Substituted tricyclic compounds as PARP inhibitors and their uses

Abstract

Provided are substituted tricyclic compounds and their use as PARP inhibitors.The compounds are represented by the following formula (I), in which rings Z, Z1, Z2, A1, A2, A3, L and Cy are defined herein.The compounds of formula (I) are PARP inhibitors and are therefore useful for treating diseases, disorders and conditions, such as cancer, that respond to the inhibition of PARP activity.Also provided are 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. JPEG2024531477000104.jpg3948

Description

[Technical field]

[0001] The present disclosure is in the field of medicinal chemistry. In particular, the present disclosure relates to substituted tricyclic compounds and the use of these compounds as therapeutically effective PARP inhibitors and anti-cancer agents. [Background technology]

[0002] Poly(ADP-ribose) polymerase (PARP) is a donor NAD + PARP is a family of proteins that transfer the negatively charged ADP-ribose group from ADP-ribose 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 the catalytic domain (Vyas et al., 2013 Nature Communication, 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 was found to have the highest intracellular levels. PARP1 consists of 1014 amino acids (NCBI accession P09874) with a total molecular weight of approximately 116 kDa. Structurally, the enzyme is composed 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 major mechanism of DNA single-strand damage repair. PARP1 binds to the site of a single-strand break (SSB) and then 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 were found to be sensitive to PARP inhibitors, indicating that homologous recombination deficiency and PARP1 inhibition formed a pair of synthetic lethality that was validated by clinical studies.Currently, several PARP inhibitors have been approved for the treatment of breast, ovarian, pancreatic, and prostate cancers with DNA damage repair deficiencies, such as BRCA1 / 2 mutations.

[0005] PARP2 is a 559 amino acid protein with a molecular weight of approximately 62 kDa, and is composed 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 the repair of DNA damage 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 have similar inhibitory activity against PARP2. Based on the results of clinical trials, the therapeutic effects of these commercially available PARP inhibitors are comparable, but the toxicity profiles are significantly different. For example, talazoparib has similar toxicity to chemotherapy drugs, such as hair loss. Talazoparib also shows more potent inhibitory activity against TNKS1 / 2 (tankyrase 1 or tankyrase 2) in biochemical assays than other PARP inhibitors (PARPi) (Ryan et al., 2021, J Biol Chem 296:100251 / 1-100251 / 13). TNKS1 and TNKS2 share 83% sequence identity overall, 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 hematologic toxicity (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. Therefore, to improve, enhance, and expand the clinical applications of PARP inhibitors, it is important to explore highly selective PAPR1 inhibitors to reduce mechanism-related or mechanism-independent toxicities. Various PARP1 inhibitors have been disclosed, for example, in WO2011006803, WO2013014038, WO2021013735, and WO2021260092. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2011006803 [Patent Document 2] International Publication No. 2013014038 [Patent Document 3] International Publication No. 2021013735 [Patent Document 4] International Publication No. 2021260092 [Non-patent literature]

[0007] [Non-Patent Document 1] Vyas et al.,2013 Nature Communication,4:3240 / 1-3240 / 13 [Non-Patent Document 2] Ame et al.,1999 J Biol Chem 274:17860-17868 [Non-Patent Document 3] Schreiber et al.,2002 J Biol Chem 277:23028-23036 [Non-Patent Document 4] Ryan et al.,2021,J Biol Chem 296:100251 / 1-100251 / 13 [Non-Patent Document 5] Farres et al.,2013 Blood 122:44-54 [Non-Patent Document 6] Farres et al.,2015 Cell Death and Differentiation 22:1144-1157 Summary of the Invention [Means for solving the problem]

[0008] The present disclosure provides compounds represented by formula I (including formula II, formula III and formula IV) and their analogs.The compounds can be used as PARP inhibitors.In particular, the compounds of the present disclosure are selective PARP1 inhibitors 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, Formula III, and Formula IV). The pharmaceutical composition can be used to treat cancer.

[0010] In certain embodiments, the pharmaceutical composition may further comprise one or more pharma- ceutically acceptable carriers, excipients, or diluents.

[0011] In certain embodiments, the pharmaceutical composition may also include at least one known anti-cancer agent or a pharma- ceutically acceptable salt thereof.

[0012] The present disclosure is also directed to methods of preparing the novel compounds of Formula I (including Formula II, Formula III, and Formula IV).

[0013] The present disclosure also provides a method for treating or preventing a disease or condition responsive to inhibition of PARP activity (particularly PARP1 activity), the method comprising administering to a subject in need thereof an effective amount of a compound of Formula I (including Formula II, Formula III and Formula IV) or a pharma- ceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] 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 the alkyl substituent in this specification applies to any of the embodiments described herein, unless the alkyl substituent is clearly defined in the embodiment.

[0015] As used herein, the term “hydrogen (H)” includes its isotopes D and T.

[0016] The term "heteroatom" as used herein includes O, S, and N.

[0017] As used herein, the term "alkyl" refers to alkyl itself or to a straight or branched chain radical of up to ten carbons. Useful alkyl groups include straight or branched C 1-10 Alkyl groups, preferably C 1-6 In some embodiments, the alkyl group 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 group. Typical C 1-10 Alkyl groups include methyl, methyl-d3, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl (such as 3-pentyl), hexyl, and octyl groups, which may be optionally substituted.

[0018] 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 has at least one double bond between two of the carbon atoms in the chain, preferably a C 2-6Exemplary alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl.

[0019] 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 C 2-6 Exemplary alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl, and 2-butynyl.

[0020] Useful alkoxy groups include those described above for C 1-10 Alkyl groups, preferred C 1-6 Alkyl group, or C 1-4 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).

[0021] 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 3-8 R′ and R″ are each independently selected from hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6or R' and R" together with the N to which they are attached form an optionally substituted 4-7 membered cyclic amino group, which optionally contains one or more (such as 2, 3) additional heteroatoms selected from the group consisting of O, N, and S. Preferred amino groups include NH2, where at least one of R' and R" is C in -NR'R". 1-6 It is an alkyl.

[0022] As used herein, the term "oxo" refers to =O.

[0023] 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 by one or more substituents described herein.

[0024] Useful aryl groups include C 6-14 Aryl groups, preferably C 6-10 Aryl groups are typical. 6-14 Aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azuryl, biphenyl, biphenylene, and fluorenyl.

[0025] As used herein, the term "carbocyclic group" includes cycloalkyl and partially saturated carbocyclic groups. Useful cycloalkyl groups include C 3-8 In some preferred embodiments, the cycloalkyl group is C 3-6 Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Useful partially saturated carbocyclic groups include cyclopentenyl, cycloheptenyl, and cyclooctenyl, C 3-8 A carbocyclic group may be optionally substituted by one or more substituents described herein.

[0026] Useful halo or halogen groups include fluoro, chloro, bromo, and iodo.

[0027] Useful acylamino (amido) groups include any C 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.

[0028] Useful acyl groups include C 1-6 Examples of substituted acyl groups include acyl, which may be optionally substituted by a group selected from halo, amino, and aryl, and amino and aryl may be optionally substituted. When acyl is substituted by halo, the number of halogen substituents may range from 1 to 5. Examples of substituted acyl include chloroacetyl and pentafluorobenzoyl. When acyl is substituted by amino, the amino group may be substituted by one or two substituents as 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 R′ and R″ are each independently selected from hydrogen, optionally substituted C 1-4 Alkyl, or optionally substituted C 3-6 It is cycloalkyl.

[0029] 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 one to four heteroatoms independently selected from the group consisting of O, N, and S), in which the nitrogen and / or sulfur heteroatoms may be optionally oxidized, and the nitrogen may be optionally quaternized; the term also includes any bicyclic ring system in which any of the heterocyclic rings defined above are fused to a benzene ring. A heterocyclic group may be substituted at a carbon or nitrogen atom if the resulting compound is stable. A heterocyclic group may be substituted by one or more substituents described herein.

[0030] 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.

[0031] As used herein, the term "heteroaryl" refers to a group having 5-14 ring atoms, preferably 5-10 ring atoms, in which 6, 10, or 14 electrons are shared in a cyclic array. The ring atoms are carbon atoms and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Heteroaryls may be optionally substituted with one or more substituents described herein.

[0032] 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, phthalidinyl, naphthyridinyl, quinozalinyl, and the like. aryl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, tetrahydrocyclopenta[c]pyrazol-3-yl, benzoisoxazolyl, such as 1,2-benzisoxazol-3-yl, benzimidazolyl, 2-oxindolyl, thiadiazolyl, 2-oxobenzimidazolyl, imidazopyridazinyl, imidazopyridyl, triazolopyridazinyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, pyrrolopyridyl, pyrrolopyrazinyl, or triazolopyrazinyl. Where a heteroaryl group contains a nitrogen atom in a ring, such nitrogen atom may be in the form of an N-oxide, e.g., a pyridyl N-oxide, pyrazinyl N-oxide, and pyrimidinyl N-oxide.

[0033] 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 as described in any of the embodiments herein can be selected from the group consisting of 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 It may be 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 be optionally substituted. 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.

[0034] In each embodiment, it is to be understood that when the substituent is a heterocyclic group, aryl, or heteroaryl, the number is typically one.

[0035] Specifically, the present disclosure provides a compound represented by formula I: [ka] or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, wherein A1, A2, and A3 are each independently selected from N and CR1; [ka] is an optionally substituted 5- to 7-membered carbocyclic group, an optionally substituted 5- to 7-membered heterocyclic group, or an optionally substituted 5-membered heteroaryl group, * indicates the position at which the Z ring is attached to the remainder of the compound, and a dashed line indicates the optional presence of an unsaturated bond, wherein Z1 and Z2 are each independently C or N, and wherein Z1 and Z2 are not simultaneously N, and further wherein Z1 and Z2 satisfy the following conditions: (1) when the Z ring is an optionally substituted 5- to 7-membered carbocyclic group or an optionally substituted 5- to 7-membered heterocyclic group, Z (2) when the Z ring is an optionally substituted 5- to 7-membered heterocyclic group and Z2 is C, the ring atom of the Z ring bonded to Z2 is not N; (3) when the Z ring is an optionally substituted 5-membered heteroaryl group and Z1 is N, in addition to the N at the Z1 position, the 5-membered heteroaryl further contains 1 to 3 N heteroatoms, or when the Z ring is an optionally substituted 5-membered heteroaryl, Z1 is N and there are no other heteroatoms in the Z ring, and A1 is CR1; L is selected from a bond and alkylene optionally substituted by R2 and / or R3; Cy is selected from the group consisting of optionally substituted heterocyclic groups, optionally substituted aryl, and optionally substituted heteroaryl; R1 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted carbocyclic groups; R2 and R3 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 R2 and R3 together with the bonded C form a ring.

[0036] In Formula I and each formula of this disclosure, unless otherwise stated, each alkyl is independently C 1-6 Alkyl, preferably C 1-4 alkyl, each alkylene being C 1-6 Alkylene, preferably C 1-3 alkylene, each alkenyl independently being C 2-6 Alkenyl, preferably C 2-4 alkenyl, each alkynyl independently being C 2-6 Alkynyl, preferably C 2-4 alkynyl, each alkoxy being independently selected from the group consisting of C 1-6 Alkoxy, preferably C 1-4 Preferably, when the alkyl, alkenyl, alkynyl, and alkoxy are substituted, the substituents may be selected from the group consisting of cyano, hydroxyl, nitro, amino (-NR'R''), aryl, heterocyclic group, heteroaryl, halogen, and carboxyl. The number of the substituents may 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 3-6It is cycloalkyl. For example, substituted alkyl itself or as a substituent of other groups may be hydroxyalkyl, dihydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heterocyclic alkyl, aralkyl, heteroarylalkyl, haloalkyl, etc. It should be understood that when the substituent is aryl, heteroaryl, heterocyclic, cyano, nitro, and carboxyl, the number is usually 1. When the substituent is halogen, the number of the substituent can be up to 5 depending on the length of the carbon chain of the alkyl group, alkenyl group, alkynyl group, and alkoxy group, and exemplary substituents are trifluoromethyl group, pentafluoroethyl, etc.

[0037] In Formula I and each formula of this disclosure, unless otherwise stated, the number of ring carbon atoms in each carbocyclic group is preferably 3 to 8. Preferred carbocyclic groups are 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 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 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 the substituent can be up to 5.

[0038] In Formula I and each formula of the present disclosure, unless otherwise stated, aryl is C 6-14The term "aryl" refers to a 5- to 10-membered heteroaryl, and the term "heterocyclic group" refers to a 4- to 10-membered heterocyclic group. Substituents on each of the aryl, heteroaryl, and heterocyclic groups independently include C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 and 1 to 5 groups consisting of alkoxy, halogen, hydroxyl, carboxyl, amino (-NR'R''), optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, 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 R′ and R″ are each independently selected from hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 The number of substituents can be 1 to 5. The optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclic groups are optionally selected from the group consisting of C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 and optionally substituted with 1 to 5 groups selected from alkoxy, halogen, hydroxyl, carboxyl, amino (-NR'R''), aminoacyl (-C(O)-NR'R''), and carboxyl, wherein R' and R'' are preferably each independently selected from 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 the substituent can be up to 5.

[0039] In one or more embodiments of the compound of formula I, the Z ring is selected from the following groups: [ka] is selected from Preferably, the Z ring is a group: [ka] is selected from More preferably, the Z ring is a group: [ka] is selected from wherein * indicates the position at which the Z ring is attached to the remainder of the compound, and each R4 is independently selected from hydrogen, halogen, and optionally substituted alkyl, preferably hydrogen, halogen, and optionally substituted C 1-3 each R is independently selected from the group consisting of hydrogen, halogen, and optionally substituted alkyl, preferably hydrogen, halogen, and optionally substituted C 1-3 In some embodiments, each R is independently selected from the group consisting of hydrogen and optionally substituted alkyl, preferably hydrogen and optionally substituted C 1-3 alkyl.

[0040] In one or more embodiments of the compound of formula I, the Z ring is selected from the following groups: [ka] is selected from.

[0041] In one or more embodiments of the compound of formula I, the Z ring is selected from the following groups: [ka] is selected from.

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

[0043] In one or more embodiments of the compound of formula I, A1, A2, and A3 are each independently selected from N and CR1, where R1 is preferably hydrogen, halogen, optionally substituted C 1-3 Alkyl, or optionally substituted C 1-3 More preferably, R is hydrogen, C 1-3 In some embodiments, only one of A1, A2, and A3 is N, and the other two are independently CR1, preferably R1 is independently H, C 1-3 In a more preferred embodiment, A3 is CH, one of A1 and A2 is N, and the other is CR1, where R1 is H, C 1-3 In some embodiments, A1 is N and both A2 and A3 are CH. In some embodiments, A2 is N and both A1 and A3 are CH. In some embodiments, A1, A2, and A3 are all CR1, and each R1 is independently selected from H, C, 1-3 Preferably, A3 is CH and one of A1 and A2 is CR1, where R1 is halogen, more preferably, both A2 and A3 are CH and A1 is CR1, where R1 is halogen.

[0044] In one or more embodiments of the compound of formula I, the Z ring is [ka] Instead, A1, A2 and A3 are each independently selected from N and CR1, where R1 is preferably hydrogen, halogen, optionally substituted C 1-3 Alkyl, or optionally substituted C 1-3 More preferably, R is hydrogen, C 1-3 In some embodiments, only one of A1, A2, and A3 is N, and the other two are independently CR1, preferably R1 is independently H, C 1-3 In a more preferred embodiment, A3 is CH, one of A1 and A2 is N, and the other is CR1, where R1 is H, C 1-3 In some embodiments, A1 is N and both A2 and A3 are CH. In some embodiments, A2 is N and both A1 and A3 are CH. In some embodiments, A1, A2, and A3 are all CR1, and each R1 is independently selected from H, C, 1-3 Preferably, A3 is CH and one of A1 and A2 is CR1, where R1 is C 1-3 alkyl, or halogen, more preferably both A2 and A3 are CH and A1 is CR1, where R1 is C 1-3 Preferably, A2 is CH and one of A1 and A3 is CR1, where R1 is C 1-3 alkyl, or halogen, more preferably both A1 and A2 are CH and A3 is CR1, where R1 is C 1-3 It is alkyl or halogen.

