Disubstituted nitrogenous five-membered heteroaryl compound as kinase inhibitor and application of disubstituted nitrogenous five-membered heteroaryl compound

Abstract

The invention relates to a disubstituted nitrogenous five-membered heteroaryl compound serving as a kinase inhibitor and application of the disubstituted nitrogenous five-membered heteroaryl compound. The chemical structure of the disubstituted nitrogenous five-membered heteroaryl compound disclosed by the invention is shown as a formula A, the compounds of the invention are CHK1 inhibitors. Therefore, the compounds of the present invention can be used for the treatment of cancer. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a disubstituted nitrogen-containing five-membered heteroaryl compound as a kinase inhibitor and application thereof. Background Art

[0002] The process of eukaryotic cell growth and proliferation is to accurately copy the genetic information of the mother cell and produce two identical daughter cells through chromosome mitosis. This process of cell proliferation and division is called the cell cycle, which includes the entire process from the completion of one cell division to the completion of the next cell division. The cell cycle includes four phases: the G1 phase where a large amount of proteins and RNA are synthesized after mitosis, the S phase of DNA replication, the G2 phase, the preparatory phase before mitosis, and the M phase of cell mitosis. In order to ensure the integrity and correctness of the genetic material in the cell, there is a complex and precise signal pathway in the cell to monitor DNA damage and respond accordingly, such as DNA repair, cell cycle checkpoints, cell apoptosis, etc. This signal pathway network is called DNA damage response (DNA-damage-response, DDR).

[0003] When DNA damage occurs, cell cycle checkpoints are activated: cells are prevented from entering the S phase through the G1 / S phase checkpoint; S phase progress is delayed through the Intra-S phase or S phase checkpoint; cells are prevented from entering mitosis through the G2 / M phase checkpoint (Lobrich M et al., Nature reviews Cancer 2007, 7(11): 861-869). In the process of responding to DNA damage, there are a series of complex repair pathways that mediate the detection and repair of damaged DNA, and cell cycle checkpoint kinases (CHK1 and CHK2) play a very important role in the DNA damage repair signal transduction pathway.

[0004] CHK1 protein belongs to serine / threonine kinase protein (Sanchez Y et al., Science, 1997, 277 (5331): 1497-1501), and is the core component of the ATR-CHK1-CDC25C damage response pathway that regulates the G2 / M cell cycle checkpoint. After recognizing DNA damage signals, cells activate ATR, phosphorylate multiple serine sites on CHK1, activate CHK1, and the activated CHK1 further phosphorylates downstream CDC25, causing CDC25 degradation, thereby preventing CDC25 from activating CDK1 and CDK2, inactivating CDK1 and CDK2, and then preventing the cell cycle process, allowing cells to repair DNA and survive (Carrassa L et al., Cell Cycle 2011, 10 (13): 2121-2128). Therefore, targeting CHK1 can interfere with the repair of DNA damage, allowing irreparable DNA damage to accumulate and ultimately leading to cell death.

[0005] CHK1 protein kinase is highly expressed in a variety of tumors, including breast cancer, colon cancer, liver cancer, and gastric cancer. The insensitivity or resistance of some cancer cells to chemotherapy, radiotherapy, and other anticancer drugs is often related to the overactivation of CHK1 (Bao S et al., Nature 2006, 444 (7120): 756-760). The mechanism of promoting tumor cell apoptosis by relieving the blocking effect of CHK1 on cell cycle checkpoints has become a hot topic in tumor research and is also the research basis of CHK1 inhibitors.

[0006] A variety of CHK1 kinase inhibitors have been disclosed, for example, WO2010077758, WO2012064548, WO2013068755, WO2013171470, WO2015120390, WO2017132928, WO2018086546, WO2018086547, WO2021104461, WO2022251502, WO2022114189 and WO2023120696.

[0007] However, there is still a need for novel compounds that may serve as potential inhibitors of CHK1 and may be beneficial for cancer treatment. Summary of the invention

[0008] The present invention provides novel disubstituted nitrogen-containing five-membered heteroaryl compounds as shown in formula A and formula I (including IIa, IIb, IIIa and IIIb), stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-labeled compounds or pharmaceutically acceptable salts thereof, or mixtures thereof, as kinase inhibitors, particularly CHK1 kinase inhibitors.

[0009] The present invention also provides a pharmaceutical composition comprising an effective amount of a compound of Formula A and Formula I (including IIa, IIb, IIIa and IIIb), its stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-labeled compounds or pharmaceutically acceptable salts, or a mixture thereof, for treating cancer.

[0010] In one embodiment, the pharmaceutical composition may further contain one or more pharmaceutically acceptable carriers or diluents for treating cancer.

[0011] In one embodiment, the pharmaceutical composition may further contain at least one known anticancer drug or a pharmaceutically acceptable salt of the anticancer drug for treating cancer.

[0012] The present invention also relates to a method for preparing novel compounds of structures such as Formula A and Formula I (including IIa, IIb, IIIa and IIIb), their stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-labeled compounds or pharmaceutically acceptable salts, or mixtures thereof. DETAILED DESCRIPTION

[0013] It should be understood that the features of the various embodiments described herein can be arbitrarily combined to form the technical solutions of this invention; the definition of each group herein is applicable to any embodiment described herein, for example, the definition of substituents of alkyl groups herein is applicable to any embodiment described herein, unless the embodiment has clearly defined substituents of alkyl groups.

[0014] As used herein, "hydrogen (H)" includes its isotopes deuterium (D) and tritium (T).

[0015] The heteroatoms described herein include oxygen (O), sulfur (S) and nitrogen (N).

[0016] As used herein, "alkyl" refers to a straight or branched chain group containing up to ten carbon atoms. Useful alkyl groups include straight or branched chain C 1-10 Alkyl, preferably C 1-6 In certain embodiments, the alkyl group is C 1-4 Alkyl. Typical C 1-10 The alkyl group includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl groups which may be optionally substituted.

[0017] As used herein, "alkylene" refers to an alkyl group as defined above that is positioned between and serves to connect two other chemical groups. Typical alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0018] As used herein, "alkenyl" refers to a straight or branched chain containing 2 to 10 carbon atoms, unless the carbon chain length is otherwise limited, wherein at least two carbon atoms in the chain contain a double bond; preferably C 2-6 Typical alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.

[0019] As used herein, "alkynyl" refers to a straight or branched chain containing 2 to 10 carbon atoms, unless the carbon chain length is otherwise limited, wherein at least two carbon atoms in the chain contain a triple bond; preferably C 2-6 Typical alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl and 2-butynyl.

[0020] As used herein, "alkoxy" refers to a 1-10 Alkyl, preferably C 1-6 Alkyl or C 1-4 Alkyl-substituted oxy groups, such as methoxy, ethoxy, etc. The alkyl group in the alkoxy group may be optionally substituted. The substituents of the alkoxy group include, but are not limited to, halogen, amino, and carboxyl (including ester groups thereof), and the amino group includes alkylamino and dialkylamino.

[0021] The "amino group" mentioned herein can be -NR ′ R ″ Indicates that R ′ and R ″ are each independently hydrogen, optionally substituted C 1-10 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl, preferably, R ′ and R ″ are each independently H, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 cycloalkyl or optionally substituted 5-membered heteroaryl; or R ′ and R ″ Together with the N to which they are attached, they form an optionally substituted nitrogen-containing heterocyclic group or nitrogen-containing heteroaryl group, such as a 4-membered to 7-membered nitrogen-containing heterocyclic group or nitrogen-containing heteroaryl group, wherein the nitrogen-containing heterocyclic group or nitrogen-containing heteroaryl group optionally contains one or more (such as 2, 3) additional heteroatoms selected from O, N and S. Preferred amino groups include -NH2, -NHR ′ and –NHR ″ , where R ′ and R ″ Each is independently an optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Cycloalkyl and optionally substituted 3- to 6-membered heterocyclic groups.

[0022] As used herein, "oxo" refers to =0.

[0023] As used herein, "aryl" refers to an aromatic group, either by itself or as part of another group, containing 6 to 14 carbon atoms, a monocyclic, bicyclic or tricyclic aromatic group. The aryl group may be substituted with one or more substituents described herein.

[0024] Useful aromatic groups include C 6-14 Aryl, preferably C 6-10 Aryl. Typical C 6-14 Aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylene and fluorenyl.

[0025] As used herein, "carbocyclic group" includes cycloalkyl and partially saturated carbocyclic groups. Useful cycloalkyl groups are C 3-8 Cycloalkyl, such as C 3-6 Cycloalkyl or C 3-4 Cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Useful partially saturated carbocyclic groups include cycloalkenyl, such as C 3-8 Cycloalkenyl, C 3-6 Cycloalkenyl or C 3-4 Cycloalkenyl groups, such as cyclopentenyl, cycloheptenyl, and cyclooctenyl.Carbocyclic groups may be substituted with one or more substituents as described herein.

[0026] Useful halogens or halogen groups include fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0027] An acyl group is a functional group containing a carbonyl group (carbon-oxygen double bond, -C(O)-). Useful acyl groups include C 1-6 Acyl, or C 1-3 Acyl, such as acetyl. Acyl may be optionally substituted by a group selected from halogen, amino and aryl, wherein amino and aryl may be optionally substituted. When substituted by halogen, the number of halogen substituents may be in the range of 1-5. Examples of substituted acyl include chloroacetyl and pentafluorobenzoyl, etc. When substituted by amino, the amino may be substituted by one or two substituents described herein.

[0028] Useful acyl groups include C 1-6 Acyl, such as acetyl. Acyl may be optionally substituted by a group selected from halogen, amino and aryl, wherein amino and aryl are optionally substituted. When substituted by halogen, the number of halogen substituents may be in the range of 1-5. Examples of acyl substituted by halogen include chloroacetyl and pentafluorobenzoyl, etc. When substituted by amino, the amino may be substituted by 1 or 2 substituents described herein. In some embodiments, aminoacyl is -C(O)-NR ′ R ″ , where R′ and R ″ are each independently hydrogen, optionally substituted C 1-10 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl, preferably, R ′ and R ″ are each independently H, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Cycloalkyl and optionally substituted 3-6 membered heterocyclyl.

[0029] As used herein, sulfonyl refers to RS(=O)2-, wherein R can be, for example, an alkyl group as described herein. 1-4 Sulfonyl means R is C 1-4 Alkyl sulfonyl.

[0030] As used herein, "heterocyclic group" refers to a saturated or partially saturated 3-7-membered monocyclic group, a 7-12-membered bicyclic group, or an 11-14-membered tricyclic group, wherein the bicyclic or tricyclic group includes a spiral ring group, a cyclic group, and a bridged ring group, which is composed of carbon atoms and 1-4 heteroatoms selected from O, N, and S. In some embodiments, the heteroatoms nitrogen and sulfur in the heterocyclic group can be oxidized at will, and the nitrogen can also be quaternized at will. The heterocyclic group also includes a fused heterocyclic ring formed by the fusion of any heterocyclic ring defined above and a benzene ring in the bicyclic system. If the resulting compound is stable, the carbon atoms or nitrogen atoms of the heterocyclic ring can be substituted. The heterocyclic group can be substituted by one or more substituents described herein.

[0031] Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, 1,4-diazepanyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, dihydroindolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetrahydroisoquinolinyl, dihydropyrrolopyrazolyl, dihydrofuranopyridinyl, dioxopyridinyl, dihydropyridooxazinyl, pyridooxazinyl, tetronoyl and tetramoyl, which groups may be substituted with one or more substituents as described herein.

[0032] As used herein, "heteroaryl" refers to a group containing 5-14, preferably 5-10 ring atoms, and having 6, 10 or 14 π electrons shared in the ring system. The ring atoms contained in the heteroaryl group are carbon atoms and 1-3 heteroatoms selected from oxygen, nitrogen and sulfur. The heteroaryl group may be substituted with one or more substituents described herein.

