Substituted tricyclic compounds as PARP inhibitors and their uses

Abstract

Provided is a substituted tricyclic compound and its use as a PARP inhibitor.The compound is represented by the following formula (I), in which rings Z, Z1, Z2, Z3, Z4, Z5, A1, A2, A3, L and Cy are defined herein.The compound of formula I is a PARP inhibitor, and is therefore useful in treating diseases, disorders and conditions such as cancer, which respond to the inhibition of PARP activity. [Formula 1] JPEG2025508122000136.jpg6293

Description

[Technical field]

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

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

[0003] Humans are believed to express 17 PARPs, identified based on amino acid sequences that show 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 polyADP-ribose, also known as poly(ADP-ribose) modification. As a result, the PARP family is further classified into two subfamilies accordingly. Post-translational modification of poly(ADP-ribose) regulates many functional aspects of proteins, 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 with a total molecular weight of approximately 116 kDa (NCBI accession number P09874). 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 subsequently repairs DNA via BER. In response to DNA damage, cells have also evolved two major repair pathways in addition to the BER repair mechanism: homologous recombination (HR) and non-homologous end joining (NHEJ). HR-deficient tumors have been found to be sensitive to PARP inhibitors, indicating that homologous recombination deficiency and PARP1 inhibition formed a pair of synthetic lethality, which has been confirmed by clinical trials.Several PARP inhibitors are currently approved for the treatment of ovarian, breast, 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 about 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 also has a similar function to PARP1 and has been found to be 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) than other PARP inhibitors (PARPi) in biochemical assays (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. In addition, inhibition of PARP2 activity has been found to cause 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 their clinical application as well as their combination with other targeted drugs.

[0006] Therefore, to improve, enhance, and expand the clinical application of PARP inhibitors, it is important to explore highly selective PAPR1 inhibitors to reduce mechanism-related or mechanism-independent toxicities.

[0007] Various PARP1 inhibitors have been disclosed, for example, in WO2011006803, WO2013014038, WO2021013735, WO2021260092, CN115232129A, WO2022225934, WO2022222921, WO2022222964, WO2022222965, WO2022222966, WO202228387, WO2022247816, WO2022223025, and WO2022222995. Summary of the Invention

[0008] The present disclosure provides compounds represented by formula I (including formulas II, III, IV, V, VI, VII, VIII and IX) 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 Formulas II, III, IV, V, VI, VII, VIII, and IX). 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.The pharmaceutical composition can be used in the treatment of cancer.

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

[0012] The present disclosure is also directed to methods of preparing the novel compounds of Formula I (including Formulas II, III, IV, V, VI, VII, VIII, and IX). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

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

[0015] As used herein, the term "heteroatom" includes O, S, and N.

[0016] As used herein, the term "alkyl" refers to alkyl itself or to a straight or branched chain radical of up to 10 carbons. Useful alkyl groups include linear 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 (including 3-pentyl), hexyl, and octyl groups, which may be optionally substituted.

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

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

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

[0020] Useful amino and optionally substituted amino groups are -NR'R'', where R' and R'' are each independently hydrogen, optionally substituted C 1~10 Alkyl, optionally substituted C 3~8 R′ and R″ are each independently selected from hydrogen, optionally substituted C 1~4 Alkyl, optionally substituted C 3~6R′ and R″ are each independently selected from hydrogen, an optionally substituted 4- to 7-membered heterocyclic group, an optionally substituted 5-membered heteroaryl, or R′ and R″ together with the N to which they are attached form an optionally substituted 4- to 7-membered cyclic amino group, optionally containing one or more (such as 2, 3) additional heteroatoms selected from the group consisting of O, N, and S. Preferably, R′ and R″ are each independently selected from hydrogen, an optionally substituted C 1~4 Alkyl, optionally substituted C 3~6 cycloalkyl, or an optionally substituted 3- to 6-membered heterocyclic group.

[0021] As used herein, the term "oxo" refers to =O.

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

[0023] 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.

[0024] 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 3~6Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Useful partially saturated carbocyclic groups include C 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 6 3~8 Carbocyclic groups may be optionally substituted by one or more substituents described herein.

[0025] Useful halo or halogen groups include fluoro, chloro, bromo, and iodo.

[0026] Useful acylamino (amido) groups include any C 1~6 Acyl (alkanoyl), such as acetamino, propionamido, butanoylamido, pentanoylamido, and hexanoylamido, and aryl-substituted C 1~6 Acylamino groups, for example benzoylamide.

[0027] Useful acyl groups include C 1~6 Examples of substituted acyl groups include acyl, which may be optionally substituted with a group selected from halo, amino, and aryl, where amino and aryl may be optionally substituted. When acyl is substituted with halo, the number of halogen substituents may range from 1 to 5. Examples of substituted acyl include chloroacetyl and pentafluorobenzoyl. When acyl is substituted with amino, the amino group may be substituted with 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 C1~4 Alkyl, optionally substituted C 3~6 cycloalkyl, or an optionally substituted 3- to 6-membered heterocyclic group.

[0028] As used herein, the term "heterocyclic group" refers to a saturated or partially saturated 3- to 7-membered monocyclic ring, or 7- to 10-membered bicyclic ring, spirocyclic ring system, or bridged ring system consisting of carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of O, S, and S, where the nitrogen and / or sulfur heteroatoms may be optionally oxidized, the nitrogen may be optionally quaternized, and 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.

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

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

[0031] Useful heteroaryl groups include thienyl (thiophenyl), benzo[d]isothiazol-3-yl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (furanyl), pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl (pyridyls including, but not limited to, 2-pyridyl, 3-pyridyl, and 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthaldinyl, naphthyridinyl, quinoxalinyl, 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-oxiindolyl, thiadiazolyl, 2-oxobenzimidazolyl, imidazopyridazinyl, imidazopyridyl, triazolopyridazinyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, pyrrolopyridyl, pyrrolopyrazinyl or triazolopyrazinyl. Where the 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.

[0032] In this disclosure, unless otherwise stated, when substituted, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, heterocycloalkoxy, alkenyl, heterocycloalkenyl, alkynyl, amino, amido, acyloxy, carboxyl, hydroxyl, mercapto, alkylthiosulfonyl, sulfonyl, sulfinyl, aminoacyl, silyl, phosphinecarboxy, phosphono, carbocyclic, heterocyclic, aryl, or heteroaryl as described in any embodiment 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, mercapto, azido, carbonyl, alkanesulfonyl, sulfamoyl, dialkylsulfamoyl, and alkylsulfinyl. The substituents themselves may be optionally substituted. Preferred substituents include halogen, hydroxyl, carboxyl, amino, C 1~6 Amide, C 1~6 Acyloxy, C 1~6 Alkoxy, C 1~6 Alkyl, C 1~6 These include, but are not limited to, acyl, and alkanesulfonyl.

[0033] In each embodiment, when the substituent is a heterocyclic group, aryl or heteroaryl, the number is usually one.

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

[0035] [ka] or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt, or mixtures thereof, or prodrugs thereof, wherein: A 1 , A 2 and A 3 are independently N and CR 1 Selected from;

[0036] [ka] The Z ring represented by is an optionally substituted 5-membered heteroaryl group, an optionally substituted 5-membered carbocyclic group or an optionally substituted 5-membered heterocyclic group, with the * indicating the position at which the Z ring is attached to the remainder of the compound and the dashed line indicating the presence of optional unsaturated bond(s), where when said Z ring is an optionally substituted 5-membered heteroaryl group, then Z 1 , Z 2 and Z 3 are each independently 2 , N.R. 3 , O, N or S; Z 4 and Z 5 are each independently C or N, where Z 4 and Z 5 is not N and the Z ring is an optionally substituted 5-membered carbocyclic group or an optionally substituted 5-membered heterocyclic group, then Z 1 , Z 2 and Z 3 are each independently 2 R 2 ', C.R. 2 , N.R. 3 , O or S; Z 4 and Z 5 are each independently C, CH, or N; and Z 5 If N, then Z 1 , Z 2 and Z 3At least one of is N, or Z 5 is N and Z 1 , Z 2 and Z 3 All of the above are CR 2 Or CR 2 R 2 ', then A 1 is CR 1 and; L is a bond and R 4 and / or R 5 alkylene optionally substituted by Cy is selected from the group consisting of optionally substituted heterocyclic groups, optionally substituted aryl, and optionally substituted heteroaryl; R 1 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted carbocyclic groups; R 2 and R 2 each ' is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R 3 is selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl; R 4 and R 5 are each independently selected from the group consisting of halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or R 4 and R 5 forms a ring together with the attached C.

[0037] In Formula I and each formula of the present disclosure, unless otherwise stated, each alkyl is independently selected from the group consisting of C 1~6 Alkyl, preferably C 1~4 alkyl; each alkylene is C 1~6 Alkylene, preferably C 1~3 alkylene; each alkenyl is independently C 2~6 Alkenyl, preferably C 2~4 alkenyl; each alkynyl is independently selected from C 2~6 Alkynyl, preferably C 2~4 alkynyl; each alkoxy is independently 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, optionally substituted C 3~6 It is a cycloalkyl or an optionally substituted 3-6 membered heterocyclic group. For example, the substituted alkyl itself or as a substituent of another group may be hydroxyalkyl, dihydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heterocyclic alkyl, arylalkyl, heteroarylalkyl, and haloalkyl. It should be 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 depending on the carbon chain length of the alkyl, alkenyl, alkynyl, and alkoxy groups, and exemplary substituents are trifluoromethyl and pentafluoroethyl groups.

[0038] In Formula I and each of the formulae of the present disclosure, unless otherwise stated, the number of ring carbon atoms in each carbocyclic group is preferably 3 to 8. Preferred carbocyclic groups are3~8 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, optionally substituted C 3~6 It is understood that when the substituent is an aryl, heteroaryl, heterocyclic group, cyano, nitro, or carboxyl, the number of the substituents is usually 1. When the substituent is a halogen, the number of the substituents can be up to 5.

