Substituted nitrogen-containing tricyclic compound as PARP inhibitor and application thereof

Abstract

The invention provides a substituted nitrogen-containing tricyclic compound as a PARP inhibitor and application of the substituted nitrogen-containing tricyclic compound. The present invention provides compounds represented by the following formula (I) wherein the Z ring, Z1, Z2, Z3, Z4, Z5, A1, A2, A3, L, m, n, B ring and Cy are as defined herein. The compounds of formula I of the present invention are PARP inhibitors and thus are useful in the treatment of diseases, disorders and conditions responsive to PARP activity inhibition, such as cancer. The invention also relates to a pharmaceutical composition containing the compound shown in the formula I and application of the compound shown in the formula I in preparation of drugs for treating or preventing diseases or symptoms responding to PARP activity inhibition.

Description

Technical Field

[0001] The present invention relates to substituted nitrogen-containing tricyclic compounds as PARP inhibitors and applications thereof. Background Art

[0002] Poly(ADP-ribose) polymerases (PARPs) are a family of proteins that catalyze the transfer of negatively charged ADP-ribose groups from the donor NAD + Transfer to target proteins. This is one of the many ways proteins undergo post-translational modification. Therefore, PARP is also known as ADP-ribosyltransferase.

[0003] Based on homology analysis with the amino acid sequences of the catalytic domain (Vyas et al., 2013, Nature Communication, 4:3240 / 1-3240 / 13), humans are believed to express 17 PARPs. These PARPs can catalyze the addition of single ADP-ribose to target proteins, as well as the polymerization of ADP-ribose units to form poly-ADP-ribose, also known as poly(ADP-ribose) modification. Therefore, PARP family members can be further divided into two subfamilies. Post-translational modification of poly(ADP-ribose) regulates many aspects of protein function, but the physiological functions of many PARP proteins are still unclear.

[0004] PARP1 is the most representative member of the PARP family and is the most abundant protein in cells. PARP1 consists of 1014 amino acids (NCBI accession number P09874) with a total molecular weight of approximately 116 kDa. The enzyme structurally comprises two main functional domains: a DNA-binding domain and a catalytic domain. PARP1 is known to play an important role in numerous cellular functions, including gene expression, transcription, cell division, cell differentiation, apoptosis, and DNA damage response and repair. When DNA damage occurs, PARP1 is activated and participates in base excision repair (BER), a major mechanism for repairing single-strand DNA damage. PARP1 binds to single-strand breaks (SSBs) and subsequently repairs DNA through BER. To respond to DNA damage, in addition to BER repair of single-strand breaks, cells have evolved two major repair mechanisms: homologous recombination (HR) for double-strand lesions and non-homologous end joining (NHEJ). The results show that cancer cells with defects in homologous recombination repair mechanisms are sensitive to PARP1 inhibitors, that is, homologous recombination deficiency and PARP1 inhibition form a pair of synthetic lethality, and this mechanism has been clinically verified. Currently, a variety of PARP inhibitors have been approved for the treatment of ovarian cancer, breast cancer, prostate cancer, and pancreatic cancer with DNA damage repair defects such as BRCA1 / 2 mutations. In addition, PARP1 inhibitors can also be used to treat diseases caused by excessive cell death, including central nervous system (CNS) diseases such as stroke and neurodegenerative diseases (Akinori Iwashita et al., 2004, J. Pharmacol. Exp. Thera. 310: 425).

[0005] PARP2 is a 559-amino acid protein (NCBI accession number NP_005475) with a molecular weight of approximately 62 kDa. Its structure comprises a DNA-binding domain and a catalytic domain (Ame et al., 1999 J Biol Chem 274:17860-17868). The catalytic domain of PARP2 is highly similar to that of PARP1. Studies have shown that PARP2 has similar functions to PARP1 and participates in DNA damage repair through the BER mechanism (Schreiber et al., 2002 J Biol Chem 277:23028-23036). Currently marketed PARP inhibitors, such as olaparib, niraparib, talazoparib, and rucaparib, not only inhibit PARP1 but also exhibit similar inhibitory activity against PARP2. Clinical trial results have shown that these marketed PARP inhibitors have comparable therapeutic efficacy, but their toxicity profiles differ significantly. For example, talazoparib has a side effect of hair loss similar to chemotherapy drugs. A recent study comparing the selectivity of various PARP inhibitors demonstrated that talazoparib not only inhibits PARP1 and PARP2 but also has high affinity for two other members of the PARP family, TNKS1 (Tankyrase 1) and TNKS2 (Tankyrase 2) (Ryan et al., 2021, J Biol Chem 296:100251 / 1-100251 / 13). TNKS1 and TNKS2 share a high degree of amino acid sequence similarity, with an overall 83% sequence identity and an 89% identity in their catalytic domains. They play roles in DNA repair, telomere maintenance, and the Wnt / β-catenin signaling pathway. Inhibition of targets other than PARP1 may contribute to the off-target toxicities of PARP inhibitors, such as alopecia and diarrhea. In addition, inhibition of PARP2 activity can lead to hematotoxicity (Farrés et al., 2013 Blood 122:44-54; Farrés et al., 2015 Cell Death and Differentiation 22:1144-1157). The toxicity of these PARP inhibitors limits their clinical application and their combined use with other targeted drugs.

[0006] Therefore, the development of highly selective PARP1 inhibitors could reduce both mechanism-related and mechanism-independent toxicities.

[0007] A variety of selective PARP1 inhibitors have been disclosed, such as WO2011006803, WO2013014038, WO2021013735, WO2021260092, CN115232129, WO2022225934, WO2022222921, WO2022222964, WO2022222965, WO2 022222966, WO2022228387, WO2022247816, WO2022223025, WO2022222995, WO2023122140, WO2023056039, WO2023141290, WO2023146957, WO2023146960 and WO2023156386. Summary of the Invention

[0008] The present invention provides compounds represented by Formula I (including Formula II and Formula III) and analogs thereof, which can be used as PARP inhibitors. Specifically, the compounds of the present invention are selective PARP1 inhibitors relative to PARP2.

[0009] The present invention also provides a pharmaceutical composition comprising an effective amount of a compound of formula I (including formula II and III). The pharmaceutical composition can be used to treat cancer.

[0010] In a specific embodiment, the pharmaceutical composition may further contain one or more pharmaceutically acceptable carriers, excipients or diluents. The pharmaceutical composition can be used to treat cancer.

[0011] In a specific embodiment, the pharmaceutical composition may further contain at least one known anticancer drug or a pharmaceutically acceptable salt thereof. The pharmaceutical composition can be used to treat cancer.

[0012] The present invention also relates to a process for preparing the novel compounds of formula I (including formula II and III). 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 the substituent of the alkyl group herein is applicable to any embodiment described herein, unless the embodiment has clearly defined the substituent of the alkyl group.

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

[0015] As used herein, "heteroatom" includes oxygen (O), sulfur (S) and nitrogen (N).

[0016] As used herein, "alkyl" refers to an alkyl group by itself or 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 some embodiments, the alkyl group is C 1-4 In some embodiments, the alkyl group is C 1-3 In some embodiments, the alkyl group is a deuterated C 1-3 Alkyl. Typical C 1-10 Alkyl groups include optionally substituted methyl, trideuterated methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl (eg, 3-pentyl), hexyl, and octyl.

[0017] As used herein, "alkenyl" refers to a straight or branched chain group containing 2 to 10 carbon atoms, unless the chain length is otherwise limited, and the chain contains at least one double bond formed between two carbon atoms; preferably, the alkenyl is C 2-6 Alkenyl, more preferably C 2-4 Typical alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.

[0018] As used herein, "alkynyl" refers to a straight or branched chain containing 2 to 10 carbon atoms, unless the chain length is otherwise limited, and the chain contains at least one triple bond formed between two carbon atoms; preferably, the alkynyl is C 2-6 Alkynyl, more preferably C 2-4 Typical alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl, and 2-butynyl.

[0019] Useful alkoxy groups include those composed of the above-mentioned C 1-10 Alkyl-substituted oxy, preferably C 1-6 Alkyl or C 1-4 Alkyl or C 1-3 Alkyl groups include, for example, methoxy and ethoxy. The alkyl group in the alkoxy group may be optionally substituted. Substituents of the alkoxy group include, but are not limited to, halogen, morpholinyl, amino (including alkylamino and dialkylamino), and carboxyl (including ester groups thereof).

[0020] Useful amino and optionally substituted amino groups are -NR'R", wherein R' and R" are each independently hydrogen, optionally substituted C 1-10 Alkyl, optionally substituted C 3-8 Preferably, R' and R" are each independently H, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6cycloalkyl, an optionally substituted 3-6 membered heterocyclyl or an optionally substituted 5 membered heteroaryl; or R′ and R″ together with the N to which they are attached form an optionally substituted 4-7 membered cyclic amino group, the cyclic amino group optionally containing one or more (such as 2, 3) other heteroatoms selected from the following: O, N and S. Preferably, the amino group includes —NH2, —NHR′ and —NR′R″, wherein R′ and R″ are each independently selected from the following groups: optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 cycloalkyl or an optionally substituted 3- to 6-membered heterocyclic group.

[0021] As used herein, "oxo" refers to =0.

[0022] The term "aryl" as used herein alone or as part of another group refers to a monocyclic, bicyclic or tricyclic aromatic group containing 6 to 14 carbon atoms. Aryl groups can be substituted with one or more substituents as described herein.

[0023] Useful aryl 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.

[0024] As used herein, "carbocyclic group" includes cycloalkyl and partially saturated carbocyclic groups. Useful cycloalkyl groups are C 3-8 Cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Useful partially saturated carbocyclic groups include cycloalkenyl, such as C 3-8 Cycloalkenyl. 3-8 Cycloalkenyl groups include cyclopentenyl, cycloheptenyl, and cyclooctenyl.Carbocyclic groups may be substituted with one or more substituents as described herein.

[0025] Useful halogens or halogen groups include fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0026] Useful acylamino groups are C 1-6 Acyl (alkanoyl), such as acetamido, propionamido, butyramido, pentanoamido and hexanoamido, and aryl-substituted C 1-6 Acylamino, for example, benzamido.

[0027] Useful acyl groups include C 1-6Acyl, such as acetyl. The acyl group may be optionally substituted by a group selected from halogen, amino and aryl, wherein amino and aryl may be optionally substituted. When the acyl group is substituted by halogen, the number of halogen substituents may be 1-5. Examples of acyl groups substituted by halogen include chloroacetyl and pentafluorobenzoyl. When the acyl group is substituted by amino, the amino group may be substituted by 1 or 2 substituents as described herein. In some embodiments, aminoacyl is -C(O)-NR'R", wherein 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 hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 cycloalkyl or an optionally substituted 3- to 6-membered heterocyclic group.

