Substituted nitrogen-containing tricyclic compounds as PARP inhibitors and their uses

Abstract

The present disclosure provides substituted nitrogen-containing tricyclic compounds and their use as PARP inhibitors. The present disclosure provides compounds represented by the following formula I, wherein rings Z, Z1, Z2, Z3, Z4, Z5, A1, A2, A3, L, m, n, ring B, and Cy are defined herein. The compounds of formula I of the present disclosure are PARP inhibitors and are therefore useful for treating diseases, disorders, and conditions, such as cancer, that respond to the inhibition of PARP activity. The present disclosure also relates to pharmaceutical compositions comprising the compounds of formula I and the use of the compounds of formula I in the preparation of medicaments for the treatment or prevention of diseases or conditions that respond to the inhibition of PARP activity. [Formula 1] JPEG2026507185000069.jpg4697

Description

[Technical Field]

[0001] The present disclosure relates to substituted nitrogen-containing tricyclic compounds and their uses as PARP inhibitors. [Background technology]

[0002] Poly(ADP-ribose) polymerase (PARP) is a donor NAD + PARPs are a family of proteins that transfer negatively charged ADP-ribose groups from PARPs to target proteins. This is one of many post-transcriptional modifications. Therefore, PARPs are also referred to as ADP-ribose transferases.

[0003] Humans are thought to express 17 PARPs, identified based on amino acid sequence homology to their catalytic domains (Vyas et al., 2013 Nature Communications, 4:3240 / 1-3240 / 13). PARPs either catalyze the addition of a single ADP-ribose unit on target proteins or catalyze the polymerization of ADP-ribose units to form poly ADP-ribose, also known as poly(ADP-ribose) modification. As a result, the PARP family is further grouped into two subfamilies accordingly. Post-translational modification of poly(ADP-ribose) regulates many aspects of protein function, and the physiological functions of many PARPs remain to be established.

[0004] The best-characterized member of the PARP family is PARP1, which has been found to have the highest intracellular levels. PARP1 consists of 1,014 amino acids (NCBI accession P09874) with a total molecular weight of approximately 116 kDa. Structurally, this enzyme consists of two major domains, including an N-terminal DNA-binding domain and a catalytic domain. PARP1 is known to play important roles in many cellular functions, including gene expression, transcription, cell division, cell differentiation, cell apoptosis, and DNA damage response and repair. PARP1 is activated upon DNA damage and participates in base excision repair (BER), the primary mechanism for repairing DNA single-strand breaks. PARP1 binds to the site of a single-strand break (SSB) and subsequently repairs DNA via BER. In response to DNA damage, in addition to the BER repair mechanism, cells have also evolved two major repair pathways: homologous recombination (HR) and non-homologous end joining (NHEJ). HR-deficient tumors have been found to be sensitive to PARP inhibitors, indicating that homologous recombination deficiency and PARP1 inhibition form a synthetic lethal pair that has been validated in clinical studies. Currently, several PARP inhibitors have been approved for the treatment of breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer with DNA damage repair deficiency, such as BRCA1 / 2 mutations. Furthermore, 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 with a molecular weight of approximately 62 kDa (NCBI accession NP_005475) and consists of 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. PARP2 has also been found to have similar functions to PARP1 and is involved in DNA damage repair via the BER mechanism (Schreiber et al., 2002 J Biol Chem 277:23028-23036). Commercially available PARP inhibitors, such as olaparib, niraparib, talazoparib, and rucaparib, not only have inhibitory activity against PARP1 but also similar inhibitory activity against PARP2. Based on the results of clinical trials, the therapeutic effects of these commercially available PARP inhibitors are comparable, but their toxicity profiles differ significantly. For example, talazoparib has toxicities similar to chemotherapy drugs, such as hair loss. A recent study comparing the selectivity of multiple PARP inhibitors showed that talazoparib not only inhibits PARP1 and PARP2, but also has relatively 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). The amino acid sequences of TNKS1 and TNKS2 are highly similar. They share 83% overall sequence identity, and their catalytic domain sequences are 89% identical. They play roles in DNA repair, telomere maintenance, and Wnt / β-catenin signaling. Targeting PARPs other than PARP1 may be the reason why PARP inhibitors cause off-target toxicities, such as hair loss and diarrhea. Furthermore, inhibition of PARP2 activity has been found to result in hematotoxicity (Farres et al., 2013 Blood 122:44-54, Farres et al., 2015 Cell Death and Differentiation 22:1144-1157).The toxicity of these PARP inhibitors limits not only their clinical use but also their combination with other targeted agents.

[0006] Therefore, the development of highly selective PAPR1 inhibitors may reduce both mechanism-related and mechanism-independent toxicities.

[0007] Multiple selective PARP1 inhibitors, for example, WO2011 / 006803, WO2013014038, WO2021013735, WO2021260092, CN115232129, WO2022225934, WO2022222921, WO2022222964, WO2022222965, WO20222229 66, WO2022228387, WO2022247816, WO2022223025, WO2022222995, WO2023122140, WO2023056039, WO2023141290, WO2023 / 146957, WO2023 / 146960, and WO2023 / 156386. Summary of the Invention

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

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

[0010] In certain embodiments, the pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers, excipients, or diluents. The pharmaceutical composition may be used in the treatment of cancer.

[0011] In certain embodiments, the pharmaceutical composition may further comprise at least one known anti-cancer agent or a pharmaceutically acceptable salt thereof. The pharmaceutical composition may be used in the treatment of cancer.

[0012] The present disclosure is also directed to methods for preparing the novel compounds of Formula I (including Formula II and Formula III). DETAILED DESCRIPTION OF THE INVENTION

[0013] It should be understood that the features of the embodiments described herein can be arbitrarily combined to form the technical solution of the present disclosure. The definition of each group in this specification can be applied to any of the embodiments described herein. For example, the definition of an alkyl substituent in this specification can be applied to any of the embodiments described herein, unless the alkyl substituent is clearly defined in the embodiment.

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

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

[0016] As used herein, the term "alkyl" refers to alkyl itself or to a straight or branched chain radical of up to 10 carbons. Useful alkyl groups include straight or branched C 1-10 Alkyl, preferably C 1-6 In some embodiments, alkyl is C 1-4 In some embodiments, alkyl is C 1-3 In some embodiments, the alkyl is a deuterated C 1-3 It is an alkyl. Typical C 1-10 Alkyl groups include methyl, tritiated methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl (such as 3-pentyl), hexyl, and octyl groups, which may be optionally substituted.

[0017] As used herein, the term "alkenyl" refers to a straight or branched chain radical of 2 to 10 carbon atoms, unless the chain length is limited thereto, and there is at least one double bond between two of the carbon atoms in the chain; preferably, an alkenyl is a C 2-6 alkenyl, more preferably C 2-4 Exemplary alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl.

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

[0019] Useful alkoxy groups include those listed above. 1-10 Alkyl groups, preferably C 1-6 Alkyl group or C 1-4 Alkyl group or C 1-3 Included are oxygen substituted with alkyl groups such as methoxy, ethoxy, etc. The alkyl in the alkoxy group may be optionally substituted. Alkoxy group substituents include, but are not limited to, halogen, morpholino, amino (including alkylamino and dialkylamino), and carboxy (including esters thereof).

[0020] Useful amino and optionally substituted amino groups are -NR'R'', where R' and R'' are each independently hydrogen, optionally substituted C 1-10 Alkyl, optionally substituted C 3-8Preferably, R' and R" are each independently hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 or R' and R" together with the N to which they are attached form an optionally substituted 4- to 7-membered cyclic amino group, which optionally contains one or more (2, 3, etc.) additional heteroatoms selected from the group consisting of O, N, and S. Preferably, amino groups include -NH2, -NHR', and -NR'R", where R' and R" are each independently an 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, the term "oxo" refers to =O.

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

[0023] Useful aryl groups include C 6-14 Aryl groups, preferably C 6-10 Aryl groups are typical examples of C 6-14 Aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azuryl, biphenyl, biphenylene, and fluorenyl.

[0024] As used herein, the term "carbocyclic group" includes cycloalkyl and partially saturated carbocyclic groups. Useful cycloalkyl groups include C 3-8Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Useful partially saturated carbocyclic groups include C, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C2 3-8 A carbocyclic group may be optionally substituted by one or more substituents described herein.

[0025] Useful halo or halogen groups include fluoro (F), chloro (Cl), bromo (Br), and iodo (I).

[0026] Useful acylamino (amido) groups include any C 11 bonded to an amino nitrogen, e.g., acetamino, propionamido, butanoylamido, pentanoylamido, and hexanoylamido. 1-6 Acyl (alkanoyl) and aryl substituted C 1-6 Acylamino groups, for example, benzoylamide.

[0027] Useful acyl groups include C 1-6 Examples of substituted acyl groups include acyl groups. The acyl may be optionally substituted with a group selected from halo, amino, and aryl, and the amino and aryl may be optionally substituted. When the acyl is substituted with halo, the number of halogen substituents may range from 1 to 5. Examples of substituted acyl groups include chloroacetyl and pentafluorobenzoyl. When the acyl is substituted with amino, the amino group may be substituted with one or two substituents described herein. In some embodiments, aminoacyl is -C(O)-NR'R'', where R' and R'' are each independently selected from hydrogen, optionally substituted C 1-10 Alkyl, optionally substituted C 3-8 Preferably, R' and R" are each independently hydrogen, optionally substituted C1-4 Alkyl, optionally substituted C 3-6 cycloalkyl, or an optionally substituted 3- to 6-membered heterocyclic group.

