C 2-8 Alkynylthio, C 3-8 Cycloalkylthio, C 3-8 Cycloalkenylthio, C 3-8 Cycloalkynylthio, 5-8 membered heterocyclylthio, C 6-10 Arylthio, 5-8 membered heteroarylthio, -NR 17 R 18 .

[0058] According to an embodiment of the present invention, R 9 , R 11 , R 12 , R 14 are the same or different and are independently selected from H, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, C 6-10 Aryl, 5-8 membered heteroaryl, 5-8 membered heterocyclic group, -NR 17 R 18 .

[0059] According to an embodiment of the present invention, R10 , R 13 , R 14 , R 15 and R 16 are the same or different and are independently selected from H, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, C 6-10 Aryl, 5-8 membered heteroaryl, 5-8 membered heterocyclic group.

[0060] According to an embodiment of the present invention, R 17 and R 18 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, unsubstituted or optionally substituted with 1, 2 or more R f Substituted with the following groups: C 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-20 Cycloalkyl, 5-20 membered heterocyclic group, C 6-20 Aryl and 5-20 membered heteroaryl.

[0061] According to an embodiment of the present invention, R 17 and R 18 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, unsubstituted or optionally substituted with 1, 2 or more R f Substituted with the following groups: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl.

[0062] According to an embodiment of the present invention, R 17 and R 18 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, unsubstituted or optionally substituted with 1, 2 or more R f Substituted with the following groups: C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl and 5-8 membered heteroaryl.

[0063] According to an embodiment of the present invention, the compound of the structure shown in Formula I may have a structure shown in, for example, the following Formula I-1:

[0064]

[0065] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m and n independently have the definitions given above.

[0066] According to an embodiment of the present invention, the compound of the structure shown in Formula I may have a structure shown in, for example, the following Formula I-2:

[0067]

[0068] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m and n independently have the definitions given above.

[0069] According to an embodiment of the present invention, the compound of the structure shown in Formula I can be selected from at least one of the following compounds:

[0070]

[0071]

[0072]

[0073] The present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition comprises a compound having a structure as shown in Formula I or a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or an isotope compound thereof;

[0074] According to an embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or a diluent.

[0075] According to an embodiment of the present invention, in the pharmaceutical composition, the compound having the structure shown in Formula I or its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or isotope compound is present in a therapeutically effective amount.

[0076] The present invention also provides a compound having a structure of formula I, a stereoisomer and a non-toxic pharmaceutically acceptable salt, hydrate, solvate thereof, and a pharmaceutical composition containing these compounds as active ingredients for treating tumors.

[0077] The present invention also provides a method for preventing and / or treating tumors, comprising administering the compound having the structure of Formula I, stereoisomers and non-toxic pharmaceutically acceptable salts, hydrates, solvates and isotope compounds thereof to a patient in need.

[0078] According to an embodiment of the present invention, the tumor can be cancer, for example, at least one selected from the following: brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumors, urothelial carcinoma, urethral cancer, bladder cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma, preferably selected from pancreatic cancer, colorectal cancer, non-small cell lung cancer, gastric cancer and endometrial cancer.

[0079] The present invention also provides a method for preparing the compound having the structure of Formula I, its stereoisomer or its pharmaceutically acceptable salt, hydrate, solvate, isotope compound, characterized in that the preparation method comprises the following steps:

[0080]

[0081] According to an embodiment of the present invention, the preparation method comprises the following steps:

[0082] (1) Synthesis of Intermediate III

[0083] The starting material II is reacted in the presence of thionyl chloride and oxalyl chloride;

[0084] Preferably, the reaction is carried out at a temperature of 20°C to 100°C;

[0085] Preferably, the solvent of the reaction is dichloromethane, toluene or no solvent.

[0086] (2) Synthesis of Intermediate IV

[0087] Intermediate III reacts with diethyl malonate in the presence of a Lewis acid;

[0088] Preferably, the reaction temperature is carried out at a temperature of 20°C to 80°C;

[0089] Preferably, the Lewis acid is selected from anhydrous magnesium chloride, anhydrous zinc chloride, anhydrous ferric chloride;

[0090] Preferably, the base is selected from triethylamine, diisopropylethylamine, N-methylmorpholine;

[0091] Preferably, the reaction solvent is selected from acetonitrile and toluene.

[0092] (3) Synthesis of intermediate V

[0093] Intermediate IV reacts in the presence of an acid;

[0094] Preferably, the reaction temperature is carried out at a temperature of 20°C to 100°C;

[0095] Preferably, the acid is selected from 4-methylbenzenesulfonic acid, methanesulfonic acid, trifluoroacetic acid;

[0096] Preferably, the reaction solvent is selected from 1,4-dioxane, toluene and acetonitrile.

[0097] (4) Synthesis of Intermediate VI

[0098] Intermediate V reacts with DMF-DMA in the presence of an acid;

[0099] Preferably, the reaction temperature is carried out at a temperature of 20°C to 100°C;

[0100] Preferably, the acid is selected from formic acid, acetic acid, propionic acid, trifluoroacetic acid;

[0101] Preferably, the solvent is selected from toluene and 1,4-dioxane.

[0102] (5) Synthesis of Compound VIII

[0103] Intermediate VI reacts with starting material VII in the presence of a base;

[0104] Preferably, the reaction is carried out at a temperature of 20°C to 100°C;

[0105] Preferably, the base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, triethylamine, diisopropylethylamine;

[0106] Preferably, the reaction solvent is methanol, ethanol, isopropanol, acetonitrile or toluene.

[0107] (6) Synthesis of Compound IX

[0108] Intermediate VIII reacts in the presence of a reducing agent;

[0109] Preferably, the reaction is carried out at a temperature of 20°C to 100°C;

[0110] Preferably, the reducing agent is selected from iron powder / ammonium chloride, iron powder / acetic acid, zinc powder / ammonium chloride, zinc powder / acetic acid, hydrogen / palladium carbon;

[0111] Preferably, the reaction solvent is methanol, ethanol or isopropanol.

[0112] (7) Synthesis of Compound X

[0113] Intermediate IX reacts in the presence of a chlorinating agent;

[0114] Preferably, the reaction is carried out at a temperature of 20°C to 100°C;

[0115] Preferably, the chlorinating agent is selected from phosphine oxychloride and phosphorus pentachloride;

[0116] Preferably, the reaction solvent is toluene or no solvent.

[0117] (8) Synthesis of Compound XII

[0118] The intermediate X reacts with the starting material XI in the presence of a base;

[0119] Preferably, the reaction is carried out at a temperature of 20°C to 100°C;

[0120] Preferably, the base is selected from potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, sodium tert-butoxide, potassium tert-butoxide;

[0121] Preferably, the reaction solvent is tert-butyl alcohol, toluene, tetrahydrofuran, or 1,4-dioxane.

[0122] (9) Synthesis of Compound I

[0123] Intermediate XII reacts with in the presence of a base;

[0124] Preferably, the reaction is carried out at a temperature of 20°C to 140°C;

[0125] Preferably, the base is selected from potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide;

[0126] Preferably, the reaction solvent is at least one of the following mixed solvents: 1,4-dioxane and water, tert-butanol and water, n-butanol and water, ethylene glycol and water;

[0127] Optionally, the preparation method further comprises the step of preparing Compound I into at least one of its pharmaceutically acceptable salts, hydrates, solvates, isotope compounds or prodrugs.

[0128] The active compound can be prepared into a form suitable for administration by any appropriate route, and the composition of the present invention can be prepared by conventional methods using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present invention can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration. The compound of the present invention can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.

[0129] As a general guide, the active compound is preferably in a unit dosage form, or in a form that a patient can self-administer in a single dose. The unit dosage form of the compound or composition of the present invention can be tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations. Suitable unit dosages can be 0.1 to 1000 mg.

[0130] The pharmaceutical composition of the present invention may contain one or more adjuvants in addition to the active compound, and the adjuvants are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound. Tablets contain active ingredients and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets for mixing. These excipients can be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that provide a sustained release effect over a long period of time by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract. Oral preparations may also be provided in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0131] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, dispersants or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

[0132] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil, or a mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant.

[0133] The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives and antioxidants. Such preparations may also contain demulcents, preservatives, colorants and antioxidants.

[0134] The pharmaceutical composition of the present invention may be in the form of a sterile injectable aqueous solution. Acceptable vehicles or solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injection solution or microemulsion may be injected into the patient's bloodstream by local mass injection, or, preferably, the solution and microemulsion may be administered in a manner that maintains a constant circulating concentration of the compound of the present invention. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used.

[0135] The pharmaceutical composition of the present invention can be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared by known techniques using the above-mentioned suitable dispersants or wetting agents and suspending agents. The sterile injection preparation can also be a sterile injection solution or suspension prepared in an acceptable non-toxic diluent or solvent for parenteral administration. In addition, sterile fixed oil can be conveniently used as a solvent or suspension medium. For this purpose, any blended fixed oil can be used. In addition, fatty acids can also be used to prepare injections.

[0136] The compounds of this invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0137] The compounds of the invention can be administered by preparing water-dispersible powders and granules for suspension by the addition of water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent or one or more preservatives.

[0138] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the severity of the disease, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the best treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0139] Definition and explanation of terms

[0140] Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. The definitions of groups and compound structures after such combinations and combinations should be understood to be within the scope of the specification and / or claims of this application.

[0141] Unless otherwise specified, the numerical ranges recorded in this specification and claims are equivalent to recording at least each specific integer value therein. For example, the numerical range "1-40" is equivalent to recording each integer value in the numerical range "1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and each integer value in the numerical range "11-40", namely 11, 12, 13, 14, 15, ..., 35, 36, 37, 38, 39, 40. In addition, when certain numerical ranges are defined as "numbers", it should be understood that the two endpoints of the range, each integer in the range, and each decimal in the range are recorded. For example, "a number from 0 to 10" should be understood as not only recording each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least recording the sum of each integer therein and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, respectively.

[0142] It should be understood that herein, in the description of 1, 2 or more, "more" should refer to an integer greater than 2, for example, greater than or equal to 3, for example 3, 4, 5, 6, 7, 8, 9 or 10.