[0033] Useful heteroaryl groups include thienyl (phenylthio), benzo[d]isothiazol-3-yl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furanyl, pyranyl, isobenzofuranyl, chromenyl, xanthrenyl, phenoxanthiinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl (including but not limited to 2-pyridyl, 3-pyridyl and 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidine, pyrimidine, pyridinyl ... azo(hetero)phenyl, phenanthroline, phenazine, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, tetrahydropyridopyrimidinyl, tetrahydrofive-membered [c]pyrazol-3-yl, benzisoxazolyl such as 1,2-benzisoxazol-3-yl, benzimidazolyl, 2-hydroxyindolyl, thiadiazo, 2-oxobenzimidazolyl, imidazopyridazinyl, imidazopyridinyl, furopyridinyl, oxazolopyridinyl, triazolopyridazinyl, tetrahydropyridopyrimidinyl, pyrazolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrazinyl, triazolopyrazinyl, thienylquinolyl, furanoquinolyl, thiazoquinolyl, pyrazoloquinolyl, pyrroloquinolyl, imidazoquinolyl, oxazoloquinolyl, etc. When the heteroaryl group contains a nitrogen atom in a ring, such nitrogen atom may be in the form of an N-oxide, for example, pyridinyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide.

[0034] Herein, unless otherwise indicated, when substituted, the alkyl, alkenyl, alkynyl, alkoxy, amino, acyl, carbocyclyl, aryl, heterocyclyl or heteroaryl groups described in any embodiment herein may each be substituted with one or more (e.g., 1, 2, 3 or 4) substituents selected from the following groups as defined herein: halogen, hydroxy, carboxyl, amino, nitro, cyano, C 1-6 Acylamino, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Acyl, C 6-10 Aryl, C 3-8 The substituents themselves may also be optionally substituted. More preferred substituents include, but are not limited to, halogen, hydroxyl, cyano, amino, C 1-6 Alkoxy, C 1-6 Alkyl and C 1-6 Acyl.

[0035] It should be understood that in the embodiments herein, when the substituent is a carbocyclic group, a heterocyclic group, an aryl group or a heteroaryl group, the number of the carbocyclic group, the heterocyclic group, the aryl group or the heteroaryl group as a substituent is usually one.

[0036] Specifically, the present invention provides a compound as shown in the following formula I, its stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-labeled compounds or pharmaceutically acceptable salts, or mixtures thereof: wherein A1 is selected from N and CR1; A2 is selected from N and C; Q is selected from NR a , O and S; The Z1 ring is selected from optionally substituted heteroaryl and optionally substituted heterocyclyl; Cy is selected from optionally substituted heteroaryl and optionally substituted heterocyclyl; and when Cy is When D1, D2 and D3 are each independently selected from N and CR9, and at least one of D1 and D3 is N; R1 is selected from hydrogen, halogen, optionally substituted alkyl and optionally substituted alkoxy; R9 and R 15 are independently selected from hydrogen, halogen, optionally substituted C 1-4 Alkyl and optionally substituted C 1-4 Alkoxy; R a is hydrogen and optionally substituted C 1-4 alkyl.

[0037] In the formula A and formula I and the structural formulas of the present invention, when each alkyl, alkoxy, and acyl group in the definition of each group is substituted, the substituent can be independently selected from deuterium, cyano, hydroxyl, nitro, amino (-NR ′ R ″ ), aryl, heteroaryl and halogen, etc., the number of substituents can be 1, 2, 3, 4 or 5 independently, R ′ and R ″ As defined herein, R ′ and R ″ Preferably each is independently H or C 1-4 Alkyl. For example, the substituted alkyl can be a deuterated alkyl, a hydroxyalkyl, a dihydroxyalkyl, an alkylaminoalkyl, a dialkylaminoalkyl, an aralkyl, a heteroarylalkyl and a haloalkyl. It should be understood that when the substituent is an aryl, a heteroaryl, a cyano and a nitro, the number of substituents is usually 1; when the substituent is, for example, a halogen, the number of substituents can be up to 5 halogen groups according to the carbon chain length of the alkyl and alkoxy groups; exemplary substituents of this type are trifluoromethyl and pentafluoroethyl. In some embodiments, in Formula A and Formula I and each structural formula of the present invention, each alkyl, alkoxy and acyl group in the definition of each group is optionally substituted by 1, 2, 3, 4 or 5 substituents selected from deuterium, hydroxyl, nitro, amino and halogen.

[0038] In the formula A and formula I and the structural formulas of the present invention, when each cycloalkyl, heterocyclic, aryl and heteroaryl in the group definition is substituted, the number of substituents can be 1, 2, 3, 4 or 5 independently, and each substituent can be independently selected from halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 1-6 Acylamino, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Acyl, C 6-10 Aryl, C 3-8 Cycloalkyl, heteroaryl, heterocyclyl and carbonyl, preferably selected from halogen, hydroxy, cyano, amino, C 1-6 Alkoxy, C 1-6 Alkyl and C 1-6 Acyl. 1-6 Acylamino, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Each acyl group may also be optionally substituted with 1, 2, 3, 4 or 5 substituents selected from cyano, hydroxy, nitro, amino, aryl, heteroaryl and halogen. 6-10 Aryl, C 3-8 Cycloalkyl, heteroaryl, heterocyclyl may also be optionally substituted by 1, 2, 3, 4 or 5 groups selected from halogen, hydroxy, carboxyl, amino, nitro, cyano, C 1-6 Acylamino, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 The acyl and carbonyl groups are substituted with substituents.

[0039] In one or more embodiments of the compounds of formula A and formula I, R1 is hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Further, R1 is H, halogen, halogenated C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, halogenated C 1-4 Alkoxy or hydroxy substituted C 1-4 Alkoxy.

[0040] In one or more embodiments of the compounds of formula A and formula I, A1 is N or CR1, wherein R1 is hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy; in one or more embodiments, A1 is N, CH or CF, preferably, A1 is N.

[0041] In one or more embodiments of the compounds of formula A and formula I, A1 is N and A2 is C.

[0042] In one or more embodiments of the compounds of Formula A and Formula I, R a For hydrogen.

[0043] In one or more embodiments of the compounds of formula A and formula I, Q1 is NH or O; preferably, Q is NH.

[0044] In one or more embodiments of the compounds of formula A and formula I, the Z1 ring is an optionally substituted 5-6-membered heteroaryl or an optionally substituted 5-10-membered heterocyclic group; preferably, the Z1 ring is an optionally substituted 5-6-membered heteroaryl or an optionally substituted 5-10-membered heterocyclic group (preferably a 5-6-membered heterocyclic group) wherein A2 is C. The 5-6-membered heteroaryl is preferably a nitrogen-containing heteroaryl, such as a heteroaryl containing 1 or 2 nitrogen atoms, optionally further containing 1 or 2 heteroatoms selected from O and S. Preferably, A2 in the Z1 ring is C, and the Z1 ring is a 5-6-membered heteroaryl containing 1 or 2 nitrogen atoms and optionally 1 or 2 heteroatoms selected from O and S. The 5-10-membered heterocyclic group is preferably a nitrogen-containing heterocyclic group, such as a heterocyclic group containing 1 or 2 nitrogen atoms, optionally further containing 1 or 2 heteroatoms selected from O and S. Preferably, A2 in the Z1 ring is C, and the Z1 ring is a 5-10 membered heterocyclic group containing 1 or 2 nitrogen atoms and optionally 1 or 2 heteroatoms selected from O and S. In some embodiments, the 5-10 membered heterocyclic group is a 7-10 membered spirocyclic heterocyclic group containing 1 or 2 nitrogen atoms and optionally 1 or 2 heteroatoms selected from O and S, preferably A2 is C. When the 5-6 membered heteroaryl and 5-10 membered heterocyclic group are substituted, the number of substituents can be 1, 2, 3 or 4, which can be selected from halogen, cyano, =O, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-8 In some embodiments, the optionally substituted C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 substituents selected from deuterium, halogen, optionally substituted heterocyclic group and amino (-NR'R"); wherein, preferably, the heterocyclic group is a 4-10 membered heterocyclic group containing nitrogen and / or oxygen, preferably a 4-7 membered heterocyclic group containing nitrogen and / or oxygen, such as azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl and morpholinyl, and the heterocyclic group is preferably substituted by 1, 2, 3 or 4 substituents selected from halogen, hydroxyl, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, optionally substituted C 3-4 Cycloalkyl (e.g. optionally substituted by 1, 2 or 3 groups selected from halogen, C 1-4 Alkyl and halogenated C 1-4 Alkyl C3-4 cycloalkyl) and optionally substituted C 1-3 Acyl (such as halogenated C 1-3 R' and R" are as defined herein and are preferably each independently selected from hydrogen, C 1-4 Alkyl and halogenated C 1-4 In some embodiments, the optionally substituted C 3-8 The cycloalkyl radical is optionally substituted by 1, 2, 3 or 4 radicals selected from halogen, hydroxy, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy and halogenated C 1-4 In some embodiments, the optionally substituted heterocyclic group as a substituent of the Z1 ring can be a 4-10 membered monocyclic or bicyclic heterocyclic group, a 7-10 membered spirocyclic heterocyclic group or a 7-10 membered bridged heterocyclic group, each of which can be optionally substituted by 1, 2, 3 or 4 groups selected from halogen, hydroxyl, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, optionally substituted C 3-4 Cycloalkyl (e.g. optionally substituted by 1, 2 or 3 groups selected from halogen, C 1-4 Alkyl and halogenated C 1-4 Alkyl C 3-4 cycloalkyl) and optionally substituted C 1-3 Acyl (such as halogenated C 1-3 acyl) substituent; preferably, the heterocyclic group is a 4-10 membered monocyclic or bicyclic heterocyclic group containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms, a 7-10 membered spirocyclic heterocyclic group containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms, or a 7-10 membered bridged heterocyclic group containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms, such as azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, 6-azabicyclo[3.1.1]hept-3-yl and 2-azaspiro[3.3]hept-6-yl, etc.

[0045] In one or more embodiments of the compounds of formula A and formula I, Selected from the following groups: Preferably, for: More preferably, for: Wherein, * represents the connection position of the group with the amino group on the 5-membered heteroaryl group containing Q in the compound; B1 and B2 are each independently selected from N and CR2; wherein each R2 is each independently selected from hydrogen, halogen, cyano, optionally substituted C 1-4 Alkyl and optionally substituted C 1-4 Alkoxy, preferably, each R2 is independently hydrogen, fluorine, chlorine, cyano, methyl or deuterated methyl; R3 is selected from hydrogen, optionally substituted C 1-4 Alkyl and optionally substituted C 3-4 Cycloalkyl, preferably hydrogen, methyl or deuterated methyl; R4 and R5 are each independently selected from hydrogen and optionally substituted C 1-4 Alkyl, or R4 and R5 form a C 3-4 Preferably, R4 and R5 are each independently hydrogen or methyl, or R4 and R5 form a cyclopropyl group with the connected C; R6 and R7 are each independently selected from an optionally substituted 4-10 membered monocyclic or bicyclic heterocyclic group, an optionally substituted 7-10 membered spirocyclic heterocyclic group, an optionally substituted 7-10 membered bridged heterocyclic group and an optionally substituted C 1-6 alkyl.

[0046] In one or more embodiments of the compounds of formula A and formula I, the 4-10 membered monocyclic or bicyclic heterocyclic group, 7-10 membered spirocyclic heterocyclic group and 7-10 membered bridged heterocyclic group in the definition of R6 and R7 can be optionally substituted by 1, 2, 3 or 4 groups selected from halogen, hydroxyl, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, optionally substituted C 3-4 Cycloalkyl (e.g. optionally substituted by 1, 2 or 3 groups selected from halogen, C 1-4 Alkyl and halogenated C 1-4 Alkyl C 3-4 cycloalkyl) and optionally substituted C 1-3 Acyl (such as halogenated C 1-3 acyl) is substituted with a substituent; preferably, the 4-10 membered monocyclic or bicyclic heterocyclic radical, 7-10 membered spirocyclic heterocyclic radical and 7-10 membered bridged heterocyclic radical are 4-10 membered monocyclic or bicyclic heterocyclic radicals containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms, 7-10 membered spirocyclic heterocyclic radicals containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms, or 7-10 membered bridged heterocyclic radicals containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms, such as azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, 6-azabicyclo[3.1.1]hept-3-yl and 2-azaspiro[3.3]hept-6-yl, etc.