[0028] As used herein, the term "heterocyclic group" refers to a saturated or partially saturated 3- to 7-membered monocyclic or 7- to 10-membered bicyclic ring, spirocyclic ring system, or bridged ring system (consisting of carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of O, N, and S), where the nitrogen and / or sulfur heteroatoms can be optionally oxidized and the nitrogen can be optionally quaternized. The term also includes any bicyclic ring system in which any of the heterocyclic rings defined above is fused to a benzene ring. A heterocyclic group can be substituted on a carbon or nitrogen atom if the resulting compound is stable. A heterocyclic group can be optionally substituted with 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, indoline, isoindoline, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidine, pyrazolinyl, tetrahydroisoquinolyl, tetronoyl, and tetramoyl, which may be optionally substituted with one or more substituents described herein.

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

[0031] Useful heteroaryl groups include thienyl (thiophenyl), benzo[d]isothiazol-3-yl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (furanyl), pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl (pyridinyl, including but not limited to 2-pyridyl, 3-pyridyl, and 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthaldinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, Examples of such aryl include 1,2-benzisoxazol-3-yl, benzimidazolyl, 2-oxindolyl, thiadiazolyl, 2-oxobenzimidazolyl, imidazopyridazinyl, imidazopyridyl, triazolopyridazinyl, tetrahydropyridopyrimidinyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, pyrrolopyridyl, pyrrolopyrazinyl, triazolopyrazinyl, thiophenoquinolinyl, furanoquinolinyl, thiazoloquinolinyl, pyrazoquinolinyl, pyroquinolinyl, imidazoquinolinyl, and oxazoquinolinyl. Where the heteroaryl group contains a nitrogen atom in a ring, such nitrogen atom may be in the form of an N-oxide, eg, a pyridyl N-oxide, pyrazinyl N-oxide, and pyrimidinyl N-oxide.

[0032] In this disclosure, unless otherwise stated, when substituted, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, heterocycloalkoxy, alkenyl, heterocycloalkenyl, alkynyl, amino, amido, acyloxy, carboxyl, hydroxyl, mercapto, alkylthiosulfonyl, sulfonyl, sulfinyl, aminoacyl, silyl, phosphinecarboxy, phosphono, carbocyclic, heterocyclic, aryl, or heteroaryl described in any embodiment herein can be substituted with halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 1-6 Amide, C 1-6 Acyloxy, C 1-6 Alkoxy, aryloxy, alkylthio, C 1-6 Alkyl, C 1-6 Achill, C 6-10 Aryl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 The substituents may be optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents selected from the group consisting of alkynyl, heterocyclic or heteroaryl, methylenedioxy, urea group, mercapto group, azido group, carbonyl, alkanesulfonyl, sulfamoyl, dialkylsulfamoyl, alkylsulfinyl, and the like. The substituents themselves may also be optionally substituted. For example, C 1-6 Acylamide, C 1-6 Acyloxy, C 1-6 Alkoxy, aryloxy, alkylthio, C 1-6 Alkyl, C 1-6 Achill, C 6-10 Aryl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 The alkynyl, heterocyclic or heteroaryl group may be substituted with halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6The alkyl group may be optionally substituted with 1 to 5 groups selected from the group consisting of alkoxy, etc. More preferred substituents include, but are not limited to, halogen, hydroxyl, carboxyl, amino, C 1-6 Amide, C 1-6 Acyloxy, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 acyl, and alkanesulfonyl.

[0033] In each embodiment, it should be understood that when the substituent is a heterocyclic group, an aryl, or a heteroaryl, the number is typically one.

[0034] Specifically, the present disclosure provides compounds represented by formula I:

[0035] [ka] or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, wherein:

[0036] [ka] is an optionally substituted 5-membered heteroaryl group, * indicates the position at which the Z ring is attached to the remainder of the compound, Z, Z, and Z are each independently CR, NR, O, N, or S, Z and Z are each independently C or N, and Z and Z are not simultaneously N; A1, A2, and A3 are each independently selected from N and CR3; L is selected from a bond and alkylene optionally substituted by R4 and / or R5; Ring B is an optionally substituted heteroaryl or an optionally substituted heterocyclic group; 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, hydroxyl, cyano, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted carbocyclic groups; 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 carbocyclic groups; R4 and R5 are each independently selected from the group consisting of 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 bonded form a ring; m and n are each independently selected from 1 and 2;

[0037] In Formula I and each formula of the present disclosure, unless otherwise specified, preferably each alkyl is independently selected from the group consisting of C 1-6 Alkyl, preferably C 1-4 alkyl, and each alkylene is C 1-6 Alkylene, preferably C 1-3 alkylene, and each alkenyl is independently selected from C 2-6 Alkenyl, preferably C 2-4 alkenyl, each alkynyl independently being C 2-6 Alkynyl, preferably C 2-4 alkynyl, and each alkoxy is independently selected from the group consisting of C 1-6 Alkoxy, preferably C 1-4Preferably, when alkyl, alkenyl, alkynyl, and alkoxy are substituted, the substituents can be selected from the group consisting of cyano, hydroxyl, nitro, amino (-NR'R''), aryl, heterocyclic group, heteroaryl, halogen, and carboxyl. The number of substituents can be 1 to 5, and R' and R'' are preferably each independently selected from H, optionally substituted C 1-4 alkyl, or optionally substituted C 3-6 It is cycloalkyl. Preferably, the substituents of the alkyl group, alkynyl group, alkynyl group, and alkoxy group are halogen groups, hydroxyl groups, or amino groups. For example, the substituted alkyl itself or the substituent of another group may be hydroxyalkyl, dihydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heterocyclic alkyl, aralkyl, heteroarylalkyl, and haloalkyl. When the substituent is an aryl, heteroaryl, heterocyclic group, cyano, nitro, or carboxyl, it should be understood that the number is usually 1. When the substituent is a halogen, the number of substituents can be up to 5 depending on the carbon chain length of the alkyl group, alkenyl group, alkynyl group, and alkoxy group, and exemplary substituents include trifluoromethyl and pentafluoroethyl.

[0038] In Formula I and each formula of the present disclosure, unless otherwise specified, the number of ring carbon atoms in each carbocyclic group is preferably 3 to 8. Preferred carbocyclic groups are C 3-8 Cycloalkyl group or C 3-8 The substituents on the carbocyclic group are preferably C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 The substituents may be alkoxy, halogen, hydroxyl, carboxyl, amino (-NR'R''), aryl, heterocyclic group, heteroaryl, and carboxyl. The number of substituents may be 1 to 5, and R' and R'' are preferably each independently H, optionally substituted C 1-4 alkyl, or optionally substituted C3-6 It is understood that when the substituent is an aryl, heteroaryl, heterocyclic group, cyano, nitro, or carboxyl, the number is usually 1. When the substituent is a halogen, the number of substituents can be up to 5.

[0039] In Formula I and each formula of the present disclosure, unless otherwise specified, aryl is preferably C 6-14 The term "aryl" refers to a 5- to 10-membered heteroaryl, and the term "heterocyclic group" refers to a 4- to 7-membered monocyclic or 4- to 10-membered heterocyclic group such as a 7- to 10-membered bicyclic ring, a spirocyclic ring, or a bridged ring. The substituents on each of the aryl, heteroaryl, and heterocyclic groups are each independently selected from the group consisting of C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 and R′ and R″ may be selected from 1 to 5 groups consisting of alkoxy, halogen, hydroxyl, carboxyl, amino (—NR′R″), optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic group, halogen, amido, aminoacyl (—C(O)—NR′R″), and carboxyl, wherein R′ and R″ are each independently selected from hydrogen, optionally substituted C 1-10 Alkyl, optionally substituted C 3-8 Preferably, R' and R" are each independently hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 The optionally substituted C is a cycloalkyl or an optionally substituted 3- to 6-membered heterocyclic group. The number of substituents can be 1 to 5. 3-8 Cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclic groups are C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4and optionally substituted with 1 to 5 groups selected from alkoxy, halogen, hydroxyl, carboxyl, amino (—NR′R″), and aminoacyl (—C(O)—NR′R″), where R′ and R″ are preferably each independently H, optionally substituted C 1-4 alkyl, or optionally substituted C 3-6 It is understood that when the substituent is an aryl, heteroaryl, heterocyclic group, cyano, nitro, or carboxyl, the number is usually 1. When the substituent is a halogen, the number of substituents can be up to 5.

[0040] In one or more embodiments of the compound of Formula I, the alkyl, alkoxy, carbocyclic, cycloalkyl, alkenyl, and alkynyl in the definitions of R1 and R2 are each optionally substituted with 1 to 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 alkyl optionally substituted with 1 to 5 halogens. In some embodiments, R is preferably hydrogen, halogen, or 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 It is alkyl.

[0041] 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, Z5 is C, and R1 is H, halogen, C 1-4 Alkyl or halogenated C 1-4 It is alkyl.

[0042] In one or more embodiments of the compound of Formula I, the Z ring is selected from the following groups:

[0043] [ka] Preferably,

[0044] [ka] is selected from wherein * indicates the position at which the Z ring is attached to the remainder of the compound, and each R is independently selected from hydrogen, halogen, hydroxyl, cyano, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted carbocyclic groups, preferably hydrogen, halogen, and optionally substituted C 1-3 alkyl, and each R2 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl, preferably hydrogen, optionally substituted C 1-3 Alkyl and optionally substituted C 3-6 Cycloalkyl, more preferably hydrogen or optionally substituted C 1-3 Preferably, the alkyl, alkoxy, carbocyclic, cycloalkyl, alkenyl, and alkynyl are each optionally substituted with 1 to 5 groups selected from halogen, hydroxyl, and —NR′R″, where R′ and R″ are each independently H or C 1-4 More preferably, the optionally substituted alkyl is alkyl optionally substituted with 1 to 5 halogens.