[0028] As used herein, "heterocyclyl" refers to a saturated or partially saturated 3-7 membered monocyclic group, a 7-10 membered bicyclic group, a spirocyclic group, or a bridged ring group. They are composed of carbon atoms and 1-4 heteroatoms independently selected from O, N, and S, wherein the nitrogen and / or sulfur heteroatoms may be optionally oxidized, and the nitrogen may be optionally quaternized. The term also includes any bicyclic ring system in which any heterocycle as defined above is fused to a benzene ring. If the resulting compound is stable, the heterocyclyl may be substituted on a carbon atom or a nitrogen atom. The heterocyclyl may be substituted by one or more substituents described herein.

[0029] Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, 1,4-diazepanyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetrahydroisoquinolinyl, tetronoyl, and tetramoyl, which groups may be substituted with one or more substituents described herein.

[0030] As used herein, "heteroaryl" refers to a group containing 5-14 ring atoms, preferably 5-10 ring atoms, and having 6, 10, or 14 conjugated π electrons. The ring atoms of a heteroaryl group are carbon atoms and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. A heteroaryl group may be optionally substituted with one or more substituents described herein.

[0031] Useful heteroaryl groups include thienyl (phenylthio), benzo[d]isothiazol-3-yl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furanyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl (including but not limited to 2-pyridinyl, 3-pyridinyl and 4-pyridinyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridine 1,2-benzisoxazol-3-yl, benzimidazolyl, 2-oxoindole, thiadiazolyl, 2-oxobenzimidazolyl, imidazopyridazinyl, imidazopyridinyl, triazolopyridazinyl, tetrahydropyridopyrimidinyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrazinyl, triazolopyrazinyl, thienoquinolyl, furanoquinolyl, thiazoquinolyl, pyrazoloquinolyl, pyrroloquinolyl, imidazoquinolyl, oxazoloquinolyl, and the like. When the heteroaryl group contains a nitrogen atom in the ring, the nitrogen atom may be in the form of an N-oxide, such as pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide.

[0032] As used herein, unless otherwise indicated, when substituted, the alkyl, cycloalkyl, heterocycloalkyl, alkoxy, heterocycloalkoxy, alkenyl, heterocycloalkenyl, alkynyl, amino, amido, acyloxy, carboxyl, hydroxyl, thiol, alkylsulfonyl, sulfonyl, sulfinyl, aminoacyl, silyl, phosphono, phosphono, carbocyclyl, heterocyclyl, aryl, or heteroaryl groups described in any embodiment herein may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents selected from the group consisting of halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 1-6 Acylamino, C 1-6 Acyloxy, C 1-6 Alkoxy, aryloxy, alkylthio, C 1-6 Alkyl, C 1-6 Acyl, C 6-10 Aryl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, heterocyclic or heteroaryl, methylenedioxy, urea, thiol, azido, carbonyl, alkylsulfonyl, sulfamoyl, dialkylsulfamoyl and alkylsulfinyl, etc. The substituents themselves may also be optionally substituted, for example, C 1-6 Acylamino, C1-6 Acyloxy, C 1-6 Alkoxy, aryloxy, alkylthio, C 1-6 Alkyl, C 1-6 Acyl, C 6-10 Aryl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, heterocyclyl or heteroaryl etc. may be optionally substituted by 1-5 groups selected from the group consisting of halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy. More preferred substituents include but are not limited to halogen, hydroxy, carboxyl, amino, C 1-6 Acylamino, C 1-6 Acyloxy, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Acyl and alkylsulfonyl, etc.

[0033] It should be understood that in each embodiment herein, when the substituent is a heterocyclic group, an aryl group, or a heteroaryl group, the number of the heterocyclic group, the aryl group, or the heteroaryl group substituent is generally one.

[0034] Specifically, the present invention provides a compound represented by Formula I, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-substituted derivative or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof: Among them, such as The Z ring shown is an optionally substituted 5-membered heteroaryl group, * indicates the position at which the Z ring is attached to the rest of the compound, Z1, Z2 and Z3 are each independently CR1, NR2, O, N or S, Z4 and Z5 are each independently C or N, and Z4 and Z5 are not N at the same time; A1, A2 and A3 are each independently selected from N and CR3; L is selected from a bond and an alkylene group optionally substituted with R4 and / or R5; Ring B is an optionally substituted heteroaryl or an optionally substituted heterocyclyl; Cy is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; R1 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted carbocyclyl; R2 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R3 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted carbocyclyl; R4 and R5 are each independently selected from the following groups: halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl and optionally substituted alkynyl; or R4 and R5 together with the C to which they are attached form a ring; m and n are each independently selected from 1 and 2.

[0035] In the formula I and various structural formulas of the present invention, unless otherwise specified, preferably, each alkyl group is independently C 1-6 Alkyl, more preferably C 1-4 Alkyl; each alkylene group is C 1-6 Alkylene, preferably C 1-3 Alkylene; each alkenyl group is independently C 2-6 Alkenyl, preferably C 2-4 Alkenyl; each alkynyl group is independently C 2-6 Alkynyl, preferably C 2-4 Alkynyl; each alkoxy group is independently C 1-6 Alkoxy, preferably C 1-4 Alkoxy. Preferably, when alkyl, alkenyl, alkynyl and alkoxy are substituted, the substituents may be selected from the following groups: cyano, hydroxyl, nitro, amino (-NR'R"), aryl, heterocyclic, heteroaryl, halogen and carboxyl. The number of substituents may be 1-5, preferably R' and R" are each independently H, optionally substituted C 1-4 Alkyl or optionally substituted C 3-6 Cycloalkyl. Preferably, the substituents of the alkyl, alkenyl, alkynyl, and alkoxy groups are halogen, hydroxy, or amino. For example, the substituted alkyl group itself or as a substituent of another group can be hydroxyalkyl, dihydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, and haloalkyl. It should be understood that when the substituent is aryl, heteroaryl, heterocyclyl, cyano, nitro, and carboxyl, the number of substituents is generally one. When the substituent is halogen, the number of substituents can be up to five depending on the carbon chain length of the alkyl, alkenyl, alkynyl, and alkoxy groups; exemplary substituents include trifluoromethyl and pentafluoroethyl.

[0036] In the formula I and various structural formulas of the present invention, unless otherwise specified, preferably, the number of carbon atoms in each carbocyclic group is preferably 3-8. 3-8 Cycloalkyl or C 3-8 The substituents on the carbocyclic group are preferably C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4Alkoxy, halogen, hydroxy, carboxyl, amino (-NR'R"), aryl, heterocyclic, heteroaryl, halogen and carboxyl, etc. The number of substituents can be 1-5, preferably R' and R" are each independently H, optionally substituted C 1-4 Alkyl or optionally substituted C 3-6 It should be understood that when the substituent is an aryl, heteroaryl, heterocyclyl, cyano, nitro, or carboxyl group, the number of substituents is generally 1. When the substituent is a halogen, the number of substituents may be up to 5.

[0037] In the formula I and various structural formulas of the present invention, unless otherwise specified, preferably, aryl refers to C 6-14 Aryl and heteroaryl refer to 5-10 membered heteroaryl groups, and heterocyclyl refers to 4-10 membered heterocyclyl groups, such as 4-7 membered monocyclic rings, 7-10 membered bicyclic rings, spirocyclic rings or bridged rings. The substituents on each aryl, heteroaryl and heterocyclyl group can be independently selected from 1-5 groups below: C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogen, hydroxy, carboxyl, amino (-NR'R"), optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic group, halogen, acylamino, aminoacyl (-C(O)-NR'R") and carboxyl, etc. wherein R' and R" are each independently hydrogen, optionally substituted C 1-10 Alkyl, optionally substituted C 3-8 Preferably, R' and R" are each independently H, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Cycloalkyl or optionally substituted 3-6 membered heterocyclic group. The number of substituents can be 1-5. 3-8 Cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclyl may be optionally substituted with 1-5 substituents independently selected from the group consisting of: C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, halogen, hydroxy, carboxyl, amino (-NR'R") and aminoacyl (-C(O)-NR'R"); wherein R' and R" are preferably each independently H, optionally substituted C 1-4 Alkyl or optionally substituted C 3-6 It should be understood that when the substituent is an aryl, heteroaryl, heterocyclyl, cyano, nitro or carboxyl group, the number of substituents is generally 1. When the substituent is a halogen, the number of substituents may be up to 5.

[0038] In one or more embodiments of the compound of formula I, the alkyl, alkoxy, carbocyclyl, cycloalkyl, alkenyl and alkynyl groups in the definitions of R1 and R2 are each optionally substituted with 1-5 groups selected from the group consisting of halogen, hydroxyl and -NR'R"; wherein R' and R" are each independently H or C 1-4 Preferably, the optionally substituted alkyl is an alkyl optionally substituted by 1-5 halogens. In some embodiments, R1 is preferably hydrogen, halogen or an optionally substituted C 1-3 In some embodiments, R2 is preferably hydrogen, optionally substituted C 1-3 Alkyl or optionally substituted C 3-6 Cycloalkyl, more preferably hydrogen or optionally substituted C 1-3 alkyl.

[0039] In one or more embodiments of the compound of formula I, Z1 is CR1, Z2 and Z3 are each independently CH or N, Z4 is N, and Z5 is C; R1 is H, halogen, C 1-4 Alkyl or halogenated C 1-4 alkyl.

[0040] In one or more embodiments of the compound of formula I, the Z ring is selected from the following groups: Preferably wherein * represents the position where the Z ring is connected to the rest of the compound; each R1 is independently selected from the following groups: hydrogen, halogen, hydroxy, cyano, optionally substituted alkyl, optionally substituted alkoxy and optionally substituted carbocyclic group, preferably independently selected from hydrogen, halogen and optionally substituted C 1-3 Alkyl; each R2 is independently selected from the following groups: hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl and optionally substituted alkynyl, preferably independently selected from hydrogen, optionally substituted C 1-3 Alkyl and optionally substituted C 3-6 Cycloalkyl, more preferably independently selected from hydrogen or optionally substituted C 1-3 Preferably, the alkyl, alkoxy, carbocyclyl, cycloalkyl, alkenyl and alkynyl groups are each optionally substituted with 1-5 substituents selected from the group consisting of halogen, hydroxyl and -NR'R"; wherein R' and R" are each independently H or C 1-4 More preferably, the optionally substituted alkyl group is an alkyl group optionally substituted by 1 to 5 halogens.

[0041] In one or more embodiments of the compound of formula I, A1, A2 and A3 are each independently selected from N and CR3, wherein R3 is preferably hydrogen, halogen, optionally substituted C 1-3 Alkyl or optionally substituted C 1-3 Alkoxy. The optionally substituted C1-3 Alkyl and optionally substituted C 1-3 The alkoxy group may be optionally substituted with 1-5 groups selected from the group consisting of halogen, hydroxy, and -NR'R", wherein R' and R" are each independently H or C 1-4 More preferably, the optionally substituted alkyl group is an alkyl group optionally substituted with 1-5 halogens. Preferably, R3 is hydrogen, halogen or C 1-3 In one or more embodiments, A1, A2 and A3 are all CR3; preferably, R3 is each independently hydrogen, halogen or C 1-3 In some embodiments, A1 is CR3, A2 and A3 are both CH; or A1 is CH, A2 is CR3, A3 is CH; or A1 and A2 are both CH, A3 is CR3; preferably, R3 is each independently halogen or C 1-3 In some preferred embodiments, A1 and A2 are both CH, and A3 is CR3; preferably, R3 is halogen, such as fluorine.