[0047] In one or more embodiments of the compounds of formula A and formula I, the optionally substituted C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 substituents selected from deuterium, halogen, optionally substituted heterocyclic group and amino (-NR'R "); preferably, the heterocyclic group is a 4-10 membered heterocyclic group containing nitrogen and / or oxygen, preferably a 4-7 membered heterocyclic group containing nitrogen and / or oxygen, such as azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl and morpholinyl, etc., and the heterocyclic group is preferably substituted by 1, 2, 3 or 4 substituents selected from halogen, hydroxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy and halogenated C 1-4 Alkoxy is substituted by a substituent; R' and R" are as defined herein, preferably each independently selected from hydrogen, C 1-4 Alkyl and halogenated C 1-4 alkyl.

[0048] In one or more embodiments of the compounds of formula A and formula I, R6 is selected from the following groups: Wherein, * represents the connection position of the group to the rest of the compound; R8 is selected from hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 Cycloalkyl and optionally substituted C 1-3 acyl, preferably hydrogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl, cyclopropyl or C 1-3 Acyl.

[0049] In one or more embodiments of the compounds of formula A and formula I, R7 is selected from the following groups: Wherein, * represents the connection position of the group to the rest of the compound; R8 is selected from hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 Cycloalkyl and optionally substituted C 1-3 acyl, preferably hydrogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl, cyclopropyl or C 1-3 Acyl.

[0050] In one or more embodiments of the compounds of formula A and formula I, Cy is an optionally substituted 5-12 membered heteroaryl or an optionally substituted 9-12 membered heterocyclyl. Preferably, Cy is a 9-12 membered bicyclic heteroaryl or a 9-12 membered bicyclic heterocyclyl containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms. When the heteroaryl and heterocyclyl are substituted, the number of substituents may be 1, 2, 3 or 4, and the substituents may be selected from =O, halogen, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C 1-4 Alkoxy (such as halogenated C 1-4 Alkoxy or deuterated C 1-4 Preferably, the substituents of the heteroaryl and heterocyclyl groups are independently selected from =O, halogen and C 1-4 Alkoxy.

[0051] In one or more embodiments of the compounds of Formula A and Formula I, Cy is: Wherein, * indicates the connection position of the group to the rest of the compound; represents a single bond or a double bond; D1, D2 and D3 are each independently selected from N and CR9, wherein R9 is selected from =O, hydrogen, halogen, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C 1-4 Alkoxy (such as halogenated C 1-4 Alkoxy or deuterated C 1-4 alkoxy), preferably hydrogen, =O, fluorine, methoxy or deuterated methoxy; E1 and E2 are each independently selected from C and N, and are not N at the same time; X1 and X2 are each independently selected from O, S, NR 10 and CR 11 R 12 ; where R 10 is selected from hydrogen, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C 3-5 Cycloalkyl (e.g. optionally substituted by 1, 2 or 3 groups selected from halogen, C 1-4 Alkyl and halogenated C 1-4 Alkyl C 3-5 Cycloalkyl); R 11 and R 12 are each independently selected from hydrogen, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C1-4 Alkoxy (such as halogenated C 1-4 Alkoxy or deuterated C 1-4 Alkoxy), or R 11 and R 12 Form C with connected C 3-4 Cycloalkyl; Y is selected from C=O, C=S and CR 13 R 14 , where R 13 and R 14 are each independently selected from hydrogen, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C 1-4 Alkoxy (such as halogenated C 1-4 Alkoxy or deuterated C 1-4 Alkoxy), or R 13 and R 14 With the connected C to form C 3-4 Cycloalkyl; preferably, Y is C=O; Z2 ring is selected from optionally substituted 5-6 membered heteroaryl and optionally substituted 5-6 membered heterocyclyl.

[0052] In one or more embodiments of the compounds of formula A and formula I, E1 or E2 is N, is a single bond; in one or more embodiments, E1 and E2 are both C, For double bonds.

[0053] In one or more embodiments of the compounds of formula A and formula I, the Z2 ring is optionally substituted by 1, 2, 3 or 4 groups selected from halogen, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C 1-4 Alkoxy (such as halogenated C 1-4 Alkoxy or deuterated C 1-4 In one or more embodiments, the Z2 ring is a nitrogen and / or oxygen-containing 5-6 membered heteroaryl or an oxygen and / or nitrogen-containing 5-6 membered heterocyclic group.

[0054] In one or more embodiments of the compounds of formula A and formula I, Selected from the following groups: Wherein, * indicates the connection position of the group to the rest of the compound.

[0055] In one or more embodiments of the compounds of formula A and formula I, Cy is an optionally substituted 5-6 membered nitrogen-containing heteroaryl. When the heteroaryl is substituted, the number of substituents may be 1, 2, 3 or 3 and may be selected from halogen, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C 1-4 Alkoxy (such as halogenated C 1-4 Alkoxy or deuterated C 1-4 In one or more embodiments, Cy is: Wherein, * represents the connection position of the group to the rest of the compound; D1, D2 and D3 are each independently selected from N and CR9; and at least one of D1 and D3 is N; R9 is selected from hydrogen, halogen, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C 1-4 Alkoxy (such as halogenated C 1-4 Alkoxy or deuterated C 1-4 alkoxy), preferably hydrogen, fluorine, methoxy or deuterated methoxy; R 15 is selected from hydrogen, halogen, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C 1-4 Alkoxy (such as halogenated C 1-4 Alkoxy or deuterated C 1-4 alkoxy), preferably fluorine, difluoromethyl, methoxy or deuterated methoxy.

[0056] In one or more embodiments of the compounds of formula A and formula I, Selected from the following groups: Wherein, * indicates the connection position of the group to the rest of the compound.

[0057] In one or more embodiments of the compounds of formula A and formula I, when Cy is substituted, the substituent is selected from halogen, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C 1-4 Alkoxy (such as halogenated C 1-4 Alkoxy or deuterated C 1-4 alkoxy), preferably fluorine, difluoromethyl, methoxy or deuterated methoxy.

[0058] One group of preferred compounds of formula A and formula I of the present invention is represented by a compound represented by formula II (including formula IIa and IIb) or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-labeled compound or pharmaceutically acceptable salt thereof, or a mixture thereof: Wherein, D1, D2, D3, E1, E2, Q, X1, X2, Y, Z1 ring and Z2 ring are as described in any embodiment of Formula I; Indicates a single bond or a double bond.

[0059] In one or more embodiments of the compound of formula II, Q is NH or O, preferably, Q is NH.

[0060] In one or more embodiments of the compound of formula II, the Z1 ring is an optionally substituted 5-6 membered heteroaryl or an optionally substituted 5-10 membered heterocyclic group (preferably a 5-6 membered heterocyclic group). The 5-6 membered heteroaryl is preferably a nitrogen-containing heteroaryl, such as a heteroaryl containing 1 or 2 nitrogen atoms, optionally containing 1 or 2 heteroatoms selected from O and S. The 5-10 membered heterocyclic group is preferably a nitrogen-containing heterocyclic group, such as a heterocyclic group containing 1 or 2 nitrogen atoms, optionally containing 1 or 2 heteroatoms selected from O and S. In some embodiments, the 5-10 membered heterocyclic group is a 7-10 membered spirocyclic heterocyclic group containing 1 or 2 nitrogen atoms and optionally 1 or 2 heteroatoms selected from O and S. When the 5-6 membered heteroaryl and the 5-10 membered heterocyclic group are substituted, the number of substituents can be 1, 2, 3 or 4, which can be selected from halogen, cyano, =O, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-8 In some embodiments, the optionally substituted C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 substituents selected from deuterium, halogen, optionally substituted heterocyclic group and amino (-NR'R"); wherein, preferably, the heterocyclic group is a 4-10 membered heterocyclic group containing nitrogen and / or oxygen, preferably a 4-7 membered heterocyclic group containing nitrogen and / or oxygen, such as azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl and morpholinyl, and the heterocyclic group is preferably substituted by 1, 2, 3 or 4 substituents selected from halogen, hydroxyl, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, optionally substituted C 3-4 Cycloalkyl (e.g. optionally substituted by 1, 2 or 3 groups selected from halogen, C 1-4 Alkyl and halogenated C 1-4Alkyl C 3-4 cycloalkyl) and optionally substituted C 1-3 Acyl (such as halogenated C 1-3 R' and R" are as defined herein and are preferably each independently selected from hydrogen, C 1-4 Alkyl and halogenated C 1-4 In some embodiments, the optionally substituted C 3-8 The cycloalkyl radical is optionally substituted by 1, 2, 3 or 4 radicals selected from halogen, hydroxy, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy and halogenated C 1-4 In some embodiments, the optionally substituted heterocyclic group as a substituent of the Z1 ring can be a 4-10 membered monocyclic or bicyclic heterocyclic group, a 7-10 membered spirocyclic heterocyclic group or a 7-10 membered bridged heterocyclic group, each of which can be optionally substituted by 1, 2, 3 or 4 groups selected from halogen, hydroxyl, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, optionally substituted C 3-4 Cycloalkyl (e.g. optionally substituted by 1, 2 or 3 groups selected from halogen, C 1-4 Alkyl and halogenated C 1-4 Alkyl C 3-4 cycloalkyl) and optionally substituted C 1-3 Acyl (such as halogenated C 1-3 acyl) substituent; preferably, the heterocyclic group is a 4-10 membered monocyclic or bicyclic heterocyclic group containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms, a 7-10 membered spirocyclic heterocyclic group containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms, or a 7-10 membered bridged heterocyclic group containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms, such as azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, 6-azabicyclo[3.1.1]hept-3-yl and 2-azaspiro[3.3]hept-6-yl, etc.

[0061] In one or more embodiments of the compound of formula II, Selected from the following groups: Preferably, for: More preferably, for: Wherein, * represents the connection position of the group with the amino group on the 5-membered heteroaryl group containing Q in the compound; B1 and B2 are each independently selected from N and CR2; wherein each R2 is each independently selected from hydrogen, halogen, cyano, optionally substituted C 1-4 Alkyl and optionally substituted C 1-4 Alkoxy, preferably, each R2 is independently hydrogen, fluorine, chlorine, cyano, methyl or deuterated methyl; R3 is selected from hydrogen, optionally substituted C 1-4 Alkyl and optionally substituted C 3-4 Cycloalkyl, preferably hydrogen, methyl or deuterated methyl; R4 and R5 are each independently selected from hydrogen and optionally substituted C 1-4 Alkyl, or R4 and R5 form a C 3-4 Preferably, R4 and R5 are each independently hydrogen or methyl, or R4 and R5 form a cyclopropyl group with the connected C; R6 and R7 are each independently selected from an optionally substituted 4-10 membered monocyclic or bicyclic ring, an optionally substituted 7-10 membered spirocyclic heterocyclic group, an optionally substituted 7-10 membered bridged heterocyclic group and an optionally substituted C 1-6 alkyl.

[0062] In one or more embodiments of the compound of formula II, the 4-10 membered monocyclic or bicyclic heterocyclic group, 7-10 membered spirocyclic heterocyclic group and 7-10 membered bridged heterocyclic group in the definition of R6 and R7 can be optionally substituted by 1, 2, 3 or 4 groups selected from halogen, hydroxyl, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, optionally substituted C 3-4 Cycloalkyl (e.g. optionally substituted by 1, 2 or 3 groups selected from halogen, C 1-4 Alkyl and halogenated C 1-4 Alkyl C 3-4 cycloalkyl) and optionally substituted C 1-3 Acyl (such as halogenated C 1-3 acyl) is substituted with a substituent; preferably, the 4-10 membered monocyclic or bicyclic heterocyclic radical, 7-10 membered spirocyclic heterocyclic radical and 7-10 membered bridged heterocyclic radical are 4-10 membered monocyclic or bicyclic heterocyclic radicals containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms, 7-10 membered spirocyclic heterocyclic radicals containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms, or 7-10 membered bridged heterocyclic radicals containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms, such as azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, 6-azabicyclo[3.1.1]hept-3-yl and 2-azaspiro[3.3]hept-6-yl, etc.