[0045] In one or more embodiments of the compound of Formula I, A1, A2, and A3 are each independently selected from N and CR3, where R3 is preferably hydrogen, halogen, optionally substituted C 1-3 alkyl, or optionally substituted C 1-3 The optionally substituted C is alkoxy. 1-3 Alkyl and optionally substituted C1-3 The alkoxy can be optionally substituted with 1 to 5 groups selected from halogen, hydroxyl, and —NR′R″, where R′ and R″ are each independently H or C 1-4 More preferably, the optionally substituted alkyl is alkyl optionally substituted with 1 to 5 halogens. Preferably, R3 is hydrogen, halogen, or C 1-3 In one or more embodiments, A, A, and A are all CR, and preferably, each R is independently hydrogen, halogen, or C. 1-3 In some embodiments, A1 is CR3 and both A2 and A3 are CH, or A1 is CH, A2 is CR3 and A3 is CH, or both A1 and A2 are CH and A3 is CR3, preferably each R3 is independently halogen or C 1-3 In some preferred embodiments, both A1 and A2 are CH and A3 is CR3, preferably R3 is halogen, such as fluoro.

[0046] In one or more embodiments of the compound of Formula I, R and R are each independently selected from halogen and optionally substituted alkyl, preferably halogen, C 1-4 Alkyl or halogenated C 1-4 L is selected from the group consisting of 1 to 2 C alkyl 1-3 An alkylene group optionally substituted with an alkyl group, more preferably 1 to 2 C 1-3 C optionally substituted with alkyl groups 1-3 Alkylene group, preferably 1 to 2 C 1-3 It is a methylene optionally substituted with an alkyl group.

[0047] In one or more embodiments of the compounds of Formula I, L is an unsubstituted alkylene group, more preferably an unsubstituted C 1-3 It is an alkylene group, and preferably a methylene group.

[0048] In one or more embodiments of the compound of Formula I, the B ring is selected from the group consisting of halogen, amino, hydroxyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 1-6 The optionally substituted C is optionally substituted with 1 to 3 groups selected from the group consisting of alkyl. 3-8 Cycloalkyl is a halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 It can be optionally substituted with 1 to 3 groups selected from the group consisting of alkoxy, hydroxyl, and amino. 1-6 The alkyl can be optionally substituted with 1 to 3 groups selected from the group consisting of halogen, hydroxyl, and amino.

[0049] 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- to 6-membered heterocyclic group, preferably containing 1 or 2 heteroatoms selected from O, N, and S.

[0050] In one or more embodiments of the compound of formula I,

[0051] [ka] is the following group:

[0052] [ka] Preferably,

[0053] [ka] More preferably,

[0054] [ka] is selected from *1 indicates the position where the B ring is bonded to L, *2 indicates the position where the B ring is bonded to Cy, and R6 is hydrogen, halogen, amino, hydroxyl, and optionally substituted C 1-3 alkyl, and 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 alkyl is selected from the group consisting of C 1-3 The alkyl group is optionally substituted with 1 to 5 groups selected from hydroxyl, halogen, and amino.

[0055] In one or more embodiments of the compound of Formula I, both m and n are 1. In one or more embodiments, one of m and n is 2 and the other is 1.

[0056] In one or more embodiments of the compound of Formula I, Cy is an optionally substituted 6- to 14-membered aryl or an optionally substituted 5- to 10-membered heteroaryl, wherein the optionally substituted 6- to 14-membered aryl and the optionally substituted 5- to 10-membered heteroaryl are each independently selected from halogen, hydroxyl, 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 and optionally substituted with 1 to 5 substituents selected from the group consisting of cycloalkyl, amino (—NR′R″), aminoacyl (—C(O)—NR′R″), and carboxyl, wherein R′ and R″ are each independently H, optionally substituted C 1-10 Alkyl, optionally substituted C 3-8Cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl, preferably H, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 cycloalkyl, or an optionally substituted 3- to 6-membered heterocyclic group. Preferably, the optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy, optionally substituted C 2-4 Alkenyl, and optionally substituted C 2-4 Each alkynyl can be independently substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of halogen, hydroxy, oxygen, and amino, and each of the optionally substituted C 3-8 Cycloalkyl is a group that can be substituted with halogen, hydroxy, oxygen, C 1-4 and R′ and R″ may be optionally substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, and amino, and when R′ and R″ are substituted, the substituents may be halogen, hydroxy, oxygen, C 1-4 In some preferred embodiments, the substituents include at least -C(O)-NR'R'', and optionally, halogen, hydroxyl, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, and C 3-6 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, pyridazinyl, and the like. Preferably, the 5-10 membered heteroaryl or the 5-10 membered nitrogen-containing heteroaryl is at least substituted by aminoacyl (—C(O)—NR′R″), and optionally substituted with halogen, hydroxyl, cyano, C 1-4 Alkyl, halogenated C 1-4Alkyl, and C 3-6 and cycloalkyl. Preferably, in the embodiments described herein, when R' and R" are substituted, the substituents can be 1 to 5 groups selected from halogen, hydroxy, and amino.

[0057] 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 are halogen, hydroxyl, cyano, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy, C 3-6 It can be 1 to 5 groups selected from the group consisting of cycloalkyl, aminoacyl, and carboxyl. More preferably, Cy is substituted with at least one aminoacyl group, and preferably the aminoacyl group is at the para position of Cy. Preferably, the aminoacyl group is -C(O)-NR'R'', where R' and R'' are each independently selected from H, optionally substituted C 1-10 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl, preferably H, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 cycloalkyl, or an optionally substituted 3- to 6-membered heterocyclic group. Preferably, when R' and R'' are substituted, the substituents are halogen, hydroxyl, oxygen, C 1-4 In some preferred embodiments, the substituents include at least -C(O)-NR'R'', and optionally, halogen, hydroxyl, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, and C 3-6Preferably, the aminoacyl group (-C(O)-NR'R'') is located at the para position.

[0058] In one or more embodiments of the compounds of Formula I, Cy is preferably the following group:

[0059] [ka] wherein D1, D2, D3, and D4 are each independently selected from N and CR8, and R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy, optionally substituted C 3-8 Carbocyclic groups, amino (-NR'R''), optionally substituted C 2-4 Alkenyl, and optionally substituted C 2-4 R' is selected from the group consisting of optionally substituted C 1-10 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocyclic group, 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- to 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, and R8 is H, hydroxyl, halogen, cyano, C 1-3 Alkyl, C 1-3Alkoxy, halogenated C 1-3 Alkyl or C 3-6 Preferably, when R' is substituted, the substituents can be 1 to 5 groups selected from the group consisting of halogen, hydroxy, and amino. Preferably, R' is hydrogen, C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 3-6 Cycloalkyl, halogenated C 1-3 Alkyl, hydroxyl substituted C 1-3 alkyl, or a 3- to 6-membered heterocyclic group. Preferably, the 3- to 6-membered heterocyclic group is an oxygen- and / or nitrogen-containing heterocyclic group such as oxetanyl, azetidinyl, pyrrolidinyl, piperazinyl, or piperidinyl.

[0060] In one or more embodiments of the compound of Formula I, the Z ring is selected from the following groups:

[0061] [ka] is selected from Each R1 is independently hydrogen, halogen, or C 1-3 Alkyl or haloC 1-3 alkyl, preferably

[0062] [ka] In the formula (I), one of R1 is hydrogen and another R1 is halogen or C 1-3 is alkyl, R2 is C 1-3 is alkyl, A1 and A2 are both CH, A3 is CR3, and R3 is halogen; The relevant

[0063] [ka] is the following group:

[0064] [ka] is selected from In the formula, *1 indicates the position where ring B is bonded to L, *2 indicates the position where ring B is bonded to Cy, R6 is hydrogen, and R7 is hydrogen. Cy is:

[0065] [ka] D3 is N, D4 is CR8, both D1 and D2 are CH, and R8 is H, C 1-3 alkyl or halogen, and R' is C 1-3 Alkyl or C 3-6 It is cycloalkyl.

[0066] One group of preferred compounds of formula I in the present disclosure are compounds of formula II (including formula IIa, formula IIb, and formula IIc):

[0067] [ka] or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, wherein: Z1, Z2, Z3, m, the B ring, and R8 are as described in any of the previous embodiments; R9, R 10 , and R 11 each independently represents 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, where R′ and R″ are each independently hydrogen, optionally substituted C 1-10 Alkyl, optionally substituted C 3-8It is selected from cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, and heteroaryl.

[0068] In one or more embodiments of the compounds of Formula II (including Formula IIa, Formula IIb, and Formula IIc), the Z ring is selected from the following groups:

[0069] [ka] Preferably,

[0070] [ka] is selected from wherein * indicates the position where the Z ring is attached to the remainder of the compound, and R1 and R2 are as described in any of the previous embodiments.

[0071] In one or more embodiments of the compounds of Formula II (including Formula IIa, Formula IIb, and Formula IIc), R, R 10 , and R 11 When is substituted, the substituents can be 1 to 5 groups selected from the group consisting of halogen, hydroxyl, and -NR'R'', where R' and R'' are each independently H or C 1-4 In some embodiments, R, R 10 , and R 11 each independently represents hydrogen, halogen, optionally substituted C 1-3 alkyl, or optionally substituted C 1-3 Alkoxy, preferably hydrogen, halogen, or C 1-3 alkyl, preferably R, R 10 , and R 11 In one or more embodiments, at least one of R is a halogen or C 1-3 alkyl, and R 10 and R 11 are both H, or R is H and R10 is a halogen or C 1-3 alkyl, and R 11 is H, or R and R 10 Both are H and R 11 is a halogen or C 1-3 In some preferred embodiments, R and R are alkyl. 10 Both are H and R 11 is a halogen such as fluoro.

[0072] In one or more embodiments of the compounds of Formula II (including Formula IIa, Formula IIb, and Formula IIc), the B ring is selected from the group consisting of halogen, amino, hydroxyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 1-6 The optionally substituted C is optionally substituted with 1 to 3 groups selected from the group consisting of alkyl. 3-8 Cycloalkyl is a halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 It can be optionally substituted with 1 to 3 groups selected from the group consisting of alkoxy, hydroxyl, and amino. 1-6 The alkyl can be optionally substituted with 1 to 3 groups selected from the group consisting of halogen, hydroxyl, and amino.