[0039] In Formula I and each formula of the present disclosure, unless otherwise stated, aryl is C 6~14 The term "aryl" refers to a 5- to 10-membered heteroaryl, and the term "heterocyclic group" refers to a 4- to 10-membered heterocyclic group. The substituents of the aryl group, the heteroaryl group, and the heterocyclic group each independently include C 1~4 Alkyl, halogenated C 1~4 Alkyl, C 1~4 and wherein R′ and R″ are each independently selected from 1 to 5 groups consisting of alkoxy, halogen, hydroxyl, carboxyl, amino (—NR′R″), optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic groups, halogen, amido, aminoacyl (—C(O)—NR′R″), and carboxyl, and the like; 1~10 Alkyl, optionally substituted C 3~8 R′ and R″ are each independently selected from hydrogen, optionally substituted C1~4 Alkyl, optionally substituted C 3~6 The optionally substituted aryl, the optionally substituted heteroaryl and the optionally substituted heterocyclic groups are each 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, where R' and R'' are preferably each independently H, optionally substituted C 1~4 Alkyl, optionally substituted C 3~6 It is understood that when the substituents are aryl, heteroaryl, heterocyclic, cyano, nitro and carboxyl, the number is usually 1. When the substituents are halogen, the number of substituents can be up to 5.

[0040] In some embodiments, compounds of the present disclosure do not include compounds represented by the following structural formulas, or stereoisomers, solvates, or pharma- ceutically acceptable salts thereof:

[0041] [ka] [Wherein, Y is N, CH or CF; A 1 is CH 2 , C.F. 2 , CHF, CHCH 3 or C(CH 3 ) 2 And;B 1 is CH 2 , C.F. 2 , CHF, CHCH 3 or C(CH 3 ) 2 And;C 1 is O or S; and

[0042] [ka] [Wherein, Y is N, CH or CF; A 4 , H, C 1~6 Alkyl or halogenated C 1~6 Alkyl; B 4 , H, C 1~6 Alkyl or halogenated C 1~6 Alkyl; C 4 is O or S; and

[0043] [ka] [Wherein, Y is N, CH or CF; A 5 is O or S; B 5 , H, C 1~6 Alkyl or halogenated C 1~6 Alkyl; C 5 , H, C 1~6 Alkyl or halogenated C 1~6 alkyl; and

[0044] [ka] [Wherein, Y is N, CH or CF; A 6 , H, C 1~6 Alkyl or halogenated C 1~6 Alkyl; B 6 is O or S; and

[0045] [ka] [Wherein, Y is N, CH or CF; A 7 is O or S; B 7 is CH 2 , C.F. 2 , CHF, CHCH 3 or C(CH 3 ) 2 And;C7 is CH 2 , C.F. 2 , CHF, CHCH 3 or C(CH 3 ) 2 is]; and

[0046] [ka] [In the formula, R A is C 1~3 Alkyl, deuterated C 1~3 Alkyl, halogenated C 1~3 Alkyl, or C 1~3 Alkoxy; R B and R C are each independently H, halogen, or C 1~3 Alkyl, deuterated C 1~3 Alkyl, halogenated C 1~3 Alkyl, or C 1~3 alkoxy; Y is CH or N.

[0047] In some embodiments, the compound of the present disclosure is the following compound:

[0048] [ka]

[0049] [ka] Does not include.

[0050] In some embodiments, the compound of the present disclosure is the following compound:

[0051] [ka] Does not include.

[0052] In one or more embodiments of the compounds of formula I, preferred compounds are represented by formula Ia, Ib, Ic, or Id, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof:

[0053] [ka] [In the formula, A 1 , A 2 , A 3 , Z ring (Z 1 , Z 2 and Z 3 ), L and Cy are as defined in formula I.

[0054] In one or more embodiments of the compound of formula Ia: A 1 , A 2 and A 3 are independently N and CR 1 Selected from;

[0055] [ka] The Z ring depicted as: is an optionally substituted 5-membered heteroaryl group, with the * indicating the position at which the Z ring is attached to the remainder of the compound, 1 , Z 2 and Z 3 are each independently 2 , N.R. 3 , O, N or S; L is a bond and R 4 and / or R 5 alkylene optionally substituted by Cy is selected from the group consisting of optionally substituted heterocyclic groups, optionally substituted aryl, and optionally substituted heteroaryl; R 1is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted carbocyclic groups; R 2 is selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R 3 is selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl; R 4 and R 5 are each independently selected from the group consisting of halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or R 4 and R 5 forms a ring together with the attached C).

[0056] In one or more embodiments of the compounds of Formula I (including formulas Ia, Ib, Ic, and Id), the Z ring is selected from the group consisting of:

[0057] [ka] (wherein * indicates the position at which the Z ring is attached to the remainder of the compound; R 2 is hydrogen, halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably hydrogen, halogen and optionally substituted C 1~3 alkyl; R 2 ' is hydrogen, halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably hydrogen, halogen and optionally substituted C 1~3 alkyl; R 3 is hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl, preferably hydrogen and optionally substituted C 1~3 alkyl).

[0058] In one or more embodiments of the compound of Formula Ia, the Z ring is selected from the following group:

[0059] [ka] (wherein * indicates the position at which the Z ring is attached to the remainder of the compound; R 2 is hydrogen, halogen, optionally substituted C 1~6 Alkyl, and optionally substituted C 1~3 Alkoxy, preferably hydrogen, halogen, and optionally substituted C 1~3 alkyl; R 3 is hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl, preferably hydrogen and optionally substituted C 1~3 alkyl.

[0060] In one or more embodiments of the compounds of formula Ib and Ic, the Z ring is selected from the following groups:

[0061] [ka] (In the formula, R 2 and R 2 ' is as defined in any of the preceding embodiments; preferably, in these embodiments, A 2 and A 3 At least one of them is CR 1 and R 1is a halogen; in some embodiments, A 2 and A 3 Both are CR 1 and R 1 At least one of the groups is a halogen. 3 is CR 1 and R 1 is a halogen. In some embodiments, A 1 is CR 1 And A 2 and A 3 Both are CH; or A 1 is CH and A 2 is CR 1 And A 3 is CH; or A 1 and A 2 Both are CH and A 3 CR 1 where R 1 is a halogen.

[0062] In the present disclosure, the substituents on the Z ring are hydroxy, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 3~6 Cycloalkyl, halogenated C 1~4 Alkyl, halogenated C 1~4 Alkoxy, hydroxy substituted C 1~4 C substituted with alkyl, hydroxy and amino (-NR'R'') 1~4 alkoxy, wherein R′ and R″ are each preferably independently H or C 1~4 In some embodiments, the substituents on the Z ring are halogen, C 1~4 Alkyl or C 3~6 It may be 1 to 2 groups selected from cycloalkyl.

[0063] In one or more embodiments of the compounds of Formula I (including Formulas Ia, Ib, Ic, and Id), A 1 , A 2 and A3 are independently N and CR 1 wherein R 1 is preferably hydrogen, halogen, optionally substituted C 1~3 Alkyl, or optionally substituted C 1~3 More preferably, R 1 is hydrogen, halogen, or C 1~3 In some embodiments, A is alkyl. 1 and A 3 At least one of the following is CR 1 and R 1 is halogen, such as fluoro. 2 and A 3 At least one of them is CR 1 and R 1 is a halogen. In some embodiments, A 2 and A 3 Both are CR 1 and R 1 At least one of the groups is halogen. 3 is CR 1 and R 1 is halogen. In one or more embodiments, A 1 , A 2 and A 3 All of this is CR 1 And each R 1 are independently hydrogen, halogen, or C 1~3 In some embodiments, A is alkyl. 1 is CR 1 And A 2 and A 3 Both are CH; or A 1 is CH and A 2 CR 1 And A 3 is CH; or A 1 and A 2 Both are CH and A 3 is CR 1 where R 1 is halogen or C 1~3It is an alkyl.

[0064] In one or more embodiments of the compounds of Formula I (including Formulas Ia, Ib, Ic, and Id), the Z ring is

[0065] [ka] If not, A 1 , A 2 and A 3 are independently N and CR 1 wherein R 1 is preferably hydrogen, halogen, optionally substituted C 1~3 Alkyl, or optionally substituted C 1~3 More preferably, R 1 is hydrogen, halogen, or C 1~3 Preferably, A is 1 and A 3 At least one of them is CR 1 and R 1 is halogen, such as fluoro. 2 and A 3 At least one of them is CR 1 And R 1 is halogen. In some embodiments, A 2 and A 3 Both are CR 1 and R 1 At least one of the groups is a halogen. 3 is CR 1 and R 1 is halogen. In one or more embodiments, A 1 , A 2 and A 3 All of this is CR 1 And each R 1 are independently hydrogen, halogen, or C 1~3 Preferably, A is 1 is CR 1 And A 2 and A 3Both are CH; or A 1 is CH and A 2 is CR 1 And A 3 is CH; or A 1 and A 2 Both are CH and A 3 is CR 1 where R 1 is halogen or C 1~3 It is an alkyl.

[0066] In one or more embodiments of the compound of formula Ib, the Z ring is

[0067] [ka] If A 1 CR 1 And A 2 and A 3 are each independently N or CR 1 where R 1 is preferably hydrogen, halogen, optionally substituted C 1~3 Alkyl, or optionally substituted C 1~3 More preferably, R 1 is hydrogen, halogen, or C 1~3 Preferably, A is 3 is CR 1 where R 1 is halogen, such as fluoro. 2 and A 3 At least one of them is CR 1 and R 1 is halogen. In some embodiments, A 2 and A 3 Both are CR 1 and R 1 At least one of the groups is halogen. 1 , A 2 and A 3 All of this is CR 1 where R1 is hydrogen, halogen, or C 1~3 Preferably, A is 1 is CR 1 And A 2 and A 3 Both are CH or A 1 is CH and A 2 is CR 1 And A 3 is CH or A 1 and A 2 Both are CH and A 3 is CR 1 where R 1 is halogen or C 1~3 It is an alkyl.

[0068] In one or more embodiments of the compounds of Formula I (including Formulas Ia, Ib, Ic, and Id), R 1 is hydrogen, halogen, optionally substituted C 1~3 Alkyl, or optionally substituted C 1~3 Preferably, R 1 When 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, R 1 is hydrogen, halogen, or C 1~3 It is an alkyl.

[0069] In one or more embodiments of the compounds of Formula I (including Formulas Ia, Ib, and Ic), R 2 is hydrogen, halogen, cyano, C 1~3 Alkyl, or C 3~6 It is cycloalkyl.