[0143] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0144] The term "alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical. 1-40 "Alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 40 carbon atoms. For example, "C 1-10 "Alkyl" means straight chain and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 1-8 The term “alkyl” refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl or the like or isomers thereof.

[0145] The term "alkenyl" is understood to mean preferably a linear or branched monovalent hydrocarbon radical containing one or more double bonds. 2-40 "Alkenyl" is understood to mean preferably a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having 2 to 40 carbon atoms, preferably "C2-10 "C 2-10 The term "alkenyl" is understood to mean preferably a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example having 2, 3, 4, 5 or 6 carbon atoms (i.e., C 2-6 alkenyl), having 2 or 3 carbon atoms (i.e., C 2-3 It is understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from one another or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl , 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl but-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0146] The term "alkynyl" is understood to mean a straight or branched monovalent hydrocarbon radical containing one or more triple bonds. 2-40 "Alkynyl" is understood to mean a linear or branched monovalent hydrocarbon radical containing one or more triple bonds and having 2 to 40 carbon atoms, preferably "C 2-10 The term "C 2-10 "Alkynyl" is understood to mean preferably a straight or branched monovalent hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example having 2, 3, 4, 5 or 6 carbon atoms (i.e., "C 2-6Alkynyl”), having 2 or 3 carbon atoms (“C 2-3 The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4 In some embodiments, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0147] The term "cycloalkyl" refers to a saturated monovalent monocyclic, bicyclic (eg, fused, bridged, spiro) hydrocarbon ring or tricyclic alkane. The term "C 3-40 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (such as condensed, bridged, spiro) hydrocarbon ring or tricyclic alkane having 3 to 40 carbon atoms, preferably "C 3-10 The term "Cycloalkyl" 3-10 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (eg bridged, spiro) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 3-10 The cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as borneol, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonanyl, 2,6-diazaspiro[3,4]octanyl, or a tricyclic hydrocarbon group such as adamantyl.

[0148] The term "heterocyclyl" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a monocyclic, bicyclic (such as fused, bridged, spiro) or tricyclic ring system, and contains at least one, for example 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S can also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O)2-. The term "3-20 membered heterocyclyl" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, it is a 4-, 5-, 6- or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring (such as a fused ring, a bridged ring, a spirocyclic ring) or a 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system, and contains at least one, for example 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S may also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O)2- states. Preferably, the heterocyclyl may be selected from "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S and N. The heterocyclic group can be connected to the rest of the molecule by any one of the carbon atoms or the nitrogen atom (if present). The heterocyclic group can include fused or bridged rings and spirocyclic rings. In particular, the heterocyclic group can include but is not limited to: 4-membered rings, such as azetidinyl, oxetanyl; 5-membered rings, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl (tetrahydropyrrolyl), imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or 7-membered rings, such as diazepanyl. Optionally, the heterocyclic group can be benzo-fused. The heterocyclic group may be a bicyclic ring, such as but not limited to a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, a hexahydro-1H-pyrrolazinyl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The heterocyclic group may be partially unsaturated, i.e., it may contain one or more double bonds, such as but not limited to a dihydrofuranyl, a dihydropyranyl, a 2,5-dihydro-1H-pyrrolyl, a 4H-[1,3,4]thiadiazinyl, a 4,5-dihydrooxazolyl or a 4H-[1,4]thiazinyl, or it may be benzo-fused, such as but not limited to a dihydroisoquinolinyl. When the 3-20-membered heterocyclic group is connected to other groups to form the compounds of the present invention, the carbon atoms on the 3-20-membered heterocyclic group may be connected to other groups, or the heterocyclic atoms (such as N atoms) on the 3-20-membered heterocyclic group may be connected to other groups. For example, when the 3-20 membered heterocyclic group is selected from piperazinyl and tetrahydropyrrolyl, the nitrogen atom or carbon atom on the piperazinyl may be connected to other groups.Or when the 3-20 membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring or the carbon atom at the ortho, meta or para position thereof may be connected to other groups.

[0149] The term "aryl" is understood to preferably mean a monovalent aromatic or partially aromatic monocyclic, bicyclic (such as fused, bridged, spiro) or tricyclic hydrocarbon ring, which may be a single aromatic ring or multiple aromatic rings fused together. 6-20 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic (such as fused, bridged, spiro) or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, which may be a single aromatic ring or a polyaromatic ring fused together, preferably "C 6-14 The term "C 6-14 The term "aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl”), such as anthracenyl. When the C 6-20 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Also, there is no limitation on the substitution position, for example, it may be substituted at the ortho position, para position or meta position.

[0150] The term "heteroaryl" means a monovalent monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic aromatic ring system containing 1 to 5 heteroatoms independently selected from N, O and S. The term "5-20 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, for example "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S and, in each case, may additionally be benzo-fused. "Heteroaryl" also refers to a group in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclic rings, wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples of the term heteroaryl include, for example, pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, 1,2,4-, 5-, 6-, 7- or 8-thiadiazolyl, pyridazinyl; and 1-, 2-, 3-, 5-, 6-, 7- or 8-indolizinyl, 1-, 3-, 4-, 5-, 6- or 7-isoindolyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 4-, 5-, 6-, 7- or 8-purinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or 6- naphthyridinyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aHcarbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-carbazolylcarbazolyl, 1 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-pyridinyl, 2-, 3-, 4-, 5- , 6-, 8-, 9- or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenazinyl, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzoisoquinolyl, 2-, 3-, 4- or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6- or 7-2H-furo[3 , 2-b]-pyranyl, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3- or 5-1H-pyrazolo[4,3-d]-thiazolyl, 2-, 4- or 5-1H-imidazo[4,5-d]thiazolyl, 3-, 5- or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3- , 5- or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10 or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6- or 7-imidazo[1,2-b][1,2,4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-1H-pyrrolo[1,2-b][2]benzazepinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-benzo[b]thienyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl and 2-, 4-, 5-, 6- or 7-benzothiazolyl. When the 5-20 membered heteroaryl group is connected to other groups to form the compound of the present invention, it can be a carbon atom on the 5-20 membered heteroaryl ring connected to other groups, or it can be a heteroatom on the 5-20 membered heteroaryl ring connected to other groups. When the 5-20 membered heteroaryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution site, for example, the hydrogen bonded to the carbon atom on the heteroaryl ring may be substituted, or the hydrogen bonded to the heteroatom on the heteroaryl ring may be substituted.

[0151] The term "spirocyclic" refers to a ring system in which two rings share one ring-forming atom.

[0152] The term "fused ring" refers to a ring system in which two rings share two ring atoms.

[0153] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

[0154] Unless otherwise specified, heterocyclic groups, heteroaryls or heteroarylene groups include all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative non-limiting examples, forms substituted or bonded to other groups at 1, 2 or more positions in the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) may include pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-ylene and pyridin-4-ylene; thienyl or thienylene groups include thien-2-yl, thien-2-ylene, thien-3-ylene and thien-3-ylene; pyrazoles may include pyridin-2-yl, pyridin-2-ylene, pyridin-3 ...3-ylene; pyrazoles may include pyridines, pyridines, pyridines, pyridines, pyridines, pyridines, pyridines, pyridines, pyridines, pyridines, pyridines, pyridines, pyridines, pyridines, pyridines, pyridines, pyridines, pyridines, pyridines, pyridines, pyridines, pyridine -1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, tetrahydropyrrol-1-yl, tetrahydropyrrol-2-yl, tetrahydropyrrol-3-yl, morpholin-1-yl, morpholin-2-yl, morpholin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, piperazin-4-yl, hexahydro-1H-pyrrolazin-1-yl, hexahydro-1H-pyrrolazin-2-yl, hexahydro-1H-pyrrolazin-3-yl, hexahydro-1H-pyrrolazin-7a-yl.

[0155] The term "oxo" refers to a substituent in which a carbon atom, a nitrogen atom or a sulfur atom is oxidized to form an oxy group (=O).

[0156] Unless otherwise stated, the definition of a term herein also applies to groups containing the term, for example, the definition of alkyl also applies to the definition of groups containing alkyl, such as alkyloxy, alkylthio, alkylamino, alkylcarbonyl, etc.

[0157] It will be appreciated by those skilled in the art that the compounds of Formula I may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form a base addition salt; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form an internal salt.

[0158] The compounds of the present invention may exist in the form of solvates (e.g., hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of the polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0159] According to its molecular structure, the compounds of the present invention may be chiral, and therefore various enantiomeric forms may exist. Thus, these compounds may exist in racemic form or optically active form. The compounds of the present invention encompass isomers or mixtures, racemates in which each chiral carbon is in R or S configuration. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolution agent. Examples of suitable resolution agents are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids in R and S forms. Chromatographic enantiomer resolution can also be advantageously carried out with the aid of optically active resolving agents such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example, hexane / isopropanol / acetonitrile.

[0160] The corresponding stable isomers can be separated according to known methods, for example by extraction, filtration or column chromatography.

[0161] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0162] The term "therapeutically effective amount" refers to the amount of an active compound or drug that elicits the biological or medical response that a researcher, veterinarian, physician or other clinician is seeking in a tissue, system, animal, individual or human, and includes one or more of the following: (1) Preventing disease: e.g., preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but does not yet experience or develop the pathology or symptoms of the disease. (2) Inhibiting disease: e.g., inhibiting a disease, disorder or condition (i.e., preventing further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. (3) Alleviating disease: e.g., alleviating a disease, disorder or condition (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition.

[0163] "Isotopes" are all isotopes of atoms that occur in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into the compounds of the present invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, 2 H. 3 H.13 C. 14 C. 15 N. 18 O. 31 P. 32 P. 35 S. 18 F and 36 C1. The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the accompanying examples using appropriate isotopically labeled reagents in place of non-isotopically labeled reagents. Such compounds have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds have the potential to favorably alter biological, pharmacological or pharmacokinetic properties.