[0063] In one or more embodiments of the compound of formula II, the optionally substituted C1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 substituents selected from deuterium, halogen, optionally substituted heterocyclic group and amino (-NR'R "); preferably, the heterocyclic group is a 4-10 membered heterocyclic group containing nitrogen and / or oxygen, preferably a 4-7 membered heterocyclic group containing nitrogen and / or oxygen, such as azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl and morpholinyl, etc., and the heterocyclic group is preferably substituted by 1, 2, 3 or 4 substituents selected from halogen, hydroxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy and halogenated C 1-4 Alkoxy is substituted by a substituent; R' and R" are as defined herein, preferably each independently selected from hydrogen, C 1-4 Alkyl and halogenated C 1-4 alkyl.

[0064] In one or more embodiments of the compound of formula II, R6 is selected from the following groups: Wherein, * represents the connection position of the group to the rest of the compound; R8 is selected from hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 Cycloalkyl and optionally substituted C 1-3 acyl, preferably hydrogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl, cyclopropyl or C 1-3 Acyl.

[0065] In one or more embodiments of the compound of formula II, R7 is selected from the following groups: Wherein, * represents the connection position of the group to the rest of the compound; R8 is selected from hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 Cycloalkyl and optionally substituted C 1-3 acyl, preferably hydrogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl, cyclopropyl or C 1-3 Acyl.

[0066] In one or more embodiments of the compound of formula II, D1, D2 and D3 are each independently selected from N and CR9; wherein R9 is selected from hydrogen, halogen, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C 1-4 Alkoxy (such as halogenated C 1-4 Alkoxy or deuterated C1-4 In one or more embodiments, R9 is hydrogen, fluorine, methoxy or deuterated methoxy.

[0067] In one or more embodiments of the compound of formula II, E1 and E2 are each independently selected from C and N, and are not N at the same time. In one or more embodiments, E1 or E2 is N, is a single bond; in one or more embodiments, E1 and E2 are both C, For double bonds.

[0068] In one or more embodiments of the compound of formula II, X1 and X2 are each independently selected from O, S, NR 10 and CR 11 R 12 ; where R 10 is selected from hydrogen, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C 3-5 Cycloalkyl (e.g. optionally substituted by 1, 2 or 3 groups selected from halogen, C 1-4 Alkyl and halogenated C 1-4 Alkyl C 3-5 Cycloalkyl); R 11 and R 12 are each independently selected from hydrogen, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C 1-4 Alkoxy (such as halogenated C 1-4 Alkoxy or deuterated C 1-4 Alkoxy), or R 11 and R 12 With the connected C to form C 3-4 In one or more embodiments, X1 and X2 are each independently selected from O and S, In one or more embodiments, X1 and X2 are each independently selected from NR 10 and CR 11 R 12 , is a single bond or a double bond; R 10 Preferably, R 11 and R 12 Preferably, hydrogen or R 11 and R 12 Together with the attached C it forms a cyclopropyl group.

[0069] In one or more embodiments of the compound of formula II, Y is selected from C=O, C=S and CR 13 R14 ; where R 13 and R 14 are each independently selected from hydrogen, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C 1-4 Alkoxy (such as halogenated C 1-4 Alkoxy or deuterated C 1-4 Alkoxy), or R 13 and R 14 With the connected C to form C 3-4 In one or more embodiments, Y is C=O or C=S. In one or more embodiments, R 13 and R 14 are independently selected from hydrogen, methyl, or R 13 and R 14 Together with the attached C it forms a cyclopropyl group.

[0070] In one or more embodiments of the compound of formula II, the Z2 ring is selected from optionally substituted 5-6 membered heteroaryl and optionally substituted 5-6 membered heterocyclyl. In some embodiments, the Z2 ring is optionally substituted by 1, 2, 3 or 4 selected from halogen, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C 1-4 Alkoxy (such as halogenated C 1-4 Alkoxy or deuterated C 1-4 In one or more embodiments, the Z2 ring is a nitrogen and / or oxygen-containing 5-6 membered heteroaryl or an oxygen and / or nitrogen-containing 5-6 membered heterocyclic group.

[0071] In one or more embodiments of the compound of formula II, Selected from the following groups: Wherein, * indicates the connection position of the group to the rest of the compound.

[0072] In one or more embodiments of the compound of formula II, when When substituted, the number of substituents may be 1, 2, 3 or 4 and may be selected from halogen, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C 1-4 Alkoxy (such as halogenated C 1-4 Alkoxy or deuterated C 1-4 alkoxy), preferably fluorine, difluoromethyl, methoxy or deuterated methoxy.

[0073] One group of preferred compounds of formula A and formula I of the present invention is represented by a compound represented by formula III (including formula IIIa and IIIb) or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-labeled compound or pharmaceutically acceptable salt, or a mixture thereof: Wherein, B1, R2, R6, D1, D2, D3, E1, E2, X1, X2 and Y are as described in any of the above embodiments; Indicates a single bond or a double bond.

[0074] In one or more embodiments of the compound of formula III, B1 is selected from N and CR2; wherein R2 is selected from hydrogen, halogen, cyano, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C 1-4 Alkoxy (such as halogenated C 1-4 Alkoxy or deuterated C 1-4 In one or more embodiments, R2 is hydrogen, fluorine, chlorine, cyano, methyl or deuterated methyl.

[0075] In one or more embodiments of the compound of formula III, the 4-10 membered monocyclic or bicyclic heterocyclic group, the 7-10 membered spirocyclic heterocyclic group and the 7-10 membered bridged heterocyclic group in the definition of R6 can be optionally substituted by 1, 2, 3 or 4 groups selected from halogen, hydroxyl, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, optionally substituted C 3-4 Cycloalkyl (e.g. optionally substituted by 1, 2 or 3 groups selected from halogen, C 1-4 Alkyl and halogenated C 1-4 Alkyl C 3-4 cycloalkyl) and optionally substituted C 1-3 Acyl (such as halogenated C 1-3acyl) is substituted with a substituent; preferably, the 4-10 membered monocyclic or bicyclic heterocyclic radical, 7-10 membered spirocyclic heterocyclic radical and 7-10 membered bridged heterocyclic radical are 4-10 membered monocyclic or bicyclic heterocyclic radicals containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms, 7-10 membered spirocyclic heterocyclic radicals containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms, or 7-10 membered bridged heterocyclic radicals containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms, such as azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, 6-azabicyclo[3.1.1]hept-3-yl and 2-azaspiro[3.3]hept-6-yl, etc.

[0076] In one or more embodiments of the compound of formula III, the optionally substituted C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 substituents selected from deuterium, halogen, optionally substituted heterocyclic group and amino (-NR'R"); wherein, preferably, the heterocyclic group is a 4-10 membered heterocyclic group containing nitrogen and / or oxygen, preferably a 4-7 membered heterocyclic group containing nitrogen and / or oxygen, such as azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl and morpholinyl, and the heterocyclic group is preferably substituted by 1, 2, 3 or 4 substituents selected from halogen, hydroxyl, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy and halogenated C 1-4 Alkoxy is substituted by a substituent; R' and R" are as defined herein, preferably each independently selected from hydrogen, C 1-4 Alkyl and halogenated C 1-4 alkyl.

[0077] In one or more embodiments of the compound of formula III, R6 is selected from the following groups: Wherein, * represents the connection position of the group to the rest of the compound; R8 is selected from hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 Cycloalkyl and optionally substituted C 1-3 acyl, preferably hydrogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl, cyclopropyl or C 1-3 Acyl.

[0078] In one or more embodiments of the compound of formula III, D1, D2 and D3 are each independently selected from N and CR9; wherein R9 is selected from hydrogen, halogen, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C1-4 Alkoxy (such as halogenated C 1-4 Alkoxy or deuterated C 1-4 In one or more embodiments, R9 is hydrogen, fluorine, methoxy or deuterated methoxy.

[0079] In one or more embodiments of the compound of formula III, E1 and E2 are each independently selected from C and N, and are not N at the same time. In one or more embodiments, E1 or E2 is N, is a single bond; in one or more embodiments, E1 and E2 are both C, For double bonds.

[0080] In one or more embodiments of the compound of formula III, X1 and X2 are each independently selected from O, S, NR 10 and CR 11 R 12 ; where R 10 is selected from hydrogen, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C 3-5 Cycloalkyl (e.g. optionally substituted by 1, 2 or 3 groups selected from halogen, C 1-4 Alkyl and halogenated C 1-4 Alkyl C 3-5 Cycloalkyl); R 11 and R 12 are each independently selected from hydrogen, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C 1-4 Alkoxy (such as halogenated C 1-4 Alkoxy or deuterated C 1-4 Alkoxy), or R 11 and R 12 With the connected C to form C 3-4 In one or more embodiments, X1 and X2 are each independently selected from O and S, In one or more embodiments, X1 and X2 are each independently selected from NR 10 and CR 11 R 12 , is a single bond or a double bond; R 10 Preferably, R 11 and R 12 Preferably, hydrogen or R 11 and R 12 Together with the attached C it forms a cyclopropyl group.

[0081] In one or more embodiments of the compound of formula III, Y is selected from C=O, C=S and CR 13 R 14 ; where R 13 and R 14 are each independently selected from hydrogen, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C 1-4 Alkoxy (such as halogenated C 1-4 Alkoxy or deuterated C 1-4 Alkoxy), or R 13 and R 14 With the connected C to form C 3-4 In one or more embodiments, Y is C=O or C=S. In one or more embodiments, R 13 and R 14 are independently selected from hydrogen, methyl, or R 13 and R 14 Together with the attached C it forms a cyclopropyl group.

[0082] In one or more embodiments of the compound of formula III, the Z2 ring is selected from optionally substituted 5-6 membered heteroaryl and optionally substituted 5-6 membered heterocyclyl. In some embodiments, the Z2 ring is optionally substituted by 1, 2, 3 or 4 selected from halogen, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C 1-4 Alkoxy (such as halogenated C 1-4 Alkoxy or deuterated C 1-4 In one or more embodiments, the Z2 ring is a nitrogen and / or oxygen-containing 5-6 membered heteroaryl or an oxygen and / or nitrogen-containing 5-6 membered heterocyclic group.

[0083] In one or more embodiments of the compound of formula III, Selected from the following groups: Wherein, * indicates the connection position of the group to the rest of the compound.

[0084] In one or more embodiments of the compound of formula III, when When substituted, the number of substituents may be 1, 2, 3 or 4 and may be selected from halogen, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C 1-4 Alkoxy (such as halogenated C 1-4Alkoxy or deuterated C 1-4 alkoxy), preferably fluorine, difluoromethyl, methoxy or deuterated methoxy.

[0085] It should be understood that although A1, A2, B1, B2, Cy, R6, D1, D2, D3, E1, E2, X1, X2, Y, Z1 ring and Z2 ring in formula A and formula I (including formula IIa, IIb, IIIa and IIIb) are described above, each of the described features can be combined arbitrarily to form the scope of different formula A and formula I (including formula IIa, IIb, IIIa and IIIb) compounds of the present invention. For example, in some embodiments of the compounds of formula A and formula I (including formula IIa, IIb, IIIa and IIIb) of the present invention.

[0086] Preferred examples of compounds of formula A and formula I (including formula IIa, IIb, IIIa and IIIb) include but are not limited to: or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-labeled compound or pharmaceutically acceptable salt thereof, or a mixture thereof.

[0087] Some of the compounds of the present invention may exist as stereoisomers, including optical isomers. The present invention includes all stereoisomers and racemic mixtures of such stereoisomers, as well as individual enantiomers which may be separated according to methods well known to those skilled in the art.

[0088] In the present invention, examples of pharmaceutically acceptable salts include inorganic and organic acid salts, such as hydrochloride, hydrobromide, phosphate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalate; and inorganic and organic base salts formed with bases such as sodium hydroxide, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methylglucamine.

[0089] Examples of prodrugs of the compounds of the invention include simple esters of carboxylic acid-containing compounds (e.g., by reacting with C 1-4 esters obtained by condensation of hydroxyl groups (for example, by condensation of hydroxyl groups with C 1-4 Carboxylic acid, C 3-6 esters obtained by condensation of diacids or their anhydrides, such as succinic anhydride and fumaric anhydride); imines of compounds containing amino groups (for example, by reacting with C 1-4(J. Med. Chem. 42:3657-3667 (1999)); acetals or ketal of compounds containing alcohols (e.g., those obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).