[0070] In one or more embodiments of the compounds of Formula I (including Formulas Ia, Ib, Ic, and Id), R 3 is hydrogen or C 1~3It is an alkyl.

[0071] In one or more embodiments of the compounds of Formula I (including Formulas Ia, Ib, Ic, and Id), R 2 ' is hydrogen, halogen, cyano, C 1~3 Alkyl, or C 3~6 It is cycloalkyl.

[0072] In one or more embodiments of the compound of formula Id, R 2 and R 2 ' are both hydrogen.

[0073] In one or more embodiments of the compounds of Formula I (including Formulas Ia, Ib, Ic, and Id), R 4 and R 5 are each independently a halogen and C 1~3 In some embodiments, R 4 and R 5 forms a 3- to 6-membered ring together with the bonded C.

[0074] In one or more embodiments of the compounds of Formula I (including Formulas Ia, Ib, Ic, and Id), L is selected from 1 to 2 C 1~3 Alkylene optionally substituted with alkyl, more preferably 1 to 2 C 1~3 C optionally substituted with alkyl 1~3 Alkylene, preferably 1 to 2 C 1~3 It is methylene optionally substituted with alkyl.

[0075] In one or more embodiments of the compounds of Formula I (including Formulas Ia, Ib, Ic, and Id), L is an unsubstituted alkylene, preferably an unsubstituted C 1~3 It is preferably alkylene, more preferably methylene.

[0076] In one or more embodiments of the compounds of Formula I (including Formulas Ia, Ib, Ic, and Id), the aryl is preferably phenyl. The heteroaryl is a 5-10 membered heteroaryl containing one or two nitrogen atoms, including, but not limited to, pyridyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridazinyl, and indolyl. 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, dihydropyridinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydroisoquinolyl, and morpholinyl.

[0077] In one or more embodiments of the compounds of Formula I (including Formulae Ia, Ib, Ic, and Id), 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, piperidinyl, dihydropyridinyl, or pyrrolidinyl. Preferably, the substituents on Cy in the compounds of Formula I (including Formulae Ia, Ib, Ic, and Id) are halogen, optionally substituted C 1~4 Alkyl, optionally substituted C 1~4 Alkoxy, halogenated C 1~4 Alkyl, halogenated C 1~4 Alkoxy, cyano, hydroxyl, amino (-NR'R''), 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 3~8 cycloalkyl, where 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 3~8Cycloalkyl is independently halogen, cyano, C 1~4 Alkyl, C 1~4 Alkoxy, halogenated C 1~4 Alkyl, halogenated C 1~4 Alkoxy, C 3~6 and optionally substituted by 1 to 5 substituents selected from the group consisting of cycloalkyl, amino (-NR'R''), aminoacyl (-C(O)-NR'R'') and carboxyl, wherein R' and R'' are each preferably independently selected from H, optionally substituted C 1~10 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted heterocyclic groups, optionally substituted aryl or optionally substituted heteroaryl, preferably H, optionally substituted C 1~4 Alkyl, optionally substituted C 3~8 In some preferred embodiments, the aryl, aryl group, and optionally substituted 3- to 6-membered heterocyclic group are 6- to 14-membered aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclic group, and C 3~8 The substituents on the cycloalkyl include at least aminoacyl (-C(O)-NR'R''), and optionally halogen, cyano, C 1~4 Alkyl, halogenated C 1~4 Alkyl, and C 3~6 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 (such as pyridyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, pyrimidinyl, etc.). Preferably, the 5-10 membered heteroaryl or the 5-10 membered nitrogen-containing heteroaryl is substituted by at least aminoacyl (-C(O)-NR'R'') and optionally halogen, cyano, C(O)-NR'R''. 1~4 Alkyl, halogenated C 1~4 Alkyl, and C 3~6Further substituted with one or two substituents selected from the group consisting of cycloalkyl. More preferably, the aminoacyl (-C(O)-NR'R'') is in the para position. In some particularly preferred embodiments, Cy is piperazinyl substituted with an optionally substituted pyridyl, piperidinyl substituted with an optionally substituted pyridyl, or dihydropyridinyl substituted with an optionally substituted pyridyl, where the pyridyl is substituted with at least an aminoacyl (-C(O)-NR'R''). Preferably, in the embodiments described herein, when the R' and R'' are substituted, the substituents are selected from halogen, hydroxyl, C 1~4 Alkyl, C 1~4 Alkoxy, halogenated C 1~4 Alkyl, halogenated C 1~4 and may be 1-5 groups selected from the group consisting of alkoxy, amino, and the like. In some embodiments, Cy is substituted with said amino (-NR'R'') and one substituent on the amino is an optionally substituted 5-10 membered nitrogen-containing heteroaryl. Preferably, Cy is pyrrolidinyl substituted with an optionally substituted pyridylamino.

[0078] In one or more embodiments of the compound of Formula I or Ia, the Z ring is:

[0079] [ka] (wherein * indicates the position at which the Z ring is attached to the remainder of the compound; 1 is CH and A 2 is CR 1 And A 3 is CH or A 1 and A 2 Both are CH and A 3 is CR 1 where R 1 is halogen, optionally substituted C 1~3 Alkyl, or optionally substituted C 1~3alkoxy, preferably halogen, more preferably F; L and Cy are as defined in any of the preceding embodiments.

[0080] In one or more embodiments of the compound of Formula I or Ic, the Z ring is:

[0081] [ka] (wherein * indicates the position at which the Z ring is attached to the remainder of the compound, and R 2 is hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably hydrogen, halogen, optionally substituted C 1~3 Alkyl and optionally substituted C 3~6 cycloalkyl; R 2 ' is hydrogen, halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably hydrogen, halogen, optionally substituted C 1~3 Alkyl and optionally substituted C 3~6 cycloalkyl; 2 and R 2 At least one of the ' is a non-hydrogen substituent, preferably the non-hydrogen substituent is halogen, cyano, C 1~3 Alkyl or C 3~6 A is cycloalkyl; 1 is CH and A 2 is CR 1 And A 3 is CH or A 1 and A 2 Both are CH and A 3 is CR 1 where R 1 is halogen, optionally substituted C 1~3Alkyl or optionally substituted C 1~3 alkoxy, preferably halogen, more preferably F; L and Cy are as defined in any of the preceding embodiments.

[0082] In one or more embodiments of the compound of Formula I or Ic, the Z ring is:

[0083] [ka] (wherein * indicates the position at which the Z ring is attached to the remainder of the compound; R 2 ' is halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably halogen, optionally substituted C 1~3 Alkyl and optionally substituted C 3~6 cycloalkyl; A 1 is CH and A 2 is CR 1 And A 3 is CH or A 1 and A 2 Both are CH and A 3 is CR 1 where R 1 is halogen, optionally substituted C 1~3 Alkyl or optionally substituted C 1~3 alkoxy, preferably halogen, more preferably F; L and Cy are as defined in any of the preceding embodiments.

[0084] In one or more embodiments of the compounds of Formula I, preferred compounds are those represented by Formula II (including Formulas IIa, IIb, IIc, and IId), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof:

[0085] [ka] (In the formula, A 1 , A 2 , A 3 , Z 1 , Z 2 and Z 3 is as defined in any embodiment of formula I, Ia, Ib, Ic and Id; R 6 is selected from optionally substituted aryl and optionally substituted heteroaryl.

[0086] In one or more embodiments of the compound of Formula II (including Formulas IIa, IIb, IIc, and IId), the Z ring is selected from the following groups:

[0087] [ka] (wherein * indicates the position at which the Z ring is attached to the remainder of the compound; R 2 is hydrogen, halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C 1~3 Alkoxy, and optionally substituted C 3~6 Cycloalkyl, preferably hydrogen, halogen and optionally substituted C 1~3 alkyl; R 2 ' is hydrogen, halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably hydrogen, halogen and optionally substituted C 1~3 alkyl; R 3 is hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl, preferably hydrogen and optionally substituted C 1~3 ) is selected from the group consisting of alkyl.

[0088] In one or more embodiments of the compound of Formula IIa, the Z ring is selected from the following groups:

[0089] [ka] (wherein * indicates the position at which the Z ring is attached to the remainder of the compound; R 2 is hydrogen, halogen, optionally substituted C 1~6 Alkyl, and optionally substituted C 1~3 Alkoxy, preferably hydrogen, halogen, and optionally substituted C 1~3 alkyl; R 3 is hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl, preferably hydrogen and optionally substituted C 1~3 ) is selected from alkyl.

[0090] In one or more embodiments of the compounds of formula IIb and IIc, the Z ring is selected from the following groups:

[0091] [ka] (In the formula, R 2 and R 2 ' is as defined in any of the preceding embodiments; preferably, in these embodiments, A 2 and A 3 At least one of the following is CR 1 and R 1 is a halogen; in some embodiments, A 2 and A 3 Both are CR 1 and R 1 At least one of the groups is a halogen. 3 is CR 1 and R 1 is a halogen. In some embodiments, A 1 is CR 1 And A 2 and A3 Both are CH; or A 1 is CH and A 2 CR 1 And A 3 is CH; or A 1 and A 2 Both are CH and A 3 is CR 1 where R 1 is a halogen.

[0092] In one or more embodiments of the compound of Formula II (including Formulas IIa, IIb, IIc, and IId), A 1 , A 2 and A 3 are independently N and CR 1 wherein R 1 is preferably hydrogen, halogen, optionally substituted C 1~3 Alkyl, or optionally substituted C 1~3 More preferably, R 1 is hydrogen, halogen, or C 1~3 In some embodiments, A is alkyl. 1 and A 3 At least one of them is CR 1 and R 1 is halogen, such as fluoro. 2 and A 3 At least one of them is CR 1 and R 1 is halogen. In some embodiments, A 2 and A 3 Both are CR 1 and R 1 At least one of the groups is a halogen. 3 is CR 1 and R 1 is halogen. In one or more embodiments, A 1 , A 2 and A 3 All of this is CR 1 And each R 1are independently hydrogen, halogen, or C 1~3 Preferably, A is 1 is CR 1 And A 2 and A 3 Both are CH; or A 1 is CH and A 2 is CR 1 And A 3 is CH; or A 1 and A 2 Both are CH and A 3 is CR 1 where R 1 is halogen or C 1~3 It is an alkyl.