[0045] In one or more embodiments of the compound of formula I, the Z ring is [ka] A1 is CR1, A2 and A3 are each independently N or CR1, where R1 is preferably hydrogen, halogen, optionally substituted C 1-3 Alkyl, or optionally substituted C 1-3 More preferably, R is hydrogen, C 1-3 Preferably, A1, A2, and A3 are each independently CR1, where R1 is independently H, halogen, or C 1-3 In some embodiments, A is CR and both A and A are CH, where R is C 1-3 In some embodiments, A2 is CR1, and both A1 and A3 are CH, where R1 is C 1-3 In some embodiments, A3 is CR1, and both A1 and A2 are CH, where R1 is C 1-3 In some embodiments, A1, A2 and A3 are all CH. Preferably, A1 is CR1, A2 and A3 are both CH, or A1 and A2 are both CH and A3 is CR1, where R1 is C 1-3 It is alkyl or halogen.

[0046] The substituents on the Z ring are hydroxy, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxy substituted C 1-4 Alkyl, hydroxy and amino substituted C 1-4 alkoxy (-NR'R''), where R' and R'' are each independently H or C. 1-4 In some embodiments, when the Z ring is substituted, the substituents are halogen or C 1-4 It may be 1 to 3 groups selected from alkyl.

[0047] In one or more embodiments of the compound of formula I, each R is preferably independently selected from hydrogen, halogen, optionally substituted C 1-3 Alkyl or optionally substituted C 1-3 In some embodiments, R is an optionally substituted C 1-3 Preferably, when R1 is substituted, the substituents may be 1 to 5 groups selected from halogen, hydroxy, amino (-NR'R''), and the like, where R' and R'' are each preferably independently selected from H, optionally substituted C 1-4 Alkyl, or optionally substituted C 3-6 Preferably, R1 is halogen, C 1-3 Alkyl or halogenated C 1-3 In some embodiments, R is hydrogen, C 1-3 In some embodiments, R is hydrogen or halogen.

[0048] In one or more embodiments of the compound of formula I, preferably, R2 and R3 are each independently a halogen or C 1-3 In some embodiments, R and R together with the C to which they are attached form a 3-6 membered cycloalkyl.

[0049] In one or more embodiments of the compound of formula I, L is an unsubstituted alkylene, preferably an unsubstituted C 1-3 It is preferably alkylene, more preferably methylene.

[0050] In one or more embodiments of the compound of Formula I, the aryl is preferably phenyl. The heteroaryl is a 5-10 membered heteroaryl containing one or two heteroatoms selected from oxygen, sulfur, and nitrogen atoms. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl containing one or two nitrogen atoms. The heteroaryl includes, but is not limited to, pyridyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridazinyl, indolizinyl, thienyl, furyl, and thiazolyl. The carbocyclic group is preferably C 3-8 Cycloalkyl or C 3-8 The heterocyclic group is preferably a 4-10 membered heterocyclic group containing O, S and / or N, including, but not limited to, azetidinyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydroisoquinolyl, and morpholinyl.

[0051] In one or more embodiments of the compound of formula I, Cy is an optionally substituted 5- to 7-membered nitrogen-containing heterocyclic group. Preferably, the 5- to 7-membered nitrogen-containing heterocyclic group is covalently bonded to L through its ring nitrogen atom. More preferably, Cy is an optionally substituted piperazinyl. Preferably, when Cy is substituted, the substituents on Cy are halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, optionally substituted 6- to 14-membered aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered heterocyclic groups, and optionally substituted C 3-8 cycloalkyl, optionally substituted 6- to 14-membered aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered heterocyclic group, and optionally substituted C 3-8Each cycloalkyl is independently selected from halogen, optionally substituted alkyl (optionally substituted C 1-4 alkyl), optionally substituted alkoxy (optionally substituted C 1-4 alkoxy, etc.), optionally substituted carbocyclic groups (optionally substituted C 3-8 cycloalkyl), optionally substituted alkenyl (optionally substituted C 2-4 alkenyl), optionally substituted alkynyl (optionally substituted C 2-4 alkynyl, 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 3-8 Preferably, it is cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, and is H, optionally substituted C 1-4 Alkyl, or optionally substituted C 3-8 In some preferred embodiments, the substituents include at least -C(O)-NR'R'', and optionally, halogen, C 1-4 Alkyl and halogenated C 1-4 Preferably, the optionally substituted alkyl, optionally substituted alkoxy, optionally substituted carbocyclic group, optionally substituted alkenyl, and optionally substituted alkynyl are each independently selected from the group consisting of halogenated C 1-4 Alkyl and halogenated C 1-4 It may be substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxy, and amino, such as alkoxy.

[0052] In some preferred embodiments, Cy is substituted by an optionally substituted 5-10 membered heteroaryl, preferably an optionally substituted 5-10 membered nitrogen-containing heteroaryl. Preferably, the 5-10 membered heteroaryl or the 5-10 membered nitrogen-containing heteroaryl is substituted by at least -C(O)-NR'R'' or -COOH, and is substituted by halogen, C(O)-NR'R'' or -COOH. 1-4 Alkyl and halogenated C 1-4 In some particularly preferred embodiments, Cy is piperazinyl substituted with an optionally substituted pyridyl, wherein the pyridyl is at least substituted with -C(O)-NR'R''. Preferably, in the embodiments described herein, when the R' and R'' are substituted, the substituents can be 1 to 5 groups selected from the group consisting of halogen, hydroxy, and amino.

[0053] In one or more embodiments of the compound of formula I, A1, A2, and A3 are each independently CR1, and each R1 is independently H, C 1-3 L is -CH2- or -CH2CH2-; Cy is piperazinyl substituted with pyridyl, the pyridyl being substituted with -C(O)-NR'R''; halogen, C 1-4 Alkyl and halogenated C 1-4 R′ and R″ are each independently selected from the group consisting of H, C 1-4 Alkyl, or C 3-8 It is cycloalkyl.

[0054] In one or more embodiments of the compound of formula I, A1, A2, and A3 are each independently CR1, and each R1 is independently H, C 1-3 L is -CH2-, Cy is piperazinyl substituted with pyridyl, the pyridyl being substituted with -C(O)-NR'R'' and a halogen or C1-4 R′ and R″ are each independently selected from the group consisting of H, C 1-4 Alkyl, or C 3-8 It is cycloalkyl.

[0055] One group of preferred compounds of formula I in the present disclosure are compounds of formula II (including formula IIa and formula IIb): [ka] or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, wherein: A1, A2 and A3 are as defined in any embodiment of formula I; W is selected from the group consisting of CR4R5, O, S, and NR4; Z1 and Z2 are each independently C or N, provided that Z1 and Z2 are not both N; Z3, Z4, and Z5 are independently selected from the group consisting of CR4, O, S, N, and NR4; when Z1 is N, at least one of Z3, Z4, and Z5 is N; or when Z1 is N and all of Z3, Z4, and Z5 are CR4, A1 is CR1; R1 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 hydrogen, halogen, and optionally substituted alkyl; R6 is selected from optionally substituted aryl and optionally substituted heteroaryl; n and m are each independently selected from the group consisting of 0, 1, 2, and 3, with 2≦n+m≦4; When m is 0 and n is 3, W is not NH.

[0056] In one or more embodiments of the compound of formula IIa, W is CH2, O, or NC 1-3 Alkyl, preferably O, CH2, or N-CH3.

[0057] In one or more embodiments of the compound of formula IIb, Z3, Z4, and Z5 are independently selected from the group consisting of CR4, O, S, and N, and when Z1 is N, at least one of Z3, Z4, and Z5 is N, or when Z1 is N and all of Z3, Z4, and Z5 are CR4, A1 is CR1.

[0058] In one or more embodiments of the compound of Formula IIb, the Z ring is selected from the following groups: [ka] is selected from Preferably, the Z ring is a group: [ka] is selected from More preferably, the Z ring is a group: [ka] is selected from wherein * indicates the position at which the Z ring is attached to the remainder of the compound, and each R4 is independently selected from hydrogen, halogen, and optionally substituted alkyl, preferably hydrogen, halogen, and optionally substituted C 1-3 alkyl, and each R is independently selected from hydrogen, halogen, and optionally substituted alkyl, preferably hydrogen, halogen, and optionally substituted C 1-3 In some embodiments, each R is independently selected from the group consisting of hydrogen and optionally substituted alkyl, preferably hydrogen and optionally substituted C 1-3 alkyl.

[0059] In one or more embodiments of the compounds of Formula II (including Formula IIa and Formula IIb), the Z ring is selected from the group: [ka] Preferably, the Z ring is selected from the following groups: [ka] is selected from.

[0060] In one or more embodiments of the compound of Formula II (including Formula IIa and Formula IIb), A1, A2, A3 are each independently selected from N and CR1, where R1 is preferably hydrogen, halogen, optionally substituted C 1-3 Alkyl, or optionally substituted C 1-3 More preferably, R is hydrogen, C 1-3 In some embodiments, only one of A1, A2, and A3 is N, and the other two are independently CR1, preferably R1 is independently H, C 1-3 In a more preferred embodiment, A3 is CH, one of A1 and A2 is N, and the other is CR1, where R1 is H, C 1-3 In some embodiments, A1 is N and both A2 and A3 are CH. In some embodiments, A2 is N and both A1 and A3 are CH. In some embodiments, A1, A2, and A3 are all CR1, and each R1 is independently selected from H, C, 1-3 Preferably, A3 is CH and one of A1 and A2 is CR1, where R1 is halogen, more preferably, both A2 and A3 are CH and A1 is CR1, where R1 is halogen.

[0061] In one or more embodiments of the compound of Formula II (including Formula IIa and Formula IIb), each R is preferably independently selected from hydrogen, halogen, optionally substituted C 1-3 Alkyl or optionally substituted C 1-3 In some embodiments, R is an optionally substituted C 1-3 Preferably, when R1 is substituted, the substituents may be 1 to 5 groups selected from halogen, hydroxy, and amino (-NR'R''), etc., where R' and R'' are each preferably independently selected from H, optionally substituted C 1-4 Alkyl, or optionally substituted C 3-6 Preferably, R1 is C 1-3 Alkyl or halogenated C 1-3 In some embodiments, R is hydrogen, C 1-3 In some embodiments, R is hydrogen or halogen.

[0062] In one or more embodiments of the compound of formula II (including formula IIa and formula IIb), the Z ring is [ka] When not, A1, A2, A3 are each independently selected from N and CR1, where R1 is preferably hydrogen, halogen, optionally substituted C 1-3 Alkyl, or optionally substituted C 1-3 More preferably, R is hydrogen, C 1-3 In a preferred embodiment, only one of A1, A2, and A3 is N, and the other two are independently CR1, and preferably R1 is independently H, C 1-3 In a more preferred embodiment, one of A1 and A2 is N and the other is CR1, and A3 is CH, where R1 is H, C 1-3In some embodiments, A1 is N and both A2 and A3 are CH. In some embodiments, A2 is N and both A1 and A3 are CH. In some embodiments, A1, A2, and A3 are all CR1, and each R1 is independently selected from H, C, 1-3 Preferably, A3 is CH and one of A1 and A2 is CR1, where R1 is C 1-3 alkyl, or halogen, more preferably both A2 and A3 are CH and A1 is CR1, where R1 is C 1-3 Preferably, A2 is CH and one of A1 and A3 is CR1, where R1 is C 1-3 alkyl, or halogen, more preferably both A1 and A2 are CH and A3 is CR1, where R1 is C 1-3 It is alkyl or halogen.

[0063] In one or more embodiments of the compound of formula IIb, the Z ring is [ka] A1 is CR1, A2 and A3 are each independently N or CR1, where R1 is preferably hydrogen, halogen, optionally substituted C 1-3 Alkyl, or optionally substituted C 1-3 More preferably, R is hydrogen, C 1-3 Preferably, A1, A2, and A3 are each independently CR1, where R1 is independently H, halogen, or C 1-3 In some embodiments, A is CR and both A and A are CH, where R is C 1-3 In some embodiments, A2 is CR1, and both A1 and A3 are CH, where R1 is C 1-3In some embodiments, A3 is CR1, and both A1 and A2 are CH, where R1 is C 1-3 In some embodiments, A1, A2 and A3 are all CH. Preferably, A1 is CR1, A2 and A3 are both CH, or A1 and A2 are both CH and A3 is CR1, where R1 is C 1-3 It is alkyl or halogen.

[0064] In one or more embodiments of the compound of Formula II (including Formula IIa and Formula IIb), R6 is an optionally substituted 6-14 membered aryl or an optionally substituted 5-10 membered heteroaryl. An exemplary 6-14 membered aryl group is phenyl. The 5-10 membered heteroaryl is preferably a 5-10 membered nitrogen-containing heteroaryl, including but not limited to pyridyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridazinyl, and indolizinyl, preferably pyridyl, pyrimidinyl, and pyridazinyl. Preferably, when R6 is substituted, the substituents are halogen, optionally substituted alkyl (C 1-4 Alkyl and halogenated C 1-4 alkyl), optionally substituted alkoxy (C 1-4 Alkoxy and halogenated C 1-4 More preferably, R6 is substituted with at least one aminoacyl group, and preferably R6 is substituted at the para position with an optionally substituted aminoacyl group. Preferably, the optionally substituted aminoacyl is -C(O)-NR'R'', where R' and R'' are each independently selected from H, an optionally substituted C 1-10 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, preferably H, optionally substituted C 1-4Alkyl, or optionally substituted C 3-6 Preferably, when R' and R'' are substituted, the substituents may be 1 to 5 groups selected from the group consisting of halogen, hydroxyl, oxygen, and amino. Preferably, the number of carbon atoms in the optionally substituted alkyl and optionally substituted alkoxy is 1 to 4, and preferably the substituents may be 1 to 5 groups selected from the group consisting of halogen, hydroxyl, oxygen, and amino. In some preferred embodiments, the substituents on R6 include at least aminoacyl (-C(O)-NR'R''), optionally including halogen, C 1-4 Alkyl and halogenated C 1-4 Contains any one or two groups of alkyl.

[0065] In one or more embodiments of the compound of formula II, R6 is: [ka] wherein B1, B2, B3 and B4 are independently selected from the group consisting of N and CR7, R7 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted carbocyclic, optionally substituted alkenyl and optionally substituted alkynyl, and wherein R' and R'' are each independently selected from hydrogen, optionally substituted C 1-10 Alkyl, optionally substituted C 3-8 R′ and R″ are each independently selected from hydrogen, optionally substituted C 1-4 Alkyl (deuterated C 1-4 alkyl), optionally substituted C 3-6 Preferably, the group containing B1, B2, B3, and B4 is phenyl, pyridyl, pyrimidinyl, or pyridazinyl. Preferably, R7 is H, halogen, C 1-3Alkyl, C 1-3 Alkoxy or halogenated C 1-3 Preferably, B3 is N, B4 is CR7, B1 and B2 are both CH, and R7 is H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-3 Preferably, when R' and R'' are substituted, the substituents may be 1 to 5 groups selected from the group consisting of halogen, hydroxy, and amino. Preferably, R' is hydrogen and R'' is hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl or hydroxy C 1-3 In some embodiments, R' is hydrogen and R'' is hydrogen, C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 3-6 Cycloalkyl or halogenated C 1-3 It is an alkyl.

[0066] Preferably, in the embodiments described herein, R7 is an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted carbocyclic group, an optionally substituted alkenyl, or an optionally substituted alkynyl, which may be independently substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxy, and amino.

[0067] In one or more embodiments of the compound of Formula IIa, n is 1 or 2.

[0068] In one or more embodiments of the compound of Formula IIa, m is 1 or 2.

[0069] In one or more embodiments of the compound of formula IIa, when m is 0, W is O or CH 2 .