[0090] The compounds of the present invention can be prepared using methods known to those skilled in the art or the novel methods of the present invention. Specifically, the compounds of the present invention having formula A and formula I can be prepared as shown in the reaction example in reaction scheme 1. Under the catalysis of t-BuOLi, 1-(1,5-naphthyridin-4-yl)ethane-1-one reacts with CS2 and CH3I to obtain 3,3-bis(methylthio)-1-(1,5-naphthyridin-4-yl)prop-2-en-1-one. Under the catalysis of NaH, 3,3-bis(methylthio)-1-(1,5-naphthyridin-4-yl)prop-2-en-1-one reacts with tert-butyl 4-(3-amino-7-fluoro-5H-pyrrolo[2,3-b]pyrazin-5-yl)piperidine-1-carboxylate to obtain the product tert-butyl 4-(7-fluoro-3-((1-(methylthio)-3-(1,5-naphthyridin-4-yl)-3-oxoprop-1-en-1-yl)amino)-5H-pyrrolo[2,3-b]pyrazin-5-yl)piperidine-1-carboxylate. Under the catalysis of AcOH, tert-butyl 4-(7-fluoro-3-((1-(methylthio)-3-(1,5-naphthyridin-4-yl)-3-oxoprop-1-en-1-yl)amino)-5H-pyrrolo[2,3-b]pyrazin-5-yl)piperidine-1-carboxylate reacted with N2H4·H2O to obtain the product tert-butyl 4-(3-((5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)amino)-7-fluoro-5H-pyrrolo[2,3-b]pyrazin-5-yl)piperidine-1-carboxylate. Tert-butyl 4-(3-((5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)amino)-7-fluoro-5H-pyrrolo[2,3-b]pyrazin-5-yl)piperidine-1-carboxylate reacts with TFA to give the target compound N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-7-fluoro-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine. Synthesis of tert-butyl 4-(3-amino-7-fluoro-5H-pyrrolo[2,3-b]pyrazine-5-yl)piperidine-1-carboxylate: Under the catalysis of Pd2(dba)3, BINAP and Cs2CO3, tert-butyl 4-(3-chloro-7-fluoro-5H-pyrrolo[2,3-b]pyrazine-5-yl)piperidine-1-carboxylate reacts with dibenzhydrylamine to obtain the product tert-butyl 4-(3-((diphenylmethylene)amino)-7-fluoro-5H-pyrrolo[2,3-b]pyrazine-5-yl)piperidine-1-carboxylate. Tert-butyl 4-(3-((diphenylmethylene)amino)-7-fluoro-5H-pyrrolo[2,3-b]pyrazin-5-yl)piperidine-1-carboxylate was reacted with NH2OH·HCl and NaOAc to obtain the product tert-butyl 4-(3-amino-7-fluoro-5H-pyrrolo[2,3-b]pyrazin-5-yl)piperidine-1-carboxylate. Reaction Scheme 1

[0091] Other related compounds can be prepared by similar methods. For example, replacing 4-(3-amino-7-fluoro-5H-pyrrolo[2,3-b]pyrazin-5-yl)piperidine-1-carboxylic acid tert-butyl ester with 4-(3-amino-5H-pyrrolo[2,3-b]pyrazin-5-yl)piperidine-1-carboxylic acid tert-butyl ester can obtain the target compound N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine. Replacing tert-butyl 4-(3-amino-7-fluoro-5H-pyrrolo[2,3-b]pyrazine-5-yl)piperidine-1-carboxylate with tert-butyl 4-(3-amino-7-cyano-5H-pyrrolo[2,3-b]pyrazine-5-yl)piperidine-1-carboxylate can yield the target compound 3-((5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)amino)-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonitrile. Replacing tert-butyl 4-(3-amino-7-fluoro-5H-pyrrolo[2,3-b]pyrazin-5-yl)piperidine-1-carboxylate with 7-fluoro-5-(1-methylpiperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine can yield the target compound N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-7-fluoro-5-(1-methylpiperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine.

[0092] An important aspect of the present invention is the discovery that compounds of formula A and formula I (including formula IIa, IIb, IIIa and IIIb) are kinase inhibitors, particularly CHK1 kinase inhibitors. Therefore, compounds of formula A and formula I (including formula IIa, IIb, IIIa and IIIb) or their stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-labeled compounds or pharmaceutically acceptable salts, or mixtures thereof, can be used to treat diseases, disorders and conditions associated with persistent activation of CHK1 or high intrinsic DNA damage or damage during DNA replication, or for the preparation of drugs for treating diseases, disorders and conditions associated with persistent activation of CHK1 or high intrinsic DNA damage or damage during DNA replication.

[0093] In the present invention, the diseases, disorders and conditions associated with the persistent activation of CHK1 or high intrinsic DNA damage or injury during DNA replication include cancer. The cancer may be a solid tumor or a hematological tumor, including but not limited to liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoid leukemia, chronic lymphoid leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, gastric cancer, colon cancer, malignant pancreatic insulinoma, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary neoplasia, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, essential thrombocythemia, adrenocortical carcinoma, skin cancer, and prostate cancer. Preferably, the cancer is associated with persistent activation of CHK1 or high intrinsic DNA damage or injury during DNA replication; the "associated" means playing a role in the occurrence and development of cancer, such as causing the occurrence of cancer and / or promoting the development or metastasis of cancer.

[0094] Therefore, the present invention provides a method for treating or preventing diseases, disorders and conditions associated with persistent activation of CHK1 or high intrinsic DNA damage or damage during DNA replication, the method comprising administering to a subject in need an effective amount of a compound of formula A and formula I (including formula IIa, IIb, IIIa and IIIb), a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-labeled compound or pharmaceutically acceptable salt thereof, or a mixture thereof, or a pharmaceutical composition containing an effective amount of a compound of formula A and formula I (including formula IIa, IIb, IIIa and IIIb), a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-labeled compound or pharmaceutically acceptable salt thereof, or a mixture thereof. In the present invention, the subject includes mammals, more specifically humans.

[0095] When implementing the treatment method of the present invention, an effective amount of a pharmaceutical preparation is administered to a patient with one or more of these symptoms. The pharmaceutical preparation contains effective therapeutic concentrations of compounds of formula A and formula I (including formula IIa, IIb, IIIa and IIIb), which are formulated for oral, intravenous, local or external administration, and are used to treat cancer and other diseases. The dosage is an amount that effectively improves or eliminates one or more symptoms. For the treatment of a specific disease, an effective amount is an amount sufficient to improve or alleviate the symptoms associated with the disease in some way. Such a dosage can be administered as a single dose, or it can be administered according to an effective treatment regimen. The dosage may cure the disease, but the administration is usually to improve the symptoms of the disease. Repeated administration is generally required to achieve the desired symptom improvement.

[0096] In another embodiment, a pharmaceutical composition is provided, which contains compounds of formula A and formula I (including formula IIa, IIb, IIIa and IIIb) of the present invention as CHK1 inhibitors, stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-labeled compounds or pharmaceutically acceptable salts thereof, or mixtures thereof and a pharmaceutically acceptable carrier.

[0097] Another embodiment of the present invention relates to a pharmaceutical composition that can effectively treat cancer, which comprises a compound of formula A and formula I of the present invention as a CHK1 inhibitor, a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, an isotope-labeled compound or a pharmaceutically acceptable salt thereof, or a mixture thereof, and at least one known anticancer drug or a pharmaceutically acceptable salt of an anticancer drug. The at least one known anticancer drug or a pharmaceutically acceptable salt thereof includes other anticancer drugs related to DNA damage and repair mechanisms, including PARP inhibitors Olaparib, Niraparib, Rucaparib, Talazoparib and Senaparib; HDAC inhibitors Vorinostat, Romidepsin, Panobinostat and Belinostat, etc. The at least one known anticancer drug or a pharmaceutically acceptable salt thereof also includes other anticancer drugs related to cell division checkpoints, including CDK4 / 6 inhibitors such as Palbociclib, ATM inhibitors, ATR inhibitors, Wee1 inhibitors, etc. Other known anticancer drugs that can be used for anticancer combination therapy include, but are not limited to, alkylating agents such as busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, and carboplatin; topoisomerase I inhibitors such as camptothecin, irinotecan, and topotecan; topoisomerase II inhibitors such as doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxyellipticine, and menthopop; RNA / DNA antimetabolites such as 5-azacytidine, gemcitabine, 5-fluorouracil and methotrexate; DNA antimetabolites such as 5-fluoro-2′-deoxyuridine, fludarabine, nelarabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea and thioguanine; antimitotic agents such as colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel and docetaxel; antibodies such as monoclonal antibodies, panitumumab, nelazolizumab, nivolumab, pembrolizumab, Ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab tiuxetan, tositumomab, brentuximab, daratumumab, elotuzumab, T-DM1, ofatumumab, dinutuximab, blinatumomab, ipilimumab, Avastin, Herceptin, and rituximab; kinase inhibitors such as imatinib, gemtuzumab, Felotinib, erlotinib, osimertinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lapatinib, sorafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, pralsetinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cobimetinib, axitinib, temsirolimus, idelalisib, pazopanib, temozolomide, and everolimus.Other known anticancer drugs that can be used in anticancer combination therapy include tamoxifen, letrozole, fulvestrant, mitoguanidine, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegi, denosumab, thalidomide, lenalidomide, venetoclax, Aldesleukin (recombinant human interleukin-2) and Sipueucel-T (prostate cancer treatment vaccine).

[0098] In practicing the method of the present invention, the compound of the present invention and at least one known anticancer drug can be administered together as a single pharmaceutical composition. Alternatively, the compound of the present invention can also be administered separately from at least one known anticancer drug. In one embodiment, the compound of the present invention and at least one known anticancer drug are administered at about the same time, that is, all drugs are administered at the same time or successively, as long as the compound reaches a therapeutic concentration in the blood at the same time. In another embodiment, the compound of the present invention and at least one known anticancer drug are administered according to their respective dosage regimens, as long as the compound reaches a therapeutic concentration in the blood.

[0099] Another embodiment of the present invention is a bioconjugate containing the compound of the present invention, which can effectively inhibit tumors as a kinase inhibitor. The bioconjugate of the present invention contains the compound of the present invention and at least one known medical antibody, such as Herceptin or Rituxan, or a growth factor, such as EGF or FGF, or a cytokine, such as interleukin 2 or 4, or any molecule that can bind to the cell surface, or is composed of them. The antibody and other molecules can deliver the compound to its target, making it an effective anti-cancer drug. This bioconjugate can also enhance the anti-cancer effect of medical antibodies, such as Herceptin or Rituxan.

[0100] Another embodiment of the present invention relates to a pharmaceutical composition that can effectively inhibit tumors, comprising a CHK1 inhibitor represented by Formula A and Formula I (including Formula IIa, IIb, IIIa and IIIb), or a pharmaceutically acceptable salt, geometric isomer, enantiomer, diastereomer, racemate, solvate, hydrate or prodrug thereof, combined with radiotherapy. In this embodiment, the compound of the present invention and radiotherapy can be administered at the same time or at different times.

[0101] Another embodiment of the present invention relates to a pharmaceutical composition that can be effectively used for postoperative treatment of cancer, comprising a compound shown in formula A and formula I (including formula IIa, IIb, IIIa and IIIb), a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, an isotope-labeled compound or a pharmaceutically acceptable salt thereof, or a mixture thereof. The present invention also relates to a method of treating cancer in a mammal by surgically removing a tumor and then using the pharmaceutical composition of the present invention.

[0102] The pharmaceutical composition of the present invention includes a pharmaceutical preparation containing all the compounds of the present invention in an amount that can effectively achieve its intended purpose. Although each person's needs are different, those skilled in the art can determine the optimal dose of each part in the pharmaceutical preparation. Generally, the compound, or its pharmaceutically acceptable salt, is orally administered to a mammal daily in an amount of about 0.0025 to 50 mg / kg body weight. However, it is preferably administered orally at about 0.01 to 10 mg / kg per kilogram. If a known anticancer drug is also administered, its dosage should be effective to achieve its intended purpose. The optimal doses of these known anticancer drugs are well known to those skilled in the art.