[0093] In one or more embodiments of the compound of Formula II (including Formulas IIa, IIb, IIc, and IId), the Z ring is

[0094] [ka] If not, A 1 , A 2 and A 3 are independently N and CR 1 where R 1 is preferably hydrogen, halogen, optionally substituted C 1~3 Alkyl, or optionally substituted C 1~3 More preferably, R 1 is hydrogen, halogen, or C 1~3 In some embodiments, A is alkyl. 1 and A 3 At least one of them is CR 1 and R 1 is halogen, such as fluoro. 2 and A 3 At least one of them is CR 1 and R 1 is a halogen. In some embodiments, A 2 and A 3Both are CR 1 and R 1 At least one of the groups is a halogen. 3 is CR 1 and R 1 is halogen. In one or more embodiments, A 1 , A 2 and A 3 All of this is CR 1 And each R 1 are independently hydrogen, halogen, or C 1~3 Preferably, A is 1 is CR 1 And A 2 and A 3 Both are CH; or A 1 is CH and A 2 is CR 1 And A 3 is CH; or A 1 and A 2 Both are CH and A 3 is CR 1 where R 1 is halogen or C 1~3 It is an alkyl.

[0095] In one or more embodiments of the compound of Formula IIb, the Z ring is

[0096] [ka] If A 1 is CR 1 And A 2 and A 3 are each independently N or CR 1 where R 1 is preferably hydrogen, halogen, optionally substituted C 1~3 Alkyl, or optionally substituted C 1~3 More preferably, R 1 is hydrogen, halogen, or C 1~3 Preferably, A is 3 CR1 where R 1 is halogen, such as fluoro. 2 and A 3 At least one of them is CR 1 and R 1 is a halogen. In some embodiments, A 2 and A 3 Both are CR 1 and R 1 At least one of the groups is halogen. 1 , A 2 and A 3 All of this is CR 1 where R 1 is hydrogen, halogen, or C 1~3 Preferably, A is 1 is CR 1 And A 2 and A 3 Both are CH or A 1 is CH and A 2 is CR 1 And A 3 is CH or A 1 and A 2 Both are CH and A 3 is CR 1 where R 1 is halogen or C 1~3 It is an alkyl.

[0097] In one or more embodiments of the compound of Formula II (including Formulas IIa, IIb, IIc, and IId), R 6 is an optionally substituted 6- to 14-membered aryl or an optionally substituted 5- to 10-membered heteroaryl, and the optionally substituted 6- to 14-membered aryl and the optionally substituted 5- to 10-membered heteroaryl are each independently selected from halogen, cyano, C 1~4 Alkyl, C 1~4 Alkoxy, halogenated C 1~4 Alkyl, halogenated C 1~4 Alkoxy, C 3~6Cycloalkyl, amino (-NR'R''), aminoacyl (-C(O)-NR'R''), carboxyl, and C 1~4 and optionally substituted by 1 to 5 substituents selected from the group consisting of alkyl, optionally substituted by 1 to 3 substituents selected from the group consisting of heteroaryl (e.g., 5- to 10-membered nitrogen-containing heteroaryl, particularly 5- or 6-membered nitrogen-containing heteroaryl); wherein R′ and R″ are each, preferably independently, H, optionally substituted C 1~10 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted heterocyclic groups, optionally substituted aryl or optionally substituted heteroaryl; preferably H, optionally substituted C 1~4 Alkyl, optionally substituted C 3~6 cycloalkyl, or an optionally substituted 3- to 6-membered heterocyclic group. In some preferred embodiments, R 6 The substituents include at least aminoacyl (-C(O)-NR'R''), and optionally halogen, cyano, C 1~4 Alkyl, halogenated C 1~4 Alkyl, and C 3~6 In some preferred embodiments, R 6 is 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 with at least aminoacyl (-C(O)-NR'R''), and optionally further substituted with one or two substituents selected from the group consisting of halogen, cyano, C1-4 alkyl, halogenated C1-4 alkyl, and C3-6 cycloalkyl. Preferably, when the R' and R'' are substituted, the substituents may be one to five groups selected from the group consisting of halogen, hydroxyl, and amino.

[0098] Preferably, R 6 is optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, or optionally substituted pyridazinyl. 6 When is substituted, the substituents are halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, C 3~6 It may be 1 to 5 groups selected from the group consisting of cycloalkyl, aminoacyl, and carboxyl. More preferably, R 6 is substituted with at least an aminoacyl (-C(O)-NR'R''), preferably the aminoacyl is R 6 Preferably, the aminoacyl is -C(O)-NR'R'', where R' and R'' are each, preferably independently, H, optionally substituted C 1~10 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted heterocyclic groups, optionally substituted aryl or optionally substituted heteroaryl, preferably H, 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, hydroxyl, oxygen, and amino. Preferably, the optionally substituted alkyl and the optionally substituted alkoxy may be substituted with 1 to 5 groups selected from the group consisting of halogen, hydroxyl, oxygen, and amino. In a preferred embodiment, R 6 The above substituents include at least aminoacyl (-C(O)-NR'R''), and optionally halogen, cyano, C 1~4 Alkyl, halogenated C 1~4 Alkyl, and C 3~6More preferably, the aminoacyl (-C(O)-NR'R'') is in the para position.

[0099] In one or more embodiments of the compounds of Formula II (including Formulas IIa, IIb, IIc, and IId), R 6 is preferably the following group:

[0100] [ka] (In the formula, B 1 , B 2 , B 3 and B. 4 are, independently, N and CR 7 R 7 is selected from the group consisting of hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted carbocyclic, optionally substituted alkenyl, and optionally substituted alkynyl; 1~10 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted heterocyclic groups, optionally substituted aryl or optionally substituted heteroaryl, preferably hydrogen, optionally substituted C 1~4 Alkyl, optionally substituted C 3~6 Cycloalkyl and optionally substituted 3-6 membered heterocyclic groups. * indicates the position at which the group is attached to the remainder of the compound. Preferably, B 1 , B 2 , B 3 and B. 4 The group containing R is phenyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl. 7 is H, halogen, cyano, C 1~3 Alkyl, C 1~3 Alkoxy, halogenated C 1~3 Alkyl, or C3~6 Preferably, B is 3 is N and B 4 is CR 7 And B 1 and B. 2 are CH, where R 7 is H, halogen, cyano, C 1~3 Alkyl, C 1~3 Alkoxy, halogenated C 1~3 Alkyl, or 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, deuterated C 1~3 Alkyl, C 3~6 Cycloalkyl, halogenated C 1~3 Alkyl, hydroxy substituted C 1~3 Alkyl, or C 3~6 It is a heterocyclic group.

[0101] Preferably, in the embodiments described herein, the R 7 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.

[0102] In one or more embodiments of the compound of Formula IIa, the Z ring is:

[0103] [ka] (wherein * indicates the position at which the Z ring is attached to the remainder of the compound; 1 is CH and A 2 is CR 1 And A 3 is CH or A 1 and A2 Both are CH and A 3 is CR 1 where R 1 is halogen, optionally substituted C 1~3 Alkyl, or optionally substituted C 1~3 alkoxy, preferably halogen, more preferably F; R 6 is as defined in any of the preceding embodiments.

[0104] In one or more embodiments of the compound of Formula IIc, the Z ring is:

[0105] [ka] (wherein * indicates the position at which the Z ring is attached to the remainder of the compound; R 2 is hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably hydrogen, halogen, optionally substituted C 1~3 Alkyl and optionally substituted C 3~6 cycloalkyl; R 2 ' is hydrogen, halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably hydrogen, halogen, optionally substituted C 1~3 Alkyl and optionally substituted C 3~6 cycloalkyl; 2 and R 2 At least one of the ' is a non-hydrogen substituent, preferably the non-hydrogen substituent is halogen, cyano, C 1~3 Alkyl or C 3~6 A is cycloalkyl; 1 is CH and A 2 is CR 1 And A 3is CH or A 1 and A 2 Both are CH and A 3 is CR 1 where R 1 is halogen, optionally substituted C 1~3 Alkyl or optionally substituted C 1~3 alkoxy, preferably halogen, more preferably F; R 6 is as defined in any of the preceding embodiments.

[0106] In one or more embodiments of the compound of Formula IIc, the Z ring is:

[0107] [ka] (wherein * indicates the position at which the Z ring is attached to the remainder of the compound; R 2 ' is halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably halogen, optionally substituted C 1~3 Alkyl and optionally substituted C 3~6 cycloalkyl; A 1 is CH and A 2 is CR 1 And A 3 is CH or A 1 and A 2 Both are CH and A 3 is CR 1 where R 1 is halogen, optionally substituted C 1~3 Alkyl or optionally substituted C 1~3 alkoxy, preferably halogen, more preferably F; R 6 is as defined in any of the preceding embodiments.

[0108] In one or more embodiments of the compounds of Formula I, preferred compounds are those represented by Formula III (including Formulas IIIa, IIIb, IIIc, and IIId), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof:

[0109] [ka] (In the formula, Z 1 , Z 2 , Z 3 , A 1 , A 2 and A 3 is as defined in any of the preceding embodiments; B 1 , B 2 , B 3 and B. 4 are, independently, N and CR 7 Selected from; R 7 is selected from hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted carbocyclic, optionally substituted alkenyl, and optionally substituted alkynyl; R′ and R″ are independently hydrogen, optionally substituted C 1~10 optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl.

[0110] In one or more embodiments of the compound of Formula III (including Formulas IIIa, IIIb, IIIc, and IIId), the Z ring is selected from the following groups:

[0111] [ka] is selected from where * indicates the position where the Z ring is attached to the remainder of the compound; R2 is hydrogen, halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably hydrogen, halogen and optionally substituted C 1~3 Alkyl and optionally substituted C 3~6 cycloalkyl; R 2 ' is hydrogen, halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably hydrogen, halogen and optionally substituted C 1-3 Alkyl and optionally substituted C 3~6 cycloalkyl; R 3 is hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl, preferably hydrogen and optionally substituted C 1~3 alkyl.