[0073] In one or more embodiments of the compounds of Formula II (including Formula IIa, Formula IIb, and IIc), Ring B is an optionally substituted 5- or 6-membered heteroaryl or an optionally substituted 5- to 6-membered heterocyclic group, preferably containing 1 or 2 heteroatoms selected from O, N, and S.

[0074] In one or more embodiments of the compounds of Formula II (including Formula IIa, Formula IIb, and Formula IIc),

[0075] [ka] is the following group:

[0076] [ka] Preferably,

[0077] [ka] is selected from *1 indicates the position where the B ring is bonded to the methylene, *2 indicates the position where the B ring is bonded to the pyridyl, and R6 is hydrogen, halogen, amino, hydroxyl, and optionally substituted C 1-3 alkyl, and 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, optionally substituted C alkyl. 1-3 The alkyl group is optionally substituted with 1 to 5 groups selected from hydroxyl, halogen, and amino.

[0078] In one or more embodiments of the compounds of Formula II (including Formula IIa, Formula IIb, and Formula IIc), m is 1 or 2, preferably 1.

[0079] In one or more embodiments of the compounds of Formula II (including Formula IIa, Formula IIb, and Formula IIc), R8 is hydrogen, hydroxyl, halogen, cyano, optionally substituted C 1-3 Alkyl, optionally substituted C 1-3 Alkoxy or optionally substituted C 3-6 Cycloalkyl, preferably hydrogen, hydroxyl, halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl or C 3-6 Cycloalkyl, more preferably hydrogen, hydroxyl, halogen, or C 1-3 It is alkyl.

[0080] In one or more embodiments of the compound of Formula II (including Formula IIa, Formula IIb, and Formula IIc), Q is —C(O)—NR′R″ as described in any of the previous embodiments, where R′ and R″ are each independently H, optionally substituted C 1-10 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted heterocyclic, 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, and is 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 may be optionally substituted with 1 to 3 substituents selected from the group consisting of alkoxy, and is preferably pyrrolyl, pyrazolyl, imidazolyl, or triazolyl.

[0081] One group of preferred compounds of formula I in this disclosure are compounds of formula III:

[0082] [ka] or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, wherein: R8, R 11 , m, the B ring, and Q are as described in any of the previous embodiments; R 12 and R 13 each independently represents hydrogen, halogen, cyano, optionally substituted C 1-3 Alkyl and optionally substituted C1-3 Alkoxy is selected from:

[0083] In one or more embodiments of the compound of Formula III, R 12 and R 13 are each independently hydrogen, halogen, or C 1-3 Alkyl or halogenated C 1-3 In one or more embodiments, R 12 is hydrogen and R 13 is a halogen, C 1-3 Alkyl or halogenated C 1-3 In one or more embodiments, R 12 is a halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl, and R 13 is hydrogen.

[0084] In one or more embodiments of the compound of Formula III, R 11 is hydrogen, halogen, C 1-3 Alkyl or C 1-3 Preferably, R 11 is hydrogen, halogen, or C 1-3 More preferably, R 11 is a halogen such as fluoro.

[0085] In one or more embodiments of the compound of Formula III, the B ring is selected from the group consisting of halogen, amino, hydroxyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 1-6 The optionally substituted C is optionally substituted with 1 to 3 groups selected from the group consisting of alkyl. 3-8 Cycloalkyl is a halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 It can be optionally substituted with 1 to 3 groups selected from the group consisting of alkoxy, hydroxyl, and amino. 1-6The alkyl can be optionally substituted with 1 to 3 groups selected from the group consisting of halogen, hydroxyl, and amino.

[0086] 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 heterocyclic group, preferably containing 1 or 2 heteroatoms selected from O, N, and S.

[0087] In one or more embodiments of the compound of Formula III,

[0088] [ka] is the following group:

[0089] [ka] Preferably,

[0090] [ka] is selected from *1 indicates the position where the pyrrole ring is bonded to the methylene, *2 indicates the position where the B ring is bonded to the pyridyl, and R6 is hydrogen, halogen, amino, hydroxyl, and optionally substituted C 1-3 alkyl, and 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.

[0091] In one or more embodiments of the compound of formula III, m is 1 or 2, preferably 1.

[0092] In one or more embodiments of the compound of Formula III, R8 is hydrogen, hydroxyl, halogen, cyano, optionally substituted C 1-3Alkyl, optionally substituted C 1-3 Alkoxy or optionally substituted C 3-6 Cycloalkyl, preferably hydrogen, hydroxyl, halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl or C 3-6 Cycloalkyl, more preferably hydrogen, hydroxyl, halogen, or C 1-3 It is alkyl.

[0093] In one or more embodiments of the compound of Formula III, Q is —C(O)—NR′R″ as described in any of the previous embodiments, where R′ and R″ are each independently H, optionally substituted C 1-10 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted heterocyclic, 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, and is 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 may be optionally substituted with 1 to 3 substituents selected from the group consisting of alkoxy, and is preferably pyrrolyl, pyrazolyl, imidazolyl, or triazolyl.

[0094] Z1, Z2, Z3, Z4, Z5, A1, A2, A3, L, m, n, ring B, Cy, R8, R9, R in formula I (including formula II and formula III) 10 , R 11 , R 12 , R 13Although Q and Q are described separately above, it should be understood that the described features, particularly preferred features, can be combined in any way to form different ranges of compounds of Formula I (including Formulas II and III) in the present disclosure. For example, in some embodiments of compounds of Formula I (including Formulas II and III) in the present disclosure.

[0095] Preferred compounds of the present disclosure include, but are not limited to:

[0096] [Table 1-1]

[0097] [Table 1-2]

[0098] [Table 1-3]

[0099] [Table 1-4]

[0100] [Table 1-5]

[0101] or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate, or a pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof.

[0102] Some of the compounds of the present disclosure may exist as stereoisomers, including optical isomers. The present disclosure includes all stereoisomers and racemic mixtures of such stereoisomers, as well as the individual enantiomers, which may be separated according to methods well known to those skilled in the art.

[0103] Examples of pharmaceutically acceptable salts include inorganic and organic salts, such as hydrochloride, hydrobromide, phosphate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate, and oxalate salts; and inorganic and organic base salts formed with bases, such as sodium hydroxide, tris(hydroxymethyl)aminomethane (tris, tromethamine), and N-methyl-glucamine.

[0104] Examples of prodrugs of the compounds of the present disclosure include simple esters of carboxylic acid-containing compounds (e.g., C 1-4 esters of hydroxy-containing compounds (e.g., those obtained by condensation with alcohols), esters of hydroxy-containing compounds (e.g., those obtained by condensation with alcohols), 1-4 Carboxylic acid, C 3-6 diacids, or their anhydrides, such as those obtained by condensation with succinic anhydride and fumaric anhydride), imines of amino-containing compounds (e.g., C 1-4 Carbamates of amino-containing compounds, such as those described by Leu, et al., (J. Med. Chem. 42:3623-3628 (1999)) and Greenwald, et al., (J. Med. Chem. 42:3657-3667 (1999)), and acetals and ketals of alcohol-containing compounds, such as those obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art.

[0105] The compounds of the present disclosure can be prepared using methods known to those skilled in the art or novel methods of the present disclosure. Specifically, compounds of the present disclosure having Formula I (including Formula II and Formula III) can be prepared as illustrated by the exemplary reaction in Scheme 1. The reaction of 4-bromo-3-fluoro-2-nitroaniline, NaNO, SnCl·2H O, and hydrochloric acid produced (4-bromo-3-fluoro-2-nitrophenyl)hydrazine. The reaction of (4-bromo-3-fluoro-2-nitrophenyl)hydrazine and methyl-4-(dimethylamino)-3-methyl-2-oxobut-3-enoate under acetic acid catalysis produced methyl 1-(4-bromo-3-fluoro-2-nitrophenyl)-4-methyl-1H-pyrazole-5-carboxylate. The reaction of methyl 1-(4-bromo-3-fluoro-2-nitrophenyl)-4-methyl-1H-pyrazole-5-carboxylate, Fe, and acetic acid produced 7-bromo-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one. The reaction of 7-bromo-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one and (tributylstannyl)methanol (Bu3SnCH2OH) catalyzed by chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (Xphos Pd G2) produced 6-fluoro-7-(hydroxymethyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one. The reaction of 6-fluoro-7-(hydroxymethyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one and HBr produced 7-(bromomethyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one.The reaction of 7-(bromomethyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one and 5-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide under DIEA and KI catalysis produced 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.

[0106] [ka]

[0107] Other related compounds can be prepared using similar methods. For example, 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 produced 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. Replacement of 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)-6-fluoro-N-methylpicolinamide produced 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. Displacement of 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 produced 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.

[0108] The compounds of the present disclosure can be prepared using methods known to those skilled in the art or novel methods of the present disclosure. Specifically, compounds of the present disclosure having Formula I (including Formula II and Formula III) can be prepared as illustrated by the exemplary reaction in Scheme 2. The reaction of 3-bromo-2,6-difluoroaniline and 4-fluoro-1H-pyrazole-5-carbonyl chloride under the catalysis of LiHMDS produced N-(3-bromo-2,6-difluorophenyl)-4-fluoro-1H-pyrazole-5-carboxamide. The ring closure of N-(3-bromo-2,6-difluorophenyl)-4-fluoro-1H-pyrazole-5-carboxamide under basic conditions produced 7-bromo-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one. The reaction of 7-bromo-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one with Bu3SnCH2OH under Xphos Pd G2 catalysis produced 3,6-difluoro-7-(hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one. The reaction of 3,6-difluoro-7-(hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one with HBr produced 7-(bromomethyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one. The reaction of 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 under DIEA and KI catalysis produced 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.