[0164] "Prodrug" means that the compound of the present invention can be given in the form of a prodrug. Prodrug refers to a derivative of the bioactive compound of the present invention that is converted into the compound under physiological conditions in vivo, for example, by oxidation, reduction, hydrolysis, etc. (each of which is carried out using an enzyme or without the participation of an enzyme). Examples of prodrugs are compounds wherein the amine group in the compound of the present invention is acylated, alkylated, or phosphorylated, such as eicosanoylamino, alanylamide, pivaloyloxymethylamino, or wherein the hydroxyl group is acylated, alkylated, phosphorylated, or converted into a borate, such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy, or wherein the carboxyl group is esterified or amidated, or wherein the sulfhydryl group is selectively delivered to the target and / or to the cytosol of the cell. The carrier molecule, such as a peptide, forms a disulfide bridge, and these compounds can be prepared by the compound of the present invention according to known methods.

[0165] "Pharmaceutically acceptable salts" or "pharmaceutically acceptable" refer to those made from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. In the case where the compounds of the present invention contain one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically acceptable salts. Therefore, the compounds of the present invention containing acidic groups can exist in salt form and can be used according to the present invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts. If the compounds of the present invention contain both acidic and basic groups in the molecule, the present invention also includes inner salts or betaines in addition to the mentioned salt forms. The respective salts are obtained by conventional methods known to those skilled in the art, for example by contacting these with organic or inorganic acids or bases in solvents or dispersants or by anion exchange or cation exchange with other salts.

[0166] Therefore, when referring to "compound", "compound of the present invention" or "compound of the present invention" in this application, all forms of the compound, such as prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, isomers, meso-racemates, racemates, enantiomers, diastereomers and mixtures thereof are included.

[0167] As used herein, the term "tumor" includes benign tumors and malignant tumors (eg, cancer).

[0168] As used herein, the term "cancer" includes, but is not limited to, brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumors, urothelial cancer, urethral cancer, bladder cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma.

[0169] As used herein, the term "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" refers to an amount of at least one agent or compound sufficient to relieve to some extent one or more symptoms of the disease or condition being treated after administration. The result can be a reduction and / or alleviation of signs, symptoms or causes of disease or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant relief of symptoms. Techniques such as dose escalation trials can be used to determine the effective amount appropriate for any individual case.

[0170] The term "polymorph" or "polymorphism" used in the present invention means that the compounds of the present invention have multiple crystal lattice forms. Some compounds of the present invention may have more than one crystal form. The present invention covers all multiple forms or mixtures thereof.

[0171] Intermediate compounds of the compounds of the present invention and their multiple forms are also within the scope of the present invention.

[0172] Crystallization often produces a solvate of the compound of the invention. The term "solvate" as used herein refers to an association of one or more molecules of the compound of the invention with one or more solvent molecules.

[0173] The solvent may be water, in which case the solvate is a hydrate. It may also be an organic solvent. Therefore, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, etc., and the corresponding solvated forms. The compounds of the present invention may be true solvates, but in other cases, the compounds of the present invention may also only accidentally retain water or a mixture of water and some other solvents. The compounds of the present invention may react in a solvent or precipitate or crystallize in a solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.

[0174] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0175] The term "pharmaceutically acceptable" as used herein refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to a subject without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.

[0176] "Pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, auxiliary agents, deodorants, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by relevant government administrative departments for use in humans and domesticated animals.

[0177] The terms "subject", "patient", "subject" or "individual" as used herein refer to individuals suffering from diseases, disorders or conditions, etc., including mammals and non-mammals, examples of mammals include but are not limited to any member of the class mammalia. Non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, etc. Examples of non-human mammals include but are not limited to birds and fish, etc. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0178] As used herein, the term "treatment" refers to the treatment of a relevant disease or condition in a mammal, especially a human, including the prevention of a mammal, especially a mammal that has been previously exposed to a disease or condition but has not yet been diagnosed with the disease or condition, from developing the corresponding disease or condition;

[0179] To inhibit a disease or condition, that is, to control its development; to relieve a disease or condition, that is, to slow down its regression;

[0180] As used herein, the terms "disease" and "disorder" may be used interchangeably or may have different meanings because certain specific diseases or disorders do not yet have a known causative agent (so the cause of the disease is still unclear), and therefore cannot be considered a disease but can only be viewed as an unwanted condition or syndrome, the syndrome of which more or less specific symptoms have been confirmed by clinical researchers.

[0181] The terms "administering", "administering", "administering", etc. used herein refer to methods that can deliver a compound or composition to the desired site for biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In a preferred embodiment, the compounds and compositions discussed herein are administered orally. DETAILED DESCRIPTION

[0182] The technical solution of the present invention can be further described by the following examples. However, those skilled in the art should understand that the protection scope of the present application is not limited to the following examples.

[0183] The compounds of the present invention can be synthesized by synthetic techniques known to those skilled in the art, or by combining methods known in the art with the methods of the present invention. The products obtained in each step are obtained by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc. The starting materials and chemical reagents required for the synthesis can be conventionally synthesized or purchased according to the literature.

[0184] Unless otherwise stated, temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Roche or MacLean and were used directly without further purification unless otherwise stated. Unless otherwise stated, the following reactions were performed at room temperature, in anhydrous solvents, under a positive pressure of nitrogen or gas, or using a drying tube; glassware was oven-dried and / or heated to dryness.

[0185] Unless otherwise specified, column chromatography purification used 100-200 mesh or 200-300 mesh silica gel from Qingdao Ocean Chemical Plant; preparative thin layer chromatography silica gel precast plates (HSGF254) produced by Yantai Institute of Chemical Industry were used for preparative thin layer chromatography, and MS was determined using a Therno LCD Fleet (ESI) liquid chromatography-mass spectrometer.

[0186] The nuclear magnetic resonance data (1H NMR) were obtained using a Bruker Avance-500MHz z NMR instrument. The solvents used for the nuclear magnetic resonance data included CDC13, CD3OD, D2O, DMS-d6, etc., with tetramethylsilane (0.000ppm) as the benchmark. When the peak shape diversity is indicated, the following abbreviations represent different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad peak), dd (double doublet), dt (double triplet). If the coupling constant is given, it is in Hz.

[0187] Example 1

[0188] (S)-8-Fluoro-5-((1-methylpyrrolidin-2-yl)methoxy)-2-(piperazin-1-yl)pyrimido[5,4-c]quinoline

[0189]

[0190] first step:

[0191] Diethyl malonate (24.0 g, 150 mmol), magnesium chloride (18.8 g, 200 mmol) and triethylamine (20.0 g, 200 mmol) were placed in acetonitrile (400 ml) and stirred for reaction for 2 hours.

[0192] Compound 1a (18.5 g, 100.0 mmol) was dissolved in thionyl chloride (100 ml), the temperature was raised to 80°C, the reaction was kept warm for 6 hours, the thionyl chloride was removed under reduced pressure, 100 ml of acetonitrile was added, the solvent was removed by rotary evaporation, and the above reaction system was added, the reaction was stirred at room temperature for 4 hours, and the reaction was monitored by TLC. After the reaction was completed, water (500 ml) was added to quench the reaction, and ethyl acetate (500 ml×2) was used for extraction. The organic layers were combined, dried, concentrated, and separated by column chromatography to obtain 25.3 g of an oily liquid with a yield of 77.4%.

[0193] Step 2:

[0194] Compound 1C (25.0 g, 76.5 mmol) and TsOH (15.8 g, 91.7 mmol) were dissolved in toluene (300 ml), and the temperature was raised to 100°C for reaction for 12 hours. The reaction was monitored by TLC. After the reaction was completed, water was added to quench the reaction. The toluene layer was concentrated and separated by column chromatography to obtain 17.7 g of an oily liquid with a yield of 90.7%.

[0195] Step 3:

[0196] Compound 1d (17.5 g, 68.6 mmol), DMF-DMA (12.3 g, 102.9 mmol) and acetic acid (2 ml) were dissolved in toluene (100 ml). The mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC. The raw material was basically consumed. Water was added to quench the reaction. The mixture was extracted with ethyl acetate (300 ml×2). The organic layers were combined, dried, concentrated and separated by column chromatography to obtain 16.2 g of an oily liquid with a yield of 76.2%.

[0197] Step 4

[0198] Compound 1e (16.0 g, 51.6 mmol), 1f (12.4 g, 61.9 mmol) and potassium carbonate (10.7 g, 77.4 mmol) were dissolved in ethanol (100 ml), and the mixture was refluxed at elevated temperature for 8 hours. The reaction was monitored by TLC, and the raw materials were basically consumed. The solvent was removed under reduced pressure, 100 ml of water was added, stirred, filtered, and the filter cake was dried to obtain 15.0 g of a light yellow solid with a yield of 65.0%.

[0199] Step 5:

[0200] The above-obtained compound 1g (15.0g, 33.6mmol), iron powder (18.8g, 336mmol), and ammonium chloride (17.8g, 336mmol) were dissolved in ethanol (400ml) and water (200ml), and the temperature was raised to 80°C and stirred for reaction for 8 hours. The reaction was monitored by TLC. After the reaction was completed, 200ml of water was added, and the mixture was extracted with ethyl acetate (300mlX6). The organic layers were combined, dried, and concentrated to obtain 8.5g of a gray solid (used directly in the next step without purification), with a yield of 68.2%.

[0201] Step 6:

[0202] Compound 1h (3.7 g, 10 mmol) was placed in phosphorus oxychloride (30 ml), the temperature was raised to 100°C, and the reaction was stirred until the solution became clear. The reaction was monitored by TLC. After completion, the phosphorus oxychloride was removed under reduced pressure, 20 ml of acetonitrile was added, and the solvent was removed under reduced pressure. Precooled sodium bicarbonate solution was added under stirring, and the solid was washed out. The solid was filtered and dried to obtain 2.8 g of a light yellow solid with a yield of 72.0%.

[0203] Step 7:

[0204] Compound 1i (2.8 g, 7.2 mmol), SN-methylprolinol (993 mg, 8.6 mmol), and sodium tert-butoxide (688 mg, 8.6 mmol) were dissolved in dioxane (30 ml), and the temperature was raised to 100° C. The reaction was kept warm for 12 hours and monitored by TLC. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 ml×2). The organic layers were combined, dried, concentrated, and separated by column chromatography to obtain 1.6 g of an off-white solid with a yield of 47.5%.