[0103] The unit oral dose may include about 0.01 to 50 mg, preferably about 0.1 to 10 mg of the compound of the present invention. The unit dose may be administered once or more, one or more tablets per day, each tablet containing about 0.1 to 50 mg, conveniently about 0.25 to 10 mg of the compound of the present invention, its stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-labeled compound or pharmaceutically acceptable salt, or a mixture thereof.

[0104] In external preparations, the concentration of the compound of the present invention may be about 0.01 to 100 mg per gram of carrier.

[0105] The compounds of the present invention can be administered as raw drugs. The compounds of the present invention can also be administered as part of a suitable pharmaceutical preparation containing a pharmaceutically acceptable carrier (including excipients and adjuvants). These pharmaceutically acceptable carriers facilitate the processing of the compounds into pharmaceutical preparations that can be used for pharmaceutical purposes. Preferred pharmaceutical preparations, especially those oral and preferred administration types, such as tablets, lozenges and capsules, and solutions suitable for injection or oral administration, contain about 0.01% to 99%, preferably from about 0.25% to 75% of active compounds and excipients.

[0106] The scope of the present invention also includes non-toxic pharmaceutically acceptable salts of the compounds of the present invention. Acid addition salts are formed by mixing a non-toxic pharmaceutically acceptable acid solution with a solution of the compound of the present invention. The acid is, for example, hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, etc. Base addition salts are formed by mixing a non-toxic pharmaceutically acceptable base solution with a solution of the compound of the present invention. The base is, for example, sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, trishydroxymethylaminomethane, N-methyl-glucamine, etc.

[0107] The pharmaceutical preparations of the present invention can be administered to any mammal, as long as they can obtain the therapeutic effect of the compounds of the present invention. The most important of these mammals are humans and veterinary animals, although the present invention is not intended to be so limited.

[0108] The pharmaceutical preparation of the present invention can be administered by any route to achieve its intended purpose. For example, it can be administered parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, transdermally, orally, intrathecally, intracranially, nasally or externally. Alternatively or concurrently, it can be administered orally. The dosage of the drug will be determined based on the patient's age, health and weight, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic benefit.

[0109] The pharmaceutical preparations of the present invention can be manufactured in a known manner. For example, they can be manufactured by conventional mixing, granulation, tableting, dissolution, or freeze-drying processes. When manufacturing oral preparations, solid excipients and active compounds can be combined and the mixture can be selectively ground. After adding appropriate amounts of auxiliary agents as needed or necessary, the granular mixture can be processed to obtain tablets or lozenge cores.

[0110] Suitable adjuvants are in particular fillers, for example sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate; and binders, for example starch pastes, including corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. If necessary, disintegrants such as the starches mentioned above, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate, can be added. Auxiliary agents are in particular flow regulators and lubricants, for example, silica, talc, stearic acid or its salts, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. If necessary, the tablet core can be provided with a suitable coating that can resist gastric juice. For this purpose, concentrated sugar solutions can be applied. This solution may contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. To prepare a coating resistant to gastric juices, suitable cellulose solutions may be used, for example cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate. Dyes or pigments may be added to the coating of the tablet or lozenge core, for example, for identification or to characterize the combination of active ingredient doses.

[0111] Other pharmaceutical preparations for oral administration include press-fit capsules made of gelatin and sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The press-fit capsules may contain the active compound in the form of particles, mixed with a filler such as lactose; a binder such as starch; and / or a lubricant such as talc or magnesium stearate, and a stabilizer. In soft capsules, the active compound is preferably dissolved or suspended in a suitable liquid such as a fat or liquid paraffin, to which a stabilizer may be added.

[0112] Preparations suitable for parenteral administration include aqueous solutions of the active compound, such as solutions of water-soluble salts and alkaline solutions. In addition, oily injection suspensions of the appropriate active compound may be administered. Suitable lipophilic solvents or carriers include fats such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides or polyethylene glycol 400, or hydrogenated castor oil, or cyclodextrin. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, and / or dextran. Suspension stabilizers may also be contained.

[0113] According to one aspect of the present invention, the compounds of the present invention are used in topical and parenteral formulations and are useful in the treatment of skin cancer.

[0114] The topical preparation of the present invention can be made into oil, cream, emulsion, ointment, etc. by preferably using a suitable carrier. Suitable carriers include plant or mineral oil, white mineral oil (white soft paraffin), branched fat or grease, animal fat and high molecular alcohol (grease with a concentration greater than C). 12 ). Preferred carriers are those in which the active ingredient can be dissolved. Emulsifiers, stabilizers, humectants and antioxidants may also be included, as well as agents that impart color or flavor, if desired. In addition, these topical preparations may contain transdermal penetration enhancers. Examples of such enhancers can be found in U.S. Pat. Nos. 3,989,816 and 4,444,762.

[0115] Creams are preferably formulated with a mixture of mineral oil, self-emulsifying beeswax and water, mixed with the active ingredient dissolved in a small amount of oil such as almond oil. A typical cream example includes about 40 parts water, 20 parts beeswax, 40 parts mineral oil and 1 part almond oil.

[0116] Ointments can be prepared by mixing a vegetable oil containing the active ingredient, such as almond oil, with warm soft paraffin, and then allowing the mixture to cool. A typical ointment example includes about 30% by weight of almond oil and 70% by weight of white soft paraffin.

[0117] The present invention also relates to the use of the compounds of the present invention to prepare drugs for treating diseases, disorders and clinical conditions associated with persistent activation of CHK1 or high intrinsic DNA damage or injury during DNA replication. These drugs may include the above-mentioned pharmaceutical composition.

[0118] The following examples are illustrative, rather than limiting, methods and preparations of the present invention. Other suitable modifications and improvements to various conditions and parameters that are apparent to those skilled in the art and that are typically encountered in clinical treatment are within the spirit and scope of the present invention. Example General Notes All reagents used were of commercial quality, and solvents were dried and purified according to standard methods. Mass spectrometry samples were analyzed using a single quadrupole mass spectrometer (Shimadzu 2020) with electrospray ionization. Varian 400 MHz NMR was used to record 1 For H NMR spectra, chemical shifts are reported in ppm from downfield with TMS as the internal standard (0.00 ppm), and coupling constants, J values, are reported in Hz. Example 1 N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-7-fluoro-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine a) Preparation of tert-butyl 4-(3-((diphenylmethylene)amino)-7-fluoro-5H-pyrrolo[2,3-b]pyrazin-5-yl)piperidine-1-carboxylate: tert-butyl 4-(3-chloro-7-fluoro-5H-pyrrolo[2,3-b]pyrazin-5-yl)piperidine-1-carboxylate (200 mg, 0.564 mmol) was dissolved in toluene (5 mL) at room temperature, and diphenylamine (153 mg, 0.846 mmol), BINAP (70.2 mg, 0.113 mmol), Pd2(dba)3 (52 mg, 0.056 mmol) and Cs2CO3 (552 mg, 1.692 mmol) were added, and stirred at 100°C for 16 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (PE / EA=3 / 1) to obtain the target product (crude product, 280 mg, yellow solid). MS (ESI): 500.25 [M+H] + . b) Preparation of tert-butyl 4-(3-amino-7-fluoro-5H-pyrrolo[2,3-b]pyrazin-5-yl)piperidine-1-carboxylate: tert-butyl 4-(3-((diphenylmethylene)amino)-7-fluoro-5H-pyrrolo[2,3-b]pyrazin-5-yl)piperidine-1-carboxylate (230 mg, 0.46 mmol) was dissolved in MeOH (3 mL) at room temperature, and NH2OH·HCl (64 mg, 0.92 mmol) and NaOAc (75.5 mg, 0.92 mmol) were added, and stirred at room temperature for 45 minutes. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (PE / EA=1 / 1) to obtain the target product (120 mg, yellow solid, yield: 77%). MS (ESI): 336.05 [M+H] + . c) Preparation of 3,3-bis(methylthio)-1-(1,5-naphthyridin-4-yl)prop-2-en-1-one: Dissolve t-BuOLi (1.1 g, 14.1 mmol) in DMSO (20 mL) at room temperature, add 1-(1,5-naphthyridin-4-yl)ethane-1-one (1.1 g, 6.4 mmol), stir for 30 minutes, then slowly add CS2 (585 mg, 7.7 mmol), maintaining the temperature of the reaction system below 30°C. After stirring at 30°C for 2 hours, slowly add MeI (1.8 g, 12.8 mmol), maintaining the temperature of the reaction system below 30°C. The reaction solution was stirred at 30°C for 2 hours. The reaction solution was diluted with water (150 mL) and extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA=3 / 1) to obtain the target product (980 mg, yellow solid, yield: 55%). MS (ESI): 276.90 [M+H] + . d) Preparation of tert-butyl 4-(7-fluoro-3-((1-(methylthio)-3-(1,5-naphthyridin-4-yl)-3-oxoprop-1-en-1-yl)amino)-5H-pyrrolo[2,3-b]pyrazin-5-yl)piperidine-1-carboxylate: tert-butyl 4-(3-amino-7-fluoro-5H-pyrrolo[2,3-b]pyrazin-5-yl)piperidine-1-carboxylate (22 mg, 0.08 mol) was dissolved in DMF (3 mL), and NaH (60% purity, 12.7 mg, 0.32 mmol) was added at 0°C. The mixture was stirred for 2 hours and then returned to room temperature. Slowly add 3,3-bis(methylthio)-1-(1,5-naphthyridin-4-yl)prop-2-en-1-one (26.8 mg, 0.08 mmol), stir for 15 minutes, and then stir at 80°C for 2 hours. After the reaction is complete, add water (10 mL) to quench, and extract with ethyl acetate (15 mL×3). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by silica gel column chromatography (PE / EA=1 / 2) to obtain the target product (30 mg, yellow solid, yield: 77%). MS (ESI): 564.25 [M+H] + . e) Preparation of tert-butyl 4-(3-((5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)amino)-7-fluoro-5H-pyrrolo[2,3-b]pyrazin-5-yl)piperidine-1-carboxylate: tert-butyl 4-(7-fluoro-3-((1-(methylthio)-3-(1,5-naphthyridin-4-yl)-3-oxoprop-1-en-1-yl)amino)-5H-pyrrolo[2,3-b]pyrazin-5-yl)piperidine-1-carboxylate (30 mg, 0.053 mol) was dissolved in EtOH (3 mL) at room temperature, AcOH (10 mg, 0.160 mmol) and N2H4·H2O (5.3 mg, 0.106 mmol) were added, and the mixture was stirred at 65°C under nitrogen protection for 3 hours. After the reaction was complete, the reaction solution was concentrated to obtain the target product (crude product, 30 mg, yellow solid). MS (ESI): 530.25 [M+H] + . f) Preparation of N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-7-fluoro-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine: tert-Butyl 4-(3-((5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)amino)-7-fluoro-5H-pyrrolo[2,3-b]pyrazin-5-yl)piperidine-1-carboxylate (30 mg, 0.057 mmol) was dissolved in DCM (3 mL) at room temperature, TFA (0.6 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by preparative high performance liquid chromatography (C18, acetonitrile-water = 5-55%, 0.1% formic acid) to obtain the target compound (15.8 mg, yellow solid, 2-step yield: 69%). The compounds of Examples 2-58 were prepared in a similar manner. The results are shown below. Embodiment 59 Inhibitory effects of the compounds of the present invention on CHK1 and CHK2 kinases Detection of CHK1 kinase inhibition: Compounds were graded diluted with DMSO in a 384-well plate (LABCYTE, #PP-0200), and 0.05 μL of the diluted compounds were added to a 384-well plate (Greiner, #784075) using an Echo 665 instrument to ensure that the final DMSO concentration was 1% (duplicate wells). Then 2.5 μL of 0.25 nM CHK1 enzyme (Carna, #02-117) solution was added to each well, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 10 minutes. 2.5 μL of STK-S1 (1 μM) / ATP (20 μM) mixed solution was added to each well, centrifuged at 1000 rpm for 1 minute, and reacted at 25°C for 60 minutes. Then, 5 μL of Anti-Eu-STK and SA-XL665 solution (Cisbio, #62ST1PEC) was added to each well, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 60 minutes. Finally, the signal values ​​at 665 nm and 620 nm were read on a BMG (PHERAstar FSX) microplate reader and the ratio was calculated. The wells containing 1% DMSO and enzyme were used as the maximum signal control, and the wells containing 1% DMSO and buffer were used as the minimum signal control. Detection of CHK2 kinase inhibition: Compounds were graded diluted with DMSO in a 384-well plate (LABCYTE, #PP-0200), and 0.05 μL of the diluted compounds were added to a 384-well plate (Greiner, #784075) using an Echo 665 instrument to ensure that the final DMSO concentration was 1% (duplicate wells). Then 2.5 μL of 1 nM CHK2 enzyme (Carna, #02-162) solution was added to each well, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 10 minutes. 2.5 μL of STK-S1 (1 μM) / ATP (20 μM) mixed solution was added to each well, centrifuged at 1000 rpm for 1 minute, and reacted at 25°C for 60 minutes. Then, 5 μL of Anti-Eu-STK and SA-XL665 solution (Cisbio, #62ST1PEC) was added to each well, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 60 minutes. Finally, the signal values ​​at 665 nm and 620 nm were read on a BMG (PHERAstar FSX) microplate reader and the ratio was calculated. The wells containing 1% DMSO and enzyme were used as the maximum signal control, and the wells containing 1% DMSO and buffer were used as the minimum signal control. Calculate the inhibition rate % = (ratio 最大信号对照 -ratio 化合物读值 ) / (ratio 最大信号对照 -ratio 最小信号对照)×100, where the ratio is the ratio of the signal values ​​at 665nm and 620nm as described above. The data were analyzed using the software Xlfit5.5.0, with the curve equation Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)) fitting to get IC 50 value. Table 1 summarizes the inhibitory effects of the compounds on CHK1 and CHK2 kinase activities (IC 50 ). Table 1 Note: / indicates not tested. Therefore, experimental determinations have shown that the compounds of the present invention have a good inhibitory effect on CHK1 kinase and have good selectivity compared to CHK2. Embodiment 60 Inhibitory effect of the compounds of the present invention on the growth of human colorectal cancer cell LoVo Human colorectal cancer cells LoVo were cultured and subcultured until they were in good growth state, and used for experiments when the degree of confluence reached about 90%. The cells were digested with trypsin, centrifuged at 800rpm for 5min, the supernatant was discarded, and resuspended with fresh culture medium (RPMI-1640 culture medium + 10% FBS), and counted. 10,000 cells / 195μL were inoculated into 96-well cell culture plates per well, and placed in a 37℃5% CO2 incubator for overnight culture. The mother solution of the compound to be tested was serially diluted with DMSO at a ratio of 1:3 to 8 concentrations. 5μL of each concentration was added to 120μL culture medium (25-fold dilution) and oscillated to mix. Take the cells cultured overnight, and then add 5μL of the diluted compound (DMSO final concentration is 1‰). After the culture plate was placed in a 37℃5% CO2 incubator for 3 days, 20μL of CCK-8 reagent was added to each well, and the culture was continued after shaking. After 2 hours, shake for 5 minutes and place on a multifunctional reader to read the absorbance at a wavelength of 450 nm. Inhibition rate % = 100-(OD 化合物 -OD 背景 ) / (OD DMSO -OD 背景 )×100. The data were analyzed using the software Xlfit5.5.0, and the IC was obtained by fitting with the curve equation Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X)*HillSlope)) 50 value. Table 2 summarizes the inhibitory effects of the compounds on the growth of human colorectal cancer cells LoVo (IC 50 ). Table 2 Therefore, the experimental determination shows that the compound of the present invention has a good inhibitory effect on the growth of LoVo cells.