[0042] In one or more embodiments of the compound of formula I, R4 and R5 are each independently selected from the group consisting of halogen and optionally substituted alkyl, preferably independently selected from halogen, C 1-4 Alkyl or halogenated C 1-4 L is optionally substituted with 1-2 C 1-3 Alkyl substituted alkylene, more preferably optionally substituted with 1-2 C 1-3 Alkyl substituted C 1-3 Alkylene, preferably optionally substituted with 1-2 C 1-3 Alkyl-substituted methylene.

[0043] In one or more embodiments of the compound of formula I, L is an unsubstituted alkylene group, more preferably an unsubstituted C 1-3 The alkylene group is preferably a methylene group.

[0044] In one or more embodiments of the compound of formula I, the B ring is optionally substituted with 1-3 groups selected from the group consisting of halogen, amino, hydroxy, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 1-6 Alkyl. The optionally substituted C 3-8 The cycloalkyl group may be optionally substituted by 1 to 3 groups selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxy and amino. The optionally substituted C 1-6 The alkyl group may be optionally substituted with 1 to 3 groups selected from the group consisting of halogen, hydroxy, and amino.

[0045] In one or more embodiments of the compound of formula I, Ring B is an optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted 5-6-membered heterocyclyl, preferably containing 1 or 2 heteroatoms selected from O, N, and S.

[0046] In one or more embodiments of the compound of formula I, Selected from the following groups: Preferably More preferably Wherein, *1 represents the position where the B ring is connected to L; *2 represents the position where the B ring is connected to Cy; R6 is selected from hydrogen, halogen, amino, hydroxyl and optionally substituted C 1-3 Alkyl; R7 is selected from hydrogen, optionally substituted C 1-3 Alkyl and optionally substituted C 3-6 Cycloalkyl, preferably selected from hydrogen or optionally substituted C 1-3 Preferably, the optionally substituted C 1-3 The alkyl group is optionally substituted with 1-5 groups selected from hydroxy, halogen, and amino.

[0047] In one or more embodiments of the compound of formula I, m and n are both 1. In one or more embodiments, one of m and n is 2 and the other is 1.

[0048] In one or more embodiments of the compound of formula I, Cy is an optionally substituted 6-14 membered aryl or an optionally substituted 5-10 membered heteroaryl, wherein the optionally substituted 6-14 membered aryl and the optionally substituted 5-10 membered heteroaryl are each independently substituted with 1-5 groups selected from the group consisting of halogen, hydroxy, cyano, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 3-8 Cycloalkyl, amino (-NR'R"), aminoacyl (-C(O)-NR'R") and carboxyl, wherein 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 Preferably, each of the optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy, optionally substituted C2-4 Alkenyl, optionally substituted C 2-4 Each alkynyl group is optionally substituted with 1, 2, 3, 4 or 5 groups selected from the group consisting of halogen, hydroxy, oxo and amino; the optionally substituted C 3-8 The cycloalkyl group is optionally substituted with 1, 2, 3, 4 or 5 groups selected from the group consisting of halogen, hydroxy, oxo, C 1-4 Alkyl and amino; when said R' and R" are substituted, the substituents may be 1-5 groups selected from the following groups: halogen, hydroxyl, oxy, C 1-4 In some preferred embodiments, the substituents include at least aminoacyl (-C(O)-NR'R"), and optionally further include one or two groups selected from the group consisting of halogen, hydroxyl, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl and C 3-6 Cycloalkyl. In some preferred embodiments, Cy is an optionally substituted 5-10 membered heteroaryl, preferably an optionally substituted 5-10 membered nitrogen-containing heteroaryl. Preferably, the 5-10 membered nitrogen-containing heteroaryl is selected from pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl. Preferably, the 5-10 membered heteroaryl or 5-10 membered nitrogen-containing heteroaryl is at least substituted by aminoacyl (-C(O)-NR'R"), and is optionally further substituted by one or two groups selected from the following: halogen, hydroxyl, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl and C 3-6 Preferably, in the embodiments described herein, when said R' and R" are substituted, the substituents are 1 to 5 groups selected from the group consisting of halogen, hydroxyl and amino.

[0049] In one or more embodiments of the compound of formula I, Cy is an optionally substituted phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl. Preferably, when Cy is substituted, the substituents may be 1-5 groups selected from the group consisting of halogen, hydroxyl, cyano, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy, C 3-6 Cycloalkyl, aminoacyl and carboxyl. More preferably, Cy is substituted by at least one aminoacyl group, preferably, the aminoacyl group is located in the para position of Cy. Preferably, the aminoacyl group is -C(O)-NR'R"; wherein 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 each independently H, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6Preferably, when the R' and R" are substituted, the number of substituents may be 1 to 5 selected from the following groups: halogen, hydroxyl, oxo, C 1-4 In some preferred embodiments, the substituents on Cy include at least aminoacyl (-C(O)-NR'R"), and optionally include one or two groups selected from the following: halogen, hydroxyl, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl and C 3-6 More preferably, the aminoacyl group (-C(O)-NR'R") is located in the para position.

[0050] In one or more embodiments of the compound of formula I, Cy is preferably the following group: wherein D1, D2, D3 and D4 are each independently selected from N and CR8; R8 is selected from the following groups: hydrogen, halogen, hydroxyl, cyano, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy, optionally substituted C 3-8 Carbocyclyl, amino (-NR'R"), optionally substituted C 2-4 Alkenyl and optionally substituted C 2-4 Alkynyl; R' is selected from optionally substituted C 1-10 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl or optionally substituted heteroaryl, preferably optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Cycloalkyl or optionally substituted 3-6 membered heterocyclic group; * indicates the position where the group is attached to ring B. Preferably, the ring containing D1, D2, D3 and D4 is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl. Preferably, R8 is H, hydroxyl, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl or C 3-6 Preferably, D3 is N, D4 is CR8, D1 and D2 are both CH, wherein R8 is H, hydroxyl, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl or C 3-6 Preferably, when the R' is substituted, the number of substituents may be 1-5 groups selected from the following groups: halogen, hydroxyl and amino. Preferably, R' is hydrogen, C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 3-6 Cycloalkyl, halogenated C1-3 Alkyl, hydroxy substituted C 1-3 Alkyl or 3-6 membered heterocyclic group. Preferably, the 3-6 membered heterocyclic group is an oxygen and / or nitrogen containing heterocyclic group, such as oxetanyl, azetidinyl, pyrrolidinyl, piperazinyl and piperidinyl.

[0051] In one or more embodiments of the compound of formula I, the Z ring is selected from the following groups: Each R1 is independently hydrogen, halogen, C 1-3 Alkyl or halogenated C 1-3 Alkyl; preferably, In the formula, one R1 is hydrogen and the other R1 is halogen or C 1-3 alkyl; R2 is C 1-3 alkyl; A1 and A2 are both CH, A3 is CR3, wherein R3 is halogen; described Selected from the following groups: Wherein, *1 indicates the position where the B ring is connected to L, and *2 indicates the position where the B ring is connected to Cy; R6 is hydrogen; R7 is hydrogen; Cy is: Wherein, D3 is N, D4 is CR8, D1 and D2 are both CH, and R8 is H, C 1-3 Alkyl or halogen; R' is C 1-3 Alkyl or C 3-6 Cycloalkyl.

[0052] Preferred compounds of the formula I compound of the present invention are compounds of formula II (including formula IIa, formula IIb and formula IIc): or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, wherein: Z1, Z2, Z3, m, Ring B and R8 are as described in any of the above embodiments; R9, R 10 and R 11 are independently selected from hydrogen, halogen, optionally substituted C 1-3 Alkyl and optionally substituted C 1-3 alkoxy; Q is cyano, optionally substituted aminoacyl (-C(O)-NR'R") or optionally substituted heteroaryl, wherein R' and R" are each independently selected from hydrogen, optionally substituted C 1-10 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0053] In one or more embodiments of the compound of Formula II (including Formulas IIa, IIb, and IIc), the Z ring is selected from the following groups: Preferably Wherein, * indicates the position where the Z ring is connected to the rest of the compound; R1 and R2 are as described in any of the above embodiments.

[0054] In one or more embodiments of the compound of Formula II (including Formula IIa, IIb and IIc), when R9, R 10 and R 11 When substituted, the substituents may be 1-5 groups selected from the group consisting of halogen, hydroxyl, and -NR'R", wherein R' and R" are each independently H or C 1-4 In some embodiments, R9, R 10 and R 11 are independently hydrogen, halogen, optionally substituted C 1-3 Alkyl or optionally substituted C 1-3 Alkoxy; preferably, R9, R 10 and R 11 Each is independently hydrogen, halogen or C 1-3 Alkyl; preferably, R9, R 10 and R 11 At least one of R is a non-hydrogen substituent, preferably a halogen. In one or more embodiments, R is a halogen or C 1-3 Alkyl, R 10 and R 11 are all H; or R9 is H, R 10 Halogen or C 1-3 Alkyl, R 11 is H; or R9 and R 10 Both H, R 11 Halogen or C 1-3 In some preferred embodiments, R9 and R 10 Both H, R 11 is a halogen such as fluorine.

[0055] In one or more embodiments of the compound of Formula II (including Formula IIa, IIb and IIc), Ring B is optionally substituted with 1-3 groups selected from the group consisting of halogen, amino, hydroxy, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 1-6 Alkyl. The optionally substituted C 3-8 The cycloalkyl group may be optionally substituted by 1 to 3 groups selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxy and amino. The optionally substituted C 1-6 The alkyl group may be optionally substituted with 1 to 3 groups selected from the group consisting of halogen, hydroxy and amino.

[0056] In one or more embodiments of the compound of Formula II (including Formulas IIa, IIb, and IIc), Ring B is an optionally substituted 5- or 6-membered heteroaryl or an optionally substituted 5-6-membered heterocyclyl, preferably containing 1 or 2 heteroatoms selected from O, N, and S.

[0057] In one or more embodiments of the compound of Formula II (including Formulas IIa, IIb, and IIc), Selected from the following groups: Preferably Wherein, *1 represents the position where the B ring is connected to the methylene group; *2 represents the position where the B ring is connected to the pyridyl group; R6 is selected from hydrogen, halogen, amino, hydroxyl and optionally substituted C 1-3 Alkyl; R7 is selected from hydrogen, optionally substituted C 1-3 Alkyl and optionally substituted C 3-6 Cycloalkyl, preferably hydrogen or optionally substituted C 1-3 Preferably, the optionally substituted C 1-3 The alkyl group is optionally substituted with 1-5 groups selected from hydroxy, halogen, and amino.