[0070] In one or more embodiments of the compound of formula IIa, W is selected from O, CH2, and N-CH3; A1, A2, and A3 are each independently selected from N and CR1; and R6 is [ka] wherein B1, B2, B3, and B4 are independently selected from the group consisting of N and CR7; R' and R'' are each independently selected from hydrogen, optionally substituted C 1-10 Alkyl, optionally substituted C 3-8 R′ and R″ are each independently selected from hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 R1 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted carbocyclic groups, preferably H, halogen, C 1-3 R7 is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted carbocyclic, optionally substituted alkenyl, and optionally substituted alkynyl, preferably hydrogen, C 1-3 Alkyl, halogenated C 1-3 n is 1 or 2. Preferably, A1, A2, and A3 are each independently selected from N and CR1, where R1 is preferably hydrogen, halogen, optionally substituted C 1-3 Alkyl, or optionally substituted C 1-3 More preferably, R is hydrogen, C 1-3 In some embodiments, only one of A1, A2, and A3 is N, and the other two are independently CR1, preferably R1 is independently H, C 1-3In some embodiments, one of A1 and A2 is N and the other is CR1, and A3 is CH, where R1 is H, C 1-3 In some embodiments, A1 is N and both A2 and A3 are CH. In some embodiments, A2 is N and both A1 and A3 are CH. In some embodiments, A1, A2, and A3 are all CR1, and each R1 is independently selected from H, C, 1-3 Preferably, A3 is CH and one of A1 and A2 is CR1, where R1 is C 1-3 alkyl, or halogen, more preferably both A2 and A3 are CH and A1 is CR1, where R1 is C 1-3 Preferably, A2 is CH and one of A1 and A3 is CR1, where R1 is C 1-3 alkyl, or halogen, more preferably both A1 and A2 are CH and A3 is CR1, where R1 is C 1-3 In some embodiments, A2 is CR1, and both A1 and A3 are CH, where R1 is C 1-3 In some embodiments, A3 is CR1, and both A1 and A2 are CH, where R1 is C 1-3 In some embodiments, A1, A2 and A3 are all CH. Preferably, A1 is CR1, A2 and A3 are both CH, or A1 and A2 are both CH and A3 is CR1, where R1 is C 1-3 Preferably, B1, B2, B3, and B4 are independently selected from the group consisting of N and CR7, where R7 is preferably hydrogen, halogen, optionally substituted C 1-3 Alkyl, or optionally substituted C 1-3 More preferably, R7 is hydrogen, C 1-3Alkyl, halogenated C 1-3 Preferably, B1 and B2 are both CH, B3 is N, and B4 is CR7, where R7 is H, halogen, optionally substituted C 1-3 Alkyl, or optionally substituted C 1-3 More preferably, R7 is hydrogen, C 1-3 Alkyl, halogenated C 1-3 Preferably, R′ and R″ are each independently hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Preferably, when R' and R'' are substituted, the substituents may be 1 to 5 groups selected from the group consisting of halogen, hydroxy, and amino. Preferably, R' is hydrogen and R'' is hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl or hydroxy C 1-3 Preferably, R7 is hydrogen, halogen, or optionally substituted C 1-3 Preferably, R7 is hydrogen, halogen, C 1-3 Alkyl or halogenated C 1-3 Preferably, n is 1 or 2 and m is 1 or 2. More preferably, n is 1 and m is 1 or 2.

[0071] In one or more embodiments of the compound of formula IIb, the Z ring is [ka] A1, A2 and A3 are each independently N or CR1, wherein each R4 is independently selected from hydrogen, halogen and optionally substituted alkyl, preferably hydrogen, halogen and optionally substituted C 1-3each R is selected from the group consisting of hydrogen, halogen and optionally substituted alkyl, preferably hydrogen, halogen and optionally substituted C 1-3 In some embodiments, each R is independently selected from the group consisting of hydrogen and optionally substituted alkyl, preferably hydrogen and optionally substituted C 1-3 alkyl, and preferably the Z ring is [ka] is selected from Or the Z ring is [ka] A1 is selected from CR1, and A2 and A3 are independently N or CR1; R6 is selected from the group consisting of: [ka] wherein B1, B2, B3, and B4 are independently selected from the group consisting of N and CR7; R' and R'' are each independently selected from hydrogen, optionally substituted C 1-10 Alkyl, optionally substituted C 3-8 R′ and R″ are each independently selected from hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6R1 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted carbocyclic groups. R7 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted carbocyclic groups, optionally substituted alkenyl, and optionally substituted alkynyl. Preferably, A1, A2, and A3 are each independently selected from N and CR1, where R1 is preferably hydrogen, halogen, optionally substituted C 1-3 Alkyl, or optionally substituted C 1-3 More preferably, R is hydrogen, C 1-3 Preferably, only one of A1, A2, and A3 is N, and the other two are independently CR1, and preferably R1 is independently H, C 1-3 Preferably, one of A1 and A2 is N, the other is CR1, and A3 is CH, where R1 is H, C 1-3 Preferably, A1 is N and both A2 and A3 are CH. In some embodiments, A2 is N and both A1 and A3 are CH. In some embodiments, A1, A2, and A3 are all CR1, and each R1 is independently H, C 1-3 Preferably, A3 is CH and one of A1 and A2 is CR1, where R1 is C 1-3 alkyl, or halogen, more preferably both A2 and A3 are CH and A1 is CR1, where R1 is C 1-3 Preferably, A2 is CH and one of A1 and A3 is CR1, where R1 is C 1-3 alkyl, or halogen, more preferably both A1 and A2 are CH and A3 is CR1, where R1 is C 1-3Preferably, B1, B2, B3, and B4 are independently selected from the group consisting of N and CR7, where R7 is preferably hydrogen, halogen, optionally substituted C 1-3 Alkyl, or optionally substituted C 1-3 More preferably, R7 is hydrogen, C 1-3 Alkyl, halogenated C 1-3 Preferably, B1 and B2 are both CH, B3 is N, and B4 is CR7, where R7 is H, halogen, optionally substituted C 1-3 Alkyl, or optionally substituted C 1-3 More preferably, R7 is hydrogen, C 1-3 Alkyl, halogenated C 1-3 Preferably, R′ and R″ are each independently hydrogen, optionally substituted C 1-3 Alkyl, optionally substituted C 3-6 Preferably, when R' and R'' are substituted, the substituents may be 1 to 5 groups selected from the group consisting of halogen, hydroxy, and amino. Preferably, R' is hydrogen and R'' is hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl or hydroxy C 1-3 Preferably, R7 is hydrogen, halogen, C 1-3 Alkyl or halogenated C 1-3 It is an alkyl.

[0072] In one or more embodiments of the compound of formula II, A, A, and A are each independently CR, and each R is independently H, C, 1-3 alkyl, or halogen, and R6 is substituted with -C(O)-NR'R'', halogen, C 1-4 Alkyl and halogenated C 1-4R′ and R′ are each independently selected from the group consisting of H, hydroxy, and optionally substituted C 1-4 Alkyl, or C 3-8 It is cycloalkyl.

[0073] In one or more embodiments of the compound of formula II, A, A, and A are each independently CR, and each R is independently H, C, 1-3 alkyl, or halogen, and R6 is substituted with -C(O)-NR'R'', halogen and C 1-4 R′ and R″ are each independently selected from the group consisting of H, hydroxy, and optionally substituted C 1-4 Alkyl, or C 3-8 It is cycloalkyl.

[0074] One group of preferred compounds of formula I in the present disclosure are compounds of formula III (including formula IIIa and formula IIIb): [ka] or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, wherein: W, Z1, Z2, Z3, Z4, Z5, A1, A2, A3, B1, B2, B3, B4, n and m are as defined in any of the previous embodiments; R′ and R″ are each independently H, optionally substituted C 1-10 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or B3 and R'' together with the attached aminoacyl group form a six-membered heterocyclic group.

[0075] In one or more embodiments of the compound of Formula IIIa, W is O, CH, or NC. 1-3 Alkyl, preferably O, CH2, or N-CH3.

[0076] In one or more embodiments of the compound of Formula IIIb, the Z ring is selected from the following groups: [ka] is selected from Preferably, the Z ring is a group: [ka] is selected from More preferably, the Z ring is a group: [ka] is selected from wherein each R4 is independently selected from hydrogen, halogen, and optionally substituted alkyl, preferably hydrogen, halogen, and optionally substituted C 1-3 each R is independently selected from the group consisting of hydrogen, halogen, and optionally substituted alkyl, preferably hydrogen, halogen, and optionally substituted C 1-3 In some embodiments, each R is independently selected from the group consisting of hydrogen and optionally substituted alkyl, preferably hydrogen and optionally substituted C 1-3 alkyl.

[0077] In one or more embodiments of the compounds of Formula III (including Formula IIIa and Formula IIIb), the Z ring is selected from the group: [ka] and preferably selected from the following groups: [ka] is selected from.

[0078] In one or more embodiments of the compound of Formula III (including Formula IIIa and Formula IIIb), A1, A2, A3 are each independently selected from N and CR1, where R1 is preferably hydrogen, halogen, optionally substituted C 1-3 Alkyl, or optionally substituted C 1-3 More preferably, R is hydrogen, C 1-3 In some embodiments, only one of A1, A2, and A3 is N, and the other two are independently CR1, preferably R1 is independently H, C 1-3 In a more preferred embodiment, A3 is CH, one of A1 and A2 is N, and the other is CR1, where R1 is H, C 1-3 In some embodiments, A1 is N and both A2 and A3 are CH. In some embodiments, A2 is N and both A1 and A3 are CH. In some embodiments, A1, A2, and A3 are all CR1, and each R1 is independently selected from H, C, 1-3 Preferably, A3 is CH and one of A1 and A2 is CR1, where R1 is halogen, more preferably, both A2 and A3 are CH and A1 is CR1, where R1 is halogen.

[0079] In one or more embodiments of the compound of formula III (including formula IIIa and formula IIIb), the Z ring is [ka] When not, A1, A2, A3 are each independently selected from N and CR1, where R1 is preferably hydrogen, halogen, optionally substituted C 1-3 Alkyl, or optionally substituted C 1-3 More preferably, R is hydrogen, C 1-3In a preferred embodiment, only one of A1, A2, and A3 is N, and the other two are independently CR1, and preferably R1 is independently H, C 1-3 In a more preferred embodiment, one of A1 and A2 is N and the other is CR1, and A3 is CH, where R1 is H, C 1-3 In some embodiments, A1 is N and both A2 and A3 are CH. In some embodiments, A2 is N and both A1 and A3 are CH. In some embodiments, A1, A2, and A3 are all CR1, and each R1 is independently selected from H, C, 1-3 Preferably, A3 is CH and one of A1 and A2 is CR1, where R1 is C 1-3 alkyl, or halogen, more preferably both A2 and A3 are CH and A1 is CR1, where R1 is C 1-3 Preferably, A2 is CH and one of A1 and A3 is CR1, where R1 is C 1-3 alkyl, or halogen, more preferably both A1 and A2 are CH and A3 is CR1, where R1 is C 1-3 In some embodiments, A is CR, and both A and A are CH, where R is C 1-3 In some embodiments, A2 is CR1, and both A1 and A3 are CH, where R1 is C 1-3 In some embodiments, A3 is CR1, and both A1 and A2 are CH, where R1 is C 1-3 In some embodiments, A1, A2 and A3 are all CH. Preferably, A1 is CR1, A2 and A3 are both CH, or A1 and A2 are both CH and A3 is CR1, where R1 is C1-3 It is alkyl or halogen.

[0080] In one or more embodiments of the compound of formula IIIb, the Z ring is [ka] A1 is CR1, A2 and A3 are each independently N or CR1, where R1 is preferably hydrogen, halogen, optionally substituted C 1-3 Alkyl, or optionally substituted C 1-3 More preferably, R is hydrogen, C 1-3 Preferably, A1, A2, and A3 are each independently CR1, and R1 is independently H, halogen, or C 1-3 In some embodiments, A is CR and both A and A are CH, where R is C 1-3 In some embodiments, A2 is CR1, and both A1 and A3 are CH, where R1 is C 1-3 In some embodiments, A3 is CR1, and both A1 and A2 are CH, where R1 is C 1-3 In some embodiments, A1, A2 and A3 are all CH. Preferably, A1 is CR1, A2 and A3 are both CH, or A1 and A2 are both CH and A3 is CR1, where R1 is C 1-3 It is alkyl or halogen.

[0081] In one or more embodiments of the compound of Formula III (including Formula IIIa and Formula IIIb), B1, B2, B3, and B4 are independently selected from the group consisting of N and CR7, where R7 is preferably hydrogen, halogen, optionally substituted C 1-3 Alkyl, optionally substituted C 1-3 More preferably, R7 is selected from the group consisting of H, C1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 In some preferred embodiments, B1 and B2 are both CH, B3 is N, and B4 is CR7, where R7 is preferably hydrogen, halogen, optionally substituted C 1-3 Alkyl, or optionally substituted C 1-3 More preferably, R7 is hydrogen, C 1-3 Alkyl, halogenated C 1-3 It is alkyl, or halogen.

[0082] In one or more embodiments of the compound of formula III, R′ and R″ are each independently hydrogen, optionally substituted C 1-4 Alkyl, or optionally substituted C 3-6 cycloalkyl, preferably R′ is hydrogen and R″ is hydrogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl or hydroxy C 1-3 It is an alkyl.

[0083] In one or more embodiments of the compound of Formula IIIa, n is 1 or 2.

[0084] In one or more embodiments of the compound of Formula IIIa, m is 1 or 2.

[0085] In one or more embodiments of the compound of Formula IIIa, when m is 0, W is O or CH 2 .

[0086] In some preferred embodiments, in the -C(O)-NR'R'' described herein, R' and R'' are each independently selected from H, C 1-4 Alkyl, or C 3-6 In a further preferred embodiment, R' is hydrogen and R'' is hydrogen or C 1-3 It is an alkyl.

[0087] One group of preferred compounds of formula I in the present disclosure are compounds of formula IV (including formula IVa, formula IVb and formula IVc): [ka] or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, wherein: Z, Z, Z, R, R' and R'' are as defined in any of the previous embodiments; R8, R9 and R 10 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, and optionally substituted alkoxy.

[0088] In one or more embodiments of the compound of formula IV, the five-membered ring containing Z3, Z4, and Z5 is selected from the following groups: [ka] is selected from Preferably, the Z ring is a group: [ka] is selected from wherein each R4 is independently selected from hydrogen, halogen, and optionally substituted alkyl, preferably hydrogen, halogen, and optionally substituted C 1-3 each R is independently selected from the group consisting of hydrogen, halogen, and optionally substituted alkyl, preferably hydrogen, halogen, and optionally substituted C 1-3 In some embodiments, each R is independently selected from the group consisting of hydrogen and optionally substituted alkyl, preferably hydrogen and optionally substituted C 1-3 alkyl.

[0089] In one or more embodiments of the compound of formula IV (including formula IVa, formula IVb, and formula IVc), R, R and R 10 are each preferably hydrogen, halogen, optionally substituted C 1-3 Alkyl, or optionally substituted C 1-3 More preferably, R, R and R 10 are hydrogen, C 1-3 In some embodiments, R is C 1-3 R9 and R10 are alkyl or halogen; 10 are H. In some embodiments, R9 is C 1-3 R and R are alkyl or halogen. 10 In some embodiments, both R and R are H. In some embodiments, both R and R are H and R 10 is C 1-3 In some embodiments, R, R, and R are alkyl or halogen. 10 are all H. Preferably, R8 is C 1-3 R9 and R10 are alkyl or halogen; 10 are both H, or R8 and R9 are both H, and R 10 is C 1-3 It is alkyl or halogen.

[0090] In one or more embodiments of the compound of formula IV (including formula IVa, formula IVb, and formula IVc), R7 is hydrogen, halogen, optionally substituted C 1-3 Alkyl, and optionally substituted C 1-3 alkoxy, preferably R7 is selected from the group consisting of H, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 More preferably, R7 is H, C 1-3 It is alkyl, or halogen.

[0091] In one or more embodiments of the compound of formula IV, R′ and R″ are each independently hydrogen, optionally substituted C 1-4 Alkyl, or optionally substituted C 3-6 cycloalkyl, preferably R′ is hydrogen and R″ is hydrogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl, Hydroxy C 1-3 Alkyl, or C 3-6 Preferably, R' is hydrogen and R'' is hydrogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl or hydroxy C 1-3 It is an alkyl.

[0092] In one or more embodiments of the compound of formula IV, the five-membered ring containing Z3, Z4, and Z5 is selected from the following groups: [ka] is selected from wherein each R4 is independently selected from hydrogen and C 1-3 alkyl, and each R is independently selected from the group consisting of hydrogen and C 1-3 alkyl, preferably the 5-membered ring containing Z3, Z4, and Z5 is selected from the group consisting of the following groups: [ka] is selected from R7 is H, C 1-3 alkyl, or halogen; R8, R9, and R 10 are hydrogen, halogen, or C 1-3 alkyl, preferably R8 is C 1-3 R9 and R10 are alkyl or halogen; 10 are both H or R9 is C 1-3 R and R are alkyl or halogen. 10 are both H, or R and R are both H, and R 10 is C1-3 alkyl or halogen, or R8, R9, and R 10 All of are H, R' and R'' are each independently H or C 1-3 Alkyl or C 3-6 It is cycloalkyl.