[0205] Step 8:

[0206] Compound 1j (1.6 g, 3.4 mmol) and potassium hydroxide (1.1 g, 20.5 mmol) were dissolved in n-butanol (20 ml) and water (2 ml), and the temperature was raised to 105°C. The mixture was kept warm for 12 hours. The reaction was monitored by TLC. Water (50 ml) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 ml x 2). The organic layer was dried and concentrated by column chromatography to obtain 412 mg of an off-white solid with a yield of 30.6%. 1 H NMR (500MHz, DMSO-d6) δ9.22 (s, 1H), 8.70 (dd, J=8.9, 6.5Hz, 1H), 7.45 (dd, J= 10.5,2.7Hz,1H),7.37(td,J=8.9,2.7Hz,1H),5.44~5.20(m,1H),4.32~4.20( m,2H),4.06(br,4H),3.22~3.04(m,3H),2.98(br,4H),2.90~2.83(m,2H),2.2 6–1.99(m,5H),1.89~1.77(m,5H),1.74~1.67(m,2H), ESI(+)m / z=397.2[M+1].

[0207] Example 2

[0208] 8-Chloro-5-((1-methylpyrrolidin-2-yl)methoxy)-2-(piperazin-1-yl)pyrimido[5,4-c]quinoline

[0209]

[0210] Referring to Example 1, the starting material 4-chloro-2-nitrobenzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid to obtain: 1H NMR (500MHz, DMSO-d6) δ9.20 (s, 1H), 8.63 (d, J = 8.6Hz, 1H), 7.73 (d, J = 2.1Hz, 1H), 7.52 (dd, J = 8.6, 2.1Hz, 1H), 4.48 (d, J = 5.4Hz, 2H), 4.00~3 .97(m,4H),3.00~2.97(m,1H),2.86(br,4H),2.73~2.71(m,1H),2.42( s,3H),2.26~2.21(m,1H),2.05~1.98(m,1H),1.73~1.70(m,3H),ESI(+)

[0211] m / z = 413.2 [M+1].

[0212] Example 3

[0213] 8-Bromo-5-((1-methylpyrrolidin-2-yl)methoxy)-2-(piperazin-1-yl)pyrimido[5,4-c]quinoline

[0214]

[0215] Referring to Example 1, the starting material 4-bromo-2-nitrobenzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid to obtain: 1 H NMR(500MHz, DMSO-d6)δ9.26(s,1H),8.61(d,J=8.6Hz,1H),7.72(d,J=2.1Hz,1H),7.52(dd,J=8.6,2.1Hz,1H),4.49(d,J=5.4Hz,2H),4.00~3.97(m,4H ),3.00~2.98(m,1H),2.88(br,4H),2.74~2.72(m,1H),2.42(s,3H),2.26~2 .21(m,1H), 2.05~1.98(m,1H), 1.73~1.70(m,3H), ESI(+)m / z=457.1[M+1].

[0216] Example 4

[0217] 8-Trifluoromethyl-5-((1-methylpyrrolidin-2-yl)methoxy)-2-(piperazin-1-yl)pyrimido[5,4-c]quinoline

[0218]

[0219] Referring to Example 1, the starting material 4-trifluoromethyl-2-nitrobenzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid to obtain: 1H NMR (500MHz, DMSO-d6) δ9.37(s,1H),8.87(d,J=8.5Hz,1H),8.02(d,J=1.9Hz,1H),7.81(dd,J=8.5,1.9Hz,1H),4.61(d,J=5.3Hz,2H),4.22~4.18(m,4 H),3.82~3.78(m,1H),3.17(br,4H),3.07~3.04(m,1H),2.54(s,3H)2.37~2 .33(m,1H), 2.14~2.08(m,1H), 1.84~1.78(m,3H), ESI(+)m / z=447.2[M+1].

[0220] Example 5

[0221] 8-Methoxy-5-((1-methylpyrrolidin-2-yl)methoxy)-2-(piperazin-1-yl)pyrimido[5,4-c]quinoline

[0222]

[0223] Referring to Example 1, the starting material 4-methoxy-2-nitrobenzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid to obtain: 1 H NMR(500MHz,DMSO-d6)δ9.06(s,1H),8.44(d,J=8.8Hz,1H),7.07(d,J=2.5Hz,1 H),7.01(dd,J=8.8,2.5Hz,1H),4.39(d,J=5.4Hz,2H),3.99~3.86(m,4H),3.84( s,3H),2.93~2.90(m,1H),2.79~2.77(m,4H),2.67~2.62(m,1H),2.35(s,3H),2. 20~2.14(m,1H), 2.01~1.88(m,1H), 1.66~1.63(m,3H), ESI(+)m / z=409.2[M+1].

[0224] Example 6

[0225] 7-Fluoro-5-((1-methylpyrrolidin-2-yl)methoxy)-2-(piperazin-1-yl)pyrimido[5,4-c]quinoline

[0226]

[0227] Referring to Example 1, the starting material 3-fluoro-2-nitrobenzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid to obtain: 1H NMR(500MHz, DMSO-d6)δ9.29(s,1H),8.49~8.47(m,1H),7.66~7.61(m,1H),7.50~7.46(m,1H),4.55(d,J=5.2H z,2H),4.24~4.05(m,4H),3.59~3.64(m,1H),3.09~3.04(m,4H),2.88~2.86(m,1H),2.37(s,3H),2.26~2.24(m 1H), 2.07~2.04(m,1H), 1.78~1.75(m,3H), ESI(+)m / z=397.2[M+1].

[0228] Example 7

[0229] 7-Methoxy-5-((1-methylpyrrolidin-2-yl)methoxy)-2-(piperazin-1-yl)pyrimido[5,4-c]quinoline

[0230]

[0231] Referring to Example 1, the starting material 3-methoxy-2-nitrobenzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid to obtain: 1 H NMR (500MHz, DMSO-d6) δ9.21 (s, 1H), 8.22 (dd, J = 7.9, 1.3Hz, 1H), 7.41 (t, J = 7. 9Hz,1H),7.31(dd,J=7.9,1.3Hz,1H),4.48(d,J=5.3Hz,2H),3.97(br,4H),3.9 4(s,3H),3.02~2.98(m,1H),2.86(br,4H),2.76~2.73(m,1H),2.44(s,3H),2.2 7~2.22(m,1H), 2.04~1.98(m,1H), 1.75~1.70(m,3H), ESI(+)m / z=409.2[M+1].

[0232] Example 8

[0233] 5-((1-methylpyrrolidin-2-yl)methoxy)-2-(piperazin-1-yl)-[1,3]dioxolo[4,5-g]pyrimido[5,4-c]quinoline

[0234]

[0235] Referring to Example 1, the starting material 6-nitrobenzo[d][1,3]dioxolane-5-carboxylic acid was substituted for 4-fluoro-2-nitrobenzoic acid to obtain: 1H NMR(500MHz,DMSO-d6)δ9.07(s,1H),7.87(s,1H),7.07(s,1H),6.12(s,2H),4.35(d,J=5.4Hz,2H),3.88(br,4H),2.93~2.90(m,1H),2 .80~2.78(m,4H),2.64~2.61((m,1H),2.35(s,3H),2.18~2.14(m,1H),1.96~1.92(m,1H),1.68~1.63(m,3H), ESI(+)m / z=423.2[M+1].

[0236] Example 9

[0237] N,N-Dimethyl-5-((1-methylpyrrolidin-2-yl)methoxy)-2-(piperazin-1-yl)pyrimido[5,4-c]quinoline-8-carboxamide

[0238]

[0239] Referring to Example 1, the starting material 4-(dimethylaminocarbonyl)-2-nitrobenzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid to obtain: 1 H NMR(500MHz,DMSO-d6)δ9.20(s,1H),8.66(d,J=8.2Hz,1H),7.64(d,J=1.6Hz,1H ),7.47(dd,J=8.2,1.6Hz,1H),4.48(d,J=5.3Hz,2H),4.01(br,4H),3.04(s,3H), 3.01~2.98(m,1H),2.95(s,3H),2.92(br,4H),2.75~2.72(m,1H),2.43(s,3H),2 .28~2.23(m,1H), 2.04~2.00(m,1H), 1.75~1.70(m,3H), ESI(+)m / z=450.2[M+1].

[0240] Example 10

[0241] 8-Methylsulfonyl-5-((1-methylpyrrolidin-2-yl)methoxy)-2-(piperazin-1-yl)pyrimido[5,4-c]quinoline

[0242]

[0243] Referring to Example 1, the starting material 4-(methylsulfonyl)-2-nitrobenzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid to obtain: 1H NMR(500MHz,DMSO-d6)δ9.25(s,1H),8.84(d,J=8.5Hz,1H),8.18(d,J=1.9Hz, 1H),7.94(dd,J=8.5,1.9Hz,1H),4.51(d,J=5.4Hz,2H),4.05~3.90(m,4H),3.3 5(s,3H),3.00~2.97(m,1H),2.83(br,4H),2.75~2.70(m,1H),2.42(s,3H),2.2 6~2.21(m,1H), 2.06~2.01(m,1H), 1.74~1.71(m,3H), ESI(+)m / z=457.2[M+1].

[0244] Embodiment 11

[0245] 9-Fluoro-5-((1-methylpyrrolidin-2-yl)methoxy)-2-(piperazin-1-yl)pyrimido[5,4-c]quinoline

[0246]

[0247] Referring to Example 1, the starting material 5-fluoro-2-nitrobenzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid to obtain: 1 H NMR (500MHz, DMSO-d6) δ9.15 (s, 1H), 8.22 (dd, J = 9.0, 5.0 Hz, 1H), 7.70 (dd, J =8.0,2.7Hz,1H),7.61(td,J=8.2,2.7Hz,1H),4.43(d,J=5.5Hz,2H),3.92(br ,4H),3.00~2.96(m,1H),2.82(br,4H),2.72~2.65(m,1H),2.41(s,3H),2.26 ~2.19(m,1H), 2.06~1.97(m,1H), 1.79~1.70(m,3H), ESI(+)m / z=397.2[M+1].