[0109] [ka]

[0110] Other related compounds can be prepared using similar methods. For example, replacement of 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 produced 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. Replacement of 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 produced 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. Displacement of 4-fluoro-1H-pyrazole-5-carbonyl chloride with 4-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride produced 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.

[0111] An important aspect of the present disclosure is the discovery that the compounds of Formula I (including Formula II and Formula III) are PARP inhibitors, particularly selective inhibitors of PARP1. Accordingly, the compounds of Formula I (including Formula II and Formula III), or stereoisomers, tautomers, N-oxides, hydrates, isotopically substituted derivatives, solvates, or pharmaceutically acceptable salts thereof, or mixtures thereof, or prodrugs thereof, can be used to treat various diseases or conditions that respond to inhibition of PARP activity (particularly PARP1 activity), or can be used to prepare medicaments for treating or preventing diseases or conditions that respond to inhibition of PARP activity (particularly PARP1 activity).

[0112] In the present disclosure, diseases or conditions responsive to inhibition of PARP activity (particularly PARP1 activity) include cancer, which 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 (such as small cell lung cancer), Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, and primary brain cancer. , malignant melanoma, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteosarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary cancer, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocythemia, adrenocortical carcinoma, skin cancer, and prostate cancer. Preferably, the cancer responds to inhibition of PARP activity, particularly PARP1 activity.

[0113] Thus, the present disclosure includes methods for treating or preventing diseases or conditions responsive to inhibition of PARP activity (particularly PARP1 activity), the methods comprising administering to a subject (particularly a mammal, more particularly a human) in need thereof an effective amount of a compound of Formula I (including Formula II and Formula III), or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate, or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula I (including Formula II and Formula III), or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate, or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof. In the present disclosure, the subject includes a mammal, more particularly a human.

[0114] In carrying out the treatment method, an effective amount of a pharmaceutical preparation is administered to an individual who exhibits one or more symptoms of these disorders. The pharmaceutical preparation comprises a therapeutically effective amount of a compound of Formula I (including Formula II and Formula III) formulated for oral, intravenous, topical, or local application for the treatment of cancer and other diseases. The amount is effective to improve or eliminate one or more symptoms of the disorder. An effective amount of a compound for treating a specific disease is an amount that is sufficient to improve or in some way reduce the symptoms associated with the disease. Such an amount can be administered as a single dose or according to an effective regimen. Although the amount can cure the disease, it is typically administered to improve the symptoms of the disease. Typically, repeated administration is required to achieve the desired improvement in symptoms.

[0115] In another embodiment, there is provided a pharmaceutical composition comprising a compound of Formula I (including Formula II and Formula III) as a PARP inhibitor, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof.

[0116] Another embodiment of the present disclosure is directed to a pharmaceutical composition effective for treating or preventing cancer, comprising a compound of Formula I (including Formula II and Formula III) as a PARP inhibitor, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharmaceutically acceptable salt thereof and a prodrug thereof, in combination with at least one known anticancer drug or a pharmaceutically acceptable salt thereof. In particular, the compounds herein can be combined with other anticancer drugs related to DNA damage and repair mechanisms, such as ATM inhibitors, ATR inhibitors, Wee1 inhibitors, DNA-PK inhibitors; HDAC inhibitors such as vorinostat, romidepsin, panobinostat, and belinostat; other anticancer drugs related to cell division, including Chk1 / 2 inhibitors, CDK4 / 6 inhibitors such as paposinib; and other targeted anticancer drugs, including USP1 inhibitors, PRMT5 inhibitors, Polθ inhibitors, and RAD51 inhibitors. Other known anti-cancer agents that can be used in anti-cancer 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; and anti-cancer agents such as doxorubicin, epirubicin, aclacinomycin, mitoxantrone, elliptinium, and etoposide. Topoisomerase II inhibitors; RNA / DNA antimetabolites such as 5-azacytidine, gemcitabine, 5-fluorouracil, capecitabine, and methotrexate; DNA antimetabolites such as 5-fluoro-2'-deoxy-uridine, fludarabine, nelarabine, ara-C, pralatrexate, pemetrexed, hydroxyurea, and thioguanine; antimitotics such as colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, and docetaxel;mAb, panitumumab, necitumumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab, daratumumab, elotuzumab, ofatumumab, dinutuximab, brina Antibodies such as tumourab, ipilimumab, Avastin, Herceptin, and Mabtera; antibody-drug conjugates (ADCs) such as T-DM1, trastuzumab deruxtecan, trastuzumab emtansine, datopotamab deruxtecan, gemtuzumab ozogamicin, brentuximab vedotin, inotuzumab ozogamicin, sacituzumab govitecan, enfortumab vedotin, and belantamab mafodotin; androgen receptor antagonists such as abiraterone, darolutamide, enzalutamide, and prednisone; imatinib, gefitinib, erlotinib, osimertinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lapatinib, sorafenib, regorafenib, Kinase inhibitors such as vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, ponatinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cobimetinib, axitinib, temsirolimus, idelalisib, pazopanib, torisel, and everolimus are included. Other known anticancer agents that may be used in the anticancer combination therapy include tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin-2), and sipuleucel-T (a prostate cancer therapeutic vaccine);

[0117] When carrying out the method of the present disclosure, the compound of the present disclosure can be administered together with at least one known anti-cancer drug in a single pharmaceutical composition. Alternatively, the compound of the present disclosure can be administered separately from at least one known anti-cancer drug. In one embodiment, the compound of the present disclosure and at least one known anti-cancer drug are administered substantially simultaneously, i.e., all drugs are administered simultaneously or sequentially, provided that the compounds reach therapeutic blood levels at the same time. In another embodiment, the compound of the present disclosure and at least one known anti-cancer drug are administered according to individual dose schedules, provided that the compounds reach therapeutic blood levels.

[0118] Another embodiment of the present disclosure is directed to a bioconjugate for inhibiting tumors. The bioconjugate consists of a compound described herein and at least one known therapeutically useful antibody, such as trastuzumab or rituximab, or a growth factor, such as EGF or FGF, or a cytokine, such as IL-2 or IL-4, or any molecule capable of binding to a cell surface. Antibodies and other molecules can deliver the compounds described herein to their targets, making them effective anti-cancer agents. The bioconjugate can also enhance the anti-cancer effect of a therapeutically useful antibody, such as trastuzumab or rituximab.

[0119] Another embodiment of the present disclosure is directed to a pharmaceutical composition effective for inhibiting tumors comprising a PARP inhibitor of Formula I (including Formula II and Formula III), or a pharmaceutically acceptable salt thereof, or a prodrug thereof, in combination with radiation therapy. In this embodiment, the compound of the present disclosure may be administered simultaneously with or at different times from the radiation therapy.

[0120] Yet another embodiment of the present disclosure is directed to a pharmaceutical composition effective for post-operative treatment of cancer, comprising a PARP inhibitor of Formula I (including Formula II and Formula III), or a pharmaceutically acceptable salt thereof, or a prodrug thereof. The present disclosure also relates to a method of treating cancer by surgically removing a tumor and then treating a mammal with the pharmaceutical composition described herein.

[0121] The pharmaceutical compositions of the present disclosure include all pharmaceutical preparations containing the compounds of the present disclosure in an amount effective to achieve their intended purpose. While individual needs vary, determining the optimal amount of each component in a pharmaceutical preparation is within the skill of the art. Typically, the compound or a pharmaceutically acceptable salt thereof may be orally administered to a mammal at a dose of about 0.0025 to 50 mg per kg of body weight per day. Preferably, approximately 0.01 mg / kg to approximately 10 mg / kg of body weight is orally administered. When a known anti-cancer agent is also administered, it is administered in an amount effective to achieve its intended purpose. The optimal amount of such known anti-cancer agent is well known to those skilled in the art.

[0122] A unit oral dose can contain from about 0.01 to about 50 mg, preferably from about 0.1 to about 10 mg, of a compound of the present disclosure. The unit dose can be administered one or more times daily in one or more tablets, each containing from about 0.1 to about 50 mg, advantageously about 0.25 to 10 mg, of a compound of the present disclosure or a solvate thereof.

[0123] In topical formulations, the compounds of the present disclosure may be present in a concentration of approximately 0.01 to 100 mg per gram of carrier.

[0124] The compounds of the present disclosure can be administered as raw chemicals. The compounds of the present disclosure can also be administered as part of a suitable pharmaceutical preparation containing a pharmaceutically acceptable carrier (including excipients and adjuvants), which facilitates the processing of the compound into a pharmaceutically acceptable preparation. Preferably, pharmaceutical preparations, particularly oral preparations, and those used for preferred administration, such as tablets, dragees, and capsules, as well as solutions suitable for injection or oral administration, contain approximately 0.01% to 99%, preferably approximately 0.25% to 75%, of the active compound together with the excipient.

[0125] Also included within the scope of this disclosure are non-toxic pharmaceutically acceptable salts of the compounds of the present disclosure. Acid addition salts are formed by mixing a solution of the compounds of the present disclosure with a solution of a pharmaceutically acceptable non-toxic acid, such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, etc. Base addition salts are formed by mixing a solution of the compounds of the present disclosure with a solution of a pharmaceutically acceptable non-toxic base, such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, tris(hydroxymethyl)aminomethane, N-methyl-glucamine, etc.

[0126] The pharmaceutical preparations of the present disclosure can be administered to any mammal capable of experiencing the therapeutic effects of the compounds of the present disclosure, foremost among such mammals are humans and veterinary animals, although the disclosure is not intended to be so limited.