[0112] In one or more embodiments of the compound of Formula IIIa, the Z ring is selected from the following groups:

[0113] [ka] is selected from where * indicates the position where the Z ring is attached to the remainder of the compound; R 2 is hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably hydrogen, halogen, cyano, optionally substituted C 1~3 Alkyl and optionally substituted C 3~6 cycloalkyl; R 3is hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl, preferably hydrogen and optionally substituted C 1~3 alkyl.

[0114] In one or more embodiments of the compounds of formula IIIb and IIIc, the Z ring is selected from the following groups:

[0115] [ka] is selected from In the formula, R 2 and R 2 ' is as defined in any of the preceding embodiments, and preferably in these embodiments, A 2 and A 3 At least one of the following is CR 1 and R 1 is a halogen; in some embodiments, A 2 and A 3 Both are CR 1 and R 1 At least l of the groups are halogen. 3 is CR 1 And R 1 is halogen. In some embodiments, A 1 is CR 1 And A 2 and A 3 are both CH; or A 1 is CH and A 2 is CR 1 And A 3 is CH; or A 1 and A 2 Both are CH and A 3 is CR 1 where R 1 is a halogen.

[0116] In one or more embodiments of the compound of Formula III (including Formulas IIIa, IIIb, IIIc, and IIId), A 1 , A2 and A 3 are independently N and CR 1 wherein R 1 is preferably hydrogen, halogen, optionally substituted C 1~3 Alkyl, or optionally substituted C 1~3 More preferably, R 1 is hydrogen, halogen, or C 1~3 In some embodiments, A is alkyl. 1 and A 3 At least one of them is CR 1 and R 1 is halogen, such as fluoro. 2 and A 3 At least one of them is CR 1 and R 1 is a halogen. In some embodiments, A 2 and A 3 Both are CR 1 and R 1 At least one of the groups is a halogen. 3 is CR 1 and R 1 is halogen. In one or more embodiments, A 1 , A 2 and A 3 All of this is CR 1 And each R 1 are independently hydrogen, halogen, or C 1~3 Preferably, A is 1 is CR 1 And A 2 and A 3 Both are CH; or A 1 is CH and A 2 is CR 1 And A 3 is CH; or A 1 and A 2 Both are CH and A 3 is CR 1 where R 1 is halogen or C1~3 It is an alkyl.

[0117] In one or more embodiments of the compound of Formula III (including Formulas IIIa, IIIb, IIIc, and IIId), the Z ring is

[0118] [ka] If not, A 1 , A 2 and A 3 are independently N and CR 1 wherein R 1 is preferably hydrogen, halogen, optionally substituted C 1~3 Alkyl, or optionally substituted C 1~3 More preferably, R 1 is hydrogen, halogen, or C 1~3 In some embodiments, A is alkyl. 1 and A 3 At least one of them is CR 1 and R 1 is halogen, such as fluoro. 2 and A 3 At least one of them is CR 1 and R 1 is a halogen. In some embodiments, A 2 and A 3 Both are CR 1 and R 1 At least one of the groups is a halogen. 3 is CR 1 and R 1 is halogen. In one or more embodiments, A 1 , A 2 and A 3 All of this is CR 1 And each R 1 are independently hydrogen, halogen, or C 1~3 Preferably, A is 1 is CR 1 And A2 and A 3 Both are CH; or A 1 is CH and A 2 is CR 1 And A 3 is CH; or A 1 and A 2 Both are CH and A 3 is CR 1 where R 1 is halogen or C 1~3 It is an alkyl.

[0119] In one or more embodiments of the compound of formula IIIb, the Z ring is

[0120] [ka] If A 1 is CR 1 And A 2 and A 3 are each independently N or CR 1 where R 1 is preferably hydrogen, halogen, optionally substituted C 1~3 Alkyl, or optionally substituted C 1~3 More preferably, R 1 is hydrogen, halogen, or C 1~3 Preferably, A is 3 is CR 1 where R 1 is halogen, such as fluoro. 2 and A 3 At least one of them is CR 1 and R 1 is a halogen. In some embodiments, A 2 and A 3 Both are CR 1 and R 1 At least one of the groups is a halogen. 3 is CR 1 and R 1is halogen. In one or more embodiments, A 1 , A 2 and A 3 All of this is CR 1 where R 1 is hydrogen, halogen, or C 1~3 Preferably, A is 1 is CR 1 And A 2 and A 3 Both are CH; or A 1 is CH and A 2 is CR 1 And A 3 is CH; or A 1 and A 2 Both are CH and A 3 is CR 1 where R 1 is halogen or C 1~3 It is an alkyl.

[0121] In one or more embodiments of the compound of Formula III (including Formulas IIIa, IIIb, IIIc, and IIId), B 1 , B 2 , B 3 and B. 4 are, independently, N and CR 7 wherein R 7 is preferably hydrogen, halogen, cyano, optionally substituted C 1~3 Alkyl, optionally substituted C 1~3 Alkoxy or optionally substituted C 3~6 cycloalkyl, more preferably R 7 is hydrogen, C 1~3 Alkyl, halogenated C 1~3 Alkyl, halogen, cyano, or C 3~6 In a preferred embodiment, B 1 and B. 2 Both are CH and B 3 is N and B 4 is CR 7 where R 7is preferably hydrogen, halogen, optionally substituted C 1~3 Alkyl, optionally substituted C 1~3 Alkoxy or optionally substituted C 3~6 cycloalkyl, more preferably R 7 is hydrogen, C 1~3 Alkyl, halogenated C 1~3 Alkyl, halogen, cyano, or C 3~6 It is cycloalkyl.

[0122] In one or more embodiments of the compound of Formula III (including Formulas IIIa, IIIb, IIIc, and IIId), R′ and R″ are each independently hydrogen, optionally substituted C 1~3 Alkyl, optionally substituted C 3~6 Preferably, R' is hydrogen and R'' is hydrogen, C 1~3 Alkyl, deuterated C 1~3 Alkyl, C 3~6 Cycloalkyl, halogenated C 1~3 Alkyl, Hydroxy C 1~3 Alkyl, oxo C 1~3 It is an alkyl group, or a 3- to 6-membered heterocyclic group.

[0123] In a preferred embodiment, in the -C(O)-NR'R" group described herein, R' and R" are each independently selected from hydrogen, optionally substituted C 1~4 Alkyl, and optionally substituted C 3~6 In a further preferred embodiment, R' is hydrogen and R'' is hydrogen, C 1~3 Alkyl, halogenated C 1~3 Alkyl or deuterated C 1~3 It is an alkyl.

[0124] In one or more embodiments of the compound of Formula IIIa, the Z ring is:

[0125] [ka] (wherein * indicates the position at which the Z ring is attached to the remainder of the compound; 1 is CH and A 2 is CR 1 And A 3 is CH or A 1 and A 2 Both are CH and A 3 is CR 1 where R 1 is halogen, optionally substituted C 1~3 Alkyl, or optionally substituted C 1~3 alkoxy, preferably halogen, more preferably F; B 1 , B 2 , B 3 , B 4 , R′ and R″ are as defined in any of the previous embodiments.

[0126] In one or more embodiments of the compound of Formula IIIc, the Z ring is:

[0127] [ka] (wherein * indicates the position at which the Z ring is attached to the remainder of the compound; R 2 is hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably hydrogen, halogen, optionally substituted C 1~3 Alkyl and optionally substituted C 3~6 cycloalkyl; R 2 ' is hydrogen, halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably hydrogen, halogen, optionally substituted C 1~3Alkyl and optionally substituted C 3~6 cycloalkyl, wherein R 2 and R 2 At least one of the ' is a non-hydrogen substituent, preferably the non-hydrogen substituent is halogen, cyano, C 1~3 Alkyl or C 3~6 A is cycloalkyl; 1 is CH and A 2 is CR 1 And A 3 is CH or A 1 and A 2 Both are CH and A 3 is CR 1 where R 1 is halogen, optionally substituted C 1~3 Alkyl or optionally substituted C 1~3 alkoxy, preferably halogen, more preferably F; B 1 , B 2 , B 3 , B 4 , R′ and R″ are as defined in any of the previous embodiments.

[0128] In one or more embodiments of the compound of Formula IIIc, the Z ring is:

[0129] [ka] (wherein * indicates the position at which the Z ring is attached to the remainder of the compound; R 2 ' is halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably halogen, optionally substituted C 1~3 Alkyl and optionally substituted C 3~6 cycloalkyl; A 1 is CH and A 2 is CR 1 And A 3is CH or A 1 and A 2 Both are CH and A 3 is CR 1 where R 1 is halogen, optionally substituted C 1~3 Alkyl or optionally substituted C 1~3 alkoxy, preferably halogen, more preferably F; B 1 , B 2 , B 3 , B 4 , R′ and R″ are as defined in any of the previous embodiments.

[0130] In one or more embodiments of the compounds of Formula I, preferred compounds are those represented by Formula IV (including Formulas IVa, IVb, IVc, and IVd), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof:

[0131] [ka] (In the formula, Z 1 , Z 2 , Z 3 and R″ is as defined in any of the previous embodiments; R 7 is selected from hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted carbocyclic, optionally substituted alkenyl, and optionally substituted alkynyl; R 8 , R 9 and R 10 are independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted carbocyclic groups.

[0132] In one or more embodiments of the compound of formula IV (including formulas IVa, IVb, IVc, and IVd), the Z ring is selected from the following groups:

[0133] [ka] Selected from; where * indicates the position where the Z ring is attached to the remainder of the compound, and R 2 is hydrogen, halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably hydrogen, halogen, optionally substituted C 1~3 Alkyl and optionally substituted C 3~6 cycloalkyl; R 2 ' is hydrogen, halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably hydrogen, halogen, optionally substituted C 1~3 Alkyl and optionally substituted C 3~6 cycloalkyl; R 3 is hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl, preferably hydrogen and optionally substituted C 1~3 Preferably, R is selected from the group consisting of alkyl. 2 , R 2 ' and R 3 is as defined in any of the previous embodiments.

[0134] In one or more embodiments of the compounds of formula IVb and IVc, the Z ring is selected from the following groups:

[0135] [ka] Selected from; In the formula, R2 and R 2 ' is as defined in any of the preceding embodiments; preferably, in these embodiments, A 2 and A 3 At least one of them is CR 1 and R 1 is a halogen; in some embodiments, A 2 and A 3 Both are CR 1 and R 1 At least one of the groups is a halogen. 3 is CR 1 and R 1 is a halogen. In some embodiments, A 1 is CR 1 And A 2 and A 3 Both are CH; or A 1 is CH and A 2 is CR 1 And A 3 is CH or A 1 and A 2 Both are CH and A 3 is CR 1 where R 1 is a halogen.