[0058] In one or more embodiments of the compound of Formula II (including Formulas IIa, IIb, and IIc), m is 1 or 2, preferably 1.

[0059] In one or more embodiments of the compound of Formula II (including Formula IIa, IIb and IIc), R8 is hydrogen, hydroxy, halogen, cyano, optionally substituted C 1-3 Alkyl, optionally substituted C 1-3 Alkoxy or optionally substituted C 3-6 Cycloalkyl; preferably hydrogen, hydroxy, halogen, C 1-3 Alkyl, halogenated C1-3 Alkyl or C 3-6 Cycloalkyl, more preferably hydrogen, hydroxy, halogen or C 1-3 alkyl.

[0060] In one or more embodiments of the compound of Formula II (including Formula IIa, IIb and IIc), Q is -C(O)-NR'R" as described in any of the preceding embodiments, wherein 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 H, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 In one or more embodiments, Q is an optionally substituted 5-membered heteroaryl, which may be optionally substituted with 1-3 groups selected from the group consisting of halogen, cyano, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy and halogenated C 1-3 The 5-membered heteroaryl group is preferably a pyrrolyl group, a pyrazolyl group, an imidazolyl group or a triazolyl group.

[0061] Preferred compounds of the formula I compound of the present invention are compounds of formula III or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives or pharmaceutically acceptable salts thereof, or mixtures thereof, or prodrugs thereof: in, R8, R 11 , m, Ring B and Q are as described in any of the above embodiments; R 12 and R 13 are independently selected from hydrogen, halogen, cyano, optionally substituted C 1-3 Alkyl and optionally substituted C 1-3 Alkoxy.

[0062] In one or more embodiments of the compound of formula III, R 12 and R 13 Each is independently hydrogen, halogen, C 1-3 Alkyl or halogenated C 1-3 In one or more embodiments, R 12 is hydrogen, R 13 Halogen, C 1-3 Alkyl or halogenated C 1-3 In one or more embodiments, R 12 Halogen, C 1-3Alkyl or halogenated C 1-3 Alkyl, R 13 For hydrogen.

[0063] In one or more embodiments of the compound of formula III, R 11 For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Alkoxy, preferably, R 11 is hydrogen, halogen or C 1-3 Alkyl, more preferably, R 11 is a halogen such as fluorine.

[0064] In one or more embodiments of the compound of formula III, the B ring is optionally substituted with 1-3 groups selected from the group consisting of halogen, amino, hydroxy, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 1-6 The optionally substituted C 3-8 The cycloalkyl group may be optionally substituted by 1 to 3 groups selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxy and amino. The optionally substituted C 1-6 The alkyl group may be optionally substituted with 1 to 3 groups selected from the group consisting of halogen, hydroxy, and amino.

[0065] In one or more embodiments of the compound of formula III, Ring B is an optionally substituted 5- or 6-membered heteroaryl or an optionally substituted 5- to 6-membered heterocyclyl, preferably containing 1 or 2 heteroatoms selected from O, N, and S.

[0066] In one or more embodiments, Selected from the following groups: Preferably Wherein, *1 represents the position where the pyrrole ring is connected to the methylene group; *2 represents the position where the B ring is connected to the pyridyl group; R6 is selected from hydrogen, halogen, amino, hydroxyl and optionally substituted C 1-3 Alkyl; R7 is selected from hydrogen, optionally substituted C 1-3 Alkyl and optionally substituted C 3-6 Cycloalkyl, preferably hydrogen or optionally substituted C 1-3 alkyl.

[0067] In one or more embodiments of the compound of formula III, m is 1 or 2, preferably 1.

[0068] In one or more embodiments of the compound of formula III, R8 is hydrogen, hydroxy, halogen, cyano, optionally substituted C1-3 Alkyl, optionally substituted C 1-3 Alkoxy or optionally substituted C 3-6 Cycloalkyl; preferably hydrogen, hydroxy, halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl or C 3-6 Cycloalkyl, more preferably hydrogen, hydroxy, halogen or C 1-3 alkyl.

[0069] In one or more embodiments of the compound of formula III, Q is -C(O)-NR'R" as described in any of the preceding embodiments, wherein R' and R" are each independently selected from hydrogen, optionally substituted C 1-10 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl, preferably each independently H, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 In one or more embodiments, Q is an optionally substituted 5-membered heteroaryl, which is optionally substituted with 1-3 substituents selected from the group consisting of halogen, cyano, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy and halogenated C 1-3 The 5-membered heteroaryl group is preferably a pyrrolyl group, a pyrazolyl group, an imidazolyl group or a triazolyl group.

[0070] It should be understood that although the above description of Z1, Z2, Z3, Z4, Z5, A1, A2, A3, L, m, n, B ring, Cy, R8, R9, R 10 、R 11 、R 12 、R 13 and Q are described separately, but each of the features described can be combined arbitrarily to form the scope of different compounds of formula I (including formula II and III) of the present invention. For example, in some embodiments of the compounds of formula I (including formula II and III) of the present invention.

[0071] Examples of preferred compounds of the present invention include, but are not limited to: or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-substituted derivative or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof.

[0072] Some compounds of the present invention may exist as stereoisomers, including optical isomers. The present invention includes all stereoisomers and racemic mixtures of said stereoisomers, as well as single enantiomers that can be separated by methods well known to those skilled in the art.

[0073] 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.

[0074] Examples of prodrugs of the compounds of the present invention include simple esters containing carboxylic acid compounds (e.g., by methods known in the art with C 1-4 esters formed by condensation of hydroxyl groups (e.g., by methods known in the art with C 1-4 Carboxylic acid, C 3-6 esters formed by condensation of diacids or their anhydrides, such as succinic anhydride and fumaric anhydride); imines of amino-containing compounds (e.g., by methods known in the art with C 1-4 imines formed by condensation of an aldehyde or ketone); carbamates of compounds containing an amino group, such as the types described by Leu et al. (J. Med. Chem. 42: 3623-3628 (1999)) and Greenwald et al. (J. Med. Chem. 42: 3657-3667 (1999)); acetals and ketals of compounds containing an alcohol (e.g., products formed by condensation with chloromethyl methyl ether or chloromethyl ethyl ether by methods known in the art).

[0075] The compounds of the present invention can be prepared according to methods known to those skilled in the art or the novel methods of the present invention. Specifically, the compounds of Formula I (including Formula II and III) of the present invention can be prepared by referring to the exemplary reaction in Scheme 1. 4-Bromo-3-fluoro-2-nitroaniline reacts with NaNO2, SnCl2·2H2O, and hydrochloric acid to produce (4-bromo-3-fluoro-2-nitrophenyl)hydrazine. (4-Bromo-3-fluoro-2-nitrophenyl)hydrazine reacts with methyl 4-(dimethylamino)-3-methyl-2-oxobut-3-enoate in the presence of acetic acid to produce methyl 1-(4-bromo-3-fluoro-2-nitrophenyl)-4-methyl-1H-pyrazole-5-carboxylate. Methyl 1-(4-bromo-3-fluoro-2-nitrophenyl)-4-methyl-1H-pyrazole-5-carboxylate reacts with Fe and acetic acid to generate 7-bromo-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one. 7-Bromo-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one reacts with (tributyltin)methanol (Bu3SnCH2OH) in the presence of chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (Xphos Pd G2) to generate 6-fluoro-7-(hydroxymethyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one. 6-Fluoro-7-(hydroxymethyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one reacts with HBr to generate 7-(bromomethyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one. In the presence of diisopropylethylamine (DIEA) and potassium iodide (KI), 7-(bromomethyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one reacts with 5-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide to produce the target compound 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide. Solution 1

[0076] Similar methods can be used to prepare other related compounds. For example, 5-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N,6-dimethylpicolinamide can be used to replace 5-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide to prepare the target compound 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N,6-dimethylpicolinamide. The target compound 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-6-fluoro-N-methylpicolinamide was prepared by replacing 5-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide with 5-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide. The target compound 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-6-chloro-N-methylpicolinamide was prepared by replacing 5-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide with 6-chloro-5-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide.

[0077] 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 Formula I (including Formula II and III) of the present invention can be prepared by referring to the exemplary reaction in Scheme 2. 3-Bromo-2,6-difluoroaniline and 4-fluoro-1H-pyrazole-5-carbonyl chloride react under the catalysis of LiHMDS to produce N-(3-bromo-2,6-difluorophenyl)-4-fluoro-1H-pyrazole-5-carboxamide. N-(3-Bromo-2,6-difluorophenyl)-4-fluoro-1H-pyrazole-5-carboxamide undergoes ring closure under alkaline conditions to produce 7-bromo-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one. 7-Bromo-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one reacts with Bu3SnCH2OH in the presence of Xphos Pd G2 to generate 3,6-difluoro-7-(hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one. 3,6-Difluoro-7-(hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one reacts with HBr to generate 7-(bromomethyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one. 7-(Bromomethyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one and 5-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide were reacted with DIEA and KI to give the target compound 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide. Option 2

[0078] Similar methods can be used to prepare other related compounds. For example, 5-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N,6-dimethylpicolinamide can be used to replace 5-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide to prepare the target compound 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N,6-dimethylpicolinamide. The target compound 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)-N-methylpicolinamide was prepared by replacing 5-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide with N-methyl-5-(4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)picolinamide. The target compound 5-(5-((6-fluoro-4-oxo-3-trifluoromethyl-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide was prepared by replacing 4-trifluoromethyl-1H-pyrazole-5-carbonyl chloride with 4-fluoro-1H-pyrazole-5-carbonyl chloride.

[0079] An important aspect of the present invention is the discovery that compounds of Formula I (including Formulas II and III) are PARP inhibitors, particularly selective PARP1 inhibitors. Therefore, compounds of Formula I (including Formulas II and III) or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically substituted derivatives or pharmaceutically acceptable salts thereof, or mixtures thereof, or prodrugs thereof can be used to treat a variety of diseases or conditions responsive to inhibition of PARP activity (particularly PARP1 activity), or for the preparation of medicaments for treating or preventing diseases or conditions responsive to inhibition of PARP activity (particularly PARP1 activity).

[0080] In the present invention, the disease or disorder responsive to inhibition of PARP activity (especially PARP1 activity) includes cancer. The cancer can be a solid tumor or a hematological tumor, including but not limited to 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 (e.g., small cell lung cancer), Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, stomach cancer, colon cancer, malignant insulinoma, malignant carcinoid, choriocarcinoma, mycosis fungoides, head and neck cancer, osteosarcoma, 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 responsive to inhibition of PARP activity, in particular PARP1 activity.