[0093] W, Z1, Z2, Z3, Z4, Z5, A1, A2, A3, L, Cy, R6, B1, B2, B3, B4, R7, R8, R9, R 10 Although R', R'', n and m are described separately above, it should be understood that the described features, particularly the preferred features, may be combined in any manner to form a range of different compounds of formula I (including formula II, formula III, and formula IV) in the present disclosure. For example, in some embodiments of compounds of formula I (including formula II, formula III, and formula IV) in the present disclosure.

[0094] Preferred compounds of formula I include, but are not limited to: 7-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (Example 1), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (Example 2), 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (Example 3), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (Example 4), 7-((4-(2-trifluoromethyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (Example 5), 7-((4-(2-chloro-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (Example 6), 7-((4-(2-methyl-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (Example 7), 7-((4-(2-trifluoromethyl-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (Example 8), 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (Example 9), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (Example 10), 7-((4-(2-trifluoromethyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (Example 11), 7-((4-(2-chloro-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (Example 12), 7-((4-(2-methyl-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (Example 13), 7-((4-(2-trifluoromethyl-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (Example 14), 3-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydrophenanthridin-6(5H)-one (Example 15), 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one (Example 16), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one (Example 17), 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one (Example 18), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one (Example 19), 3-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7,9-dihydrofuro[3,4-c][1,5]naphthyridin-6(5H)-one (Example 20), 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-methyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,4-c]quinolin-4-one (Example 21), 8-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,2,4,6-tetrahydro-5H-pyrano[3,4-c]quinolin-5-one (Example 22), 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,2,4,6-tetrahydro-5H-pyrano[3,4-c]quinolin-5-one (Example 23), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (Example 24), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)imidazo[1,2-a]quinoxalin-4(5H)-one (Example 25), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)imidazo[1,5-a]quinoxalin-4(5H)-one (Example 26), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one (Example 27), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 28), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-[1,2,4]triazolo[1,5-a]quinoxalin-4(5H)-one (Example 29), 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)imidazo[1,5-c]quinazolin-5(6H)-one (Example 30), 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)imidazo[1,2-c]quinazolin-5(6H)-one (Example 31), 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-[1,2,4]triazolo[4,3-c]quinazolin-5(6H)-one (Example 32), 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one (Example 33), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (Example 34), 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (Example 35), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 36), 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 37), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)imidazo[1,5-a]quinoxalin-4(5H)-one (Example 38), 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)imidazo[1,5-a]quinoxalin-4(5H)-one (Example 39), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoropyrrolo[1,2-a]quinoxalin-4(5H)-one (Example 40), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoropyrrolo[1,2-a]quinoxalin-4(5H)-one (Example 41), 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoropyrrolo[1,2-a]quinoxalin-4(5H)-one (Example 42), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 43), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 44), 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 45), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-chloropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 46), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-chloropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 47), 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrrolo[1,2-c]quinazolin-5(6H)-one (Example 48), 7-((4-(2-methyl-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one (Example 49), 7-((4-(2-chloro-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one (Example 50), 8-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)imidazo[1,2-c]quinazolin-5(6H)-one (Example 51), 8-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)imidazo[1,2-c]quinazolin-5(6H)-one (Example 52), 8-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-10-fluoroimidazo[1,2-c]quinazolin-5(6H)-one (Example 53), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1-methylpyrrolo[1,2-a]quinoxalin-4(5H)-one (Example 54), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-methylpyrrolo[1,2-a]quinoxalin-4(5H)-one (Example 55), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylpyrrolo[1,2-a]quinoxalin-4(5H)-one (Example 56), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 57), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 58), 7-((4-(2-methyl-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (Example 59), 7-((4-(2-fluoro-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (Example 60), 7-((4-(2-chloro-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (Example 61), 7-((4-(2-methyl-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 62), 7-((4-(2-methyl-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (Example 63), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (Example 64), 7-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (Example 65), 7-((4-(2-methyl-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoropyrrolo[1,2-a]quinoxalin-4(5H)-one (Example 66), 7-((4-(2-fluoro-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoropyrrolo[1,2-a]quinoxalin-4(5H)-one (Example 67), 7-((4-(2-chloro-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoropyrrolo[1,2-a]quinoxalin-4(5H)-one (Example 68), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 69), 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 70), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 71), 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 72), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 73), 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 74), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 75), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 76), 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 77), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 78), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one (Example 79), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one (Example 80), 7-((4-(2-methyl-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one (Example 81), 7-((4-(2-fluoro-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one (Example 82), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[3,4-c]quinolin-4(5H)-one (Example 83), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[2,3-c]quinolin-4(5H)-one (Example 84), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[3,2-c]quinolin-4(5H)-one (Example 85), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluorothieno[3,4-c]quinolin-4(5H)-one (Example 86), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-chloro-9-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 87), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-chloro-9-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 88), 7-((4-(2-methyl-6-(carbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 89), 7-((4-(2-methyl-6-((methyl-d3)-carbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 90), 7-((4-(2-methyl-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 91), 7-((4-(2-methyl-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 92), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-8-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 93), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 94), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 95), 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-10-fluoroimidazo[1,2-c]quinazolin-5(6H)-one (Example 96), 7-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 97), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-chloropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 98), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-chloropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 99), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-chloropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 100), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2,3-dimethylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 101), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 102), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-2-chloropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 103), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[2,3-c]quinolin-4(5H)-one (Example 104), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (Example 105), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (Example 106), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-furo[2,3-c]quinolin-4(5H)-one (Example 107), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-furo[2,3-c]quinolin-4(5H)-one (Example 108), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 109), 7-((4-(2-fluoro-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 110), 7-((4-(2-fluoro-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 111), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-2-chloropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 112), 7-((4-(2-methyl-4-(methylcarbamoyl)phenyl)piperazin-1-yl)methyl)-9-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 113), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluorothieno[2,3-c]quinolin-4(5H)-one (Example 114), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 115), 7-((4-(2-methyl-6-carboxypyridin-3-yl)piperazin-1-yl)methyl)-9-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 116), 7-((4-(2-methyl-6-(N-(hydroxymethyl)carbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 117), 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-c]quinazolin-5(6H)-one (Example 118), 8-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-10-fluoroimidazo[1,2-c]quinazolin-5(6H)-one (Example 119), 8-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-10-fluoroimidazo[1,2-c]quinazolin-5(6H)-one (Example 120), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[3,2-c]quinolin-4(5H)-one (Example 121), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thiazolo[4,5-c]quinolin-4(5H)-one (Example 122), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-chloropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 123), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 124), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2,3-dimethylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 125), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-chloro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 126), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-chloro-9-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 127), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoropyrrolo[1,2-a]quinoxalin-4(5H)-one (Example 128), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 129), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-chloropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 130), 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-10-fluoropyrrolo[1,2-c]quinazolin-5(6H)-one (Example 131), 8-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-10-fluoropyrrolo[1,2-c]quinazolin-5(6H)-one (Example 132), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 133), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-chloropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 134), 7-((4-(2-methyl-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 135), 6-Fluoro-7-((4-(2-fluoro-6-((methyl-d3)carbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 136), 6-Fluoro-7-((4-(2-methyl-6-((methyl-d3)carbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 137), 6-Fluoro-7-((4-(2-fluoro-6-((methyl-d3)carbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[2,3-c]quinolin-4(5H)-one (Example 138), 6-Fluoro-7-((4-(2-methyl-6-((methyl-d3)carbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[2,3-c]quinolin-4(5H)-one (Example 139), 6-Fluoro-7-((4-(2-methyl-6-((methyl-d3)carbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-chloropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 140), 9-Fluoro-7-((4-(2-fluoro-6-((methyl-d3)carbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 141), 6-Fluoro-7-((4-(2-fluoro-6-((methyl-d3)carbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-chloropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 142), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-furo[2,3-c]quinolin-4(5H)-one (Example 143), 7-((4-(2-methyl-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 144), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoropyrrolo[1,2-a]quinoxalin-4(5H)-one (Example 145), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-methyl-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (Example 146), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-chloro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 147), 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,9-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 148), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-furo[2,3-c]quinolin-4(5H)-one (Example 149), 8-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoropyrrolo[1,2-c]quinazolin-5(6H)-one (Example 150), or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate, or a pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof.

[0095] 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 known to those of ordinary skill in the art.

[0096] Examples of pharma- ceutically acceptable salts include inorganic and organic salts, such as hydrochloride, hydrobromide, phosphate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate, and oxalate salts; as well as inorganic and organic base salts formed with bases, such as sodium hydroxide, tris(hydroxymethyl)aminomethane (TRIS, tromethamine), and N-methyl-glucamine.

[0097] Examples of prodrugs of the compounds of the present disclosure include simple esters of carboxylic acid-containing compounds (e.g., C 1-4 alcohols), esters of hydroxy-containing compounds (e.g., those obtained by condensation with C according to methods known in the art), 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 1-4aldehydes or ketones), 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.

[0098] The compounds of the present disclosure may be prepared using methods known to those skilled in the art or novel methods of the present disclosure. Specifically, the compounds of the present disclosure having formula I (including formula II, formula III, and formula IV) may be prepared as illustrated by the exemplary reaction of Scheme 1. The reaction of methyl 4-oxotetrahydrofuran-3-carboxylate and trifluoromethanesulfonic anhydride (Tf2O) under the catalysis of N,N-diisopropylethylamine (DIEA) produced methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-carboxylate. The Suzuki reaction of methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-carboxylate and (4-(methoxycarbonyl)-2-nitrophenyl)boronic acid under the catalysis of Pd2(dba)3 produced methyl 4-(4-(methoxycarbonyl)-2-nitrophenyl)-2,5-dihydrofuran-3-carboxylate. The reaction of methyl 4-(4-(methoxycarbonyl)-2-nitrophenyl)-2,5-dihydrofuran-3-carboxylate with Fe / AcOH under AcOH catalysis gave methyl 4-oxo-1,3,4,5-tetrahydrofuro[3,4-c]quinoline-7-carboxylate. The reduction of methyl 4-oxo-1,3,4,5-tetrahydrofuro[3,4-c]quinoline-7-carboxylate with lithium aluminum hydride (LiAlH4) gave 7-(hydroxymethyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one. Chlorination of 7-(hydroxymethyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one with SOCl2 gave 7-(chloromethyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one. DIEA- and KI-catalyzed displacement reaction of 7-(chloromethyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one and N-methyl-5-(piperazin-1-yl)picolinamide afforded the target compound 7-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one. [ka]

[0099] Other related compounds can be prepared using similar methods. For example, replacing N-methyl-5-(piperazin-1-yl)picolinamide with 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one. Replacing N-methyl-5-(piperazin-1-yl)picolinamide with 6-chloro-N-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one. Substitution of N-methyl-5-(piperazin-1-yl)picolinamide with N,6-dimethyl-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one. Substitution of N-methyl-5-(piperazin-1-yl)picolinamide with 6-chloro-N-ethyl-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-chloro-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one. Substitution of N-methyl-5-(piperazin-1-yl)picolinamide with N-ethyl-6-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-methyl-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one.

[0100] The compounds of the present disclosure can be prepared as illustrated by the exemplary reactions in Scheme 2. Substitution reaction of methyl 4-fluoro-3-nitrobenzoate and methyl 1H-pyrrole-2-carboxylate under the catalysis of Cs2CO3 produced methyl 1-(4-(methoxycarbonyl)-2-nitrophenyl)-1H-pyrrole-2-carboxylate. Reaction of methyl 1-(4-(methoxycarbonyl)-2-nitrophenyl)-1H-pyrrole-2-carboxylate and Fe / AcOH under the catalysis of AcOH produced methyl 4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxaline-7-carboxylate. Reduction reaction of methyl 4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxaline-7-carboxylate and LiAlH4 produced 7-(hydroxymethyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one. DMF-catalyzed chlorination of 7-(hydroxymethyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one with SOCl2 afforded 7-(chloromethyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one. DIEA- and KI-catalyzed displacement reaction of 7-(chloromethyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one and N,6-dimethyl-5-(piperazin-1-yl)picolinamide afforded the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one. [ka]

[0101] Other related compounds can be prepared using similar methods. For example, replacing 1H-pyrrole-2-carboxylate with 1H-imidazole-2-carboxylate produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)imidazo[1,2-a]quinoxalin-4(5H)-one. Replacing 1H-pyrrole-2-carboxylate with 1H-imidazole-5-carboxylate produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)imidazo[1,5-a]quinoxalin-4(5H)-one. Replacing 1H-pyrrole-2-carboxylate with 1H-pyrazole-5-carboxylate produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one. Replacing 1H-pyrrole-2-carboxylate with 5-methyl-1H-pyrrole-2-carboxylate produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1-methylpyrrolo[1,2-a]quinoxalin-4(5H)-one.

[0102] The compounds of the present disclosure can be prepared as illustrated by the exemplary reaction in Scheme 3. The reduction reaction of methyl 4-fluoro-3-nitrobenzoate and H2 under the catalysis of Pd / C produced methyl 3-amino-4-fluorobenzoate. The reaction of methyl 3-amino-4-fluorobenzoate and 1H-pyrazole-5-carboxylic acid under the catalysis of DIEA and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) produced methyl 4-fluoro-3-(1H-pyrazole-5-carboxamido)benzoate. The intramolecular ring closure reaction of methyl 4-fluoro-3-(1H-pyrazole-5-carboxamido)benzoate under the catalysis of K2CO3 produced methyl 4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxylate. Reduction of methyl 4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxylate with LiAlH4 gave 7-(hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one. Chlorination of 7-(hydroxymethyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one with SOCl2 gave 7-(chloromethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one. DIEA- and KI-catalyzed substitution reaction of 7-(chloromethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one and N,6-dimethyl-5-(piperazin-1-yl)picolinamide afforded the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one. [ka]

[0103] Other related compounds can be prepared using similar methods. For example, replacing N,6-dimethyl-5-(piperazin-1-yl)picolinamide with 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one. Replacing N,6-dimethyl-5-(piperazin-1-yl)picolinamide with 6-chloro-N-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one. Substitution of 3-amino-4-fluorobenzoic acid methyl with 3-amino-4,5-difluorobenzoic acid methyl produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one. Substitution of 3-amino-4-fluorobenzoic acid methyl with 3-amino-5-chloro-4-fluorobenzoic acid methyl produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-chloropyrazolo[1,5-a]quinoxalin-4(5H)-one. Substitution of 1H-pyrazole-5-carboxylic acid with 3-methyl-1H-pyrazole-5-carboxylic acid produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one.

[0104] Compounds of the present disclosure can be prepared as illustrated by the exemplary reactions in Scheme 4. Reaction of methyl 4-formyl-3-nitrobenzoate, glyoxal, and NH3-MeOH produced methyl 4-(1H-imidazol-2-yl)-3-nitrobenzoate. Reduction of methyl 4-(1H-imidazol-2-yl)-3-nitrobenzoate with SnCl2·2H2O produced methyl 3-amino-4-(1H-imidazol-2-yl)benzoate. Reaction of methyl 3-amino-4-(1H-imidazol-2-yl)benzoate and triphosgene (BTC) produced methyl 5-oxo-5,6-dihydroimidazo[1,2-c]quinazoline-8-carboxylate. Reduction of methyl 5-oxo-5,6-dihydroimidazo[1,2-c]quinazolin-8-carboxylate with LiAlH4 gave 8-(hydroxymethyl)imidazo[1,2-c]quinazolin-5(6H)-one. Reaction of 8-(hydroxymethyl)imidazo[1,2-c]quinazolin-5(6H)-one with SOCl2 gave 8-(chloromethyl)imidazo[1,2-c]quinazolin-5(6H)-one. The reaction of 8-(chloromethyl)imidazo[1,2-c]quinazolin-5(6H)-one and N,6-dimethyl-5-(piperazin-1-yl)picolinamide produced the target compound 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)imidazo[1,2-c]quinazolin-5(6H)-one. [ka]

[0105] Other related compounds can be prepared using similar methods. For example, replacing N,6-dimethyl-5-(piperazin-1-yl)picolinamide with 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 8-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)imidazo[1,2-c]quinazolin-5(6H)-one. Replacing N,6-dimethyl-5-(piperazin-1-yl)picolinamide with 6-chloro-N-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 8-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)imidazo[1,2-c]quinazolin-5(6H)-one.