[0136] In one or more embodiments of the compound of formula IV (including formulas IVa, IVb, IVc, and IVd), R 7 is hydrogen, halogen, cyano, optionally substituted C 1~3 Alkyl, or optionally substituted C 1~3 Alkoxy, preferably hydrogen, C 1~3 Alkyl, halogenated C 1~3 alkyl, or halogen.

[0137] In one or more embodiments of the compound of formula IV (including formulas IVa, IVb, IVc, and IVd), R 8 , R 9 and R 10 each independently represents hydrogen, halogen, or optionally substituted C1~3 Alkyl, or optionally substituted C 1~3 Alkoxy, preferably R 8 , R 9 and R 10 are each independently hydrogen, halogen, or C 1~3 alkyl; preferably, R 8 , R 9 and R 10 At least one of R is a non-hydrogen substituent, and preferably the non-hydrogen substituent is a halogen. 8 is halogen or C 1~3 is alkyl, R 9 and R 10 are both H; or R 8 is H and R 9 is halogen or C 1~3 is alkyl, R 10 is H; or R 8 and R 9 Both are H and R 10 is halogen or C 1~3 In some embodiments, R 9 and R 10 At least one of R is halogen, and preferably at least R 10 is a halogen such as fluoro.

[0138] In one or more embodiments of the compound of formula IV (including formulas IVa, IVb, IVc, and IVd), R″ is hydrogen, optionally substituted C 1~4 Alkyl, optionally substituted C 3~6 Cycloalkyl and optionally substituted 3- to 6-membered heterocyclic groups, preferably hydrogen, C 1~3 Alkyl, deuterated C 1~3 Alkyl, C 3~6 Cycloalkyl, halogenated C 1~3 It is an alkyl group, or a 3- to 6-membered heterocyclic group.

[0139] In one or more embodiments of the compound of Formula IVa, the Z ring is:

[0140] [ka] (wherein * indicates the position at which the Z ring is attached to the remainder of the compound; R 8 is H and R 9 and R 10 One of the two is halogen or C 1~3 alkyl, and the other is hydrogen; R 7 and R″ is as defined in any of the preceding embodiments.

[0141] In some embodiments of the compound of formula IVc, the Z ring is:

[0142] [ka] (wherein * indicates the position at which the Z ring is attached to the remainder of the compound; R 2 is hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably hydrogen, halogen, optionally substituted C 1~3 Alkyl and optionally substituted C 3~6 cycloalkyl; R 2 ' is hydrogen, halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably hydrogen, halogen, optionally substituted C 1~3 Alkyl and optionally substituted C 3~6 cycloalkyl; 2 and R 2 At least one of the ' is a non-hydrogen substituent, preferably the non-hydrogen substituent is halogen, cyano, C 1~3 Alkyl or C 3~6 Cycloalkyl; R 8 , R9 and R 10 Any one of the groups is a halogen or C 1~3 alkyl and the others are hydrogen, preferably R 8 is halogen or C 1~3 is alkyl, R 9 and R 10 are both H or R 8 is H and R 9 is halogen or C 1~3 is alkyl, R 10 is H or R 8 and R 9 Both are H and R 10 is halogen or C 1~3 R is alkyl; 7 and R″ is as defined in any of the preceding embodiments.

[0143] In one or more embodiments of the compound of formula IVc, the Z ring is:

[0144] [ka] (wherein * indicates the position at which the Z ring is attached to the remainder of the compound; R 2 ' is halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C 1~3 Alkoxy, and optionally substituted C 3~6 Cycloalkyl, preferably halogen, optionally substituted C 1~3 Alkyl, and optionally substituted C 3~6 cycloalkyl; R 8 is H and R 9 and R 10 One of the two is halogen or C 1~3 alkyl, and the other is hydrogen; R 7 and R″ is as defined in any of the preceding embodiments.

[0145] In one or more embodiments of the compounds of Formula I, preferred compounds are represented by Formula V (including Formulas Va, Vb, Vc, and Vd), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof:

[0146] [ka] (In the formula, Z 1 , Z 2 , Z 3 , R 8 , R 9 , R 10 , B 1 , B 2 , B 3 and B. 4 is as defined in any of the preceding embodiments; D ring is an optionally substituted 4-12 membered N-containing heterocyclic group; said N-containing heterocyclic group containing at least one N atom is selected from a 4-12 membered monocyclic group, or a 5-12 membered spirocyclic group, said N-containing heterocyclic group may also contain 1-4 heteroatoms selected from N, O or S, and may be optionally further substituted by one or more R'''; W is a bond, O, or -NR'-; Q is an optionally substituted aminoacyl (-C(O)-NR'R'') or an optionally substituted heteroaryl; R′ and R″ are each independently hydrogen, optionally substituted C 1~10 selected from alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl; R''' is halogen, hydroxyl, cyano, or C 1~6 alkyl, 1~6The alkyl is optionally further substituted with one or more substituents selected from hydroxyl, halogen, or cyano; or any two R''' can form a 3-8 membered ring).

[0147] In one or more embodiments of the compound of formula V (including formulas Va, Vb, Vc, and Vd), the Z ring is selected from the following groups:

[0148] [ka] Selected from; where * indicates the position where the Z ring is attached to the remainder of the compound; R 2 is hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably hydrogen, halogen, optionally substituted C 1~3 Alkyl and optionally substituted C 3~6 cycloalkyl; R 2 ' is hydrogen, halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably hydrogen, halogen, optionally substituted C 1~3 Alkyl and optionally substituted C 3~6 cycloalkyl; R 3 is hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl, preferably hydrogen and optionally substituted C 1~3 Preferably, R is selected from the group consisting of alkyl. 2 , R 2 ' and R 3 is as defined in any of the previous embodiments.

[0149] In one or more embodiments of the compounds of formula Vb and Vc, the Z ring is selected from the following groups:

[0150] [ka] Selected from; In the formula, R 2 and R 2 ' is as defined in any of the preceding embodiments, and preferably in these embodiments, A 2 and A 3 At least one of the following is CR 1 and R 1 is a halogen; in some embodiments, A 2 and A 3 Both are CR 1 and R 1 At least one of the groups is halogen. 3 is CR 1 and R 1 is a halogen. In some embodiments, A 1 is CR 1 And A 2 and A 3 Both are CH; or A 1 is CH and A 2 is CR 1 And A 3 is CH; or A 1 and A 2 Both are CH and A 3 is CR 1 where R 1 is a halogen.

[0151] In one or more embodiments of the compound of Formula V (including Formulas Va, Vb, Vc, and Vd), R 8 , R 9 and R 10 each independently represents hydrogen, halogen, or optionally substituted C 1~3 Alkyl, or optionally substituted C 1~3 Alkoxy, preferably R 8 , R 9 and R 10 are each independently hydrogen, halogen, or C1~3 alkyl; preferably, R 8 , R 9 and R 10 At least one of R is a non-hydrogen substituent, and preferably the non-hydrogen substituent is a halogen. 8 is halogen or C 1~3 is alkyl, R 9 and R 10 are both H; or R 8 is H and R 9 is halogen or C 1~3 is alkyl, R 10 is H; or R 8 and R 9 Both are H and R 10 is halogen or C 1~3 In some embodiments, R 9 and R 10 At least one of R is halogen, and preferably at least R 10 is a halogen such as fluoro.

[0152] In one or more embodiments of the compound of Formula V (including Formulas Va, Vb, Vc, and Vd), L is selected from 1 to 2 C 1~3 Alkylene optionally substituted with an alkyl group, more preferably 1 to 2 C 1~3 C optionally substituted with an alkyl group 1~3 Alkylene, preferably 1 to 2 C 1~3 It is methylene optionally substituted by alkyl.

[0153] In one or more embodiments of the compound of formula V (including formulas Va, Vb, Vc, and Vd), ring D is an optionally substituted 4-7 membered monocyclic ring containing at least one N atom; preferably ring D is an optionally substituted piperazinyl, an optionally substituted piperidinyl, an optionally substituted dihydropyridinyl, or an optionally substituted pyrrolidinyl. When ring D is substituted, the substituents are halogen, hydroxyl, cyano, optionally substituted C1~3 Alkyl, optionally substituted C 1~3 Alkoxy, and optionally substituted C 3~6 It may be 1 to 3 groups selected from the group consisting of cycloalkyl.

[0154] In one or more embodiments of the compound of Formula V (including Formulas Va, Vb, Vc, and Vd), the D ring is selected from the following groups:

[0155] [ka] Preferably, the D ring is selected from

[0156] [ka] and; In the formula, *1 indicates the position where the D ring is bonded to L; *2 indicates the position where the D ring is bonded to W.

[0157] In one or more embodiments of the compound of Formula V (including Formulas Va, Vb, Vc, and Vd), W is a bond or -NH-.

[0158] In one or more embodiments of the compound of formula V (including formulas Va, Vb, Vc, and Vd), Ring D is an optionally substituted piperazinyl, an optionally substituted piperidinyl, or an optionally substituted dihydropyridinyl, and W is a bond. In one or more embodiments, Ring D is an optionally substituted pyrrolidinyl, and W is -NH-.

[0159] In one or more embodiments of the compound of formula V (including formulas Va, Vb, Vc and Vd), B 1 , B 2 , B 3 and B. 4 are, independently, N and CR 7 wherein R 7 is preferably hydrogen, halogen, cyano, optionally substituted C 1~3Alkyl, optionally substituted C 1~3 Alkoxy or optionally substituted C 3~6 cycloalkyl, more preferably R 7 is hydrogen, C 1~3 Alkyl, halogenated C 1~3 Alkyl, halogen, cyano, or C 3~6 In a preferred embodiment, B 1 and B. 2 Both are CH and B 3 is N and B 4 is CR 7 where R 7 is preferably hydrogen, halogen, optionally substituted C 1~3 Alkyl, optionally substituted C 1~3 Alkoxy or optionally substituted C 3~6 cycloalkyl, more preferably R 7 is hydrogen, C 1~3 Alkyl, halogenated C 1~3 Alkyl, halogen, cyano, or C 3~6 It is cycloalkyl.