[0081] Therefore, the present invention provides a method for treating or preventing a disease or condition responsive to inhibition of PARP activity (particularly PARP1 activity), comprising administering to a subject in need thereof an effective amount of a compound of Formula I (including Formulas II and III) or its stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically substituted derivatives or pharmaceutically acceptable salts, or mixtures thereof, or prodrugs thereof, or a pharmaceutical composition containing an effective amount of a compound of Formula I (including Formulas II and III) or its stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically substituted derivatives or pharmaceutically acceptable salts, or mixtures thereof, or prodrugs thereof. In the present invention, the subject includes mammals, more particularly humans.

[0082] When practicing a therapeutic method, an effective amount of a pharmaceutical preparation is administered to an individual who exhibits symptoms of one or more of these diseases. The pharmaceutical preparation contains a therapeutically effective amount of a compound of Formula I (including Formulas II and III) and is formulated for oral, intravenous, local or external administration for the treatment of cancer and other diseases. An effective dose can effectively improve or eliminate one or more symptoms of a disease. An effective dose for treating a specific disease refers to a dose that is sufficient to improve or alleviate the symptoms associated with the disease in some way. The dose can be administered as a single dose or can be administered according to an effective dosing regimen. Although the dose may cure the disease, the purpose of the general administration is to improve the symptoms of the disease. Generally speaking, repeated administration is required to achieve the desired symptom improvement effect.

[0083] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula I (including Formulas II and III) as a PARP inhibitor or its stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically substituted derivatives or pharmaceutically acceptable salts, or mixtures thereof, or prodrugs thereof.

[0084] Another embodiment of the present invention relates to a pharmaceutical composition for effectively treating or preventing cancer, comprising a compound of formula I (including formula II and III) as a PARP inhibitor, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-substituted derivative thereof, or a pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, in combination with at least one known anticancer drug or a pharmaceutically acceptable salt thereof. In particular, the compounds described herein can be used in combination with other anticancer drugs involved in DNA damage and repair mechanisms, such as ATM inhibitors, ATR inhibitors, Wee1 inhibitors, DNA-PK inhibitors, HDAC inhibitors, such as vorinostat, romidepsin, panobinostat, belinostat, and other anticancer drugs related to cell division, including Chk1 / 2 inhibitors, CDK4 / 6 inhibitors such as palbociclib, and other targeted anticancer drugs, including USP1 inhibitors, PRMT5 inhibitors, Polθ inhibitors, RAD51 inhibitors, and the like.Other known anticancer drugs that can be used in 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 etoposide; RNA / DNA antimetabolites such as 5-azacytidine, gemcitabine, 5-fluorouracil, carboplatin, and cytochrome P60 inhibitors. betadine 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 the monoclonal antibodies panitumumab, necituzumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, and nab-terminus. uximab, alemtuzumab, ibritumomab tiuxetan, tositumomab, brentuximab, daratumumab, elotuzumab, ofatumumab, denosumab, belintozumab, ipilimumab, Avastin, Herceptin, and rituximab; antibody-drug conjugates (ADCs) such as trastuzumab-emtansine conjugate T-DM1, detrastuzumab, emtansine, dedaburumab, gemtuzumab ozogamicin, brentuximab vedotin, otuzumab, goxatuzumab, venetoclax, and belantamab oxadiazine; androgen receptor antagonists antagonists such as abiraterone, darolutamide, enzalutamide, and prednisone; kinase inhibitors such as imatinib, gefitinib, erlotinib, osimertinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lafatinib, sorafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, ponatinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cobimetinib, axitinib, temsirolimus, adranib, pazopanib, temsirolimus, 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 prostate cancer therapeutic vaccines.

[0085] In practicing the methods of the present invention, the compounds of the present invention may be administered together with at least one known anticancer drug as a single pharmaceutical composition. Alternatively, the compounds of the present invention may be administered separately from the at least one known anticancer drug. In one embodiment, the compounds of the present invention and the at least one known anticancer drug are administered substantially simultaneously, i.e., all drugs are administered simultaneously or sequentially, provided that therapeutic blood concentrations of the compounds are achieved simultaneously. In another embodiment, the compounds of the present invention and the at least one known anticancer drug are administered according to separate dosage regimens, provided that therapeutic blood concentrations of the compounds are achieved.

[0086] Another embodiment of the present invention relates to a tumor-suppressing bioconjugate. This bioconjugate comprises a compound described herein and at least one known therapeutic antibody, such as Herceptin or Rituximab, or a growth factor, such as EGF or FGF, or a cytokine, such as IL-2 or IL-4, or any other molecule that binds to a cell surface. These antibodies and other molecules can deliver the compounds described herein to their targets, making them effective anti-cancer agents. This bioconjugate can also enhance the anti-cancer effects of therapeutic antibodies, such as Herceptin or Rituximab.

[0087] Another embodiment of the present invention relates to a pharmaceutical composition that is effective in inhibiting tumors, comprising a PARP inhibitor of Formula I (including Formula II and III), or a pharmaceutically acceptable salt thereof, or a prodrug thereof, used in combination with radiotherapy. In this embodiment, the compound of the present invention can be administered at the same time or at a different time as the radiotherapy.

[0088] Another embodiment of the present invention relates to a pharmaceutical composition effective for post-operative treatment of cancer, comprising a PARP inhibitor of Formula I (including Formula II and III), or a pharmaceutically acceptable salt thereof, or a prodrug thereof. The present invention also relates to a method for treating cancer in a mammal by surgically resecting a tumor followed by administration of the pharmaceutical composition of the present invention.

[0089] The pharmaceutical compositions of the present invention include pharmaceutical preparations of the compounds of the present invention in amounts that are effective for achieving their intended purpose. Although individual needs vary, those skilled in the art can determine the optimal dosage of each component in the pharmaceutical preparation. Generally, the compound, or a pharmaceutically acceptable salt thereof, can be orally administered to a mammal at approximately 0.0025 to 50 mg / kg body weight per day. Preferably, about 0.01 mg / kg to 10 mg / kg is administered orally. If a known anticancer drug is also administered, the amount administered should be effective for achieving its intended purpose. The optimal dosage of such known anticancer drugs is well known to those skilled in the art.

[0090] The unit oral dose may comprise about 0.01 to 50 mg, preferably about 0.1 to 10 mg of a compound of the present invention. The unit dose may be administered once or multiple times, with one or more tablets administered daily, each tablet containing about 0.1 to 50 mg of a compound of the present invention or a solvate thereof, conveniently about 0.25 to 10 mg.

[0091] In topical formulations, the concentration of the compounds of the present invention may be from about 0.01 to 100 mg / g of carrier.

[0092] The compounds of the present invention can be administered as raw chemicals. The compounds of the present invention can also be administered as part of a suitable pharmaceutical formulation containing a pharmaceutically acceptable carrier (including excipients and adjuvants), which facilitates processing of the compound into a pharmaceutically acceptable formulation. Preferably, the pharmaceutical formulation, particularly oral formulations and formulations for preferred administration, such as tablets, lozenges, capsules, and solutions suitable for injection or oral administration, contains from about 0.01% to 99% of the active compound and excipients, preferably from about 0.25% to 75%.

[0093] Non-toxic pharmaceutically acceptable salts of the compounds of the present invention are also within the scope of the present invention. Acid addition salts are formed by mixing a solution containing the compound of the present invention with a non-toxic pharmaceutically acceptable acid solution. Examples of such acids include hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, and oxalic acid. Base addition salts are formed by mixing a solution containing the compound of the present invention with a non-toxic pharmaceutically acceptable base solution. Examples of such bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, tris(hydroxymethyl)aminomethane, and N-methyl-glucamine.

[0094] The pharmaceutical preparations of the present invention can be administered to any mammal, provided 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 disclosure is not intended to be limited thereto.

[0095] The pharmaceutical preparation of the present invention can be administered by any route that can achieve its intended purpose. For example, administration can be carried out by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, intracranial, intranasal or topical routes. Alternatively or in parallel, administration can be by oral route. The dosage used depends on the age, health status and weight of the recipient, the type of simultaneous treatment, the frequency of treatment and the nature of the desired effect.

[0096] The pharmaceutical preparations of the present invention can be manufactured in a known manner. For example, by conventional mixing, granulation, tableting, dissolution, or lyophilization processes. Oral pharmaceutical preparations can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, and processing the granular mixture after adding suitable adjuvants as needed or necessary to obtain tablets or lozenge cores.

[0097] Suitable excipients are, in particular, fillers, for example sugars such as lactose, 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, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone. If necessary, disintegrants may be added, for example the above-mentioned starches as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliary agents are, in particular, flow regulators and lubricants, for example, silicon dioxide, talc, stearic acid or a salt thereof, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. If necessary, the tablet core may be provided with a suitable coating that is resistant to gastric juices. For this purpose, concentrated carbohydrate solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. To produce a coating resistant to gastric juices, solutions of suitable cellulose derivatives, such as cellulose acetate phthalate or hydroxypropylmethylcellulose phthalate, can be used. Pigments or lakes can be added to the coating of tablets or lozenge cores, for example for identification purposes or to characterize the active ingredient dosage combination.

[0098] Other pharmaceutical preparations for oral administration include push-in capsules made of gelatin and sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-in capsules may contain the active compound in the form of particles, which may be 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 the soft capsules, the active compound is preferably dissolved or suspended in a suitable liquid such as oil or liquid paraffin. In addition, a stabilizer may be added.

[0099] Formulations suitable for parenteral administration include aqueous solutions of the active compound, such as aqueous 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 oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides or polyethylene glycol-400, polyoxyethylene castor oil, or cyclodextrins. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, and / or dextran. Optionally, a suspension stabilizer may also be included.

[0100] According to one aspect of the present disclosure, the compounds of the present invention are used in the form of topical and parenteral formulations and are used to treat skin cancer.

[0101] The topical preparations of the present invention are preferably prepared into oils, creams, emulsions, ointments, etc. by selecting suitable carriers. Suitable carriers include vegetable oils, mineral oils, white mineral oil (white soft paraffin), branched fats, greases, animal fats, and high molecular weight alcohols (greases greater than C). 12 ). Preferred carriers are those in which the active ingredient is soluble. If desired, emulsifiers, stabilizers, humectants, and antioxidants, as well as agents that impart color or fragrance, may also be included. In addition, these topical formulations may also contain transdermal penetration enhancers. Examples of such enhancers can be found in U.S. Patent Nos. 3,989,816 and 4,444,762.

[0102] Creams are preferably made from a mixture of mineral oil, self-emulsifying beeswax, and water, with the active ingredient, such as almond oil, dissolved in a small amount of oil. Typical examples of creams include a cream containing about 40 parts water, 20 parts beeswax, 40 parts mineral oil, and 1 part almond oil.

[0103] Ointment can be prepared like this, can be by dissolving active ingredient in vegetable oil such as almond oil to form solution, and after mixing with warm soft paraffin, cooling and shaping.Typical example of ointment comprises ointment containing about 30% weight of almond oil and 70% weight of white soft paraffin.

[0104] The present invention also relates to the use of the compound of the present invention in the preparation of a medicament for treating clinical symptoms caused by PARP activity inhibition. The medicament may include the above-mentioned pharmaceutical composition.