[0248] Example 12

[0249] 9-Chloro-5-((1-methylpyrrolidin-2-yl)methoxy)-2-(piperazin-1-yl)pyrimido[5,4-c]quinoline

[0250]

[0251] Referring to Example 1, the starting material 5-chloro-2-nitrobenzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid to obtain: 1H NMR(500MHz,DMSO-d6)δ9.18(s,1H),8.53(d,J=2.0Hz,1H),7.75(dd,J=8.7,2.0Hz,1H),7.69(d,J=8.7Hz,1H),4.45(d,J=5.4Hz,2H),3.94(br,4H), 3.00~2.96(m,1H),2.82(br,4H),2.72~2.67(m,1H),2.41(s,3H),2.24~2. 20(m,1H), 2.06~1.98(m,1H), 1.75~1.67(m,3H), ESI(+)m / z=413.2[M+1].

[0252] Example 13

[0253] 9-Methoxy-5-((1-methylpyrrolidin-2-yl)methoxy)-2-(piperazin-1-yl)pyrimido[5,4-c]quinoline

[0254]

[0255] Referring to Example 1, the starting material 5-methoxy 2-nitrobenzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid to obtain: 1 H NMR(500MHz,DMSO-d6)δ9.17(s,1H),8.00(d,J=3.0Hz,1H),7.63(d,J=8.9Hz,1H ),7.37(dd,J=8.9,3.0Hz,1H),4.42(dd,J=5.5,1.4Hz,2H),3.96(br,4H),3.91( s,3H),3.00~2.97(m,1H),2.93~2.75(m,4H),2.71~2.68(m,1H),2.42(s,3H),2. 26~2.18(m,1H), 2.06~1.98(m,1H), 1.76~1.65(m,3H), ESI(+)m / z=409.2[M+1].

[0256] Embodiment 14

[0257] 8-(Pyrrolidin-1-yl)-5-((1-methylpyrrolidin-2-yl)methoxy)-2-(piperazin-1-yl)pyrimido[5,4-c]quinoline

[0258]

[0259] Referring to Example 1, the starting material 2-nitro-4-(pyrrolidin-1-yl)benzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid to obtain: 1H NMR(500MHz,DMSO-d6)δ8.99(s,1H),8.36(d,J=8.8Hz,1H),6.78(dd,J=8.8,2.4 Hz,1H),6.61(d,J=2.4Hz,1H),4.41(d,J=5.5Hz,2H),3.92(br,4H),3.40~3.37( m,4H),3.00~2.96(m,1H),2.83–2.80(m,4H),2.70~2.66(m,1H),2.41(s,3H),2. 24~2.20(m,1H), 2.02~1.99(m,5H), 1.75~1.68(m,3H), ESI(+)m / z=448.2[M+1].

[0260] Embodiment 15

[0261] 8-Fluoro-9-dimethylamino-5-((1-methylpyrrolidin-2-yl)methoxy)-2-(piperazin-1-yl)pyrimido[5,4-c]quinoline

[0262]

[0263] Referring to Example 1, the starting material 5-(dimethylamino)-4-fluoro-2-nitrobenzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid to obtain: 1 H NMR (500MHz, DMSO-d) δ9.16 (s, 1H), 8.05 (d, J = 8.0Hz, 1H), 7.40 (d, J = 4.9Hz, 1H), 4.42 (d, J = 5.5Hz, 2H), 3.92 (br, 4H), 3.03 (s, 6H), 3.00~2. 96(m,1H),2.82(br,4H),2.72~2.65(m,1H),2.41(s,3H),2.26~2.19(m,1H),2.06~1.97(m,1H),1.79~1.70(m,3H), ESI(+)m / z=440.2[M+1].

[0264] Example 16

[0265] 8-Fluoro-9-(pyrrolidin-1-yl)-5-((1-methylpyrrolidin-2-yl)methoxy)-2-(piperazin-1-yl)pyrimido[5,4-c]quinoline

[0266]

[0267] Referring to Example 1, the starting material 4-fluoro-2-nitro-5-(pyrrolidin-1-yl)benzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid to obtain: 1H NMR(500MHz,DMSO-d6)δ9.13(s,1H),7.75(d,J=9.9Hz,1H),7.36(d,J=14.8Hz,1H),4.39(dd,J=5.6,1.5Hz,2H),3.91(br,4H),2.99~2.96(m,1H),2.8 2~2.80(m,4H),2.70~2.65(m,1H),2.41(s,3H),2.25~2.19(m,1H),2.10~1 .89(m,6H),1.87~1.83(m,3H),1.75~1.64(m,3H), ESI(+)m / z=466.2[M+1].

[0268] Embodiment 17

[0269] 8-Bromo-9-dimethylamino-5-((1-methylpyrrolidin-2-yl)methoxy)-2-(piperazin-1-yl)pyrimido[5,4-c]quinoline

[0270]

[0271] Referring to Example 1, the starting material 5-(dimethylamino)-4-bromo-2-nitrobenzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid to obtain: 1 H NMR (500MHz, DMSO-d6) δ9.18 (s, 1H), 8.25 (s, 1H), 7.91 (s, 1H), 4.44 (d, J = 5.5Hz, 2H), 4.05~3.92 (m, 4H), 3.01~ 2.97(m,1H),2.90(br,4H),2.72~2.70(m,1H),2.42(s,3H),2.27~2.22(m,1H),2.05~1.98(m,1H),1.74~1.68(m 3H), ESI(+)m / z=500.2[M+1].

[0272] Embodiment 18

[0273] 8-Fluoro-9-methoxy-5-((1-methylpyrrolidin-2-yl)methoxy)-2-(piperazin-1-yl)pyrimido[5,4-c]quinoline

[0274]

[0275] Referring to Example 1, the starting material 4-fluoro-5-methoxy-2-nitrobenzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid to obtain: 1H NMR (500MHz, DMSO-d6) δ9.11 (s, 1H), 8.03 (d, J = 9.4Hz, 1H), 7.43 (d, J = 12.3 Hz,1H),4.38(d,J=5.6Hz,2H),3.98(s,3H),3.96~3.90(m,4H),2.99~2.97(m ,1H),2.88~2.79(m,4H),2.67(dd,J=8.5,5.6Hz,1H),2.42(s,3H),2.23(q,J =8.5Hz,1H),2.09~1.96(m,1H),1.81~1.61(m,3H), ESI(+)m / z=427.2[M+1].

[0276] Embodiment 19

[0277] 8,9-Difluoro-5-((1-methylpyrrolidin-2-yl)methoxy)-2-(piperazin-1-yl)pyrimido[5,4-c]quinoline

[0278]

[0279] Referring to Example 1, the starting material 4,5-difluoro-2-nitrobenzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid to obtain: 1 H NMR(500MHz,DMSO-d6)δ9.20(s,1H),8.50(dd,J=11.1,9.1Hz,1H),7.70(dd,J=11.1,7.4Hz,1H),4.45(d,J=5.2Hz,2H),3.96(br,4H),3.00~2 .97(m,1H),2.86(br,4H),2.72~2.69(m,1H),2.42(s,3H),2.25~2.21( m,1H), 2.04~2.01(m,1H), 1.74~1.68(m,3H), ESI(+)m / z=415.2[M+1].

[0280] Embodiment 20

[0281] 8-Chloro-9-fluoro-5-((1-methylpyrrolidin-2-yl)methoxy)-2-(piperazin-1-yl)pyrimido[5,4-c]quinoline

[0282]

[0283] Referring to Example 1, the starting material 4-chloro-5-fluoro-2-nitrobenzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid to obtain: 1H NMR (500MHz, DMSO-d6) δ9.19(s,1H),8.44(d,J=9.6Hz,1H),7.89(d,J=6.9Hz,1H),4.45(d,J=5.4Hz,2H),4.00~3.95(m,4H),3.01~2.97( m,1H),2.85(br,4H),2.73~2.69(m,1H),2.42(s,3H),2.26~2.21(m,1H),2.05~2.00(m,1H),1.76~1.68(m,3H), ESI(+)m / z=431.2[M+1].

[0284] Embodiment 21

[0285] 8-Chloro-9-fluoro-5-((1-methylpyrrolidin-2-yl)methoxy)-2-(piperazin-1-yl)pyrimido[5,4-c]quinoline

[0286]

[0287] Referring to Example 1, the starting material 4-bromo-5-fluoro-2-nitrobenzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid to obtain: 1 H NMR(500MHz,DMSO-d6)δ9.27(s,1H),8.16(d,J=8.7Hz,1H),7.74(d,J=10.0Hz,1H),4.51(s,2H),4.10(br,4H),3.17~3.14(m,1H) ,3.04(br,4H),2.84~2.81(m,1H),2.47(s,3H),2.40~2.26(m,1H),2.02~1.98(m,1H),1.79~1.70(m,3H), ESI(+)m / z=475.1[M+1].

[0288] Embodiment 22

[0289] 7,9-Difluoro-5-((1-methylpyrrolidin-2-yl)methoxy)-2-(piperazin-1-yl)pyrimido[5,4-c]quinoline

[0290]

[0291] Referring to Example 1, the starting material 3.5-difluoro-2-nitrobenzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid to obtain: 1H NMR (500MHz, DMSO-d6) δ9.07(s,1H),8.23~8.18(m,1H),7.88~7.87(m,1H),4.39(d,J=5.5Hz,2H),3.92(br,4H),3.00~2.97(m 1H), 2.82(br,4H), 2.70~2.66(m,1H), 2.42(s,3H), 2.25~2.21(m,1H), 2.04~2.00(m,1H), 1.74~1.70(m,3H), ESI(+)m / z=415.2[M+1].