[0160] In one or more embodiments of the compound of formula V (including formulas Va, Vb, Vc, and Vd), Q is —C(O)—NR′R″, where R′ and R″ are each independently hydrogen, optionally substituted C 1~10 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted heterocyclic groups, optionally substituted aryl or optionally substituted heteroaryl, preferably hydrogen, optionally substituted C 1~4 Alkyl, optionally substituted C 3~6 In one or more embodiments, Q is a halogen, cyano, C 1~3 Alkyl, halogenated C 1~3 Alkyl, C 1~3 Alkoxy and halogenated C 1~3and 5-membered heteroaryl optionally substituted with 1 to 3 substituents selected from alkoxy, wherein the 5-membered heteroaryl is preferably pyrrolyl, pyrazolyl, imidazolyl, or triazolyl.

[0161] In one or more embodiments of the compound of formula Va, the Z ring is:

[0162] [ka] (wherein * indicates the position at which the Z ring is attached to the remainder of the compound; R 8 is H and R 9 and R 10 One of the two is halogen or C 1~3 Alkyl, the other is hydrogen, L, ring D, W, B 1 , B 2 , B 3 , B 4 and Q is as defined in any of the preceding embodiments.

[0163] In some embodiments of the compound of formula Vc, the Z ring is:

[0164] [ka] (wherein * indicates the position at which the Z ring is attached to the remainder of the compound; R 2 is hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably hydrogen, halogen, optionally substituted C 1~3 Alkyl and optionally substituted C 3~6 cycloalkyl; R 2 ' is hydrogen, halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6Cycloalkyl, preferably hydrogen, halogen, cyano, optionally substituted C 1~3 Alkyl and optionally substituted C 3~6 cycloalkyl, wherein R 2 and R 2 At least one of the ' is a non-hydrogen substituent, preferably the non-hydrogen substituent is halogen, cyano, C 1~3 Alkyl or C 3~6 Cycloalkyl; R 8 , R 9 and R 10 One of the following is halogen or C 1~3 alkyl and the others are hydrogen, preferably R 8 is halogen or C 1~3 is alkyl, R 9 and R 10 are both H or R 8 is H and R 9 is halogen or C 1~3 is alkyl, R 10 is H or R 8 and R 9 Both are H and R 10 is halogen or C 1~3 Alkyl; L, ring D, W, B 1 , B 2 , B 3 , B 4 and Q is as defined in any of the preceding embodiments.

[0165] In one or more embodiments of the compound of formula Vc, the Z ring is:

[0166] [ka] (wherein * indicates the position at which the Z ring is attached to the remainder of the compound, and R 2 ' is halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6Cycloalkyl, preferably halogen, cyano, optionally substituted C 1~3 Alkyl and optionally substituted C 3~6 cycloalkyl; R 8 is H and R 9 and R 10 One of the two is halogen or C 1~3 alkyl, and the other is hydrogen; L, ring D, W, B 1 , B 2 , B 3 , B 4 and Q is as defined in any of the preceding embodiments.

[0167] In one or more embodiments of the compounds of Formula I, preferred compounds are those represented by Formula VI (including Formulas VIa, VIb, and VIc), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof:

[0168] [ka] (In the formula, Z 1 , Z 2 , Z 3 , R 7 , D 1 and Q is as defined in any of the previous embodiments; R 7 ' is hydrogen, halogen, cyano, optionally substituted C 1~3 Alkyl, optionally substituted C 1~3 Alkoxy or optionally substituted C 3~6 is cycloalkyl; R 9 and R 10 each independently represents hydrogen, halogen, or optionally substituted C 1~3 Alkyl, or optionally substituted C 1~3 Alkoxy, R 9 and R 10 at least one of is not hydrogen; D 1 is N or CR 11 and; R 11 is H, halogen, cyano, hydroxyl, optionally substituted C 1~3 Alkyl, or optionally substituted C 1~3 (alkoxy).

[0169] In one or more embodiments of the compound of Formula VI (including Formulas VIa, VIb, and VIc), the Z ring is selected from the following groups:

[0170] [ka] Selected from; where * indicates the position where the Z ring is attached to the remainder of the compound; R 2 is hydrogen, halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably hydrogen, halogen, cyano, optionally substituted C 1~3 Alkyl and optionally substituted C 3~6 cycloalkyl; R 2 ' is hydrogen, halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably hydrogen, halogen, cyano, optionally substituted C 1~3 Alkyl and optionally substituted C 3~6 cycloalkyl; R 3 is hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl, preferably hydrogen and optionally substituted C 1~3 Preferably, R is selected from the group consisting of alkyl. 2 , R 2 ' and R 3is as defined in any of the previous embodiments.

[0171] In one or more embodiments of the compounds of formula VIb and VIc, the Z ring is selected from the following groups:

[0172] [ka] Selected from; In the formula, R 2 and R 2 ' is as defined in any of the preceding embodiments; preferably, in these embodiments, A 2 and A 3 At least one of them is CR 1 and R 1 is a halogen; in some embodiments, A 2 and A 3 Both are CR 1 and R 1 At least one of the groups is halogen. 3 is CR 1 and R 1 is a halogen. In some embodiments, A 1 is CR 1 And A 2 and A 3 Both are CH; or A 1 is CH and A 2 is CR 1 And A 3 is CH; or A 1 and A 2 Both are CH and A 3 is CR 1 where R 1 is a halogen.

[0173] In one or more embodiments of the compound of Formula VI (including Formulas VIa, VIb, and VIc), R 9 is hydrogen, and R 10 is halogen or C 1~3 In one or more embodiments, R 9 is halogen or C1~3 is alkyl, R 10 is hydrogen. In some embodiments, R 9 is hydrogen, and R 10 is a halogen; or R 9 is a halogen, and R 10 is hydrogen. The halogen is preferably F.

[0174] In one or more embodiments of the compound of Formula VI (including Formulas VIa, VIb, and VIc), D 1 is N or CH.

[0175] In one or more embodiments of the compound of Formula VI (including Formulas VIa, VIb, and VIc), R 7 and R 7 ' are each independently hydrogen, halogen, cyano, optionally substituted C 1~3 Alkyl, optionally substituted C 1~3 Alkoxy or optionally substituted C 3~6 Cycloalkyl, preferably R 7 and R 7 ' are each independently hydrogen, C 1~3 Alkyl, halogenated C 1~3 Alkyl, halogen, cyano or C 3~6 More preferably, R 7 and R 7 ' are independently hydrogen, C 1~3 Alkyl, halogenated C 1-3 alkyl, cyano or halogen; preferably, R 7 and R 7 At least one of R ′ is not hydrogen. 7 is C 1~3 Alkyl, halogenated C 1~3 Alkyl, halogen, cyano, or C 3~6 cycloalkyl, R 7 ' is hydrogen; or R 7 is hydrogen, and R 7 ' is C 1~3 Alkyl, halogenated C 1~3Alkyl, halogen, cyano, or C 3~6 More preferably, R 7 is C 1~3 Alkyl, halogenated C 1~3 Alkyl, halogen, cyano, or C 3~6 cycloalkyl, R 7 ' is hydrogen.

[0176] In one or more embodiments of the compound of Formula VI (including Formulas VIa, VIb, and VIc), Q is —C(O)—NR′R″ as described in any of the previous embodiments, where R′ and R″ are each independently hydrogen, optionally substituted C 1~10 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted heterocyclic groups, optionally substituted aryl or optionally substituted heteroaryl, preferably hydrogen, optionally substituted C 1~4 Alkyl, optionally substituted C 3~6 In one or more embodiments, Q is a halogen, cyano, C 1~3 Alkyl, halogenated C 1~3 Alkyl, C 1~3 Alkoxy and halogenated C 1~3 and 5-membered heteroaryl optionally substituted with 1 to 3 substituents selected from alkoxy, wherein the 5-membered heteroaryl is preferably pyrrolyl, pyrazolyl, imidazolyl, or triazolyl.

[0177] In one or more embodiments of the compound of formula VIa, Z 1 , Z 2 and Z 3 One of them is O and the other two are CR 1 where R 1 is hydrogen, halogen and C 1~3 Preferably, Z is selected from alkyl. 1 is O and Z 2 and Z 3and R are both CH. Preferably, in some embodiments, R 9 is a non-hydrogen substituent, such as halogen, optionally substituted C 1~3 Alkyl or optionally substituted C 1~3 Alkoxy, preferably halogen, more preferably F. Even more preferably, in some embodiments, R 10 is hydrogen, halogen or C 1~3 alkyl, preferably hydrogen; D 1 is N or CH; R 7 is hydrogen, C 1~3 Alkyl, halogenated C 1~3 Alkyl, halogen, cyano or C 3~6 Cycloalkyl, preferably hydrogen, halogen, C 1~3 Alkyl or halogenated C 1~3 R is alkyl; 7 ' is hydrogen, C 1~3 Alkyl, halogenated C 1~3 Alkyl, halogen, cyano or C 3~6 Q is -C(O)-NR'R'' or halogen and C 1~3 pyrrolyl, pyrazolyl, imidazolyl, or triazolyl optionally substituted with 1 to 2 groups selected from alkyl, wherein R′ and R″ are each independently hydrogen, C 1~4 Alkyl, or C 3~6 cycloalkyl.

[0178] In one or more embodiments of the compound of formula VIa, Z 1 , Z 2 and Z 3 One of them is O and the other two are CR 1 and preferably Z 1 is O and Z 2 and Z 3 Both are CH and R 1 is hydrogen, halogen and C 1~3 alkyl; R 10 is a non-hydrogen substituent, such as halogen, optionally substituted C1~3 Alkyl or optionally substituted C 1~3 alkoxy, preferably halogen, more preferably F; R 9 is hydrogen, halogen or C 1~3 alkyl, preferably hydrogen; D 1 is N or CH, R 7 is hydrogen, C 1~3 Alkyl, halogenated C 1~3 Alkyl, halogen, cyano or C 3~6 Cycloalkyl, preferably hydrogen, halogen, C 1~3 Alkyl or halogenated C 1~3 R is alkyl; 7 ' is hydrogen, C 1~3 Alkyl, halogenated C 1~3 Alkyl, halogen, cyano or C 3~6 Q is -C(O)-NR'R'' or halogen and C 1~3 pyrrolyl, pyrazolyl, imidazolyl, or triazolyl optionally substituted with 1 to 2 groups selected from alkyl, wherein R′ and R″ are each independently hydrogen, C 1~4 Alkyl, or C 3~6 cycloalkyl, preferably in these embodiments, R 9 is H and R 10 is F and R 7 is methyl, D 1 is N and R 7 ' is H and Q is -C(O)-NH(CH 3 ) or -C(O)-NH(CD 3 ), and R 9 is H and R 10 is F and R 7 is F and D 1 is N and R 7 ' is H and Q is -C(O)-NH(CH 3 ) or -C(O)-NH(CD 3 ) are excluded.