[0105] The following examples are intended to illustrate and are not intended to limit the methods and compositions of the present invention. It will be apparent to those skilled in the art that other suitable modifications and adjustments to various conditions and parameters commonly encountered in clinical treatment are within the spirit and scope of the present invention. Example General Notes All reagents were of commercial quality. Solvents were dried and purified according to standard methods. Mass spectrometry samples were analyzed using a single quadrupole mass spectrometer (Platform II, Agilent 6110) with electrospray ionization. The spectra were recorded using a Brücker Ascend 400 NMR spectrometer at 400 MHz. 1 H NMR spectra. Chemical shifts are reported in ppm downfield from TMS as the internal standard (0.00 ppm), and coupling constants, J, are reported in Hz. Example 1 (1-1 and 1-2) 5-(5-((6-Fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide and 5-(5-((6-Fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)-N-methylpicolinamide a) Preparation of tert-butyl 2-(6-(methylcarbamoyl)pyridin-3-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate and tert-butyl 1-(6-(methylcarbamoyl)pyridin-3-yl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate: To a solution of 5-bromo-N-methylpicolinamide (500 mg, 2.3 mmol) in DMSO (6 mL) were added tert-butyl 2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (490 mg, 2.3 mmol), CuI (44 mg, 0.23 mol), K2CO3 (965 mg, 6.9 mmol) and tetramethylethylenediamine (TMEDA, 26.7 mg, 0.23 mmol) at room temperature under N2 atmosphere. The resulting mixture was stirred at 130 ° C overnight. The mixture was slowly cooled to room temperature. Water (10 mL) was added to the reaction mixture for extraction, and extracted several times with ethyl acetate (10 mL×3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was slurried three times with petroleum ether / ethyl acetate (PE / EA) (20:1-10:1-1:1) to give the product (160 mg, crude product, light yellow solid). MS (ESI): 344.10 [M+H] + . b) Preparation of 5-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide and 5-(5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)-N-methylpicolinamide: To a solution of a mixture of tert-butyl 2-(6-(methylcarbamoyl)pyridin-3-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate and tert-butyl 1-(6-(methylcarbamoyl)pyridin-3-yl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (130 mg, 0.38 mmol) in ethyl acetate (3 mL) was added HCl / EA (1 mL, 3.8 mol). The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a product mixture (130 mg, crude product, light yellow solid). MS (ESI): 244.05 [M+H]+ . c) Preparation of (4-bromo-3-fluoro-2-nitrophenyl)hydrazine: To a solution of 4-bromo-3-fluoro-2-nitroaniline (5.0 g, 21.3 mmol) in concentrated hydrochloric acid (36% aq., 50 mL) was slowly added dropwise an aqueous solution of NaNO2 (14.4 g, 64.0 mmol, 50 mL) at -10°C. The resulting mixture was stirred at -10°C for 1 hour and then cooled to -30°C. To the above mixture was slowly added dropwise a solution of SnCl2·2H2O (1.6 g, 23.4 mmol) in concentrated hydrochloric acid (36% aq., 50 mL). The resulting mixture was stirred at -30°C for 1 hour. After the reaction was completed, water (200 mL) was poured into the reaction mixture, and the pH of the solution was adjusted to 7-8 with solid NaHCO3. The resulting mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the target product (4.3 g, crude product, yellow solid, yield: 81%). d) Preparation of methyl 1-(4-bromo-3-fluoro-2-nitrophenyl)-4-methyl-1H-pyrazole-5-carboxylate: To a solution of (4-bromo-3-fluoro-2-nitrophenyl)hydrazine (1.0 g, 4.0 mmol) in acetic acid (10 mL) was added a solution of methyl 4-(dimethylamino)-3-methyl-2-oxobut-3-enoate (0.82 g, 4.8 mmol) in acetic acid (10 mL) at room temperature. The resulting mixture was stirred at 80°C overnight. After completion of the reaction, the reaction mixture was poured into ice water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 15:1) to obtain the desired product (0.83 g, yellow solid, 58% yield). 1 H NMR (400MHz, DMSO-d6): δ8.16-8.14(m,1H),7.78(s,1H),7.61-7.59(m,1H),3.71(s,3H),2.25(s,3H). e) Preparation of 7-bromo-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one: To a solution of methyl 1-(4-bromo-3-fluoro-2-nitrophenyl)-4-methyl-1H-pyrazole-5-carboxylate (0.83 g, 2.3 mmol) in acetic acid (10 mL) at room temperature was added iron powder (0.65 g, 11.6 mmol, 5.0 eq). The mixture was stirred at 80°C overnight. After completion of the reaction, the reaction was filtered, and the filtrate was diluted with water (50 mL) and ethyl acetate (5 mL). The solid was then filtered to obtain the desired product (370 mg, off-white solid, 55% yield). MS (ESI): 295.90 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ11.90 (br, 1H), 7.91 (s, 1H), 7.77 (d, J = 8.0Hz, 1H), 7.50-7.46 (m, 1H), 2.38 (s, 3H). f) Preparation of 6-fluoro-7-(hydroxymethyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one: To a solution of 7-bromo-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (5.0 g, 16.9 mmol) in dioxane (100 mL) was added BuSnCHOH (10.9 g, 33.9 mmol) and XphosPdG (1.3 g, 1.7 mmol) at room temperature. The mixture was stirred at 90°C under a nitrogen atmosphere for 16 hours. After the reaction was completed, 1M aqueous KF solution (1M, 100 mL) was added to the reaction mixture at room temperature. The mixture was stirred at the same temperature for 10 minutes and filtered. The filtrate was extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was slurried with a PE / EA mixture (v / v=1:1), and the solid was collected by filtration to obtain the desired product (2.8 g, gray solid, yield 67%). MS (ESI): 248.05 [M+H] + . g) Preparation of 7-(Bromomethyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one: Dissolve 6-fluoro-7-(hydroxymethyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (2.8 g, 11.3 mmol) in HBr (48% aqueous solution, 30 mL) and stir at 80°C for 2 hours. After the reaction, concentrate under reduced pressure to give the desired product (2.7 g, crude, yellow solid). MS (ESI): 309.90 [M+H] + . h) Preparation of 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide and 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)-N-methylpicolinamide: 5-(5,6-dihydropyrrolo[3 To a solution of a mixture of 5-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide and 5-(5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)-N-methylpicolinamide (95.0 mg, 0.39 mmol) in acetonitrile (3 mL) were added 7-(bromomethyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (120.0 mg, 0.4 mmol), KI (6.5 mg, 0.039 mol), and DIEA (151.0 mg, 1.2 mmol). The resulting suspension was stirred at 80°C for 0.5 hours. After completion of the reaction, the solvent was removed in vacuo. The crude product was purified by preparative HPLC (C18, acetonitrile / water, 5-55%, 0.1% formic acid) to give the target compounds 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide (1-1, 3.4 mg, white solid, yield 1.8%) and 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)-N-methylpicolinamide (1-2, 4.7 mg, white solid, yield 2.5%). The compounds of Examples 2-12 can be prepared using a synthetic method similar to that of Example 1 (Scheme 1). The results are shown below. Example 13 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide a) Preparation of N-(3-bromo-2,6-difluorophenyl)-4-fluoro-1H-pyrazole-5-carboxamide: To a solution of 3-bromo-2,6-difluoroaniline (1.5 g, 7.4 mmol) in THF (15 mL) was added a 1 M solution of LiHMDS in THF (20.2 mL, 20.2 mmol) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 0°C for 30 minutes. To this mixture was added a solution of 4-fluoro-1H-pyrazole-5-carbonyl chloride (1.0 g, 6.7 mmol) in THF (10 mL) dropwise. The resulting reaction mixture was stirred at 0°C for 30 minutes, then warmed to room temperature and stirred for 1.5 hours. The reaction mixture was quenched with water (20 mL) and extracted with EA (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA=5 / 1) to obtain the product (yellow solid, 1.5 g, yield 72%). MS (ESI): 319.95 [M+H] + . b) Preparation of 7-bromo-3,6-difluoropyrazolo[1,5-a]quinoxaline-4(5H)-one: To a solution of N-(3-bromo-2,6-difluorophenyl)-4-fluoro-1H-pyrazole-5-carboxamide (1.5 g, 4.7 mmol) in DMSO (15 mL) was added K2CO3 (2.6 g, 18.7 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 100°C overnight and then cooled to room temperature. Water (15 mL) was added to the mixture and extracted with EA (20 mL x 3). The organic phase was then concentrated under reduced pressure. The crude product was purified by flash chromatography (C18, water / acetonitrile = 55 / 45) to give the product and a mixture of its positional isomers (1.2 g, white solid), which was used directly in the next reaction. MS (ESI): 300.00 [M+H] + . c) Preparation of 3,6-difluoro-7-(hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one: To a solution of the above-described 7-bromo-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one and a mixture of its positional isomers (1.2 g, 4.0 mmol) in anhydrous dioxane (12 mL) was added Xphos Pd G2 (314.7 mg, 0.4 mmol) and (tributyltinyl)methanol (3.9 g, 12 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 80°C for 4 hours, then cooled to room temperature, and aqueous KF solution (1 M, 24 mL) was added. The resulting mixture was filtered, and the filtrate was extracted with EA (20 mL x 3). The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel (DCM / MeOH = 1 / 0 → 100 / 1 → 80 / 1 → 50 / 1) to obtain the desired product (260.0 mg, white solid, two-step yield: 22%). MS (ESI): 252.10 [M+H] + . 1 HNMR (400MHz, DMSO-d6): δ11.94(s,1H),8.20(d,J=3.8Hz,1H),7.89(d,J=8. 6Hz, 1H), 7.36 (t, J = 7.7Hz, 1H), 5.44 (t, J = 5.8Hz, 1H), 4.61 (d, J = 5.5Hz, 2H). d) Preparation of 7-(bromomethyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one: Under a nitrogen atmosphere, a solution of 3,6-difluoro-7-(hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (200.0 mg, 0.8 mmol) in aqueous HBr (48%, 20 mL) was stirred at 80°C for 2 hours. The resulting mixture was concentrated under reduced pressure to afford the product (261.0 mg, white solid, yield: 96%). LCMS: 313.95 [M+H] - . e) Preparation of 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide: To a solution of 5-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide (60.0 mg, 0.2 mmol) in acetonitrile (3 mL) was added 7-(bromomethyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (77.0 mg, 0.2 mmol), KI (4.0 mg, 0.02 mol) and DIEA (95.0 mg, 0.7 mmol) at room temperature under nitrogen atmosphere. The resulting suspension was stirred at 85° C. for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure and the residue was purified by Prep-HPLC to obtain the target compound (10.3 mg, white solid, yield 9%). The compounds of Examples 14-30, 40-48, 53-62, and 65-66 were prepared using a method similar to Example 13 (Scheme 2). The compounds of Examples 31-39, 49-52, and 63-64 were prepared using a method similar to Example 1 (Scheme 1). The results are shown below. Example 67 PARP1 and PARP2 chemiluminescence detection Recombinant poly(ADP-ribose) polymerase 1 and 2 (PARP1 and PARP2) solutions (40 ng enzyme / well) were mixed with the test compound and added to a 96-well plate coated with the recombinant protein mixture. The plates were incubated at room temperature for 1 hour, followed by the addition of 50 μL of 0.3 ng / mL streptavidin-HRP to each well. The plates were incubated at room temperature for 30 minutes. Finally, the plates were treated with streptavidin-HRP and an ELISA electrochemiluminescence (ECL) substrate was added to generate a chemiluminescent signal, which was detected using a chemiluminescence reader. The inhibition rate of the test compound on PAPP1 and PARP2 enzyme activity was calculated according to the following formula. IC 50The values ​​were obtained by fitting the sigmoidal dose-response curve equation using XL Fit software. The curve equation is Y = 100 / (1 + 10^(log C - log IC 50 )), C is the concentration of the compound. Table 1 summarizes the inhibitory effects of the compounds on PARP1 and PARP2 enzyme activities (IC 50 ). Table 1 Most compounds have potent and selective inhibitory effects on PARP1 enzyme activity relative to PARP2. Example 68 Growth inhibition assay of BRCA-mutated human breast cancer MDA-MB-436 cells The cells were cultured in complete culture medium (DMEM medium + 10% FBS + insulin + glutathione). When the cell confluence reached about 80%, the cells were digested and separated by gently blowing from the bottom of the culture dish with a 1 mL pipette. The cell suspension was collected and centrifuged at 500 rpm for 3 minutes. The supernatant was discarded and the cell pellet was resuspended in complete culture medium. The cells were inoculated into culture dishes in appropriate proportions and cultured in a 37°C, 5% CO2 incubator. The experiment was carried out when the cells were in optimal condition and the confluence reached 80%. Cells in the logarithmic growth phase were centrifuged and the culture supernatant was removed. The cells were resuspended in fresh culture medium and counted. The resuspended cells were inoculated into a 96-well plate at 3000 / well and cultured in a 37°C, 5% CO2 incubator overnight. The compound preparation method is as follows: 5 μL of 1000× compound solution was added to 120 μL of culture medium (25-fold dilution), and the 1000× test compound solution was diluted to 40× test compound solution. The solution was mixed by shaking. 0.1% DMSO was used as a control. The next day, remove the 96-well plate inoculated with cells from the incubator and remove the culture supernatant. Then, add 195 μL / well fresh culture medium and 5 μL / well of the above-mentioned 40× test compound solution to the 96-well plate, and finally place the culture plate in a 37°C, 5% CO2 incubator for 7 days. On the 4th day, replace the culture medium containing the compound. After 7 days, add 20 μL of CCK-8 to each well, shake gently, and culture for 4 hours. After incubation, shake for 5 minutes and read the absorbance at 450nm and 650nm wavelengths using a multi-function reader (OD value = absorbance value). 450 nm-absorbance 650 nm). The data were analyzed by GraphPad Prism 6.0. The inhibitory activity of the compound on cell proliferation was plotted using cell survival rate and compound concentration as coordinates. Cell survival rate % = (OD化合物 -OD 背景 ) / (OD DMSO -OD 背景 )×100. IC 50 The values ​​were fitted with a S-shaped dose-response curve equation, and the curve equation was: Y = 100 / (1 + 10^(LogC-LogIC 50 )), C is the concentration of the compound. Table 2 summarizes the inhibitory effect of the compounds on the growth of human breast cancer cells MDA-MB-436 (IC 50 ). Table 2 The test compound has a good inhibitory effect on the proliferation of BRCA-mutated human breast cancer cells MDA-MB-436. Example 69 Inhibitory effects of compounds on PDE3A A multistep fluorescence polarization (FP) assay for PDE3A was performed in a black round-bottom 384-well plate (Corning, #4514). First, the test compound was serially diluted from a stock solution in DMSO to 11 concentrations, with a dilution factor of 3. Fifty nanoliters of the compound dilution was mixed with 5 μL of reaction buffer (10 mM Tris-HCl, pH 7.2, 10 mM MgCl₂, 0.05% NaN₃, 0.1% phosphate-free BSA) containing 0.2 μM FAM-cAMP (BPS, 60200) and 2 nM PDE3A enzyme (Sino Biological, 11908-H20B1). The reaction was incubated at 25°C for 60 minutes. Then, 15 μL of binding agent mix (Molecular Devices, R8124) was added to each well and incubated at 25°C for 60 minutes. The plate was loaded onto the BMG PHERAstar FSX and the fluorescence polarization (FP) values ​​were read under the following settings: Ex: 485 nm and Em: 520 nm. The emission intensity parallel to the polarizer (Em ‖ ) and the emission intensity perpendicular to the polarizer (Em ┴ ). mP value is calculated using the following formula: Polarization (mP) = (Signal Em‖ -Signal Em┴ ) / (Signal Em‖ +Signal Em┴ ). Data Analysis: 1) The calculation of the inhibition rate % of the compound dose is as follows: %Inh=(mP max -mP 化合物 ) / (mP max -mP min )×100%, where mP Min and mP Max Polarization readouts under substrate-only and substrate + enzyme conditions are represented, respectively. 2) The IC was calculated by nonlinear fitting using the commercial fitting software GraphPad Prism 9.2.0 using the following regression equation: 50 Value: Y = bottom + (top - bottom) / (1 + 10^((LogIC 50 -X)×Hillslope)), where X represents the Log value of the compound concentration and Y represents the inhibition rate%. Table 3 summarizes the inhibitory effects of the compounds on PDE3A (IC 50 ). Table 3 Example <![CDATA[IC 50 (μM)]]> Example <![CDATA[IC 50 (μM)]]> 1-1 >30 28 29.4 1-2 >25 29 >30 6 >30 39 >30 8 >30 42 >30 11 >30 48 >30 12 >30 49 >30 13 >30 51 >30 14 >30 52 >30 15 >30 54 >30 16 >30 55 >30 18 >30 57 >30 19 >30 58 2.41 27 >30 59 >30 The results showed that the compounds of the present invention had low or even very low inhibitory effects on PDE3A (IC 50 >30 μM).