[0119] Although the present invention has been fully described, it will be appreciated by those skilled in the art that the same implementation can be performed in a wide range of and equivalent conditions, formulations and other parameter ranges without affecting the scope of the present invention or any embodiment thereof. All patents, patent applications and publications cited herein are incorporated herein by reference in their entirety.

Claims

1. A compound represented by the following formula A, its stereoisomer, isotope-labeled compound or pharmaceutically acceptable salt, or a mixture thereof: Where: A1 is selected from N and CR1; A2 is selected from N and C; Q1 is selected from NR a , O and S; Q2 is selected from NR a , CH, O and S; The Z1 ring is selected from optionally substituted heteroaryl and optionally substituted heterocyclyl; Cy is selected from optionally substituted heteroaryl and optionally substituted heterocyclyl; and when Cy is When D1, D2 and D3 are each independently selected from N and CR9, and at least one of D1 and D3 is N; R1 is selected from hydrogen, halogen, optionally substituted alkyl and optionally substituted alkoxy; R9 and R 15 are independently selected from hydrogen, halogen, optionally substituted C 1-4 Alkyl and optionally substituted C 1-4 Alkoxy; R a independently selected from hydrogen and optionally substituted C 1-4 alkyl.

2. The compound according to claim 1, its stereoisomer, isotope-labeled compound or pharmaceutically acceptable salt, or a mixture thereof, characterized in that: The compound of formula A has the structure shown in the following formula I: wherein A1 is selected from N and CR1; A2 is selected from N and C; Q is selected from NR a , O and S; The Z1 ring is selected from optionally substituted heteroaryl and optionally substituted heterocyclyl; Cy is selected from optionally substituted heteroaryl and optionally substituted heterocyclyl; and when Cy is When D1, D2 and D3 are each independently selected from N and CR9, and at least one of D1 and D3 is N; R1 is selected from hydrogen, halogen, optionally substituted alkyl and optionally substituted alkoxy; R9 and R 15 are independently selected from hydrogen, halogen, optionally substituted C 1-4 Alkyl and optionally substituted C 1-4 Alkoxy; R a independently selected from hydrogen and optionally substituted C 1-4 alkyl.

3. The compound according to claim 1 or 2, its stereoisomer, isotope-labeled compound or pharmaceutically acceptable salt, or a mixture thereof, characterized in that: R1 is hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy; preferably, R1 is H, halogen, halogenated C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, halogenated C 1-4 Alkoxy or hydroxy substituted C 1-4 Alkoxy; and / or A1 is N or CR1, wherein R1 is hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy; preferably, A1 is N, CH or CF; preferably, A1 is N, A2 is C; and / or Q is NH or O; and / or R a For H.

4. The compound according to claim 1 or 2, its stereoisomer, isotope-labeled compound or pharmaceutically acceptable salt, or a mixture thereof, characterized in that: Z1 ring is an optionally substituted 5-6 membered heteroaryl or an optionally substituted 5-10 membered heterocyclyl; preferably, the Z1 ring is an optionally substituted 5-6 membered heteroaryl or an optionally substituted 5-10 membered heterocyclyl wherein A2 is C; Preferably, A2 in the Z1 ring is C, and the Z1 ring is a 5-6 membered heteroaryl containing 1 or 2 nitrogen atoms and optionally 1 or 2 heteroatoms selected from O and S; or A2 in the Z1 ring is C, and the Z1 ring is a 5-10 membered heterocyclic group containing 1 or 2 nitrogen atoms and optionally 1 or 2 heteroatoms selected from O and S; preferably, the 5-10 membered heterocyclic group is a 7-10 membered spirocyclic heterocyclic group containing 1 or 2 nitrogen atoms and optionally 1 or 2 heteroatoms selected from O and S; Preferably, when the 5-6 membered heteroaryl and 5-10 membered heterocyclic group are substituted, the number of substituents is 1, 2, 3 or 4, selected from halogen, cyano, =O, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-8 cycloalkyl and optionally substituted heterocyclic group; preferably, the optionally substituted C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 substituents selected from deuterium, halogen, optionally substituted heterocyclic group and -NR'R", wherein the heterocyclic group is a 4-10 membered heterocyclic group containing nitrogen and / or oxygen, preferably a 4-7 membered heterocyclic group containing nitrogen and / or oxygen, preferably substituted by 1, 2, 3 or 4 substituents selected from halogen, hydroxyl, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, optionally substituted C 3-4 Cycloalkyl (e.g. optionally substituted by 1, 2 or 3 groups selected from halogen, C 1-4 Alkyl and halogenated C 1-4 Alkyl C 3-4 cycloalkyl) and optionally substituted C 1-3 Acyl (such as halogenated C 1-3 R' and R" are preferably each independently selected from hydrogen, C 1-4 Alkyl and halogenated C 1-4 Alkyl; the optionally substituted C 3-8 The cycloalkyl radical is optionally substituted by 1, 2, 3 or 4 radicals selected from halogen, hydroxy, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy and halogenated C 1-4 The optionally substituted heterocyclic group is a 4-10 membered monocyclic or bicyclic heterocyclic group, a 7-10 membered spirocyclic heterocyclic group or a 7-10 membered bridged heterocyclic group, each of which is optionally substituted by 1, 2, 3 or 4 groups selected from halogen, hydroxyl, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, optionally substituted C 3-4 Cycloalkyl (e.g. optionally substituted by 1, 2 or 3 groups selected from halogen, C 1-4 Alkyl and halogenated C 1-4 Alkyl C 3-4 cycloalkyl) and optionally substituted C 1-3 Acyl (such as halogenated C 1-3 acyl) is substituted with a substituent; Preferably, the Selected from the following groups: Preferably, for: More preferably, for: Wherein, * represents the connection position of the group with the amino group on the 5-membered heteroaryl group containing Q in the compound; B1 and B2 are each independently selected from N and CR2; wherein each R2 is each independently selected from hydrogen, halogen, cyano, optionally substituted C 1-4 Alkyl and optionally substituted C 1-4 Alkoxy; R3 is selected from hydrogen, optionally substituted C 1-4 Alkyl and optionally substituted C 3-4 Cycloalkyl; R4 and R5 are each independently selected from hydrogen and optionally substituted C 1-4 Alkyl, or R4 and R5 form a C 3-4 R6 and R7 are each independently selected from an optionally substituted 4-10 membered monocyclic or bicyclic heterocyclic group, an optionally substituted 7-10 membered spirocyclic heterocyclic group, an optionally substituted 7-10 membered bridged heterocyclic group, and an optionally substituted C 1-6 alkyl.

5. The compound according to claim 4, its stereoisomer, isotope-labeled compound or pharmaceutically acceptable salt, or a mixture thereof, characterized in that: The 4-10 membered monocyclic or bicyclic heterocyclic group, 7-10 membered spirocyclic heterocyclic group and 7-10 membered bridged heterocyclic group in the definition of R6 and R7 are each optionally substituted by 1, 2, 3 or 4 groups selected from halogen, hydroxyl, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, optionally substituted C 3-4 Cycloalkyl (e.g. optionally substituted by 1, 2 or 3 groups selected from halogen, C 1-4 Alkyl and halogenated C 1-4 Alkyl C 3-4 cycloalkyl) and optionally substituted C 1-3 Acyl (such as halogenated C 1-3 acyl) is substituted with a substituent; The optionally substituted C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 substituents selected from deuterium, halogen, optionally substituted heterocyclic group and -NR'R"; preferably, the heterocyclic group is a 4-10 membered heterocyclic group containing nitrogen and / or oxygen, preferably a 4-7 membered heterocyclic group containing nitrogen and / or oxygen, and the heterocyclic group is preferably substituted by 1, 2, 3 or 4 substituents selected from halogen, hydroxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy and halogenated C 1-4 Alkoxy is substituted by a substituent; R' and R" are as defined herein, preferably each independently selected from hydrogen, C 1-4 Alkyl and halogenated C 1-4 alkyl; Preferably, R6 is selected from the following groups: Wherein, * represents the connection position of the group to the rest of the compound; R8 is selected from hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 Cycloalkyl and optionally substituted C 1-3 acyl, preferably hydrogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl, cyclopropyl or C 1-3 acyl group; Preferably, R7 is selected from the following groups: Wherein, * represents the connection position of the group to the rest of the compound; R8 is selected from hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3-4 Cycloalkyl and optionally substituted C 1-3 acyl, preferably hydrogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl, cyclopropyl or C 1-3 Acyl.