[0292] Embodiment 23

[0293] 2-((S)-2-methylpiperazin-1-yl)-5-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimido[5,4-c]quinoline

[0294]

[0295] Referring to Example 1, the starting material 2-nitrobenzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid, and (S)-4-amidino-3-methylpiperazine-1-carboxylic acid ethyl ester was substituted for 4-amidinopiperazine-1-carboxylic acid ethyl ester to obtain, 1 H NMR(500MHz,DMSO-d6)δ9.46(s,1H),8.71(dd,J=8.0,1.5Hz,1H),7.86~7.82(m,1H), 7.76(dd,J=8.4,1.2Hz,1H),7.60~7.53(m,1H),4.85~4.73(m,2H),3.77~3.72(m,1H) ,3.53(br,2H),3.47~3.47(m,4H),3.29~3.26(m,1H),3.14~3.02(m,1H),2.91(s,3H) ,2.31~2.26(m,1H),2.14~1.92(m,4H),1.40(d,J=7.1Hz,3H)ESI(+)m / z=393.2[M+1].

[0296] Embodiment 24

[0297] 5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-((S)-2-methylpiperazin-1-yl)pyrimido[5,4-c]quinoline

[0298]

[0299] Referring to Example 1, the starting material 2-nitrobenzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid.

[0300] (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizine-7-yl]methanol replaces (S)-(1-methylpyrrolidin-2-yl)methanol, and (S)-4-amidino-3-methylpiperazine-1-carboxylic acid ethyl ester replaces 4-amidinopiperazine-1-carboxylic acid ethyl ester to obtain the obtained product. 1 HNMR(500MHz, DMSO-d6)9.18(s,1H),8.48(dd,J=8.1,1.5Hz,1H),7.75~7.60(m,1H),7.34(d ,J=8.1Hz,1H),7.29(d,J=7.6Hz,1H),5.36~5.11(m,1H),4.38(d,J=5.4Hz,2H),3.77~3.72( m,1H),3.53(br,2H),3.47~3.47(m,4H),3.21~3.02(m,4H),2.91~2.82(m,2H),2.26~1.99(m ,1H),1.82~1.76(m,2H),1.74~1.66(m,1H),1.40(d,J=7.1Hz,3H), ESI(+)m / z=437.2[M+1].

[0301] Embodiment 25

[0302] 8-Fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrazol-7a(5H)-yl)methoxy)-2-(piperazin-1-yl)pyrimido[5,4-c]quinoline

[0303]

[0304] Referring to Example 1, the starting material (2R, 8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizine-7-yl]methanol was substituted for (S)-(1-methylpyrrolidin-2-yl)methanol to synthesize, 1 H NMR (500MHz, DMSO-d6) δ9.22 (s, 1H), 8.70 (dd, J=8.9, 6.5Hz, 1H), 7.45 (dd, J= 10.5,2.7Hz,1H),7.37(td,J=8.9,2.7Hz,1H),5.44~5.20(m,1H),4.32~4.20( m,2H),4.06(br,4H),3.22~3.04(m,4H),2.98(br,4H),2.90~2.83(m,1H),2.2 4~1.99(m,2H), 1.89~1.77(m,2H), 1.74~1.67(m,1H), ESI(+)m / z=441.2[M+1].

[0305] Embodiment 26

[0306] 9-Fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrazol-7a(5H)-yl)methoxy)-2-(piperazin-1-yl)pyrimido[5,4-c]quinoline

[0307]

[0308] Referring to Example 1, the starting material 5-fluoro-2-nitrobenzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid.

[0309] (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizine-7-yl]methanol was substituted for (S)-(1-methylpyrrolidin-2-yl)methanol to synthesize. 1 H NMR(500MHz, DMSO-d6)δ9.17(s,1H),8.00(d,J=3.0Hz,1H),7.63(d,J=8.9Hz,1H),7.37(dd,J=8.9,3.0Hz,1H),5.46~5.21(m,1H),4.31~4.21(m,2H), 4.08(br,4H),3.21~3.02(m,4H),2.96(br,4H),2.91~2.82(m,2H),2.26~1 .99(m,1H),1.82~1.76(m,2H),1.74~1.66(m,1H), ESI(+)m / z=441.2[M+1].

[0310] Embodiment 27

[0311] (S)-8-Chloro-9-hydroxy-5-((1-methylpyrrolidin-2-yl)methoxy)-2-(piperazin-1-yl)pyrimido[5,4-c]quinoline

[0312]

[0313] Referring to Example 1, the starting material 4-fluoro-5-hydroxy-2-nitrobenzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid to obtain, 1H NMR (500MHz, DMSO-d6) δ9.11(s,1H),8.21(d,J=11.6Hz,1H),7.70(d,J=10.2Hz,1H),7.30(br,1H),4.43(s,2H),3.94(br,4H),3.00~2.97(m ,1H),2.85~2.84(m,4H),2.72~2.67(m,1H),2.42(s,3H),2.26~2.21( m,1H), 2.05~1.98(m,1H), 1.74~1.65(m,3H), ESI(+)m / z=413.2[M+1].

[0314] Embodiment 28

[0315] (S)-5-(((9-chloro-2-(piperazin-1-yl)pyrimido[5,4-c]quinolin-5-yl)oxy)methyl)-1-methylpyrrol-2-one

[0316]

[0317] Referring to Example 1, the starting material 5-chloro-2-nitrobenzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid.

[0318] (S)-5-(Hydroxymethyl)-1-methylpyrrol-2-one was synthesized by replacing (S)-(1-methylpyrrolidin-2-yl)methanol. 1 H NMR (500MHz, DMSO-d6) δ9.12(s,1H),8.49(d,J=2.1Hz,1H),7.75(dd,J=8.7,2.1Hz,1H),7.68(d,J=8.7Hz,1H),4.79~4.49(m,2H),3.95( br,4H),3.31~3.26(m,1H),2.86(br,4H),2.82(s,3H),2.42~2.36(m,1H),2.27~2.20(m,2H),2.00~1.93(m,1H), ESI(+)m / z=427.2[M+1].

[0319] Embodiment 29

[0320] (3R,5S)-5-(((9-chloro-2-(piperazin-1-yl)pyrimido[5,4-c]quinolin-5-yl)oxy)methyl)-1-methylpyrrol-3-ol

[0321]

[0322] Referring to Example 1, the starting material 5-chloro-2-nitrobenzoic acid was substituted for 4-fluoro-2-nitrobenzoic acid.

[0323] (3R,5S)-5-(Hydroxymethyl)-1-methylpyrrol-3-ol was synthesized by replacing (S)-(1-methylpyrrolidin-2-yl)methanol. 1 H NMR(500MHz,DMSO-d6)δ9.17(s,1H),8.52(d,J=2.6Hz,1H),7.73(dd,J=8.7,2.6Hz ,1H),7.68(d,J=8.7Hz,1H),4.50~4.38(m,2H),4.24~4.18(m,1H),3.95(br,4H),3 .22(dd,J=9.4,6.0Hz,2H),2.96~2.92(m,1H),2.85(br,4H),2.41(s,3H),2.35~2. 27(m,1H), 2.17(dd,J=9.4,6.0Hz,1H), 1.87~1.82(m,1H), ESI(+)m / z=429.2[M+1].

[0324] Embodiment 30

[0325] (R)-N-((1-ethylpyrrolidin-2-yl)methyl)-8-fluoro-2-(piperazin-1-yl)pyrimido[5,4-c]quinolin-5-amine

[0326]

[0327] Referring to Example 1, the starting material (R)-(1-ethylpyrrolidin-2-yl)methylamine was substituted for (S)-(1-methylpyrrolidin-2-yl)methanol to obtain: 1 H NMR(500MHz,DMSO-d6)δ9.46(s,1H),8.52(dd,J=8.9,6.8Hz,1H),8.08(br,1H),7.10(dd, J=11.1,2.6Hz,1H),7.05(td,J=8.9,2.6Hz,1H),3.99~3.94(m,4H),3.42~3.34(m,2H),3. 18~3.13(m,1H),3.04~3.00(m,2H),2.90~2.87(m,4H),2.55~2.52(m,1H),2.39~2.29(m,1 H), 1.89~1.85(m,1H), 1.76~1.69(m,3H), 1.15(d,J=7.1Hz,3H), ESI(+)m / z=410.2[M+1].

[0328] Embodiment 31

[0329] (R)-N-((1-ethylpyrrolidin-2-yl)methyl)-8-fluoro-N-methyl-2-(piperazin-1-yl)pyrimido[5,4-c]quinolin-5-amine

[0330]

[0331] Referring to Example 1, the starting material (R)-1-(1-ethylpyrrolidin-2-yl)-N-methylmethylamine was substituted for (S)-(1-methylpyrrolidin-2-yl)methanol to obtain: 1 H NMR(500MHz,DMSO-d6)δ9.46(s,1H),8.52(dd,J=8.9,6.8Hz,1H),.10(dd,J=11.1,2.6Hz ,1H),7.05(td,J=8.9,2.6Hz,1H),3.99~3.94(m,4H),3.42~3.34(m,2H),3.21(s,3H),3.1 8~3.13(m,1H),3.04~3.00(m,2H),2.90~2.87(m,4H),2.55~2.52(m,1H),2.39~2.30(m,1 H), 1.89~1.85(m,1H), 1.76~1.70(m,3H), 1.15(d,J=7.1Hz,3H), ESI(+)m / z=424.2[M+1].

[0332] Example 32 Biological Activity Test

[0333] Tumor cell proliferation inhibition assay (PANC-1)

[0334] Adherent cell test method: prepare complete culture medium (RPMI-1640 + 10% FBS + 1% P / S) to resuscitate PANC-1 cells (Hefei Puruisheng), pass about two generations, digest with 0.25% trypsin, collect cells in logarithmic growth phase by centrifugation and count, resuspend the cells to an appropriate concentration, inoculate the cell suspension in a 96-well plate, add 100 μL of cell suspension to each well, the plate density is 3000 cells / well, and culture in a 37°C, 5% carbon dioxide incubator overnight. After overnight, remove 50 μL of supernatant and add 45 μL of fresh culture medium. Prepare the test compound into storage solution with DMSO, and dilute it step by step with DMSO at 10 mM as the highest concentration to obtain 7 concentration gradients. Dilute the test compound 50 times with culture medium, take 5 μL and add it to 96-well cell plate containing 95 μL of cell solution, add culture medium without cells (containing 0.1% DMSO) to Min control well, add 5 μL DMSO-cell culture medium mixture (DMSO final concentration is 0.1%) to Max control, and incubate in 37°C, 5% carbon dioxide incubator for 72h. Add 50 μL / well CellTiter Glo to end the reaction, incubate at room temperature in the dark for 30 minutes, shake gently and detect in Envision. Read the fluorescence value RLU of each well, and calculate the cell growth inhibition rate % according to the formula = 100-(RLU Drug -RLU Min ) / (RLU Max -RLU Min )*100% to calculate the inhibition rate. Input the inhibition rate Inh% (Y) corresponding to each concentration (X) in Graphpadprism 7.0, and use the software to calculate the maximum inhibition rate, minimum inhibition rate and half inhibition concentration IC of each compound according to the built-in four-parameter fitting formula. 50 value.