[0106] The compounds of the present disclosure can be prepared as illustrated by the exemplary reaction of Scheme 5. The reaction of methyl 3-amino-4-bromobenzoate and (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid under the catalysis of Pd(PPh3)2Cl2 and Na2CO3 produced methyl 5-oxo-5,6-dihydropyrrolo[1,2-c]quinazoline-8-carboxylate. The reduction of methyl 5-oxo-5,6-dihydropyrrolo[1,2-c]quinazoline-8-carboxylate with LiAlH4 produced 8-(hydroxymethyl)pyrrolo[1,2-c]quinazolin-5(6H)-one. The triethylamine-catalyzed reaction of 8-(hydroxymethyl)pyrrolo[1,2-c]quinazolin-5(6H)-one and methanesulfonyl chloride gave (5-oxo-5,6-dihydropyrrolo[1,2-c]quinazolin-8-yl)methyl methanesulfonate. The DIEA- and KI-catalyzed reaction of (5-oxo-5,6-dihydropyrrolo[1,2-c]quinazolin-8-yl)methyl methanesulfonate and N,6-dimethyl-5-(piperazin-1-yl)picolinamide gave the target compound 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrrolo[1,2-c]quinazolin-5(6H)-one. [ka]

[0107] Other related compounds can be prepared using similar methods. For example, replacing (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid with (1-(tert-butoxycarbonyl)-1H-pyrazol-5-yl)boronic acid produced the target compound 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-c]quinazolin-5(6H)-one.

[0108] Compounds of the present disclosure can be prepared as illustrated by the exemplary reaction in Scheme 6. DIEA-catalyzed esterification of methyl 2-oxocyclopentane-1-carboxylate and trifluoromethanesulfonic anhydride produced methyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-1-ene-1-carboxylate. Pd(dppf)Cl2.CH2Cl2-catalyzed borylation of methyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-1-ene-1-carboxylate and bis(pinacolato)diboron produced methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-1-ene-1-carboxylate. The Suzuki reaction of methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-1-ene-1-carboxylate and methyl 4-bromo-3-fluoro-5-nitrobenzoate catalyzed by Pd(PPh3)2Cl2 gave methyl 3-fluoro-4-(2-(methoxycarbonyl)cyclopent-1-en-1-yl)-5-nitrobenzoate. The reaction of methyl 3-fluoro-4-(2-(methoxycarbonyl)cyclopent-1-en-1-yl)-5-nitrobenzoate with Fe / AcOH gave methyl 9-fluoro-4-oxo-2,3,4,5-tetrahydro-1H-cyclopenta[c]quinoline-7-carboxylate. Reduction of methyl 9-fluoro-4-oxo-2,3,4,5-tetrahydro-1H-cyclopenta[c]quinoline-7-carboxylate with LiAlH4 gave 9-fluoro-7-(hydroxymethyl)-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one. Chlorination of 9-fluoro-7-(hydroxymethyl)-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one with SOCl2 in DMF catalyzed afforded 9-fluoro-7-(chloromethyl)-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one.The reaction of 9-fluoro-7-(chloromethyl)-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one and N,6-dimethyl-5-(piperazin-1-yl)picolinamide under DIEA and KI catalysis afforded the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one. [ka]

[0109] Other related compounds can be prepared using similar methods. For example, replacing N,6-dimethyl-5-(piperazin-1-yl)picolinamide with 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one. Substitution of N,6-dimethyl-5-(piperazin-1-yl)picolinamide with N-cyclopropyl-6-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-methyl-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one. Substitution of N,6-dimethyl-5-(piperazin-1-yl)picolinamide with N-cyclopropyl-6-fluoro-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-fluoro-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one.

[0110] The compounds of the present disclosure can be prepared as illustrated by the exemplary reaction in Scheme 7. The reaction of 3-methyl-1H-pyrazole-5-carbonyl chloride and 5-bromo-2,3-difluoroaniline under NaH catalysis produced N-(5-bromo-2,3-difluorophenyl)-5-methyl-1H-pyrazole-3-carboxamide. The reaction of N-(5-bromo-2,3-difluorophenyl)-5-methyl-1H-pyrazole-3-carboxamide and K2CO3 produced 7-bromo-9-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one. The reaction of 7-bromo-9-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one and (tributylstannyl)methanol catalyzed by XphosPdG2 gave 9-fluoro-7-(hydroxymethyl)-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one. The reaction of 9-fluoro-7-(hydroxymethyl)-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one and SOCl2 catalyzed by DMF gave 7-(chloromethyl)-9-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one. The reaction of 7-(chloromethyl)-9-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide under KI and DIEA catalysis afforded the target compound 7-((4-(2-fluoro-6-(methylcarbamoyl)quinoxal-3-yl)piperazin-1-yl)methyl)-9-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one. [ka]

[0111] Other related compounds can be prepared using similar methods. For example, replacing 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide with N,6-dimethyl-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)quinoxal-3-yl)piperazin-1-yl)methyl)-9-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one. Substitution of 3-methyl-1H-pyrazole-5-carbonyl chloride with 4-methyl-1H-pyrazole-5-carbonyl chloride produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)quinoxal-3-yl)piperazin-1-yl)methyl)-9-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one. Substitution of 3-methyl-1H-pyrazole-5-carbonyl chloride with 3-chloro-1H-pyrazole-5-carbonyl chloride produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)quinoxal-3-yl)piperazin-1-yl)methyl)-2-chloro-9-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one. Substitution of 3-methyl-1H-pyrazole-5-carbonyl chloride with 1H-pyrazole-5-carbonyl chloride, 5-bromo-2,3-difluoroaniline with 3-bromo-2,6-difluoroaniline, and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide with N,6-dimethyl-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one.Substitution of 3-bromo-2,6-difluoroaniline for 5-bromo-2,3-difluoroaniline and N,6-dimethyl-5-(piperazin-1-yl)picolinamide for 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)quinoxal-3-yl)piperazin-1-yl)methyl)-6-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one. Substitution of 3-chloro-1H-pyrazole-5-carbonyl chloride with 1H-pyrazole-5-carbonyl chloride, 5-bromo-2,3-difluoroaniline with 3-bromo-2,6-difluoroaniline, and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide with N,6-dimethyl-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-2-chloropyrazolo[1,5-a]quinoxalin-4(5H)-one.

[0112] The compounds of the present disclosure can be prepared as illustrated by the exemplary reaction of Scheme 8. The reaction of methyl 4-bromothiophene-3-carboxylate and (2-amino-4-(methoxycarbonyl)phenyl)boronic acid under the catalysis of NaOAc and Pd(dppf)Cl2 produced methyl 4-oxo-4,5-dihydrothieno[3,4-c]quinoline-7-carboxylate. The reaction of methyl 4-oxo-4,5-dihydrothieno[3,4-c]quinoline-7-carboxylate and LiAlH4 produced 7-(hydroxymethyl)thieno[3,4-c]quinolin-4(5H)-one. The reaction of 7-(hydroxymethyl)thieno[3,4-c]quinolin-4(5H)-one and SOCl2 under the catalysis of DMF produced 7-(chloromethyl)thieno[3,4-c]quinolin-4(5H)-one. The KI- and DIEA-catalyzed reaction of 7-(chloromethyl)thieno[3,4-c]quinolin-4(5H)-one and N,6-dimethyl-5-(piperazin-1-yl)picolinamide afforded the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)quinolin-3-yl)piperazin-1-yl)methyl)thieno[3,4-c]quinolin-4(5H)-one. [ka]

[0113] Other related compounds can be prepared using similar methods. For example, replacing 4-bromothiophene-3-carboxylate with 2-bromothiophene-3-carboxylate produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)quinolin-3-yl)piperazin-1-yl)methyl)thieno[3,2-c]quinolin-4(5H)-one. Replacing 4-bromothiophene-3-carboxylate with 3-bromothiophene-2-carboxylate produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[2,3-c]quinolin-4(5H)-one. Substitution of methyl 4-bromothiophene-3-carboxylate with methyl 5-bromothiazole-4-carboxylate afforded the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thiazolo[4,5-c]quinolin-4(5H)-one.

[0114] An important aspect of the present disclosure is the discovery that the compound of formula I (including formula II, formula III, and formula IV) is a PARP inhibitor, particularly a selective PARP1 inhibitor.Therefore, the compound of formula I (including formula II, formula III, and formula IV), or stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate, or their pharmaceutically acceptable salt, or their mixture, or their prodrug, can be used to treat various diseases or conditions that respond to the inhibition of PARP activity (particularly PARP1 activity), or can be used to prepare a medicament for treating or preventing diseases or conditions that respond to the inhibition of PARP activity (particularly PARP1 activity).

[0115] In the present disclosure, diseases or conditions responsive to inhibition of PARP activity (particularly PARP1 activity) include cancer. Cancer can be a solid tumor or a hematological tumor, including, but not limited to, liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer (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, and the like. The cancers include 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.

[0116] Thus, the present disclosure includes methods for the treatment or prevention of a disease or condition responsive to inhibition of PARP activity (particularly PARP1 activity), the method 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, Formula III, and Formula IV), or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate, or a pharma- ceutically 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, Formula III, and Formula IV), or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate, or a pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof.

[0117] In carrying out the treatment method, an effective amount of the 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, formula III, and formula IV) 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. The effective amount of a compound for treating a particular disease is an amount that is sufficient to improve or in some way reduce 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 of symptoms.

[0118] In another embodiment, there is provided a pharmaceutical composition comprising a compound of Formula I (including Formula II, Formula III, and Formula IV) as a PARP inhibitor, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, and a pharma- ceutically acceptable carrier.

[0119] 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, formula III, and formula IV) as a PARP inhibitor, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharma- ceutically acceptable salt thereof and a prodrug thereof, in combination with at least one known anticancer drug or its pharma- ceutically acceptable salt.In particular, the compounds herein can be combined with other anticancer drugs related to the mechanism of DNA damage and repair, such as ATM inhibitors, ATR inhibitors, Wee1 inhibitors, DNA-PK inhibitors; HDAC inhibitors such as Volinota, Romididesin, Papiseta, and Bailesta; other anticancer drugs related to cell division, including Chk1 / 2 inhibitors, CDK4 / 6 inhibitors such as paposinib; other targeted anticancer drugs including USP1 inhibitors, PRMT5 inhibitors, Polθ inhibitors, and RAD51 inhibitors. Other known anti-cancer drugs that may be used in the 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 cyclosporine inhibitors 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;Antibodies such as mAbs, panitumumab, necitumumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab, daratumumab, elotuzumab, ofatumumab, dinutuximab, blinatumomab, ipilimumab, Avastin, Herceptin, and MabTera; T-DM1, trastuzumab deruxtecan, trastuzumab emtansine, datopotamab deruxtecan, gemtuzumab ozogamicin, brentuximab vedotin, inotuzumab ozogamicin, sacitus Antibody-drug conjugates (ADCs) such as mab govitecan, enfortumab vedotin, and belantamab mafodotin; kinase inhibitors such as imatinib, gefitinib, erlotinib, osimertinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lapatinib, sorafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, ponatinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cobimetinib, axitinib, temsirolimus, idelalisib, pazopanib, torisel, and everolimus. Other known anti-cancer drugs that may be used in the anti-cancer 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 (prostate cancer treatment vaccine);

[0120] In 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 levels in blood 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 levels in blood.

[0121] Another embodiment of the present disclosure is directed to a bioconjugate for inhibiting tumors. The bioconjugate is composed of the 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 that can bind to a cell surface. The antibody and other molecules can deliver the compound described herein to its target, making it an effective anti-cancer drug. The bioconjugate can also enhance the anti-cancer effect of a therapeutically useful antibody, such as trastuzumab or rituximab.

[0122] 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, Formula III, and Formula IV), or a pharma- ceutically 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 radiation therapy.

[0123] Yet another embodiment of the present disclosure is directed to a pharmaceutical composition comprising a PARP inhibitor of Formula I (including Formula II, Formula III, and Formula IV), or a pharma- ceutically acceptable salt thereof, or a prodrug thereof, effective for post-operative treatment of cancer. The present disclosure also relates to a method of treating cancer by surgically removing a tumor and then treating a mammal with a pharmaceutical composition described herein.

[0124] The pharmaceutical compositions of the present disclosure include all pharmaceutical preparations that contain the compounds of the present disclosure in an amount effective to achieve its intended purpose. Although 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 pharma- ceutically 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 body weight to approximately 10 mg / kg 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 agents is well known to those skilled in the art.

[0125] A unit oral dose may 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 may be administered one or more times daily in one or more tablets, each containing from about 0.1 to about 50 mg, conveniently about 0.25 to 10 mg, of a compound of the present disclosure or a solvate thereof.

[0126] In a topical formulation, the compounds of the present disclosure may be present in a concentration of approximately 0.01 to 100 mg per gram of carrier.

[0127] The compounds of the present disclosure may be administered as chemical raw materials. The compounds of the present disclosure may also be administered as part of a suitable pharmaceutical preparation that includes a pharmaceutically acceptable carrier (including excipients and auxiliary agents), which facilitates the processing of the compound into a pharmaceutically acceptable preparation. Preferably, pharmaceutical preparations, especially oral preparations, and those used for preferred administration, such as tablets, draggers, and capsules, as well as solutions suitable for injection or oral administration, contain approximately 0.01%-99%, preferably approximately 0.25%-75% of the active compound together with excipients.

[0128] Also included within the scope of the present 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.

[0129] The pharmaceutical preparations of the present disclosure may be administered to any mammal so long as the mammal can experience the therapeutic effects of the compounds of the present disclosure. Foremost among such mammals are humans and veterinary animals, although the present disclosure is not intended to be so limited.

[0130] 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 simultaneously, 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.

[0131] The pharmaceutical preparations of the present disclosure are prepared in a known manner, for example, by conventional mixing, granulation, dragee making, dissolving or lyophilization processes.The pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding the mixture obtained, and processing the mixture of granules after adding suitable auxiliary agents as required or necessary, thereby obtaining tablets or dragee cores.

[0132] 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, and carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate. Auxiliaries are in particular flow regulators and lubricants, such as silica, talc, stearic acid or its salts, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. Dragee cores are, if desired, provided with suitable coatings that are resistant to gastric juices. For this purpose, concentrated sugar solutions may be used, which may 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 may be added to tablets or dragee coatings, for example, for identification or to characterize combinations of active compound doses.

[0133] Other pharmaceutical preparations that can be used orally include the push-fit capsule made of gelatin, and the soft sealed capsule made of gelatin, and a plasticizer such as glycerol or sorbitol.The push-fit capsule may contain the active compound in the form of granules, which may be mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and a stabilizer.In the soft capsule, the active compound is preferably dissolved or suspended in a suitable liquid, such as fatty oil or liquid paraffin.In addition, a stabilizer may be added.

[0134] Suitable preparations for parenteral administration include aqueous solutions of active compounds, such as aqueous solutions of water-soluble salts and alkaline solutions.In addition, suspensions of active compounds may be administered as suitable oily injection suspensions.Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or 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.

[0135] According to one aspect of the disclosure, the compounds of the disclosure are used in topical and parenteral formulations for the treatment of skin cancer.

[0136] The topical formulations of the present disclosure are preferably formulated as oils, creams, lotions, ointments, etc., by selection of the 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 12The preferred carriers are those in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants, and antioxidants may also be included, as well as agents that impart color or fragrance, if desired. Additionally, transdermal penetration enhancers may be used in these topical formulations. Examples of such enhancers are found in U.S. Patents 3,989,816 and 4,444,762.

[0137] 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 is one that contains approximately 40 times the amount of water, approximately 20 times the amount of beeswax, approximately 40 times the amount of mineral oil, and approximately 1 time the amount of almond oil.

[0138] 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 is one that contains approximately 30% by weight of almond oil and approximately 70% by weight of white soft paraffin.