6. The compound according to claim 1 or 2, its stereoisomer, isotope-labeled compound or pharmaceutically acceptable salt, or a mixture thereof, characterized in that: (1) Cy is an optionally substituted 5-12 membered heteroaryl or an optionally substituted 9-12 membered heterocyclic group, preferably a 9-12 membered bicyclic heteroaryl or a 9-12 membered bicyclic heterocyclic group containing 1 or 2 nitrogen atoms and optionally 1 or 2 oxygen atoms; preferably, when Cy is substituted, the number of substituents is 1, 2, 3 or 4, and the substituents are selected from =O, halogen, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C 1-4 Alkoxy (such as halogenated C 1-4 Alkoxy or deuterated C 1-4 Alkoxy); Preferably, Cy is: Wherein, * indicates the connection position of the group to the rest of the compound; represents a single bond or a double bond; D1, D2 and D3 are each independently selected from N and CR9, wherein R9 is selected from =O, hydrogen, halogen, optionally substituted C 1-4 Alkyl and optionally substituted C 1-4 Alkoxy is preferably hydrogen, =O, fluorine, methoxy or deuterated methoxy; E1 and E2 are each independently selected from C and N, and are not N at the same time; X1 and X2 are each independently selected from O, S, NR 10 and CR 11 R 12 ; where R 10 is selected from hydrogen, optionally substituted C 1-4 Alkyl and optionally substituted C 3-5 Cycloalkyl; R 11 and R 12 are each independently selected from hydrogen, optionally substituted C 1-4 Alkyl and optionally substituted C 1-4 Alkoxy, or R 11 and R 12 With the connected C to form C 3-4 Cycloalkyl; Y is selected from C=O, C=S and CR 13 R 14 , where R 13 and R 14 are each independently selected from hydrogen, optionally substituted C 1-4 Alkyl (such as halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl) and optionally substituted C 1-4 Alkoxy, or R 13 and R 14 With the connected C to form C 3-4 Cycloalkyl; preferably, Y is C=O; Z2 ring is selected from optionally substituted 5-6 membered heteroaryl and optionally substituted 5-6 membered heterocyclyl; Preferably, Selected from the following groups: Wherein, * indicates the connection position of the group to the rest of the compound; or (2) Cy is an optionally substituted 5-6 membered nitrogen-containing heteroaryl group; preferably, when the heteroaryl group is substituted, the number of substituents is 1, 2, 3 or 3 selected from halogen, optionally substituted C 1-4 Alkyl and optionally substituted C 1-4 Alkoxy; Preferably, Cy is: Wherein, * represents the connection position of the group to the rest of the compound; D1, D2 and D3 are each independently selected from N and CR9; and at least one of D1 and D3 is N; R9 is selected from hydrogen, halogen, optionally substituted C 1-4 Alkyl and optionally substituted C 1-4 Alkoxy, preferably hydrogen, fluorine, methoxy or deuterated methoxy; R 15 is selected from hydrogen, halogen, optionally substituted C 1-4 Alkyl and optionally substituted C 1-4 Alkoxy, preferably fluorine, difluoromethyl, methoxy or deuterated methoxy; Preferably, Selected from the following groups: Wherein, * indicates the connection position of the group to the rest of the compound.

7. The compound according to claim 1 or 2, its stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-labeled compound or pharmaceutically acceptable salt, or a mixture thereof, characterized in that: The compound is a compound represented by the following formula IIa, IIb, IIIa or IIIb or its stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-labeled compound or pharmaceutically acceptable salt, or a mixture thereof: In formula IIa and IIb, D1, D2, D3, E1, E2, Q, X1, X2, Y, Z1 ring and Z2 ring are as described in any one of claims 1 to 6; in formula IIIa and IIIb, B1, R2, R6, D1, D2, D3, E1, E2, X1, X2 and Y are as described in any one of claims 1 to 6; Indicates a single bond or a double bond.

8. The compound according to claim 1, its stereoisomer, isotope-labeled compound or pharmaceutically acceptable salt, or a mixture thereof, characterized in that: The compound is selected from: N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-7-fluoro-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-7-fluoro-5-(1-methylpiperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; 7-Fluoro-N-(5-(3-methoxypyridin-4-yl)-1H-pyrazol-3-yl)-5-(1-methylpiperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; 7-Fluoro-N-(5-(3-methoxypyridin-4-yl)-1H-pyrazol-3-yl)-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-5-(piperidin-4-ylmethyl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(3-methoxypyridin-4-yl)-1H-pyrazol-3-yl)-5-(piperidin-4-ylmethyl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-5-(pyrrolidin-3-ylmethyl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-5-(azetidin-3-ylmethyl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; 3-((5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)amino)-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonitrile; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-7-chloro-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-7-methyl-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-5-(6-azabicyclo[ 3.1.1]hept-3-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-5-(3-azabicyclo[ 3.1.1]hept-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-5-(2-amino-2-methylpropyl)-7-fluoro-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-5-(3-amino-3-methylbutyl)-7-fluoro-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-7-fluoro-5-(2-azaspiro[3.3]hept-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-7-fluoro-5-(tetrahydro-2H-pyran-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(2,3-dihydrofuro[3,2-b]pyridin-7-yl)-1H-pyrazol-3-yl)-7-fluoro-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-([1,3]dioxacyclo[4,5-b]pyridin-7-yl)-1H-pyrazol-3-yl)-7-fluoro-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)-1H-pyrazol-3-yl)-7-fluoro-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)-1H-pyrazol-3-yl)-7-fluoro-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; 7-Fluoro-N-(5-(furo[3,2-b]pyridin-7-yl)-1H-pyrazol-3-yl)-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; 7-Fluoro-N-(5-(oxazolo[4,5-b]pyridin-7-yl)-1H-pyrazol-3-yl)-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; 7-Fluoro-N-(5-(oxazolo[5,4-b]pyridin-7-yl)-1H-pyrazol-3-yl)-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; 7-Fluoro-N-(5-(imidazo[1,2-a]pyridin-8-yl)-1H-pyrazol-3-yl)-5-(1-methylpiperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; 7-Fluoro-N-(5-(imidazo[1,2-a]pyridin-8-yl)-1H-pyrazol-3-yl)-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; 4-(3-((7-fluoro-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)amino)-1H-pyrazol-5-yl)pyrido[2,3-b]pyrazin-3(4H)-one; 4-(3-((7-fluoro-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)amino)-1H-pyrazol-5-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; N-(5-(2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)-1H-pyrazol-3-yl)-7-fluoro-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-1-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyrazin-6-amine; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-1-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-6-(1-methylpiperidin-4-yl)imidazo[1,5-a]pyrimidin-3-amine; 5-((5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)amino)-1-methyl-3-(piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one; 5-((5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)amino)-3-(piperidin-4-yl)oxazolo[4,5-b]pyrazin-2(3H)-one; 5-((5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)amino)-3-(piperidin-4-yl)thiazolo[4,5-b]pyrazin-2(3H)-one; 3'-((5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)amino)-5'-(piperidin-4-yl)spiro[cyclopropane-1,7'-pyrrolo[2,3-b]pyrazin]-6'(5'H)-one; N-(5-(1,6-naphthyridin-8-yl)-1H-pyrazol-3-yl)-7-fluoro-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(1,7-naphthyridin-8-yl)-1H-pyrazol-3-yl)-7-fluoro-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(1,6-naphthyridin-4-yl)-1H-pyrazol-3-yl)-7-fluoro-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(1,7-naphthyridin-4-yl)-1H-pyrazol-3-yl)-7-fluoro-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(1,8-naphthyridin-4-yl)-1H-pyrazol-3-yl)-7-fluoro-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-7-fluoro-5-(piperidin-4-ylmethyl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(imidazo[1,2-a]pyridin-8-yl)-1H-pyrazol-3-yl)-5-(piperidin-4-ylmethyl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(2,3-dihydrofuro[3,2-b]pyridin-7-yl)-1H-pyrazol-3-yl)-5-(piperidin-4-ylmethyl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)-1H-pyrazol-3-yl)-5-(piperidin-4-ylmethyl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-5-((4-fluoropiperidin-4-yl)methyl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-5-((3-fluoroazetidin-3-yl)methyl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; 5-(1,5-naphthyridin-4-yl)-N-(5-(piperidin-4-ylmethyl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)isoxazol-3-amine; N-(7-fluoro-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)-5-(1,5-naphthyridin-4-yl)isoxazol-3-amine; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-5-((1-methylpiperidin-4-yl)methyl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-5-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(7-fluoro-5-(1-methylpiperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)-5-(1,5-naphthyridin-4-yl)thiazol-2-amine; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-7-fluoro-5-(1-methylazetidin-3-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-7-fluoro-5-(1-methylpyrrolidin-3-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; N-(5-(1,5-naphthyridin-4-yl)-1H-pyrazol-3-yl)-7-fluoro-5-((1-methylazetidin-3-yl)methyl)-5H-pyrrolo[2,3-b]pyrazin-3-amine; and N-(5-(2,3-dihydrofuro[3,2-b]pyridin-7-yl)-1H-pyrazol-3-yl)-7-fluoro-5-(1-methylpiperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-amine.

9. Use of a compound according to any one of claims 1 to 8 in the preparation of a medicament for treating or preventing diseases, disorders and conditions associated with persistent activation of CHK1 or high intrinsic DNA damage or damage during DNA replication; preferably, the disease, disorder and condition is cancer; Preferably, the cancer is selected from liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, gastric cancer, colon cancer, malignant pancreatic insulinoma, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary neoplasia, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, essential thrombocythemia, adrenocortical carcinoma, skin cancer and prostate cancer; Preferably, the drug further comprises at least one known anticancer drug, or a pharmaceutically acceptable salt of the anticancer drug; preferably, the anticancer drug is selected from one or more of the following groups: busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxyellipticine, mingtopop, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate , 5-fluoro-2'-deoxyuridine, fludarabine, nelarabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, monoclonal antibody, panitumumab, necrotizumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab tiuxetan, tositumomab, brentuximab , Daratumumab, Elotuzumab, T-DM1, Ofatumumab, Dinutuximab, Blinatumomab, Ipilimumab, Avastin, Herceptin, Rituximab, Imatinib, Gefitinib, Erlotinib, Osimertinib, Afatinib, Ceritinib, Alectinib, Crizotinib, Erlotinib, Lapatinib, Sorafenib, Sunitinib, Nilotinib, Dasatinib, Pazopanib, Tecan, Everolimus, Vorinostat, Romidepsin, Panobinostat, Belinostat, Tamoxifen Fen, letrozole, fulvestrant, mitoguanidine, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegi, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin-2), sipueucel-T (prostate cancer treatment vaccine), palbociclib, olaparib, niraparib, rucaparib, talazoparib and senaparib; Preferably, the medicament is used in combination with radiation therapy.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier; preferably, the pharmaceutical composition further comprises at least one known anticancer drug, or a pharmaceutically acceptable salt of the anticancer drug; preferably, the at least one known anticancer drug is selected from the group consisting of busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxyrosemide, alkali, mingtopop, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxyuridine, fludarabine, nelarabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, monoclonal antibody, panitumumab, nexitumomab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alendronate Monoclonal antibody, Ibritumomab Tiuxetan, Tositumomab, Brentuximab, Daratumumab, Elotuzumab, T-DM1, Ofatumumab, Dinutuximab, Blinatumomab, Ipilimumab, Avastin, Herceptin, Rituximab, Imatinib, Gefitinib, Erlotinib, Osimertinib, Afatinib, Ceritinib, Alectinib, Crizotinib, Erlotinib, Lapatinib, Sorafenib, Sunitinib, Nilotinib, Dasatinib, Pazopanib, Tecan, Everolimus, Vorinostat, Romidepsin, Panibix He, belinostat, tamoxifen, letrozole, fulvestrant, mitoguanidine, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegi, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin-2), sipueucel-T (prostate cancer treatment vaccine), palbociclib, olaparib, niraparib, rucaparib, talazoparib and senaparib.

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