[0335] Tumor cell proliferation inhibition assay (GP2D)

[0336] Adherent cell test method: prepare complete culture medium (DMEM + 10% FBS + 1% P / S) to resuscitate GP2D cells (Hefei Puruisheng), pass about two generations, digest with 0.25% trypsin, collect cells in logarithmic growth phase by centrifugation and count, resuspend the cells to an appropriate concentration, inoculate the cell suspension in a 96-well plate, add 100 μL of cell suspension to each well, the plate density is 5000 cells / well, and culture overnight in a 37°C, 5% carbon dioxide incubator. After overnight, remove 50 μL of supernatant and add 40 μL of fresh culture medium. Prepare the test compound into storage solution with DMSO, and gradually dilute it 3 times with DMSO with 0.25 mM as the highest concentration to obtain 7 concentration gradients; dilute the test compound 25 times with culture medium, take 10 μL and add it to 96-well cell plates containing 90 μL of cell solution, add culture medium without cells (containing 0.4% DMSO) to the Min control well, add 10 μL DMSO-cell culture medium mixture (DMSO final concentration is 0.4%) to the Max control, and incubate in a 37°C, 5% carbon dioxide incubator for 72 hours. Add 50 μL / well CellTiter Glo to end the reaction, incubate at room temperature in the dark for 30 minutes, and detect it in Envision after gentle shaking. Read the fluorescence value RLU of each well, and according to the formula, cell growth inhibition rate % = 100-(RLU Drug -RLU Min ) / (RLU Max -RLU Min )*100% to calculate the inhibition rate. Input the inhibition rate Inh% (Y) corresponding to each concentration (X) in Graphpadprism 7.0, and use the software to calculate the maximum inhibition rate, minimum inhibition rate and half inhibition concentration IC of each compound according to the built-in four-parameter fitting formula. 50 value.

[0337] Tumor cell proliferation inhibition experiment (HCT116, HepG2, MDA-MB-231, A549)

[0338] The sample concentration was prepared into 10 different concentration gradients for later use;

[0339] HCT116 (HepG2, MDA-MB-231, A549) (90% DMEM + 10% FBS + 1% PS) cells were seeded in a 96-well plate (90ul / well, 5000 cells / well) and cultured overnight at 37°C and 5% CO2. After adding 10ul of drug to each well, the cells were placed in an incubator and incubated for 72 hours. CCK-8 detection: Take out the cells from the incubator and observe the status of each group of cells under a microscope. Then add 10ul of cck-8 to each well, shake gently, and incubate in the incubator for about 1 hour. Observe that the color of the solution changes to orange-yellow and take it out. Use an enzyme reader to detect the OD value at 450nm, and calculate the IC value of the compound.50 value.

[0340] The test results of the compounds of the present invention are summarized in the following table:

[0341]

[0342] From the above experimental results, it can be seen that some compounds of the present invention have good proliferation inhibitory activity on PANC-1, GP2D, HCT116, HepG2, MDA-MB-231, and A549 cells. The inhibitory activity of compound 3, compound 6, and compound 22 on PANC1 cells is less than 10 nM, and their inhibitory activity on GP2D, HCT116, and MDA-MB-231 cells is around 100 nM, showing strong anti-tumor inhibitory activity.

[0343] The above is a description of the exemplary embodiments of the present invention. However, the protection scope of the present application is not limited to the above embodiments. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present invention shall be included in the protection scope of the claims of the present application.

Claims

1. A compound having a structure as shown in Formula I or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug thereof: in, Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; X is selected from -O-, -S- and -NR 8 -; Each R 1 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an oxo group (═O), a thio group (═S), unsubstituted or optionally substituted with 1, 2 or more R a Substituted groups: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, cycloalkynyloxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, cycloalkenylthio, cycloalkynylthio, -NR 17 R 18 ; Each R 2 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, unsubstituted or optionally substituted with 1, 2 or more R b Substituted alkyl; Each R 3 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, a nitro group, an oxo group (═O), a thio group (═S), unsubstituted or optionally substituted with 1, 2 or more R c Substituted groups: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, cycloalkynyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, cycloalkenylthio, cycloalkynylthio, heterocyclylthio, arylthio, heteroarylthio, -NR 17 R 18 ; R 4 , R 5 , R 5 and R 6 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, unsubstituted or optionally substituted with 1, 2 or more R d Substituted groups: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, cycloalkynyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, cycloalkenylthio, cycloalkynylthio, heterocyclylthio, arylthio, heteroarylthio, -NR 17 R 18 、-C(O)R 9 、-C(O)OR 10 、-OC(O)R 11 、-S(O)2R 12 、-S(O)2OR 13 、-OS(O)2R 14 、-P(O)(OR 15 )(OR 16 ); Or, R 4 , R 5 , R 5 and R 6 The adjacent substituents in the d Substituted from the following groups: cycloalkenyl, heterocyclyl, aryl or heteroaryl; R 8 is selected from a hydrogen atom, a deuterium atom, unsubstituted or optionally substituted with 1, 2 or more R e Substituted: alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Each R a , R b , R c , R d and R e are the same or different and are each independently selected from a deuterium atom, a halogen, a cyano group, a hydroxyl group, a nitro group, an oxo group (═O), a thio group (═S), unsubstituted or optionally substituted with 1, 2 or more R f Substituted groups: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, cycloalkynyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, cycloalkenylthio, cycloalkynylthio, heterocyclylthio, arylthio, heteroarylthio, -NR 17 R 18 、-C(O)R 9 、-C(O)OR 10 、-OC(O)R 11 、-S(O)2R 12 、-S(O)2OR 13 、-OS(O)2R 14 、-P(O)(OR 15 )(OR 16 ); R 9 , R 11 , R 12 , R 14 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, an aryl group, a heteroaryl group, a heterocyclic group, -NR 17 R 18 ; R 10 , R 13 , R 14 , R 15 and R 16 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, an aryl group, a heteroaryl group, and a heterocyclic group; R 17 and R 18 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; Each R f are the same or different and are each independently selected from the group consisting of a deuterium atom, a halogen, a cyano group, a hydroxyl group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, a heterocyclyl group, an aryl group, a heteroaryl group, an alkyloxy group, an alkenyloxy group, an alkynyloxy group, a cycloalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxy group, a heterocyclyloxy group, an aryloxy group, a heteroaryloxy group, an alkylthio group, an alkenylthio group, an alkynylthio group, a cycloalkylthio group, a cycloalkenylthio group, a cycloalkynylthio group, a heterocyclylthio group, an arylthio group, a heteroarylthio group, 17 R 18 ; m and n are the same or different and are each independently selected from 0, 1, 2, 3, 4 or 5.

2. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug, wherein: Ring A is selected from C 3-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl and 5- to 8-membered heteroaryl, for example tetrahydropyrrolyl, piperidinyl, piperazinyl, hexahydro-1H-pyrrolazinyl; X is selected from -O- and -NR 8 -; R 8 is selected from a hydrogen atom, a deuterium atom, unsubstituted or optionally substituted with 1, 2 or more R e Substituted with the following groups: C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl and 5-8 membered heteroaryl; Each R 1 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, an oxo group (═O), a thio group (═S), unsubstituted or optionally substituted with 1, 2 or more R a Substituted with the following groups: C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy, C 2-8 Alkynyloxy, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, C 1-8 Alkylthio, C 2-8 Alkenylthio, C 2-8 Alkynylthio, C 3-8 Cycloalkylthio, C 3-8 Cycloalkenylthio, C 3-8 Cycloalkynylthio, -NR 17 R 18 ; Each R 2 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, unsubstituted or optionally substituted with 1, 2 or more R b Substituted C 1-8 alkyl; Each R 3 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, a nitro group, unsubstituted or optionally substituted with 1, 2 or more R c Substituted with the following groups: C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, 5-8 membered heterocyclic group, C 6-10 Aryl, 5-8 membered heteroaryl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy, C 2-8 Alkynyloxy, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, 5-8 membered heterocyclyloxy, C 6-20 Aryloxy, 5-8 membered heteroaryloxy, C 1-8 Alkylthio, C 2-8 Alkenylthio, C 2-8 Alkynylthio, C 3-8 Cycloalkylthio, C 3-8 Cycloalkenylthio, C 3-8 Cycloalkynylthio, 5-8 membered heterocyclylthio, C 6-10 Arylthio, 5-8 membered heteroarylthio, -NR 17 R 18 ; R 4 , R 5 , R 5 and R 6 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, unsubstituted or optionally substituted with 1, 2 or more R d Substituted with the following groups: C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, 5-8 membered heterocyclic group, C 6-10 Aryl, 5-8 membered heteroaryl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy, C 2-8 Alkynyloxy, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, 5-8 membered heterocyclyloxy, C 6-20 Aryloxy, 5-8 membered heteroaryloxy, C 1-8 Alkylthio, C 2-8 Alkenylthio, C 2-8 Alkynylthio, C 3-8 Cycloalkylthio, C 3-8 Cycloalkenylthio, C 3-8 Cycloalkynylthio, 5-8 membered heterocyclylthio, C 6-10 Arylthio, 5-8 membered heteroarylthio, -NR 17 R 18 、-C(O)R 9 、-C(O)OR 10 、-OC(O)R 11 、-S(O)2R 12 、-S(O)2OR 13 、-OS(O)2R 14 、-P(O)(OR 15 )(OR 16 ); Or, R 4 , R 5 , R 5 and R 6 The adjacent substituents in the d Substituted with the following groups: C 3-8 Cycloalkenyl, 5-8 membered heterocyclic group, C 6-10 Aryl or 5-8 membered heteroaryl; For example, R 4 and R 5 The atoms to which it is attached together form an unsubstituted or optionally substituted group consisting of 1, 2 or more R d Substituted with the following groups: C 3-8 Cycloalkenyl, 5-8 membered heterocyclic group, C 6-10 Aryl or 5-8 membered heteroaryl; or R 5 and R 6 The atoms to which it is attached together form an unsubstituted or optionally substituted group consisting of 1, 2 or more R d Substituted with the following groups: C 3-8 Cycloalkenyl, 5-8 membered heterocyclic group, C 6-10 Aryl or 5-8 membered heteroaryl; or R 6 and R 7 The atoms to which it is attached together form an unsubstituted or optionally substituted group consisting of 1, 2 or more R d Substituted with the following groups: C 3-8 Cycloalkenyl, 5-8 membered heterocyclic group, C 6-10 Aryl or 5-8 membered heteroaryl; Each R a , R b , R c , R d and R e are the same or different and are each independently selected from a deuterium atom, a halogen, a cyano group, a hydroxyl group, a nitro group, an unsubstituted group or an optionally substituted group with 1, 2 or more R f Substituted with the following groups: C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, 5-8 membered heterocyclic group, C 6-10 Aryl, 5-8 membered heteroaryl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy, C 2-8 Alkynyloxy, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, 5-8 membered heterocyclyloxy, C 6-10 Aryloxy, 5-8 membered heteroaryloxy, C 1-8 Alkylthio, C 2-8 Alkenylthio, C 2-8 Alkynylthio, C 3-8 Cycloalkylthio, C 3-8 Cycloalkenylthio, C 3-8 Cycloalkynylthio, 5-8 membered heterocyclylthio, C 6-10 Arylthio, 5-8 membered heteroarylthio, -NR 17 R 18 、-C(O)R 9 、-C(O)OR 10 、-OC(O)R 11 、-S(O)2R 12 、-S(O)2OR 13 、-OS(O)2R 14 、-P(O)(OR 15 )(OR 16 ); Each R f are the same or different and are each independently selected from a deuterium atom, a halogen, a cyano group, a hydroxyl group, a nitro group, a C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, 5-8 membered heterocyclic group, C 6-10 Aryl, 5-8 membered heteroaryl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy, C 2-8 Alkynyloxy, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, 5-8 membered heterocyclyloxy, C 6-10 Aryloxy, 5-8 membered heteroaryloxy, C 1-8 Alkylthio, C 2-8 Alkenylthio, C 2-8 Alkynylthio, C 3-8 Cycloalkylthio, C 3-8 Cycloalkenylthio, C 3-8 Cycloalkynylthio, 5-8 membered heterocyclylthio, C 6-10 Arylthio, 5-8 membered heteroarylthio, -NR 17 R 18 ; R 17 and R 18 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, unsubstituted or optionally substituted with 1, 2 or more R f Substituted with the following groups: C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl and 5-8 membered heteroaryl.

3. The compound according to claim 1 or 2, or a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate, an isotope compound or a prodrug thereof, wherein: Ring A is selected from tetrahydropyrrol-1-yl, tetrahydropyrrol-2-yl, tetrahydropyrrol-3-yl, such as Or selected from hexahydro-1H-pyrrolazine-1-yl, hexahydro-1H-pyrrolazine-2-yl, hexahydro-1H-pyrrolazine-3-yl, hexahydro-1H-pyrrolazine-7a-yl, such as Each R 1 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkyloxy, halogenated C 1-8 Alkyl, halogenated C 1-8 Alkyloxy, cyano, amino, -CH-NR 17 R 18 , hydroxyl and hydroxyl C 1-8 alkyl; Each R 2 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a C 1-8 Alkyl, halogenated C 1-8 Alkyl and hydroxyl C 1-8 alkyl; Each R 3 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkyloxy, halogenated C 1-8 Alkyl, halogenated C 1-8 Alkyloxy, cyano, amino, nitro, hydroxy, hydroxy C 1-8 Alkyl, C 3-8 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl and 5-8 membered heteroaryl; R 4 , R 5 , R 5 and R 6 are the same or different and are each independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, methoxy, dimethylamino, trifluoromethyl, methylsulfonyl, dimethylaminocarbonyl, pyrrolidin-1-yl; Or, R 4 and R 5 The atoms to which it is attached together form an unsubstituted or optionally substituted group consisting of 1, 2 or more R d Substituted with the following groups: or, R 5 and R 6 The atoms to which it is attached together form an unsubstituted or optionally substituted group consisting of 1, 2 or more R d Substituted with the following groups: or, R 6 and R 7 The atoms to which it is attached together form an unsubstituted or optionally substituted group consisting of 1, 2 or more R d Substituted with the following groups: in, represents the chemical bonds within the phenyl group connected to the above ring structure; R 9 , R 11 , R 12 , R 14 are the same or different and are independently selected from H, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, C 6-10 Aryl, 5-8 membered heteroaryl, 5-8 membered heterocyclic group, -NR 17 R 18 ; R 10 , R 13 , R 14 , R 15 and R 16 are the same or different and are independently selected from H, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, C 6-10 Aryl, 5-8 membered heteroaryl, 5-8 membered heterocyclyl; m and n are the same or different and are each independently selected from 0, 1, 2, 3 or 4.

4. The compound according to any one of claims 1 to 3 or its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug, wherein the compound has a structure such as shown in the following formula I-1: in, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m and n independently have the definitions as described in any one of claims 1-3.

5. The compound according to any one of claims 1 to 3 or its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug, wherein the compound has a structure such as shown in the following formula I-2: in, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m and n independently have the definitions as described in any one of claims 1-3.

6. The compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, isotope compound or prodrug, wherein the compound is selected from at least one of the following:

7. A method for preparing a compound according to any one of claims 1 to 6 or a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate, an isotopic compound or a prodrug thereof, characterized in that: The preparation method comprises the following steps:

8. The preparation method according to claim 7, wherein the preparation method comprises the following steps: (1) Synthesis of Intermediate III The starting material II is reacted in the presence of thionyl chloride and oxalyl chloride; Preferably, the reaction is carried out at a temperature of 20°C to 100°C; Preferably, the solvent of the reaction is dichloromethane, toluene or no solvent. (2) Synthesis of Intermediate IV Intermediate III reacts with diethyl malonate in the presence of a Lewis acid; Preferably, the reaction temperature is carried out at a temperature of 20°C to 80°C; Preferably, the Lewis acid is selected from anhydrous magnesium chloride, anhydrous zinc chloride, anhydrous ferric chloride; Preferably, the base is selected from triethylamine, diisopropylethylamine, N-methylmorpholine; Preferably, the reaction solvent is selected from acetonitrile and toluene. (3) Synthesis of intermediate V Intermediate IV reacts in the presence of an acid; Preferably, the reaction temperature is carried out at a temperature of 20°C to 100°C; Preferably, the acid is selected from 4-methylbenzenesulfonic acid, methanesulfonic acid, trifluoroacetic acid; Preferably, the reaction solvent is selected from 1,4-dioxane, toluene and acetonitrile. (4) Synthesis of Intermediate VI Intermediate V reacts with DMF-DMA in the presence of an acid; Preferably, the reaction temperature is carried out at a temperature of 20°C to 100°C; Preferably, the acid is selected from formic acid, acetic acid, propionic acid, trifluoroacetic acid; Preferably, the solvent is selected from toluene and 1,4-dioxane. (5) Synthesis of Compound VIII Intermediate VI reacts with starting material VII in the presence of a base; Preferably, the reaction is carried out at a temperature of 20°C to 100°C; Preferably, the base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, triethylamine, diisopropylethylamine; Preferably, the reaction solvent is methanol, ethanol, isopropanol, acetonitrile or toluene. (6) Synthesis of Compound IX Intermediate VIII reacts in the presence of a reducing agent; Preferably, the reaction is carried out at a temperature of 20°C to 100°C; Preferably, the reducing agent is selected from iron powder / ammonium chloride, iron powder / acetic acid, zinc powder / ammonium chloride, zinc powder / acetic acid, hydrogen / palladium carbon; Preferably, the reaction solvent is methanol, ethanol or isopropanol. (7) Synthesis of Compound X Intermediate IX reacts in the presence of a chlorinating agent; Preferably, the reaction is carried out at a temperature of 20°C to 100°C; Preferably, the chlorinating agent is selected from phosphine oxychloride and phosphorus pentachloride; Preferably, the reaction solvent is toluene or no solvent. (8) Synthesis of Compound XII The intermediate X reacts with the starting material XI in the presence of a base; Preferably, the reaction is carried out at a temperature of 20°C to 100°C; Preferably, the base is selected from potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, sodium tert-butoxide, potassium tert-butoxide; Preferably, the reaction solvent is tert-butyl alcohol, toluene, tetrahydrofuran, or 1,4-dioxane. (9) Synthesis of Compound I Intermediate XII reacts with in the presence of a base; Preferably, the reaction is carried out at a temperature of 20°C to 140°C; Preferably, the base is selected from potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide; Preferably, the reaction solvent is at least one of the following mixed solvents: 1,4-dioxane and water, tert-butanol and water, n-butanol and water, ethylene glycol and water; Optionally, the preparation method further comprises the step of preparing Compound I into at least one of its pharmaceutically acceptable salts, hydrates, solvates, isotope compounds or prodrugs.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate, an isotope compound or a prodrug thereof, and a pharmaceutically acceptable carrier, a diluent or an excipient.

10. Use of a compound according to any one of claims 1 to 6 or a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate, an isotopic compound or a prodrug thereof in the preparation of a medicament for treating and / or preventing a disease or condition, wherein the disease or condition is a tumor, such as cancer; Preferably, the disease or condition is selected from at least one of the following: brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumors, urothelial carcinoma, urethral cancer, bladder cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma; preferably selected from pancreatic cancer, colorectal cancer, non-small cell lung cancer, endometrial cancer and gastric cancer.

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