[0127] The pharmaceutical preparations of the present disclosure can be administered by any means that achieves their intended purpose. For example, administration can be parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal, or topical. Alternatively, or concurrently, administration can be oral. The dosage administered will depend on the age, health, and weight of the recipient, the type of concurrent treatment, the frequency of treatment, and the nature of the desired effect.

[0128] The pharmaceutical preparations of the present disclosure are manufactured in a known manner, for example, by conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Pharmaceutical preparations for oral use may be obtained by combining the active compound with a solid excipient, optionally grinding the resulting mixture, and adding suitable adjuvants, if desired or necessary, followed by processing the granular mixture to obtain tablets or dragee cores.

[0129] Suitable excipients are, in particular, sugars, such as lactose or sucrose, fillers such as mannitol or sorbitol; cellulose preparations and / or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate; and binders, such as starch pastes, including, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. If desired, disintegrants may be added, such as the above-mentioned starches, carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, for example, sodium alginate. Auxiliaries are, in particular, flow regulators and lubricants, such as silica, talc, stearic acid or a salt thereof, for example, magnesium stearate or calcium stearate, and / or polyethylene glycol. If desired, the dragee core may be provided with a suitable coating that is resistant to gastric juices. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.To produce coatings that are resistant to gastric juice, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate are used.Dyes or pigments can be added to tablets or dragee coatings, for example, for identification or to characterize the combination of active compound doses.

[0130] Other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, and soft sealed capsules made of gelatin, and plasticizers such as glycerol or sorbitol.Push-fit capsules may contain the active compound in the form of granules, which may be mixed with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and stabilizers.In soft capsules, the active compound is preferably dissolved or suspended in a suitable liquid, such as fatty oil or liquid paraffin.In addition, stabilizers may be added.

[0131] Suitable formulations for parenteral administration include aqueous solutions of the active compound, such as aqueous solutions of water-soluble salts and alkaline solutions. In addition, suspensions of the active compound may be administered as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate, triglycerides, or polyethylene glycol-400, or cremophor, or cyclodextrin. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, and / or dextran. Optionally, suspension stabilizers may also be included.

[0132] According to one aspect of the present disclosure, the compounds of the present disclosure are used in topical and parenteral formulations for the treatment of skin cancer.

[0133] The topical formulations of the present disclosure are preferably formulated as oils, creams, lotions, ointments, etc., by selection of an appropriate carrier. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats, and high molecular weight alcohols (C 12(larger). Preferred carriers are those in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants, and antioxidants may also be included, as well as agents imparting color or fragrance, if desired. Additionally, transdermal penetration enhancers may be used in these topical formulations. Examples of such enhancers can be found in U.S. Patent Nos. 3,989,816 and 4,444,762.

[0134] Creams are preferably formulated from a mixture of mineral oil, self-emulsifying beeswax, and water, into which the active ingredient dissolved in a small amount of oil, such as almond oil, is mixed. A typical example of such a cream contains approximately 40 parts water, approximately 20 parts beeswax, approximately 40 parts mineral oil, and approximately 1 part almond oil.

[0135] Ointments can be formulated by mixing a solution of the active ingredient in a vegetable oil such as almond oil with warm soft paraffin and allowing the mixture to cool. A typical example of such an ointment contains approximately 30% by weight of almond oil and approximately 70% by weight of white soft paraffin.

[0136] The present disclosure also involves the use of a compound of the present disclosure for the manufacture of a medicament for treating a clinical condition responsive to inhibition of the activity of PARP. The medicament can include the pharmaceutical composition described above.

[0137] The following examples are illustrative, but not limiting, of the methods and compositions of the present disclosure. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy and obvious to those skilled in the art are within the spirit and scope of the present disclosure.

[0138] Example Overview All reagents were of commercial quality. Solvents were dried and purified by standard methods. Mass spectra were recorded on a Platform II (Agilent 6110) quadrupole mass spectrometer equipped with an electrospray interface. 1H NMR spectra were recorded at 400 MHz on a Bruecker Ascend 400 instrument. Chemical shifts are reported in parts per million (ppm) downfield from TMS (0.00 ppm) and J coupling constants are reported in Hertz (Hz).

[0139] 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: 5-bromo-N-methylpicoline in DMSO (6 mL) To a solution of the amide (500 mg, 2.3 mmol), tert-butyl 2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (490 mg, 2.3 mmol), CuI (44 mg, 0.23 mol), KCO (965 mg, 6.9 mmol), and tetramethylethylenediamine (TMEDA, 26.7 mg, 0.23 mmol) were added at room temperature under a N atmosphere. The resulting mixture was stirred at 130 °C overnight. The mixture was slowly cooled to room temperature. The resulting reaction mixture was partitioned by adding water (10 mL) and extracted with EA (10 mL × 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was triturated three times with PE / EA (20:1-10:1-1:1) to give the product mixture (160 mg, crude, pale 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 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 EA (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 resulting reaction mixture was concentrated under reduced pressure to give a product mixture (130 mg, crude, pale 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% aqueous solution, 50 mL) was added dropwise an aqueous solution of NaNO (14.4 g, 64.0 mmol) in HO (50 mL) at −10 °C. The mixture was stirred at −10 °C for 1 h. The mixture was cooled to −30 °C, and a solution of SnCl·2HO (1.6 g, 23.4 mmol) in concentrated hydrochloric acid (36% aqueous solution, 50 mL) was added dropwise. The mixture was stirred at −30 °C for 1 h. After the reaction was complete, the mixture was poured into water (200 mL), and the pH of the solution was adjusted to 7–8 with solid NaHCO. The resulting mixture was extracted with EA (100 mL × 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the target product (4.3 g, crude, yellow solid, yield: 81%). d) Preparation of 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 dropwise 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 mixture was stirred at 80 °C overnight. After the reaction was completed, the mixture was poured into ice water (100 mL) and extracted with EA (100 mL × 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel (PE:EA = 15:1) to give the target product (0.83 g, yellow solid, yield: 58%). 1 H NMR (400 MHz, DMSO-d6): δ 8.16-8.14 (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) was added Fe dust (0.65 g, 11.6 mmol, 5.0 equiv.) at room temperature. The mixture was stirred at 80 °C overnight. After the reaction was complete, the mixture was filtered, the filtrate was diluted with water (50 mL) and ethyl acetate (5 mL), and the solid was collected by filtration to give the target product (370 mg, off-white solid, yield: 55%). MS (ESI): 295.90 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 11.90 (br, 1H), 7.91 (s, 1H), 7.77 (d, J = 8.0 Hz, 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), BuSnCHOH (10.9 g, 33.9 mmol) and Xphos Pd G (1.3 g, 1.7 mmol) were added at room temperature. The mixture was stirred at 90 °C under a nitrogen atmosphere for 16 h. After the reaction was complete, an aqueous solution of KF (1 M, 100 mL) was added at room temperature. The mixture was stirred at the same temperature for 10 min and filtered. The filtrate was extracted with EA (200 mL × 3). The combined organic phase was washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was triturated with a mixture of PE / EA (v / v=1:1), and the solid was collected by filtration to give the target 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: A solution of 6-fluoro-7-(hydroxymethyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (2.8 g, 11.3 mmol) in HBr (30 mL, 48% in HO) was stirred at 80° C. for 2 hours. After completion of the reaction, the reaction was concentrated under reduced pressure to give the target 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: Dissolve 5-(5 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), 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 mmol), and DIEA (151.0 mg, 1.2 mmol) were added at room temperature under N2. The resulting suspension was stirred at 80 °C for 0.5 h. After the reaction was complete, the solvent was removed in vacuo. The residue was purified by preparative HPLC (C18, ACN in water, 5-55%, 0.1 HCOOH) to give the title 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%).

[0140] The following compounds of Examples 2-12 were prepared using synthetic methods similar to those described in Example 1 (Scheme 1).

[0141] [Table 2-1]

[0142] [Table 2-2]

[0143] [Table 2-3]

[0144] 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 LiHMDS (1 M in THF, 20.2 mL, 20.2 mmol) under nitrogen at 0° C. The mixture was stirred at 0° C. for 30 min, and 4-fluoro-1H-pyrazole-5-carbonyl chloride (1.0 g, 6.7 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min and warmed to room temperature for 1.5 h. The mixture was quenched with water (20 mL) and extracted with EA (20 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel (PE / EA=5 / 1) to give the product (1.5 g, yellow solid, yield: 72%). MS (ESI): 319.95 [M+H] + . b) Preparation of 7-bromo-3,6-difluoropyrazolo[1,5-a]quinoxalin-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 nitrogen. The mixture was stirred at 100 °C overnight. The mixture was cooled to room temperature. Water (15 mL) was added, and the mixture was extracted with EA (20 mL × 3). The organic phase was then concentrated under reduced pressure. The residue was purified by flash chromatography (C18, water / acetonitrile = 55 / 45) to give a mixture of the product and its regioisomer (1.2 g, white solid), which was used directly in the next step. 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 7-bromo-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one and its regioisomer (1.2 g, 4.0 mmol) in dry dioxane (12 mL) was added Xphos Pd G2 (314.7 mg, 0.4 mmol) and (tributylstannyl)methanol (3.9 g, 12 mmol) under nitrogen. The mixture was stirred at 80 °C for 4 h. The mixture was 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 × 3). The organic phase was concentrated under reduced pressure. The residue was purified by silica gel (DCM / MeOH=1 / 0→100 / 1→80 / 1→50 / 1) to give the title compound (260.0 mg, white solid, 2-step yield: 22%). MS (ESI): 252.10 [M+H] + . 1 H NMR(400 MHz,DMSO-d6):δ 11.94(s,1H),8.20(d,J=3.8 Hz,1H),7.89(d,J=8.6 Hz,1H),7.36(t,J=7.7 Hz,1H),5.44(t,J=5.8 Hz,1H),4.61(d,J=5.5 Hz,2H). d) Preparation of 7-(bromomethyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one: A solution of 3,6-difluoro-7-(hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (200.0 mg, 0.8 mmol) in HBr (48% in water, 20 mL) was stirred at 80° C. under nitrogen for 2 hours. The mixture was concentrated under reduced pressure to give the product (261.0 mg, white solid, 96% yield). MS (ESI): 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 ACN (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), DIEA (95.0 mg, 0.7 mmol) under N at room temperature. The resulting suspension was stirred at 85° C. for 2 hours. After completion of the reaction, the solvent was removed under reduced pressure. The residue was purified by preparative HPLC to give the title compound (10.3 mg, white solid, yield: 9%).