[0106] Although the present invention has been fully described, it will be understood by those skilled in the art that the same implementation can be carried out within a wide range of equivalent conditions, formulations and other parameters 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 of formula I, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-substituted derivative, or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, characterized in that: Among them, such as The Z ring shown is an optionally substituted 5-membered heteroaryl group, * indicates the position at which the Z ring is attached to the rest of the compound, Z1, Z2 and Z3 are each independently CR1, NR2, O, N or S, Z4 and Z5 are each independently C or N, and Z4 and Z5 are not N at the same time; A1, A2 and A3 are each independently selected from N and CR3; L is selected from a bond and an alkylene group optionally substituted with R4 and / or R5; Ring B is an optionally substituted heteroaryl or an optionally substituted heterocyclyl; Cy is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; R1 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted carbocyclyl; R2 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R3 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted carbocyclyl; R4 and R5 are each independently selected from the following groups: halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl and optionally substituted alkynyl; or R4 and R5 together with the C to which they are attached form a ring; m and n are each independently selected from 1 and 2.

2. The compound of claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-substituted derivative or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, wherein: The Z ring is selected from the following groups: Preferably, the Z ring is Wherein, * indicates the position where the Z ring is connected to the rest of the compound.

3. The compound of claim 1 or 2, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-substituted derivative or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, wherein: The alkyl, alkoxy and carbocyclic groups of R1 are each optionally substituted with 1 to 5 groups selected from the group consisting of halogen, hydroxy and -NR'R", wherein R' and R" are each independently H or C 1-4 Alkyl; preferably R1 is hydrogen, halogen or optionally substituted C 1-3 alkyl; The alkyl, alkoxy, cycloalkyl, alkenyl and alkynyl groups are each optionally substituted with 1 to 5 groups selected from the group consisting of halogen, hydroxy and -NR'R", wherein R' and R" are each independently H or C 1-4 Alkyl; preferably R2 is hydrogen, optionally substituted C 1-3 Alkyl and optionally substituted C 3-6 Cycloalkyl, more preferably hydrogen or optionally substituted C 1-3 alkyl.

4. The compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-substituted derivative or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, characterized in that: A1, A2 and A3 are each independently selected from N and CR3, wherein R3 is preferably hydrogen, halogen, optionally substituted C 1-3 Alkyl or optionally substituted C 1-3 Alkoxy; preferably, the optionally substituted C 1-3 Alkyl and optionally substituted C 1-3 The alkoxy group may be optionally substituted with 1 to 5 groups selected from the group consisting of halogen, hydroxy and -NR ′ R″, where R ′ and R" are each independently H or C 1-4 Preferably, R3 is hydrogen, halogen or C 1-3 alkyl; Preferably, A1, A2 and A3 are all CR3; wherein R3 is independently hydrogen, halogen or C 1-3 Alkyl; or A1 is CR3, A2 and A3 are CH, or A1 is CH, A2 is CR3, A3 is CH; or A1 and A2 are CH, A3 is CR3, wherein R3 are each independently halogen or C 1-3 Alkyl; more preferably, A1 and A2 are both CH, A3 is CR3, preferably, R3 is halogen, such as fluorine.

5. The compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-substituted derivative or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, wherein: Ring B is an optionally substituted 5-membered or 6-membered heteroaryl or an optionally substituted 5-6-membered heterocyclic group, preferably containing 1 or 2 heteroatoms selected from O, N and S; preferably, Ring B is optionally substituted by 1-3 groups selected from the following: halogen, amino, hydroxyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 1-6 Alkyl; wherein the optionally substituted C 3-8 The cycloalkyl group is optionally substituted by 1-3 groups selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxy and amino; the optionally substituted C 1-6 The alkyl group is optionally substituted with 1 to 3 groups selected from the group consisting of halogen, hydroxy, and amino; Preferably, the Selected from the following groups: More preferably Wherein, *1 represents the position where the B ring is connected to L; *2 represents the position where the B ring is connected to Cy; R6 is selected from hydrogen, halogen, amino, hydroxyl and optionally substituted C 1-3 Alkyl; R7 is selected from hydrogen, optionally substituted C 1-3 Alkyl and optionally substituted C 3-6 Cycloalkyl, preferably hydrogen or optionally substituted C 1-3 alkyl.