[0139] The present disclosure also involves the use of the compounds 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. EXAMPLES

[0140] 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. Overview All reagents were of commercial quality. Solvents were dried and purified by standard methods. Mass spectral analyses 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 Brucker 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). Example 1 7-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one a) Preparation of methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-carboxylate: To a solution of methyl 4-oxotetrahydrofuran-3-carboxylate (1.00 g, 0.69 mmol) in dry DCM (40 mL) was added DIEA (2.68 g, 2.07 mmol) at −78° C. under N2 atmosphere and the solution was stirred at −78° C. for 30 min. Then Tf2O (5.87 g, 2.07 mmol, 3.0 equiv.) was added slowly. The mixture was stirred at −78° C. for 30 min and at room temperature for 1.5 h. After completion, the mixture was quenched with water (5 mL) and the mixture was extracted with DCM (20 mL×2). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (petroleum ether:ethyl acetate=20 / 1 to 10 / 1) to give the title compound (1.60 g, yellow oil, yield: 83%). b) Preparation of methyl 4-(4-(methoxycarbonyl)-2-nitrophenyl)-2,5-dihydrofuran-3-carboxylate: To a mixture of methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-carboxylate (2.00 g, 7.24 mmol), (4-(methoxycarbonyl)-2-nitrophenyl)boronic acid (1.95 g, 8.69 mmol), KF (1.38 g, 23.89 mmol) in THF (40 mL) and HO (2 mL) was added Pd2(dba)3 (0.66 g, 0.72 mmol) and tri-tert-butylphosphine tetrafluoroborate (0.50 g, 1.73 mmol). The mixture was degassed and purged with N2 three times and stirred at 70 °C under N2 atmosphere for 16 h. After completion, the mixture was quenched with water (20 mL) and the mixture was extracted with DCM (30 mL x 2). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (petroleum ether:ethyl acetate = 10 / 1 to 3 / 1) to give the title compound (1.76 g, yellow oil, yield: 76%). c) Preparation of methyl 4-oxo-1,3,4,5-tetrahydrofuro[3,4-c]quinoline-7-carboxylate: To a solution of methyl 4-(4-(methoxycarbonyl)-2-nitrophenyl)-2,5-dihydrofuran-3-carboxylate (1.76 g, 5.71 mmol) in AcOH (17 mL) was added Fe powder (1.60 g, 28.57 mmol). The resulting mixture was stirred at 80° C. for 2 h. After completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with DCM (20 mL×3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (1.40 g, red-brown solid, crude). MS (ESI, m / z): 246.05 [M+H] + . d) Preparation of 7-(hydroxymethyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one: To a suspension of methyl 4-oxo-1,3,4,5-tetrahydrofuro[3,4-c]quinoline-7-carboxylate (1.00 g, crude, 4.10 mmol) in THF (10 mL) was added LiAlH4 (0.78 g, 20.40 mmol) at 0° C. under N2. The resulting mixture was stirred at 0° C. for 20 min and then warmed to room temperature. After completion, the mixture was quenched with ice water (10 mL) and the pH was adjusted to 3 with 1 M aqueous HCl. The resulting mixture was extracted with EtOAc (30 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.13 g, pale yellow solid, 15% yield). MS(ESI,m / z):218.21[M+H] + . e) Preparation of 7-(chloromethyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one: To a suspension of 7-(hydroxymethyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (0.13 g, 0.60 mmol) in DCM (3 mL) was added DMF (4.00 mg, 0.06 mmol) and SOCl2 (0.43 g, 3.60 mmol) at 0°C. The resulting mixture was stirred at room temperature for 2 h. After completion, the mixture was concentrated to give the title compound (0.14 g, grey solid, crude). MS (ESI, m / z): 236.03 [M+H] + . f) Preparation of 7-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one: To a suspension of 7-(chloromethyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (90.00 mg, crude), KI (13.92 mg, 0.80 mmol), and N-methyl-5-(piperazin-1-yl)picolinamide hydrochloride (115.14 mg, 0.57 mmol) in CH3CN (4 mL) was added DIEA (245.00 mg, 1.90 mmol) at room temperature. The resulting suspension was stirred at 80° C. for 2 h. After completion, the solvent was removed under vacuum. The residue was purified by preparative HPLC (C18, CH3CN / H2O, 10-30%, with 0.1% HCOOH) to give the target compound (40.00 mg, white solid, yield: 25%). The following compounds, Examples 2-23, were prepared using synthetic methods similar to those described in Example 1. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] Example 24 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one a) Preparation of 1-(4-(methoxycarbonyl)-2-nitrophenyl)-1H-pyrrole-2-methyl carboxylate: To a solution of methyl 4-fluoro-3-nitrobenzoate (1.00 g, 5.03 mmol) in DMF (20 mL), Cs2CO3 (1.97 g, 6.04 mmol) and 1H-pyrrole-2-methyl carboxylate (0.63 g, 5.03 mmol) were added. The mixture was stirred at 60 °C for 4 h. After completion, the mixture was added with water (50 mL) and extracted with DCM (40 mL x 2). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (petroleum ether:ethyl acetate = 100 / 1 to 50 / 1) to give the title compound (0.8 g, yellow solid, yield: 52.3%). MS (ESI, m / z): 305.05 [M+H] + . b) Preparation of methyl 4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxaline-7-carboxylate: To a solution of methyl 1-(4-(methoxycarbonyl)-2-nitrophenyl)-1H-pyrrole-2-carboxylate (800.0 mg, 2.6 mmol) in AcOH (16 mL) was added Fe powder (736.8 mg, 13.2 mmol). The resulting mixture was stirred at 80° C. for 2 h. After completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (200 mg, yellow solid, 31.4% yield). MS (ESI, m / z): 243.05 [M+H] + . c) Preparation of 7-(hydroxymethyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one: To a solution of methyl 4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxaline-7-carboxylate (100.0 mg, 0.4 mmol) in THF (5 mL) was added LiAlH4 (0.06 g, 1.6 mmol) under N2 at 0°C. The resulting mixture was stirred at 0°C for 20 min and then warmed to room temperature. After stirring for 4 h, the mixture was added DCM (30 mL) and quenched with water (0.06 mL), followed by 15% aqueous sodium hydroxide solution (0.06 mL) and water (0.18 mL). The mixture was stirred at room temperature for 15 min. The mixture was dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with MeOH (60 mL). The filtrate was concentrated under reduced pressure to give the title compound (120 mg, crude, white solid). MS (ESI, m / z): 215.25 [M+H] + . d) Preparation of 7-(chloromethyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one: To a suspension of 7-(hydroxymethyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (100 mg, 0.46 mmol) in DCM (10 mL) was added DMF (2 drops) and SOCl2 (220.3 mg, 1.85 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. After completion, the mixture was concentrated to give the title compound (140 mg, crude, grey solid). MS (ESI, m / z): 233.15 [M+H] + . e) Preparation of 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one: To a suspension of 7-(chloromethyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (30.0 mg, crude, 0.13 mmol), KI (2.1 mg, 0.01 mmol), and N,6-dimethyl-5-(piperazin-1-yl)picolinamide (30.3 mg, 0.13 mmol) in CH3CN (5 mL) was added DIEA (83.9 mg, 0.65 mmol) at room temperature. The resulting suspension was stirred at 80° C. overnight. After completion, the solvent was removed under vacuum. The residue was purified by preparative TLC (DCM:MeOH=10:1) to give the target compound (23.8 mg, white solid, yield: 42.9%). The following compounds, Examples 25-27, were prepared using synthetic methods similar to those described in Example 1 or Example 24. [Table 4] Example 28 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one a) Preparation of methyl 3-amino-4-fluorobenzoate: To a solution of methyl 4-fluoro-3-nitrobenzoate (500 mg, 2.5 mmol) in MeOH (6 mL) was added Pd / C (50 mg). The resulting mixture was stirred under H2 at room temperature overnight. After completion, the reaction mixture was filtered and the filtrate was concentrated to give the title compound (400 mg, white solid, 94% yield). MS (ESI, m / z): 170.15 [M+H] + . b) Preparation of methyl 4-fluoro-3-(1H-pyrazole-5-carboxamido)benzoate: To a solution of methyl 3-amino-4-fluorobenzoate (400 g, 2.4 mmol) in DMF (20 mL) was added 1H-pyrazole-5-carboxylic acid (398 mg, 3.6 mmol) and HATU (1.35 g, 3.6 mmol) and DIEA (1.2 g, 9.5 mmol). The mixture was stirred at 80° C. for 16 h. After completion, the mixture was added with water (50 mL) and extracted with DCM (40 mL×2). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (petroleum ether:ethyl acetate=100 / 1 to 50 / 1) to give the title compound (340 mg, yellow solid, yield: 54%). MS(ESI,m / z):264.05[M+H] + . c) Preparation of methyl 4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxylate: To a solution of methyl 4-fluoro-3-(1H-pyrazole-5-carboxamido)benzoate (120.0 mg, 0.46 mmol) in DMF (5 mL) was added K2CO3 (126 mg, 0.9 mmol). The mixture was stirred at 120° C. for 16 h. After completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (100 mg, yellow solid, 90% yield). MS (ESI, m / z): 244.05 [M+H] + . d) Preparation of 7-(hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one: To a solution of methyl 4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxylate (100.0 mg, 0.4 mmol) in THF (5 mL) was added LiAlH4 (1.6 mL, 1.6 mmol) under N2 at 0°C. The resulting mixture was stirred at 0°C for 20 min and then warmed to room temperature. After stirring for 4 h, the mixture was added DCM (30 mL) and quenched with water (0.06 mL), followed by 15% aqueous sodium hydroxide solution (0.06 mL) and water (0.18 mL). The mixture was stirred at room temperature for 15 min. The mixture was dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with MeOH (60 mL). The filtrate was concentrated under reduced pressure to give the title compound (120 mg, crude, white solid). MS (ESI, m / z): 216.25 [M+H] + . e) Preparation of 7-(chloromethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one: To a suspension of 7-(hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (120 mg, 0.56 mmol) in DCM (10 mL) was added DMF (2 drops) and SOCl2 (398.0 mg, 3.35 mmol) at 0°C. The resulting mixture was stirred at room temperature for 2 h. After completion, the mixture was concentrated to give the title compound (130 mg, crude, grey solid). MS (ESI, m / z): 234.12 [M+H] + . f) Preparation of 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one: To 7-(chloromethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (130.0 mg, crude, 0.56 mmol), KI (18 mg, 0.01 mmol), and N,6-dimethyl-5-(piperazin-1-yl)picolinamide (130.5 mg, 0.56 mmol) in CH3CN (5 mL) was added DIEA (360.0 mg, 2.79 mmol) at room temperature. The resulting suspension was stirred at 80° C. overnight. After completion, the solvent was removed under vacuum. The residue was purified by preparative TLC (DCM:MeOH=10:1) to give the target compound (17.3 mg, white solid, yield: 10% for three steps). The compound of Example 29 was prepared using synthetic methods similar to those described in Example 28. [Table 5] The compound of Example 30 was prepared using synthetic methods similar to those described in Example 31. Example 31 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)imidazo[1,2-c]quinazolin-5(6H)-one a) Preparation of methyl 4-(1H-imidazol-2-yl)-3-nitrobenzoate: To a suspension of methyl 4-formyl-3-nitrobenzoate (4.5 g, 21.5 mmol) in MeOH (100.0 mL), NH3-MeOH (7 mol / L, 45.0 mL) and glyoxal (40 wt% in H2O, 22.0 mL) were added under N2 at room temperature for 16 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 100 / 1 to 20 / 1) to give the title compound (540.0 mg, yellow solid, 10% yield). MS (ESI, m / z): 248.05 [M+H] + . b) Preparation of methyl 3-amino-4-(1H-imidazol-2-yl)benzoate: A solution of methyl 4-(1H-imidazol-2-yl)-3-nitrobenzoate (540.0 mg, 2.2 mmol), SnCl2-H2O (2.1 g, 10.9 mmol) in EA (20.0 mL) was stirred at 80 °C for 2 h. After completion, the mixture was adjusted to pH = 8 with aqueous NaHCO3 and extracted with EA (40.0 mL x 3). The combined organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 50 / 1 to 5 / 1) to give the title compound (230.0 mg, yellow solid, 48% yield). MS (ESI, m / z): 218.25 [M+H] + . c) Preparation of methyl 5-oxo-5,6-dihydroimidazo[1,2-c]quinazoline-8-carboxylate: To a suspension of methyl 3-amino-4-(1H-imidazol-2-yl)benzoate (230.0 mg, 1.1 mmol) in dioxane (10 mL) was added BTC (330.0 mg, 1.1 mmol) under N2. The resulting mixture was stirred at 80° C. for 16 h. After completion, the mixture was concentrated. The residue was washed with water to give the title compound (crude, 380.0 mg, yellow solid). MS (ESI, m / z): 244.05 [M+H] + . d) Preparation of 8-(hydroxymethyl)imidazo[1,2-c]quinazolin-5(6H)-one: To a suspension of methyl 5-oxo-5,6-dihydroimidazo[1,2-c]quinazolin-8-carboxylate (380.0 mg, 1.6 mmol) in THF (5 mL) was added LiAlH4-THF (1 mol / L, 3.2 ml) at 0° C. under N2. The mixture was warmed to room temperature and stirred for 2 h. After completion, the mixture was quenched with 1 M aqueous hydrochloric acid (1.0 mL) and concentrated. The residue was diluted with water (10 mL) to give a yellow suspension. The solid was collected by filtration, washed with water (10.0 mL), diethyl ether (10.0 mL) and dried to give the title compound (crude, 270.0 mg, yellow solid). e) Preparation of 8-(chloromethyl)imidazo[1,2-c]quinazolin-5(6H)-one: To a suspension of 8-(hydroxymethyl)imidazo[1,2-c]quinazolin-5(6H)-one (270.0 mg, crude, 1.3 mmol) in DCM (10 mL) was added DMF (19.0 mg, 0.3 mmol) and thionyl chloride (773.5 mg, 6.5 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature for 1 h. After completion, the mixture was concentrated to give the title product (crude, 270.0 mg, grey solid) which was used directly in the next step without further purification. MS (ESI, m / z): 234.00 [M+H] + . f) Preparation of 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)imidazo[1,2-c]quinazolin-5(6H)-one: To a solution of 8-(chloromethyl)imidazo[1,2-c]quinoquinazolin-5(6H)-one (270.0 mg, 1.15 mmol), KI (19.1 mg, 0.1 mmol), and N,6-dimethyl-5-(piperazin-1-yl)picolinamide (322.9 mg, 1.4 mmol) in CH3CN (10.0 mL) was added DIEA (741.8 mg, 5.8 mmol) at room temperature. The resulting solution was stirred at 80° C. for 3 h. After completion, the solvent was removed under vacuum. The residue was purified by preparative TLC to give the target compound (27.0 mg, white solid, yield: 6% for four steps). The following compounds, Examples 32-33, were prepared using synthetic methods similar to those described in Example 31. The following compounds, Examples 34-35, were prepared using synthetic methods similar to those described in Example 24. The following compounds, Examples 36-47, were prepared using synthetic methods similar to those described in Example 28. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] Example 48 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrrolo[1,2-c]quinazolin-5(6H)-one a) Preparation of methyl 5-oxo-5,6-dihydropyrrolo[1,2-c]quinazoline-8-carboxylate: To a mixture of methyl 3-amino-4-bromobenzoate (1.0 g, 7.2 mmol), (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid (2.0 g, 8.7 mmol), Na2CO3 (1.4 g, 23.9 mmol) in ACN (20.0 mL) was added Pd(PPh3)2Cl2 (660.0 mg, 0.7 mmol). The mixture was degassed and purged with N2 three times. The mixture was stirred at 80 °C under N2 atmosphere for 35 min. The mixture was diluted with water (20.0 mL) and extracted with DCM (30.0 mL x 2). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was washed with MTBE to give the title compound (0.4 g, yellow solid, yield: 39%). b) Preparation of 8-(hydroxymethyl)pyrrolo[1,2-c]quinazolin-5(6H)-one: To a suspension of methyl 5-oxo-5,6-dihydropyrrolo[1,2-c]quinazolin-8-carboxylate (0.3 g, 1.2 mmol) in THF (10 mL) was added LiAlH4 (1 M in THF, 5.0 mL, 4.9 mmol) under N2 at 0 °C. The mixture was warmed to room temperature and stirred for 2 h. The mixture was quenched with ice water (10.0 mL) and adjusted to pH = 3 with 1 M aqueous hydrochloric acid. The resulting mixture was extracted with EA (20.0 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (200.0 mg, white solid, 75% yield). c) Preparation of (5-oxo-5,6-dihydropyrrolo[1,2-c]quinazolin-8-yl)methyl methanesulfonate: To a suspension of 8-(hydroxymethyl)pyrrolo[1,2-c]quinazolin-5(6H)-one (60.0 mg, 0.3 mmol) in DCM (5 mL) was added TEA (84.9 mg, 0.8 mmol) and methanesulfonyl chloride (48.3 mg, 0.4 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to give the title compound (crude, 90.0 mg, yellow solid). d) Preparation of 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrrolo[1,2-c]quinazolin-5(6H)-one: To a solution of (5-oxo-5,6-dihydropyrrolo[1,2-c]quinazolin-8-yl)methyl methanesulfonate (90.0 mg, 0.3 mmol), KI (10.0 mg, 0.1 mmol) and N,6-dimethyl-5-(piperazin-1-yl)picolinamide (90.0 mg, 0.4 mmol) in CH3CN (10.0 mL) was added DIEA (193.5 mg, 1.5 mmol) at room temperature. The resulting solution was stirred at 80° C. for 7 h. The mixture was cooled to room temperature and filtered. The filter cake was washed with methanol (3.0 mL). The solid was purified by preparative TLC (MeOH / DCM=25 / 1) to give the target compound (7.0 mg, white solid, yield: 5% for two steps). The following compounds, Examples 49-50 and 63-64, were prepared using synthetic methods similar to those described in Example 1. The following compounds, Examples 51-53, were prepared using synthetic methods similar to those described in Example 31. The following compounds, Examples 54-58, 62, and 66-72, were prepared using synthetic methods similar to those described in Example 28. The following compounds, Examples 59-61 and 65, were prepared using synthetic methods similar to those described in Example 24. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] Example 73 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one a) Preparation of N-(5-bromo-2,3-difluorophenyl)-5-methyl-1H-pyrazole-3-carboxamide: To a solution of 5-bromo-2,3-difluoroaniline (1.2 g, 5.7 mmol) in anhydrous THF (50 mL) was added NaH (912.0 mg, 22.8 mmol) at 0° C. The mixture was stirred at room temperature for 15 min. Then, a solution of 3-methyl-1H-pyrazole-5-carbonyl chloride (826.0 mg, 5.7 mmol) in anhydrous THF was added dropwise at 0° C. The resulting solution was stirred at room temperature for 2 h. After completion, the reaction was quenched with saturated aqueous NH4Cl (5 mL) and the residue was diluted with water (50 mL) and extracted with EA (50 mL×3). The combined organic phase was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the title compound (1.1 g, crude, off-white solid, yield: 61%). b) Preparation of 7-bromo-9-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one: A mixture of N-(5-bromo-2,3-difluorophenyl)-5-methyl-1H-pyrazole-3-carboxamide (1.1 g, 3.48 mmol) and K2CO3 (1.4 g, 10.44 mmol) in DMSO (25 mL) was stirred at 120° C. overnight. After completion of the reaction, the residue was diluted with water (50 mL) and extracted with EA (50 mL×3). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was triturated with DCM (5 mL) and the solid was collected by filtration to give the title compound (440.1 mg, white solid, 43% yield). MS (ESI, m / z): 295.95 [M+H] + . c) Preparation of 9-fluoro-7-(hydroxymethyl)-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one: To a solution of 7-bromo-9-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (400.0 mg, 1.35 mmol) in dioxane (25 mL) was added (tributylstannyl)methanol (877.0 mg, 2.70 mmol) and XphosPdG2 (106.0 mg, 0.135 mmol) at room temperature. The mixture was stirred overnight at 90° C. under N2 atmosphere. After completion, a solution of KF (1M, 10 mL) was added at room temperature, the mixture was stirred at the same temperature for 10 min, filtered and the filtrate was extracted with EA (50 mL×3). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was triturated with a mixed solvent of PE and EA (PE:EA=1:1, 50 mL) and the solid was collected by filtration to give the title compound (280 mg, white solid, yield: 84%). MS (ESI, m / z): 248.10 [M+H] + . d) Preparation of 7-(chloromethyl)-9-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one: To a solution of methyl 9-fluoro-7-(hydroxymethyl)-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (230.0 mg, 0.93 mmol) in DCM (5 mL) was added SOCl2 (554.0 mg, 4.95 mmol) and DMF (1 drop) under N2 at 0°C. The mixture was allowed to warm to room temperature and stirred for 2 h. The solvent was then concentrated under reduced pressure and the residue was triturated with DCM (5 mL) and the solid was collected by filtration to give the title compound (160.0 mg, white solid, 65% yield). e) Preparation of 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one: To a solution of 7-(chloromethyl)-9-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (40.0 mg, 0.15 mmol), KI (3.0 mg, 0.015 mmol) and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (43.0 mg, 0.18 mmol) in CH3CN (10 mL) was added DIEA (97.1 mg, 0.75 mmol) at room temperature. The resulting solution was stirred at 80° C. for 2 hours. After completion of the reaction, the solvent was removed under vacuum. The residue was purified by preparative TLC (DCM:MeOH=10:1) to give the target compound (21.9 mg, white solid, yield: 31%). The following compounds, Examples 74-78, were prepared using synthetic methods similar to those described in Example 73. [Table 8-1] [Table 8-2] Example 79 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoro-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one a) Preparation of methyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-1-ene-1-carboxylate: To a solution of methyl 2-oxocyclopentane-1-carboxylate (2.0 g, 14.1 mmol) in dry DCM (40.0 mL) was added DIEA (5.5 g, 42.2 mmol) at −78° C. under N2 and stirred for 30 min. Then Tf2O (11.9 g, 42.2 mmol) was added slowly. The mixture was stirred at −78° C. for 30 min and at room temperature for 12 h. The mixture was quenched with water (5.0 mL) and extracted with DCM (20.0 mL×2). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate=100 / 1 to 50 / 1) to give the title compound (2.8 g, 72% yield) as a yellow oil. b) Preparation of methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-1-ene-1-carboxylate: To a mixture of methyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-1-ene-1-carboxylate (1.2 g, 4.4 mmol), bis(pinacolato)diboron (1.3 g, 5.3 mmol), KOAc (0.9 g, 8.8 mmol, 2.0 equiv.) in THF (40 mL), Pd(dppf)Cl2-CH2Cl2 (0.4 g, 0.4 mmol, 0.1 equiv.) was added. The mixture was degassed and purged with N2 three times and stirred under N2 at 100 °C for 4 h. After the reaction was complete. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (1.2 g, crude) as a black solid. c) Preparation of methyl 3-fluoro-4-(2-(methoxycarbonyl)cyclopent-1-en-1-yl)-5-nitrobenzoate: In a sealed tube, to a solution of methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-1-ene-1-carboxylate (1.2 g, 4.8 mmol), methyl 4-bromo-3-fluoro-5-nitrobenzoate (1.3 g, 4.8 mmol), and K2CO3 (1.6 g, 23.7 mmol) in THF (10.0 mL) and H2O (2.0 mL) was added Pd(PPh3)Cl2 (0.3 g, 0.5 mmol). The mixture was degassed and purged with N2 for 2 min and stirred at 85 °C under N2 for 16 h. After the reaction was complete. The mixture was diluted with water (20.0 mL) and extracted with DCM (30.0 mL x 2). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10 / 1 to 3 / 1) to give the title compound (0.5 g, impure) as a yellow solid. d) Preparation of methyl 9-fluoro-4-oxo-2,3,4,5-tetrahydro-1H-cyclopenta[c]quinoline-7-carboxylate: To a solution of methyl 3-fluoro-4-(2-(methoxycarbonyl)cyclopent-1-en-1-yl)-5-nitrobenzoate (0.5 g, crude) in AcOH (20 mL) was added Fe powder (0.4 g, 28.6 mmol). The resulting mixture was stirred at 80° C. for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10.0 mL) and extracted with DCM (50.0 mL×3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.8 g, impure) as a brown solid. LC-MS: 262.05 [M+1] + . e) Preparation of 9-fluoro-7-(hydroxymethyl)-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one: To a suspension of methyl 9-fluoro-4-oxo-2,3,4,5-tetrahydro-1H-cyclopenta[c]quinoline-7-carboxylate (0.8 g, impure) in THF (10.0 mL) was added LiAlH4 (1 M in THF, 1.5 mL, 1.5 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 20 min and at room temperature for 4 h. The mixture was quenched with ice water (10.0 mL) and adjusted to pH = 3 with aqueous HCl (1 M). The resulting mixture was extracted with EA (50.0 mL × 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (170.0 mg, 17% yield, 4 steps) as a white solid. f) Preparation of 7-(chloromethyl)-9-fluoro-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one: To a suspension of 9-fluoro-7-(hydroxymethyl)-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one (40.0 mg, 0.2 mmol) in DCM (3 mL), DMF (5.0 mg, 0.1 mmol) and SOCl2 (142.8 mg, 1.2 mmol) were added at 0°C. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated to give the compound (50.0 mg, impure) as a grey solid. LC-MS: 252.05 [M+1] + . g) Preparation of 5-(4-((9-fluoro-4-oxo-2,3,4,5-tetrahydro-1H-cyclopenta[c]quinolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide: To a suspension of 7-(chloromethyl)-9-fluoro-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one (50.0 mg, impure, 1.0 equiv.), KI (7.0 mg, 0.1 mmol) and N,6-dimethyl-5-(piperazin-1-yl)picolinamide (56.0 mg, 0.2 mmol) in CH3CN (4.0 mL) was added DIEA (129.0 mg, 1.9 mmol) at room temperature. The resulting suspension was stirred at 80° C. for 2 h. The mixture was cooled to room temperature and filtered. The filter cake was washed with methanol (2.0 mL). The solid was purified by preparative TLC (MeOH / DCM=20 / 1) to give the target compound (21.0 mg, yield: 27%) as a white solid. The following compounds, Examples 80-82, were prepared using synthetic methods similar to those described in Example 79. [Table 9] Example 83 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[3,4-c]quinolin-4(5H)-one a) Preparation of methyl 4-oxo-4,5-dihydrothieno[3,4-c]quinoline-7-carboxylate: To a solution of methyl 4-bromothiophene-3-carboxylate (350.0 mg, 1.6 mmol) in DMF (5 mL) was added 2-amino-4-(methoxycarbonyl)phenylboronic acid (549.8 mg, 2.4 mmol), NaOAc (196.8 mg, 2.4 mmol), Pd(dppf)Cl2 (347.8 mg, 0.47 mmol). The reaction mixture was stirred at 130 °C under N2 in a microwave for 15 min. After completion, the reaction mixture was filtered and the filtrate was concentrated. The residue was diluted with water (20 mL) and extracted with EA (20 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=20 / 1) to give the title compound (108.0 mg, yellow solid, yield: 26%). MS (ESI, m / z): 259.95 [M+H] + . b) Preparation of 7-(hydroxymethyl)thieno[3,4-c]quinolin-4(5H)-one: To a suspension of methyl 4-oxo-4,5-dihydrothieno[3,4-c]quinoline-7-carboxylate (108.0 mg, 0.4 mmol) in THF (3 mL) was added LiAlH4 (1 M in THF, 1.7 mL, 1.7 mmol) under N2 at 0 °C. The mixture was warmed to room temperature and stirred for 2 h. The mixture was quenched with water (2 mL) and extracted with EA (10 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (72.0 mg, crude, white solid). MS (ESI, m / z): 232.00 [M+H] + . c) Preparation of 7-(chloromethyl)thieno[3,4-c]quinolin-4(5H)-one: To a suspension of 7-(hydroxymethyl)thieno[3,4-c]quinolin-4(5H)-one (72.0 mg, 0.3 mmol) in DCM (3 mL) was added DMF (2 drops) and thionyl chloride (222.3 mg, 1.9 mmol, 6.0 equiv) dropwise at 0° C. The resulting mixture was stirred at room temperature for 10 min. After completion, the mixture was concentrated to give the title compound (40.0 mg, crude, white solid). MS (ESI, m / z): 250.20 [M+H] + . d) Preparation of 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[3,4-c]quinolin-4(5H)-one: To a solution of 7-(chloromethyl)thieno[3,4-c]quinolin-4(5H)-one (40.0 mg, 0.2 mmol) in CH3CN was added N,6-dimethyl-5-(piperazin-1-yl)picolinamide (37.4 mg, 0.1 mmol), DIEA (103.2 mg, 0.8 mmol), KI (5.0 mg, 0.03 mmol) under N2. The resulting solution was stirred at 80° C. for 2 h. After completion, the solvent was removed in vacuo. The residue was purified by preparative TLC (DCM / MeOH=20 / 1, 0.1% TEA) to give the target compound (9.2 mg, white powder, yield: 5% for three steps). The following compounds, Examples 84-85 and 104, were prepared using synthetic methods similar to those described in Example 83. The following compounds, Examples 86-103, were prepared using synthetic methods similar to those described in Example 73. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] [Table 10-6] Example 105 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one a) Preparation of ethyl-2-(4-bromo-2-nitrobenzoyl)-3-(dimethylamino)acrylate: A solution of 4-bromo-2-nitrobenzoic acid (3.0 g, 12.2 mmol) in SOCl2 (10 ml) was stirred at 50° C. for 3 h under nitrogen. After completion, the solution was concentrated under reduced pressure. Toluene (3 mL) was added to the residue and concentrated again under reduced pressure. A solution of the obtained acid chloride in acetonitrile (8 mL) was added dropwise to a solution of ethyl 3-dimethylaminoacrylate (1.7 g, 12.2 mmol) and TEA (4.0 g, 36.6 mmol) in acetonitrile (30 mL) at room temperature and stirred overnight. Water (20 mL) was added to the obtained reaction mixture and extracted with EA (20 mL×3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EA=1 / 1) to give the title compound (2.0 g, yellow oil, yield: 44%). MS (ESI, m / z): 371.15 [M+H] + . b) Preparation of ethyl 5-(4-bromo-2-nitrophenyl)-1-methyl-1H-pyrazole-4-carboxylate: To a solution of ethyl-2-(4-bromo-2-nitrobenzoyl)-3-(dimethylamino)acrylate (0.8 g, 2.2 mmol) in acetonitrile (8 mL) was added methylhydrazine (40% in H2O, 0.4 g, 2.6 mmol). The mixture was stirred at 50° C. for 1 h. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EA (20 mL×3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (PE / EA=10 / 1) to give the title compound (0.6 g, yellow solid, yield: 78%). MS (ESI, m / z): 354.15 [M+H] + . c) Preparation of 7-bromo-1-methyl-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one: To a solution of ethyl 5-(4-bromo-2-nitrophenyl)-1-methyl-1H-pyrazole-4-carboxylate (0.3 g, 0.8 mmol) in acetic acid (6 mL) was added iron powder (0.3 g, 5.4 mmol) under nitrogen. The resulting mixture was stirred at 80° C. for 2 hours. After the reaction was complete, the mixture was cooled to room temperature. The mixture was filtered, the filtrate was poured into ice water, and the suspension was filtered. The solid was dried under reduced pressure to give the title compound (0.1 g, white solid, 48%). MS (ESI, m / z): 277.95 [M+H] + . d) Preparation of 7-(hydroxymethyl)-1-methyl-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one: To a solution of 7-bromo-1-methyl-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (0.7 g, 2.5 mmol) in dioxane (20 mL) was added (tributylstannyl)methanol (1.5 g, 5.0 mmol) and Xphos Pd G2 (165.0 mg, 0.2 mmol) at room temperature. The mixture was stirred overnight at 90° C. under nitrogen atmosphere. The reaction was cooled to room temperature and a solution of KF (1 M, 10 mL) was added and the mixture was stirred for 10 min and filtered. The filtrate was extracted with EA (50 mL×3). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was triturated with PE:EA=1:1 (10 mL) and the solid was collected by filtration to give the title compound (0.5 g, white solid, yield: 87%). MS (ESI, m / z): 230.30 [M+H] + . e) Preparation of 7-(bromomethyl)-1-methyl-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one: A solution of 7-(hydroxymethyl)-1-methyl-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (200 mg, 0.87 mmol) in HBr (48% in water, 10 mL) was stirred at 80° C. for 3 h. The reaction mixture was concentrated under reduced pressure. Acetonitrile (3 mL) was added and the reaction mixture was concentrated under reduced pressure to give the title compound (crude, 254 mg, off-white solid). MS (ESI, m / z): 292.55 [M+H] + . f) Preparation of 7-((4-(2-methyl-6-(methylcarbamoyl)quinolin-3-yl)piperazin-1-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one: To a solution of 7-(bromomethyl)-1-methyl-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (60.0 mg, 0.2 mmol), KI (7.0 mg, 0.1 mmol) and N,6-dimethyl-5-(piperazin-1-yl)picolinamide (45.3 mg, 0.2 mmol) in CH3CN (3 mL) was added DIEA (123.0 mg, 1.0 mmol) at room temperature under N2. The resulting suspension was stirred at 80° C. for 30 min. After completion, the solvent was removed under vacuum. The residue was purified by preparative HPLC to give the target compound (11.0 mg, white solid, yield: 12%). Example 106 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one a) Preparation of ethyl 5-(4-bromo-2-nitrophenyl)-1H-pyrazole-4-carboxylate: To a solution of ethyl 2-(4-bromo-2-nitrobenzoyl)-3-(dimethylamino)acrylate (1.0 g, 2.69 mmol) in acetonitrile (8 mL) was added hydrazine hydrate (50% in water, 323 mg, 2.69 mmol). The resulting mixture was stirred at 50° C. for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EA (20 mL×3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (PE / EA=4 / 1) to give the title compound (800 mg, yellow solid, yield: 88%). MS (ESI, m / z): 339.90 [M+H] + . b) Preparation of 7-bromo-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one: To a solution of ethyl 5-(4-bromo-2-nitrophenyl)-1H-pyrazole-4-carboxylate (800 mg, 2.36 mmol) in acetic acid (6 mL) was added iron powder (662 mg, 11.83 mmol) under nitrogen. The resulting mixture was stirred at 80° C. for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered. The solid was dried under reduced pressure to give the title compound (400 mg, white solid, 67.6%). MS (ESI, m / z): 261.95 [M+H] + . c) Preparation of tert-butyl 7-bromo-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-1-carboxylate: To a solution of 7-bromo-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (400 mg, 1.4 mmol) in DMF (4 mL) was added di-tert-butyl dicarbonate (325 mg, 1.4 mmol) and DMAP (4-dimethylaminopyridine, 20 mg, 0.14 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. Water (20 mL) was added to the mixture and extracted with EA (2×40 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified on silica gel (DCM / MeOH=10:1) to give the title compound (500 mg, yellow solid, 73%). MS(ESI,m / z):364.00[M+H] + . d) Preparation of tert-butyl 7-(hydroxymethyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-1-carboxylate: To a solution of tert-butyl 7-bromo-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-1-carboxylate (500 mg, 1.37 mmol) in dioxane (20 mL) was added (tributylstannyl)methanol (881 mg, 2.7 mmol) and Xphos Pd G2 (80 mg, 0.13 mmol) at room temperature. The mixture was stirred overnight at 90° C. under nitrogen atmosphere. After completion, a solution of KF (1 M, 10 mL) was added at room temperature. The mixture was stirred for 10 min at the same temperature, filtered and the filtrate was extracted with EA (50 mL×3). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was triturated with PE:EA=1:1 (10 mL) and the solid was collected by filtration to give the title compound (crude, 450 mg, white solid, yield: 90%). MS (ESI, m / z): 316.05 [M+H] + . e) Preparation of 7-(bromomethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one: A solution of tert-butyl 7-(hydroxymethyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-1-carboxylate (450 mg, 1.3 mmol) in HBr (48% in water, 10 mL) was stirred at 85° C. for 3 h. The reaction mixture was concentrated under reduced pressure. Acetonitrile (3 ml) was added to the crude product and the mixture was concentrated under reduced pressure to give the title compound (crude, off-white solid, 300 mg). MS (ESI, m / z): 275.85 [M+H] + . f) Preparation of tert-butyl 7-(bromomethyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-1-carboxylate: To a solution of 7-(bromomethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (353 mg, 1.2 mmol) in DMF (4 mL) was added di-tert-butyl dicarbonate (287 mg, 1.3 mmol) and DMAP (20 mg, 0.14 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. Water (20 ml) was added to the mixture and extracted with EA (40 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel (DCM / MeOH=10:1) to give the title compound (131 mg, yellow solid, 33%). MS(ESI,m / z):378.00[M+H] + . g) Preparation of tert-butyl 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-1-carboxylate: To a solution of tert-butyl 7-(bromomethyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-1-carboxylate (13 mg, 0.34 mmol), KI (10.0 mg, 0.1 mmol) and N,6-dimethyl-5-(piperazin-1-yl)picolinamide (81 mg, 0.34 mmol) in acetonitrile (3 mL), DIEA (140.0 mg, 1.0 mmol) was added at room temperature under N2. The resulting suspension was stirred at 80° C. for 30 min. After completion, the solvent was removed under reduced pressure. The organic phase was dried over anhydrous sodium sulfate and concentrated to give a residue, which was washed with acetonitrile to give the title compound (95.0 mg, white solid, yield: 52%). MS (ESI, m / z): 532.25 [M+H] + . h) Preparation of 7-((4-(2-methyl-6-(methylcarbamoyl)quinolin-3-yl)piperazin-1-yl)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one: To a solution of tert-butyl 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-1-carboxylate (95 mg, 0.17 mmol) in dioxane (5 mL) was added HCl / dioxane (5 mL) under N2. The resulting suspension was stirred at room temperature for 2 hours. After completion, the solvent was removed under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=10 / 1) to give the target compound (5.0 mg, white solid, yield: 6%). The following compounds, Examples 107-108, 121-122, 138-139, 143 and 149, were prepared using synthetic methods similar to those described in Example 83. The following compounds, Examples 109-117, 123-130, 133-137, 140-142, 144, and 146-148, were prepared using synthetic methods similar to those described in Example 73. The compound of Example 118 was prepared using synthetic methods similar to those described in Example 48. The following compounds, Examples 119-120, were prepared using synthetic methods similar to those described in Example 31. The following compounds, Examples 131-132, and 150, were prepared using synthetic methods similar to those described in Example 48. The compound of Example 145 was prepared using synthetic methods similar to those described in Example 24. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5] [Table 11-6] [Table 11-7] [Table 11-8] [Table 11-9] [Table 11-10] [Table 11-11] Example 151 PARP1 and PARP2 chemiluminescence assays 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, respectively. The solutions were added to the 96-well plate coated with 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 against PARP1 / 2 enzyme activity was calculated according to the following formula:

number

[0141] Although the present disclosure has now been fully described, those skilled in the art will appreciate 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 of its embodiments. All patents, patent applications, and publications cited herein are hereby fully incorporated by reference in their entirety.

Claims

Claim 1: A compound of formula IIIb: 【Chemical 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: Z 1 and Z 2 are independently C or N, but Z 1 and Z 2 are not simultaneously N, and Z 3 , Z 4 , and Z 5 are independently selected from CR 4 , O, S, N, and NR 4 , and when Z 1 is N, at least one of Z 3 , Z 4 , and Z 5 is N, or when Z 1 is N and all of Z 3 , Z 4 , and Z 5 are CR 4 , then A 1 is CR 1 ; each R 4 is independently selected from hydrogen, halogen, and optionally substituted alkyl; A 1 , A 2 , and A 3 are independently selected from N and CR 1 ; R 1 is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted carbocyclic groups; B 1 , B 2 , B 3 , and B 4 are independently selected from N and CR 7 ; each R 7 is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted carbocyclic, optionally substituted alkenyl, and optionally substituted alkynyl; R' and R'' are independently selected from hydrogen, optionally substituted C 1-10 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, and optionally R' and R'' are independently deuterated C 1-3 alkyl; or B 3 and R″ together with the attached aminoacyl group form a 6-membered heterocyclic group; A compound, 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.

2. The Z ring is: 【Chemistry 2】 is selected from 2. The compound of claim 1, wherein R 4 and R 4 ' are independently selected from hydrogen, halogen, and optionally substituted alkyl, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharmaceutically acceptable salt thereof, or prodrug thereof, or mixture thereof.

3. The Z ring 【Chemistry 3】 and 3. The compound of claim 2, wherein R 4 and R 4 ' are independently selected from hydrogen, halogen, and optionally substituted alkyl, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharmaceutically acceptable salt thereof, or prodrug thereof, or mixture thereof.

4. The compound of claim 3, wherein each R 1 is independently selected from hydrogen, C 1-3 alkyl, and halogen, 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.

5. The compound of claim 4, 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 each R 7 is independently hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, or halogenated C 1-3 alkyl.

6. The compound of claim 5, wherein each R 7 is independently selected from hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl, and halogen, 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.

7. The compound of claim 5, wherein R' and R'' are independently hydrogen, optionally substituted C 1-3 alkyl, or optionally substituted C 3-6 cycloalkyl, and optionally R' and R'' are independently deuterated C 1-3 alkyl, 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.

8. The compound of claim 7, wherein R' is hydrogen and R'' is hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, or deuterated C 1-3 alkyl, 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.

9. The compound of claim 8, 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 R 4 and R 4 ' are independently selected from hydrogen, halogen, and optionally substituted C 1-3 alkyl. Claim 10: A compound of formula IVb: 【Chemistry 4】 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: Z 3 , Z 4 , and Z 5 are independently selected from CR 4 , O, S, N, and NR 4 ; each R 4 is independently selected from hydrogen, halogen, and optionally substituted alkyl; R 7 is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted carbocyclic, optionally substituted alkenyl, and optionally substituted alkynyl; R' and R'' are independently selected from hydrogen, optionally substituted C 1-10 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; optionally, R' and R'' are independently deuterated C 1-3 alkyl; R 8 , R 9 , and R 10 are independently selected from hydrogen, halogen, optionally substituted alkyl, and optionally substituted alkoxy; A compound, 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.

11. The method of claim 10, wherein the five-membered ring containing Z 3 , Z 4 , and Z 5 is: 【Chemistry 5】 is selected from 11. The compound of claim 10, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharmaceutically acceptable salt thereof, or prodrug thereof, or mixture thereof, wherein R 4 and R 4 ' are independently selected from hydrogen, halogen, and optionally substituted alkyl.

12. Z ring 【Chemistry 6】 and 12. The compound of claim 11, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharmaceutically acceptable salt thereof, or prodrug thereof, or mixture thereof, wherein R 4 and R 4 ' are independently selected from hydrogen, halogen, and optionally substituted alkyl.

13. The compound of claim 12, wherein R 4 and R 4 ' are independently selected from hydrogen, halogen, and optionally substituted C 1-3 alkyl, 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.

14. The compound of claim 13, wherein R 7 is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkyl, or halogen, 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.

15. The compound of claim 14, wherein R 7 is hydrogen, C 1-3 alkyl, or halogen, 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.

16. The compound of claim 15, wherein R' and R'' are independently hydrogen, optionally substituted C 1-3 alkyl, or optionally substituted C 3-6 cycloalkyl, and optionally R' and R'' are independently deuterated C 1-3 alkyl, 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.

17. The compound of claim 16, wherein R' is hydrogen and R'' is hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, or deuterated C 1-3 alkyl, 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.

18. The compound of claim 17, wherein R 8 , R 9 and R 10 are independently hydrogen, C 1-3 alkyl, or halogen, 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.

19. The compound of claim 18, wherein R 8 is C 1-3 alkyl or halogen, and both R 9 and R 10 are hydrogen, 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.

20. The compound of claim 18, wherein both R 8 and R 9 are hydrogen and R 10 is C 1-3 alkyl or halogen, 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.

21. [Chemical 7] 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 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.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21, 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, and a pharmaceutically acceptable carrier.

23. The pharmaceutical composition of claim 22, further comprising at least one known anticancer agent or a pharmaceutically acceptable salt thereof.

24. The at least one known anticancer drug is selected from the group consisting of busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxyellipticine, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, capecitabine, methotrexate, 5-fluoro-2'-deoxy-uridine, and fludarabine. Rabin, nelarabine, arabin-C, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, mAb, panitumumab, necitumumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab, daratumumab, elotuzumab, T -DM1, dinutuximab, blinatumomab, ipilimumab, Avastin, Herceptin, MabTera, trastuzumab deruxtecan, trastuzumab emtansine, datopotamab deruxtecan, gemtuzumab ozogamicin, brentuximab vedotin, inotuzumab ozogamicin, sacituzumab govitecan, enfortumab vedotin, belantamab mafotin, imatinib, gefitinib, erlotinib, ostinib, afatinib, ceritinib, alectinib, crizotinib, lapatinib, solutinib, rafenib, regorafenib, belantamab mafodotin Murafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, platinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cavitinib, axitinib, temsirolimus, idelalisib, pazopanib, everolimus, tamoxifen, letrozole, fulvestrant, mitoguanhydrazone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide,The pharmaceutical composition of claim 23, wherein the compound is selected from venetoclax, aldesleukin (recombinant human interleukin-2), and sipuleucel-T (a prostate cancer therapeutic vaccine).

25. Use of a compound according to any one of claims 1 to 21, 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, in the manufacture of a medicament for use in a method for treating or preventing a disease or condition responsive to the inhibition of PARP activity, said method comprising administering to a subject in need of such treatment or prevention an effective amount of a compound according to any one of claims 1 to 21, 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.

26. The use of claim 25, wherein the disease or condition responsive to inhibition of PARP activity is cancer.

27. 27. The use of claim 26, wherein the cancer is selected from liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer (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 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.

28. The use of claim 25, wherein the method further comprises administering to the subject in need of treatment or prevention an effective amount of at least one known anticancer agent or a pharmaceutically acceptable salt thereof.

29. The at least one known anticancer drug is selected from the group consisting of busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxyellipticine, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, capecitabine, methotrexate, 5-fluoro-2'-deoxy-uridine, and fludarabine. Rabin, nelarabine, arabin-C, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, mAb, panitumumab, necitumumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab, daratumumab, elotuzumab, T -DM1, dinutuximab, blinatumomab, ipilimumab, Avastin, Herceptin, MabTera, trastuzumab deruxtecan, trastuzumab emtansine, datopotamab deruxtecan, gemtuzumab ozogamicin, brentuximab vedotin, inotuzumab ozogamicin, sacituzumab govitecan, enfortumab vedotin, belantamab mafotin, imatinib, gefitinib, erlotinib, ostinib, afatinib, ceritinib, alectinib, crizotinib, lapatinib, solutinib, rafenib, regorafenib, belantamab mafodotin Murafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, platinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cavitinib, axitinib, temsirolimus, idelalisib, pazopanib, everolimus, tamoxifen, letrozole, fulvestrant, mitoguanhydrazone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide,The use according to claim 28, wherein the therapeutic agent is selected from venetoclax, aldesleukin (recombinant human interleukin-2), and sipuleucel-T (a prostate cancer therapeutic vaccine).

30. Use of the pharmaceutical composition of claim 22 in the manufacture of a medicament for use in a method for treating or preventing a disease or condition responsive to inhibition of PARP activity, said method comprising administering to a subject in need of treatment or prevention an effective amount of the pharmaceutical composition of claim 22.

31. The use of claim 30, wherein the disease or condition responsive to inhibition of PARP activity is cancer.

32. 32. The use of claim 31, wherein the cancer is selected from liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer (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 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.

33. The use of claim 30, wherein the method further comprises administering to the subject in need of treatment or prevention an effective amount of at least one known anticancer agent or a pharmaceutically acceptable salt thereof.

34. The at least one known anticancer drug is selected from the group consisting of busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxyellipticine, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, capecitabine, methotrexate, 5-fluoro-2'-deoxy-uridine, and fludarabine. Rabin, nelarabine, arabin-C, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, mAb, panitumumab, necitumumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab, daratumumab, elotuzumab, T -DM1, dinutuximab, blinatumomab, ipilimumab, Avastin, Herceptin, MabTera, trastuzumab deruxtecan, trastuzumab emtansine, datopotamab deruxtecan, gemtuzumab ozogamicin, brentuximab vedotin, inotuzumab ozogamicin, sacituzumab govitecan, enfortumab vedotin, belantamab mafotin, imatinib, gefitinib, erlotinib, ostinib, afatinib, ceritinib, alectinib, crizotinib, lapatinib, solutinib, rafenib, regorafenib, belantamab mafodotin Murafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, platinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cavitinib, axitinib, temsirolimus, idelalisib, pazopanib, everolimus, tamoxifen, letrozole, fulvestrant, mitoguanhydrazone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide,The use according to claim 33, wherein the therapeutic agent is selected from venetoclax, aldesleukin (recombinant human interleukin-2), and sipuleucel-T (a prostate cancer therapeutic vaccine).

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