[0145] The following compounds, Examples 14-30, 40-48, 53-62, and 65-66, were prepared using synthetic methods similar to those described in Example 13 (Scheme 2). The following compounds, Examples 31-39, 49-52, and 63-64, were prepared using synthetic methods similar to those described in Example 1 (Scheme 1).

[0146] [Table 3-1]

[0147] [Table 3-2]

[0148] Table 3-3

[0149] Table 3-4

[0150] Table 3-5

[0151] Table 3-6

[0152] Table 3-7

[0153] Table 3-8

[0154] Table 3-9

[0155] Table 3-10

[0156] Table 3-11

[0157] Table 3-12

[0158] Example 67 PARP1 and PARP2 chemiluminescence assay Solutions of recombinant poly(ADP-ribose) polymerase 1 and 2 (PARP1 and PARP2) (40 ng enzyme / well) were mixed with the compounds to be tested. The solutions were added to a 96-well plate coated with the histone mixture and incubated at room temperature for 1 hour. Then, 50 μL of 0.3 ng / mL streptavidin-HRP was added to each well. The plate was incubated at room temperature for 30 minutes. Finally, the plate was treated with streptavidin-HRP, followed by the addition of ELISA ECL substrate to generate chemiluminescence, which can be measured using a chemiluminescence reader. The inhibition of the test compound on PARP1 / 2 enzyme activity was calculated according to the following formula:

[0159]

number

[0160] Table 1 shows the enzyme activity (IC 50 ) and summarize the inhibitory effects of the compounds on the

[0161] [Table 4]

[0162] Most of the tested compounds have potent and selective inhibitory effects on the PARP1 enzyme compared to the PARP2 enzyme.

[0163] Example 68 Growth inhibition assay against BRCA-mutated human breast cancer MDA-MB-436 cell line Cells were cultured in complete medium (DMEM medium + 10% FBS + insulin + glutathione). When the confluence reached approximately 80%, the cells were digested and gently dispensed from the bottom of the 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 medium. The cells were seeded into culture dishes at an appropriate ratio and then cultured in a 37°C, 5% CO2 incubator. The assay was performed when the cells were in optimal condition and reached 80% confluence. Cells in the logarithmic growth phase were centrifuged, and the culture supernatant was removed. The cells were resuspended in fresh complete medium and counted. The resuspended cells were seeded at 3000 / well in a 96-well plate and incubated overnight in a 37°C, 5% CO2 incubator. Compounds were prepared as follows: 1000x diluted test compound solution to 40x test compound solution by adding 5 μL of 1000x compound solution to 120 μL of medium (25x dilution). The solution was mixed by shaking. 0.1% DMSO was used as a control.

[0164] The next day, the 96-well plate containing the cells was removed from the incubator, and the culture supernatant was removed. Then, 195 μL / well and 5 μL / well of 40× test compound solution were added to the 96-well plate, respectively, as described above. Finally, the plate was incubated in a 37°C, 5% CO2 incubator for 7 days. The compound-containing medium was replaced on the fourth day. After 7 days, 20 μL of CCK-8 was added to each well, gently shaken, and then cultured for 4 hours. The plate was shaken for 5 minutes after incubation. The absorbance values ​​at 450 nm or 650 nm wavelength were recorded using a multi-function readout instrument (OD = absorbance value 450 nm - absorbance value 650 nm), respectively.

[0165] The data were analyzed by the software GraphPad Prism 6.0. The inhibitory activity of the compounds on cell proliferation was plotted using cell viability versus compound concentration as the coordinate. Cell viability % = (OD 化合物 -OD バックグラウンド ) / (OD DMSO -OD バックグラウンド) x 100. IC 50 Values ​​are expressed as a function of the sigmoidal dose-response curve equation: Y = 100 / (1 + 10^(logC-logIC) 50 )) where C was the compound concentration.

[0166] Table 2 shows the inhibitory effect data (IC) of compounds on the proliferation of human breast cancer cells MDA-MB-436. 50 ) is summarized below.

[0167] [Table 5]

[0168] The tested compounds have good inhibitory effects on the proliferation of BRCA-mutated human breast cancer cells MDA-MB-436.

[0169] Example 69 Inhibitory effect of compounds on PDE3A A multi-step PDE3A fluorescence polarization (FP) assay was performed using a black round-bottom 384-well plate (Corning, 4514). Test compounds were serially diluted from stock solutions to 11 concentrations using DMSO at 3-fold dilution factors. 50 nL of compound dilution was mixed with 5 μL of reaction buffer (10 mM Tris-HCl, pH 7.2, 10 mM MgCl, 0.05% NaN, 0.1% phosphate-free BSA) containing 0.2 μM FAM-cAMP (BPS, 60200) and 2 nM PDE3A (Sino Biological, 11908-H20B1) enzyme and incubated at 25°C for 60 minutes. Then, 15 μL of binder mixture (Molecular Devices, R8124) was added to each well, and the plate was incubated at 25°C for 60 minutes. The plate was loaded into a BMG PHERAstar FSX and the fluorescence polarization (FP) values ​​were read using the following settings: Ex: 485 nm and Em: 520 nm. The emitted light intensity with the polarizer parallel (Em

[0170]

number

[0171]

number

[0172]

number

[0173] Data Analysis: 1) The % inhibition of a compound dose is calculated as follows: Inhibition % = (mP 最大 -mP 化合物 ) / (mP 最大 -mP 最小 )×100% In the formula, mP 最小 and mP 最大 refers to the polarization readings in the substrate only and substrate + enzyme conditions, respectively. 2) IC 50 Values ​​were calculated from non-linear curve fits using the commercially available curve fitting software GraphPad Prism 9.2.0, using the following regression equation: Y=Bottom+(Top Bottom) / (1+10^((LogIC 50 -X) × Hill gradient) where X refers to the logarithm of the compound concentration and Y refers to the % inhibition.

[0174] Table 3 shows the PDE3A enzyme activity (IC 50 ) and summarize the inhibitory effects of the compounds on the

[0175] [Table 6]

[0176] The results show that the compounds of the present disclosure inhibit PDE3A (IC 50 These results show that the inhibitors have low or very low inhibitory effects against α-glucan (>30 μM).

[0177] Having now fully described this disclosure, those skilled in the art will recognize that the same may be practiced within a wide equivalent range of conditions, formulations, and other parameters without affecting the scope of the present disclosure or any embodiment thereof. All patents, patent applications, and publications cited herein are hereby fully incorporated by reference in their entirety.

Claims

1. A compound of formula I, 【Chemistry 1】 or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a mixture thereof, wherein: 【Chemistry 2】 and the Z ring, depicted as: is an optionally substituted 5-membered heteroaryl group, and * indicates the position at which the Z ring is attached to the remainder of the compound; and Z １ , Z ２ , and Z ３ are each independently, CR １ , N.R. ２ , O, N, or S, and Z ４ and Z ５ are each independently C or N, and Z ４ and Z ５ But at the same time, it is not N, A １ , A ２ , and A ３ are each independently N and CR ３ is selected from L is a bond and R ４ and / or R ５ and selected from alkylene optionally substituted by Ring B is an optionally substituted heteroaryl or an optionally substituted heterocyclic group; Cy is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; R １ is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted carbocyclic groups; R ２ is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R ３ is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted carbocyclic groups; R ４ and R ５ are each independently selected from the group consisting of halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl, or R ４ and R ５ forms a ring together with the bonded C, A compound of Formula I, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a mixture thereof, wherein m and n are each independently selected from 1 and 2.

2. The Z ring is one of the following groups: 【Transformation 3】 Preferably, 【Chemistry 4】 is selected from 2. The compound of claim 1, 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 * indicates the position at which the Z ring is attached to the remainder of the compound.

3. R １ wherein said alkyl, alkoxy, and carbocyclic groups are each optionally substituted with 1 to 5 groups selected from halogen, hydroxyl, and —NR′R″, and R′ and R″ are each independently H or C １－４ alkyl, preferably R １ is hydrogen, halogen, or optionally substituted C １－３ is alkyl, wherein said alkyl, alkoxy, cycloalkyl, alkenyl, and alkynyl are each optionally substituted with 1 to 5 groups selected from halogen, hydroxyl, and —NR′R″, and R′ and R″ are each independently H or C １－４ alkyl, preferably R ２ is hydrogen, optionally substituted C １－３ Alkyl, and optionally substituted C ３－６ Cycloalkyl, more preferably hydrogen or optionally substituted C １－３ 3. The compound of claim 1 or 2, wherein R is alkyl, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof.

4. A １ , A ２ , and A ３ are each independently N and CR ３ and R ３ 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 can be optionally substituted with 1 to 5 groups selected from halogen, hydroxyl, and —NR′R″, where R′ and R″ are each independently H or C １－４ alkyl, preferably R ３ is hydrogen, halogen, or C １－３ is alkyl, Preferably, A １ , A ２ , and A ３ All of this is CR ３ and R ３ are each independently hydrogen, halogen, or C １－３ alkyl or A １ But, CR ３ and A ２ and A ３ are both CH or A １ is CH, and A ２ But, CR ３ and A ３ is CH, or A １ and A ２ are both CH, and A ３ But, CR ３ and R ３ are each independently a halogen or C １－３ alkyl, more preferably A １ and A ２ are both CH, and A ３ But, CR ３ and preferably, R ３ is halogen such as fluoro, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof.