6. The compound of any one of claims 1 to 5, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-substituted derivative or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, wherein: Cy is a 6-14 membered aryl or a 5-10 membered heteroaryl, wherein the 6-14 membered aryl and the 5-10 membered heteroaryl are each independently and optionally substituted with 1-5 groups selected from the group consisting of halogen, hydroxy, cyano, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 3-8 Cycloalkyl, amino (–NR ′ R″), aminoacyl (-C(O)-NR ′ R″) and carboxyl, wherein R ′ and R" are each independently hydrogen, optionally substituted C 1-10 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted heterocyclic, 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 3-6 membered heterocyclic group; preferably, the substituents of Cy include at least -C(O)-NR ′ R", optionally further comprises one or two groups selected from the group consisting of halogen, hydroxy, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl and C 3-6 Cycloalkyl; Preferably, Cy is optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl or optionally substituted pyridazinyl, wherein the optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl or optionally substituted pyridazinyl is optionally substituted with 1-5 groups selected from the group consisting of halogen, hydroxyl, cyano, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy, C 3-6 Cycloalkyl, aminoacyl and carboxyl; preferably, Cy is substituted by at least one aminoacyl group, preferably, the aminoacyl group is located in the para position of Cy; preferably, the aminoacyl group is -C(O)-NR ′ R″, wherein the R ′ and R" are each independently hydrogen, optionally substituted C 1-10 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted heterocyclic, 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 an optionally substituted 3-6 membered heterocyclic group; Preferably, Cy is: wherein D1, D2, D3 and D4 are each independently selected from N and CR8; R8 is selected from the following groups: hydrogen, halogen, hydroxyl, cyano, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy, optionally substituted C 3-8 Carbocyclyl, amino, optionally substituted C 2-4 Alkenyl and optionally substituted C 2-4 Alkynyl; R ′ Selected from optionally substituted C 1-10 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl or optionally substituted heteroaryl, preferably optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 cycloalkyl or an optionally substituted 3-6 membered heterocyclic group; * indicates the position where the group is connected to the B ring; preferably, the ring containing D1, D2, D3 and D4 is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; preferably, R8 is H, hydroxyl, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl or C 3-6 Preferably, D3 is N, D4 is CR8, D1 and D2 are CH, wherein R8 is H, hydroxyl, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl or C 3-6 Cycloalkyl.

7. The compound of claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-substituted derivative or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, wherein: The compound of formula I has a structure shown in formula IIa, formula IIb, formula IIc or formula III: Wherein, Z1, Z2, Z3 and Z ring are as described in any one of claims 1-3; m is as described in claim 1; Ring B is as described in claim 1 or 5; R8 is as described in claim 6; R9, R 10 and R 11 are independently selected from hydrogen, halogen, optionally substituted C 1-3 Alkyl and optionally substituted C 1-3 alkoxy; Q is cyano, optionally substituted aminoacyl or optionally substituted heteroaryl, wherein R ′ and R" are each independently selected from hydrogen, optionally substituted C 1-10 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R 12 and R 13 are independently selected from hydrogen, halogen, cyano, optionally substituted C 1-3 Alkyl and optionally substituted C 1-3 Alkoxy.

8. A compound according to claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-substituted derivative or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, wherein: The Z ring is selected from the following groups: Each R1 is independently hydrogen, halogen, C 1-3 Alkyl or halogenated C 1-3 Alkyl; preferably, In which one R1 is hydrogen and the other R1 is halogen or C 1-3 alkyl; R2 is C 1-3 alkyl; A1 and A2 are both CH, A3 is CR3, wherein R3 is halogen; described Selected from the following groups: Wherein, *1 indicates the position where the B ring is connected to L, and *2 indicates the position where the B ring is connected to Cy; R6 is hydrogen; R7 is hydrogen; Cy is: Wherein, D3 is N, D4 is CR8, D1 and D2 are both CH, and R8 is H, C 1-3 Alkyl or halogen; R ′ It is C 1-3 Alkyl or C 3-6 Cycloalkyl.

9. A compound selected from the group consisting of: 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide; 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)-N-methylpicolinamide; 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N,6-dimethylpicolinamide; 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-6-fluoro-N-methylpicolinamide; 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-6-chloro-N-methylpicolinamide; 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-6-hydroxy-N-methylpicolinamide; 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-ethylpicolinamide; N-ethyl-6-fluoro-5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)picolinamide; 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-cyclopropylpicolinamide; N-cyclopropyl-6-fluoro-5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)picolinamide; 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)-N-methylpicolinamide; 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-N-methylpicolinamide; 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)-N,6-dimethylpicolinamide; 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)-6-fluoro-N-methylpicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N,6-dimethylpicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-6-fluoro-N-methylpicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-6-chloro-N-methylpicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-6-hydroxy-N-methylpicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-ethylpicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-ethyl-6-fluoropicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-cyclopropylpicolinamide; N-cyclopropyl-5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-6-fluoropicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)-N-methylpicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)-N,6-dimethylpicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)-6-fluoro-N-methylpicolinamide; 5-(5-((6-fluoro-4-oxo-3-trifluoromethyl-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide; 5-(5-((6-fluoro-4-oxo-3-trifluoromethyl-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-6-fluoro-N-methylpicolinamide; 5-(5-((2,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide; 5-(5-((6-fluoro-4-oxo-4,5-dihydrofuro[2,3-c]quinolin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide; 5-(5-((6-fluoro-2-methyl-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]quinolin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide; 5-(5-((6-fluoro-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinolin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide; 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-3-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide; 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-N-methylpicolinamide; 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-N-methylpicolinamide; 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-N-methylpicolinamide; 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-N-methylpicolinamide; 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-N-methylpicolinamide; 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydro-4H-furo[2,3-c]pyrrol-2-yl)-N-methylpicolinamide; 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)-N-methylpicolinamide; 5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrrol-2(4H)-yl)-N-methylpicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-3-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-N-methylpicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-N-methylpicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-N-methylpicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-N-methylpicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-N-methylpicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydro-4H-furo[2,3-c]pyrrol-2-yl)-N-methylpicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)-N-methylpicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrrol-2(4H)-yl)-N-methylpicolinamide; 5-(5-((7-fluoro-2-methyl-5-oxo-5,6-dihydroimidazo[1,2-c]quinazolin-8-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide; N-ethyl-5-(5-((7-fluoro-2-methyl-5-oxo-5,6-dihydroimidazo[1,2-c]quinazolin-8-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)picolinamide; 6-Fluoro-5-(5-((7-fluoro-2-methyl-5-oxo-5,6-dihydroimidazo[1,2-c]quinazolin-8-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide; N-ethyl-6-fluoro-5-(5-((7-fluoro-2-methyl-5-oxo-5,6-dihydroimidazo[1,2-c]quinazolin-8-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)picolinamide; N-ethyl-5-(5-((6-fluoro-4-oxo-4,5-dihydrofuro[2,3-c]quinolin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)picolinamide; 6-Fluoro-5-(5-((6-fluoro-4-oxo-4,5-dihydrofuro[2,3-c]quinolin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide; N-ethyl-6-fluoro-5-(5-((6-fluoro-4-oxo-4,5-dihydrofuro[2,3-c]quinolin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)picolinamide; 5-(5-((2,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-6-fluoro-N-methylpicolinamide; 5-(5-((2,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-ethyl-6-fluoropicolinamide; (R)-3-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazolidin-7-yl)methyl -9-formamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-6-fluoro-N-methylpicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-3a,5,6,6a-tetrahydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-N-methylpicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-6-fluoro-N-methylpicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrrol-2(4H)-yl)-6-fluoro-N-methylpicolinamide; 6-Fluoro-5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydropyrrolo[3,4-c]pyrrol-2(4H)-yl)-N-methylpicolinamide; 6-Fluoro-5-(5-((6-fluoro-3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-methylpicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydro-4H-pyrrolo[1,5-a]quinoxalin-7-yl)methyl)- [3,4-d]oxazol-2-yl)-6-fluoro-N-methylpicolinamide; 5-(5-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-5,6-dihydro-4H-furo [2,3-c]pyrrol-2-yl)-6-fluoro-N-methylpicolinamide; or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-substituted derivative or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof.

10. Use of the compound according to any one of claims 1 to 9, or its stereoisomer, tautomer, N-oxide, hydrate, solvate, isotope-substituted derivative or pharmaceutically acceptable salt, or mixture thereof, or prodrug thereof, or mixture thereof in the preparation of a medicament for treating or preventing a disease or condition responsive to inhibition of PARP activity; Preferably, the disease or disorder 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 (e.g., small cell lung cancer), Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant Melanoma, stomach cancer, colon cancer, malignant insulinoma, malignant carcinoid tumor, choriocarcinoma, mycosis fungoides, head and neck cancer, osteosarcoma, 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, or prostate cancer; Preferably, the drug further comprises at least one known anticancer drug or a pharmaceutically acceptable salt thereof; preferably, the anticancer drug is selected from one or more of the following groups: vorinostat, romidepsin, panobinostat, belinostat, palbociclib, busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxyellipticine, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, capecitabine , methotrexate, 5-fluoro-2'-deoxyuridine, fludarabine, nelarabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, monoclonal antibodies, panitumumab, necituzumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab tiuxetan, tositumomab, brentuximab, daratumumab, elotuzumab Monoclonal antibody, ofatumumab, denosumab, belintoxizumab, ipilimumab, Avastin, Herceptin, rituximab, T-DM1, detrastuzumab, emtansine, dedabruzumab, gemtuzumab ozogamicin, brentuximab vedotin, otuzumab, goxatuzumab, venetuzumab, belantamab, abiraterone, darolutamide, enzalutamide, prednisone, imatinib, gefitinib, erlotinib, osimertinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lafatinib, sorafenib, regorafenib, vemurafenib, dabrafenib Rafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, ponatinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cobimetinib, axitinib, temsirolimus, adranib, pazopanib, temsirolimus, everolimus, tamoxifen, letrozole, fulvestrant, mitoguanzone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegi, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin and prostate cancer therapeutic vaccines; preferably, the drug is used in combination with radiotherapy.

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9, or its stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives or pharmaceutically acceptable salts, or mixtures thereof, or prodrugs thereof and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition according to claim 11, wherein The pharmaceutical composition further contains at least one known anticancer drug, or a pharmaceutically acceptable salt thereof; preferably, the at least one known anticancer drug is selected from the following group: vorinostat, romidepsin, panobinostat, belinostat, palbociclib, busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxyellipticine, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil , capecitabine, methotrexate, 5-fluoro-2'-deoxyuridine, fludarabine, nelarabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, monoclonal antibody, panitumumab, necituzumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab tiuxetan, tositumomab, brentuximab, daratumumab Monoclonal antibody, elotuzumab, ofatumumab, denosumab, belintozumab, ipilimumab, Avastin, Herceptin, rituximab, T-DM1, detrastuzumab, emtansine, dedabruzumab, gemtuzumab ozogamicin, brentuximab vedotin, otuzumab, goxatuzumab, venetuzumab, belantamab, abiraterone, darolutamide, enzalutamide, prednisone, imatinib, gefitinib, erlotinib, osimertinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lafatinib, sorafenib , regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, ponatinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cobimetinib, axitinib, temsirolimus, adranib, pazopanib, temsirolimus, everolimus, tamoxifen, letrozole, fulvestrant, mitoguanzone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegi, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin, and prostate cancer treatment vaccines.

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