5. The B ring is preferably an optionally substituted 5- or 6-membered heteroaryl or an optionally substituted 5- to 6-membered heterocyclic group containing 1 or 2 heteroatoms selected from O, N, and S, and preferably the B ring is selected from halogen, amino, hydroxyl, optionally substituted C ３－８ Cycloalkyl, optionally substituted C １－６ and optionally substituted with 1 to 3 groups selected from the group consisting of alkyl, ３－８ Cycloalkyl is halogen, C １－４ Alkyl, C １－４ Alkoxy, halogenated C １－４ Alkyl, halogenated C １－４ Optionally substituted with 1 to 3 groups selected from the group consisting of alkoxy, hydroxyl, and amino, wherein said optionally substituted C １－６ the alkyl is optionally substituted with 1 to 3 groups selected from the group consisting of halogen, hydroxyl, and amino; Preferably, 【Transformation 5】 is the following group: 【Transformation 6】 More preferably, 【Transformation 7】 is selected from *1 indicates the position where the B ring is bonded to L, *2 indicates the position where the B ring is bonded to Cy, and R ６ is selected from hydrogen, halogen, amino, hydroxyl, and optionally substituted C １－３ alkyl, and R ７ is hydrogen, optionally substituted C １－３ Alkyl, and optionally substituted C ３－６ Cycloalkyl, preferably hydrogen or optionally substituted C １－３ 5. The compound of any one of claims 1 to 4, 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 the compound is selected from the group consisting of:

6. Cy is halogen, hydroxyl, 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 a 6- to 14-membered aryl or a 5- to 10-membered heteroaryl, each independently and optionally substituted by 1 to 5 substituents selected from the group consisting of cycloalkyl, amino (—NR′R″), aminoacyl (—C(O)—NR′R″), and carboxyl, wherein said R′ and R″ are each independently selected from H, optionally substituted C １－１０ Alkyl, optionally substituted C ３－８ Cycloalkyl, optionally substituted heterocyclic group, optionally substituted aryl, or optionally substituted heteroaryl, preferably H, optionally substituted C １－４ Alkyl, optionally substituted C ３－６ cycloalkyl, or an optionally substituted 3- to 6-membered heterocyclic group, preferably wherein the substituents on Cy include at least —C(O)—NR′R″, and optionally include halogen, hydroxyl, cyano, C １－４ Alkyl, halogenated C １－４ Alkyl, and C ３－６ cycloalkyl; Preferably, Cy is halogen, hydroxyl, cyano, optionally substituted C １－４ Alkyl, optionally substituted C １－４ Alkoxy, C ３－６ and phenyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl optionally substituted by 1 to 5 substituents selected from the group consisting of cycloalkyl, aminoacyl, and carboxyl, preferably wherein Cy is substituted by at least one aminoacyl group, preferably wherein said aminoacyl group is at the para position of Cy, preferably wherein said aminoacyl group is -C(O)-NR'R'', wherein R' and R'' are each independently selected from H, optionally substituted C １－１０ Alkyl, optionally substituted C ３－８ Cycloalkyl, optionally substituted heterocyclic group, optionally substituted aryl, or optionally substituted heteroaryl, preferably H, optionally substituted C １－４ Alkyl, optionally substituted C ３－６ cycloalkyl, or an optionally substituted 3- to 6-membered heterocyclic group; Preferably, Cy is: 【Transformation 8】 D １ , D ２ , D ３ , and D ４ are each independently N and CR ８ and R ８ is hydrogen, halogen, hydroxyl, cyano, optionally substituted C １－４ Alkyl, optionally substituted C １－４ Alkoxy, optionally substituted C ３－８ Carbocyclic groups, amino (—NR′R″), optionally substituted C ２－４ Alkenyl, and optionally substituted C ２－４ alkynyl, and R' is selected from the group consisting of optionally substituted C １－１０ Alkyl, optionally substituted C ３－８ cycloalkyl, optionally substituted heterocyclic group, 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- to 6-membered heterocyclic group, where * indicates the position where said group is attached to the B ring, and preferably D １ , D ２ , D ３ , and D ４ is phenyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, preferably R ８ H, hydroxyl, halogen, cyano, C １－３ Alkyl, C １－３ Alkoxy, halogenated C １－３ Alkyl, or C ３－６ cycloalkyl, preferably D ３ is N and D ４ But, CR ８ and D １ and D ２ are both CH and R ８ H, hydroxyl, halogen, cyano, C １－３ Alkyl, C １－３ Alkoxy, halogenated C １－３ Alkyl, or C ３－６ 6. The compound of any one of claims 1 to 5, 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 the compound is cycloalkyl.

7. The compound of formula I is represented by formula IIa, IIb, IIc, or III shown below: 【Chemistry 9】 During the ceremony, Z １ , Z ２ , Z ３ and the Z ring is as defined in any one of claims 1 to 3, m is as defined in claim 1; Ring B is as defined in claim 1 or 5; R ８ is as defined in claim 6, R ９ , R １０ , and R １１ are each independently 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; R′ and R″ are each independently hydrogen, optionally substituted C １－１０ Alkyl, optionally substituted C ３－８ selected from cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, and heteroaryl; R １２ and R １３ are each independently hydrogen, halogen, cyano, optionally substituted C １－３ Alkyl, and optionally substituted C １－３ alkoxy, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof.

8. The Z ring is one of the following groups: 【Chemistry 10】 is selected from Each R １ are independently hydrogen, halogen, C １－３ Alkyl or haloC １－３ alkyl, preferably 【Chemistry 11】 In this case, R １ is hydrogen and another R １ is halogen or C １－３ is alkyl, R ２ But C １－３ is alkyl, A １ and A ２ are both CH, and A ３ But, CR ３ and R ３ is a halogen, The aforementioned 【Chemistry 12】 is the following group: 【Chemistry 13】 is selected from In the formula, *1 indicates the position where the B ring is bonded to L, *2 indicates the position where the B ring is bonded to Cy, and R ６ is hydrogen, and R ７ is hydrogen, Cy is: 【Chemistry 14】 D ３ is N and D ４ But, CR ８ and D １ and D ２ are both CH and R ８ But H, C １－３ alkyl, or halogen, and R' is C １－３ Alkyl or C ３－６ 2. The compound of claim 1, 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 the compound is cycloalkyl.

9. A compound selected from: 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]oxazepine-9-carboxamide, 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[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, isotopically substituted derivative, solvate, or a pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof.

10. 10. Use of a compound according to any one of claims 1 to 9, or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate, or pharmaceutically acceptable salt thereof, or prodrug thereof, or a mixture thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition responsive to the inhibition of PARP activity, Preferably, the disease or condition is cancer, and preferably, the cancer is 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 (such as small cell lung cancer), Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant tumors, or the like. selected from melanoma, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteosarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary cancer, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocythemia, adrenocortical carcinoma, skin cancer, or prostate cancer; Preferably, the medicament further comprises at least one known anti-cancer drug or a pharmaceutically acceptable salt thereof, and preferably, the anti-cancer drug is selected from the group consisting of vorinostat, romidepsin, panobinostat, belinstat, palbociclib, busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxybenzoate, methylpropional ... Lipticine, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, capecitabine, methotrexate, 5-fluoro-2'-deoxy-uridine, fludarabine, nelarabine, ara-C, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, mAb, panitumumab, necitumumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetaxel Ximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab, daratumumab, elotuzumab, ofatumumab, dinutuximab, blinatumomab, ipilimumab, Avastin, Herceptin, MabTera, T-DM1, trastuzumab deruxtecan, trastuzumab emtansine, datopotamab deruxtecan, gemtuzumab ozogamicin, brentuximab vedotin, inotuzumab ozogamicin, sacituzumab govitecan, enfortumab vedotin, belantamab mafodotin, Biraterone, darolutamide, enzalutamide, prednisone, imatinib, gefitinib, erlotinib, osimertinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, rafenib, sorafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, ponatinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cobimetinib, axitinib, temsirolimus, idelalisib, pazopanib, torisel, everolimus,selected from the group consisting of tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin-2), and sipuleucel-T (prostate cancer treatment vaccine); Preferably, the agent is used in combination with radiotherapy.

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9, or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a mixture thereof, and a pharmaceutically acceptable carrier.

12. The composition further comprises at least one known anticancer drug or a pharmaceutically acceptable salt thereof, and preferably, the at least one known anticancer drug is selected from the group consisting of vorinostat, romidepsin, panobinostat, belinstat, palbociclib, busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, and methylprednisolone. Hydroxyellipticine, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, capecitabine, methotrexate, 5-fluoro-2'-deoxy-uridine, fludarabine, nelarabine, ara-C, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, mAb, panitumumab, necitumumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab Ibuprofen, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab, daratumumab, elotuzumab, ofatumumab, dinutuximab, blinatumomab, ipilimumab, Avastin, Herceptin, MabTera, T-DM1, trastuzumab deruxtecan, trastuzumab emtansine, datopotamab deruxtecan, gemtuzumab ozogamicin, brentuximab vedotin, inotuzumab ozogamicin, sacituzumab govitecan, enfortumab vedotin, belantamab Fodotin, abiraterone, darolutamide, enzalutamide, prednisone, imatinib, gefitinib, erlotinib, ostinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lapatinib, soltinibrafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, platinib, brutinib, cabozantinib, lenvatinib, vandetanib, trametinib, chabimetinib, axitinib, temsirolimus, idelalisib, pazopanib, everolimus,The pharmaceutical composition according to claim 11, which is selected from the group consisting of tamoxifen, letrozole, fulvestrant, mitoguanhydrazone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin-2), and sipuleucel-T (prostate cancer therapeutic vaccine).

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