[0179] In some embodiments of the compound of formula VIc, the Z ring is:

[0180] [ka] (wherein * indicates the position at which the Z ring is attached to the remainder of the compound; R 2 is hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably hydrogen, halogen, cyano, optionally substituted C 1~3 Alkyl and optionally substituted C 3~6 cycloalkyl; R 2 ' is hydrogen, halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably hydrogen, halogen, cyano, optionally substituted C 1~3 Alkyl and optionally substituted C 3~6 cycloalkyl; 2 and R 2 At least one of the ' is a non-hydrogen substituent, preferably the non-hydrogen substituent is halogen, cyano, C 1~3 Alkyl or C 3~6 cycloalkyl, R 9 and R 10 One of the two is halogen or C 1~3 alkyl and the other is hydrogen; D 1 is N or CH, R 7 is hydrogen, C 1~3 Alkyl, halogenated C 1~3 Alkyl, halogen, cyano or C 3~6 Cycloalkyl, preferably hydrogen, halogen, C 1~3 Alkyl or halogenated C 1~3 R is alkyl; 7 ' is hydrogen, C 1~3 Alkyl, halogenated C1~3 Alkyl, halogen, cyano or C 3~6 cycloalkyl, preferably hydrogen or halogen, and Q is -C(O)-NR'R'' or halogen and C 1~3 pyrrolyl, pyrazolyl, imidazolyl, or triazolyl optionally substituted with 1 to 2 groups selected from alkyl, wherein R′ and R″ are each independently hydrogen, C 1~4 Alkyl or C 3~6 cycloalkyl).

[0181] In one or more embodiments of the compound of formula VIc, the Z ring is:

[0182] [ka] (In the formula, R 2 ' is halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C 1~3 Alkoxy and optionally substituted C 3~6 Cycloalkyl, preferably halogen, cyano, optionally substituted C 1~3 Alkyl and optionally substituted C 3~6 cycloalkyl; R 8 is H and R 9 and R 10 One of the two is halogen or C 1~3 alkyl, the other is hydrogen, D 1 is N or CH; R 7 is hydrogen, C 1~3 Alkyl, halogenated C 1~3 Alkyl, halogen, cyano or C 3~6 Cycloalkyl, preferably hydrogen, halogen, C 1~3 Alkyl or halogenated C 1~3 R is alkyl; 7 ' is hydrogen, C 1~3 Alkyl, halogenated C 1~3 Alkyl, halogen, cyano or C 3~6cycloalkyl, preferably hydrogen or halogen; Q is -C(O)-NR'R'' or halogen and C 1~3 pyrrolyl, pyrazolyl, imidazolyl, or triazolyl optionally substituted with 1 to 2 groups selected from alkyl, wherein R′ and R″ are each independently hydrogen, C 1~4 Alkyl or C 3~6 cycloalkyl).

[0183] In one or more embodiments of the compounds of Formula I, preferred compounds are those represented by Formula VII, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof:

[0184] [ka] (In the formula, R 9 and R 10 is as defined in formula VI; L and Cy are as defined in any of the preceding embodiments. R 12 and R 13 each independently represents hydrogen, halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C 1~3 Alkoxy, and optionally substituted C 3~6 cycloalkyl; R 12 and R 13 at least one of which is not hydrogen.

[0185] In one or more embodiments of the compound of formula VII, R 12 and R 13 each independently represents hydrogen, halogen, cyano, optionally substituted C 1~3 Alkyl, or optionally substituted C 3~6 In one or more embodiments, R 12 is hydrogen, and R 13is halogen, cyano, optionally substituted C 1~3 Alkyl, or optionally substituted C 3~6 In one or more embodiments, R 12 is halogen, cyano, optionally substituted C 1~3 Alkyl, or optionally substituted C 3~6 cycloalkyl, R 13 is hydrogen. In a preferred embodiment, R 12 is halogen, cyano, optionally substituted C 1~3 Alkyl, or optionally substituted C 3~6 cycloalkyl, R 13 is hydrogen. More preferably, R 12 is a halogen, C 1~3 Alkyl, halogenated C 1~3 is alkyl, R 13 is hydrogen.

[0186] In one or more embodiments of the compound of formula VII, R 9 is hydrogen, and R 10 is halogen or C 1~3 In one or more embodiments, R 9 is halogen or C 1~3 is alkyl, R 10 is hydrogen. In some embodiments, R 9 is hydrogen, and R 10 is a halogen; or R 9 is a halogen, and R 10 is hydrogen. Preferably, the halogen is F.

[0187] In one or more embodiments of the compound of Formula VII, L is selected from 1 to 2 C 1~3 Alkylene optionally substituted with alkyl, more preferably 1 to 2 C 1~3 C optionally substituted with alkyl 1~3 Alkylene, preferably 1 to 2 C 1~3 It is methylene optionally substituted by alkyl.

[0188] In one or more embodiments of the compound of Formula VII, L is an unsubstituted alkylene, preferably an unsubstituted C 1~3 It is preferably alkylene, more preferably methylene.

[0189] In one or more embodiments of the compound of formula VII, 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, piperidinyl, or dihydropyridinyl. Preferably, the substituents on Cy in the compound of formula VII are halogen, optionally substituted C 1~4 Alkyl, optionally substituted C 1~4 Alkoxy, halogenated C 1~4 Alkyl, halogenated C 1~4 Alkoxy, cyano, hydroxyl, amino (-NR'R''), 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 3~8 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 3~8 Cycloalkyl is independently halogen, cyano, C 1~4 Alkyl, C 1~4 Alkoxy, halogenated C 1~4 Alkyl, halogenated C 1~4 Alkoxy, C 3~6 and each of R′ and R″ is preferably independently selected from the group consisting of H, optionally substituted C(O)-C ... 1~10 Alkyl, optionally substituted C 3~8Cycloalkyl, optionally substituted heterocyclic groups, optionally substituted aryl or optionally substituted heteroaryl, preferably H, optionally substituted C 1~4 Alkyl, optionally substituted C 3~8 In some preferred embodiments, the aryl, aryl group, and optionally substituted 3- to 6-membered heterocyclic group are 6- to 14-membered aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclic group, and C 3~8 The substituents on the cycloalkyl include at least aminoacyl (-C(O)-NR'R''), and optionally halogen, cyano, C 1~4 Alkyl, halogenated C 1~4 Alkyl, and C 3~6 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 (such as pyridyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, pyrimidinyl, etc.). Preferably, the 5-10 membered heteroaryl or the 5-10 membered nitrogen-containing heteroaryl is substituted by at least aminoacyl (-C(O)-NR'R'') and optionally halogen, cyano, C(O)-NR'R''. 1~4 Alkyl, halogenated C 1~4 Alkyl, and C 3~6 Further substituted with one or two substituents selected from the group consisting of cycloalkyl. More preferably, the aminoacyl (-C(O)-NR'R'') is in the para position. In some particularly preferred embodiments, Cy is piperazinyl substituted with optionally substituted pyridyl, piperidinyl substituted with optionally substituted pyridyl, or dihydropyridinyl substituted with optionally substituted pyridyl, where the pyridyl is substituted with at least aminoacyl (-C(O)-NR'R''). Preferably, in the embodiments described herein, when the R' and R'' are substituted, the substituents are selected from halogen, hydroxyl, C 1~4 Alkyl, C 1~4 Alkoxy, halogenated C1~4 Alkyl, halogenated C 1~4 It may be 1 to 5 groups selected from the group consisting of alkoxy, amino, and the like.

[0190] In one or more embodiments of the compounds of Formula I, preferred compounds are those represented by Formula VIII, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof:

[0191] [ka] (In the formula, R 9 and R 10 is as defined in formulas VI and VII; R 12 and R 13 is as defined in formula VII; D ring and Q are as defined in formula V; R 7 is as defined in formulas IV and VI).

[0192] In one or more embodiments of the compound of Formula VIII, R 12 and R 13 each independently represents hydrogen, halogen, cyano, optionally substituted C 1~3 Alkyl, or optionally substituted C 3~6 In one or more embodiments, R 12 is hydrogen, and R 13 is halogen, cyano, optionally substituted C 1~3 Alkyl, or optionally substituted C 3~6 In one or more embodiments, R 12 is halogen, cyano, optionally substituted C 1~3 Alkyl, or optionally substituted C 3~6 cycloalkyl, R 13 is hydrogen. In a preferred embodiment, R 12 is halogen, cyano, optionally substituted C1~3 Alkyl, or optionally substituted C 3~6 cycloalkyl, R 13 is hydrogen. More preferably, R 12 is a halogen, C 1~3 Alkyl or halogenated C 1~3 R is alkyl; 13 is hydrogen.

[0193] In one or more embodiments of the compound of Formula VIII, R 9 is hydrogen, and R 10 is halogen or C 1~3 In one or more embodiments, R 9 is halogen or C 1~3 is alkyl, R 10 is hydrogen. In some embodiments, R 9 is hydrogen, and R 10 is a halogen; or R 9 is a halogen, and R 10 is hydrogen. Preferably, the halogen is F.

[0194] In one or more embodiments of the compound of formula VIII, the D ring is an optionally substituted 4-7 membered monocyclic ring containing at least one N atom; preferably, the D ring is an optionally substituted piperazinyl, an optionally substituted piperidinyl, or an optionally substituted dihydropyridinyl. When the D ring is substituted, the substituents are halogen, hydroxyl, cyano, optionally substituted C 1~3 Alkyl, optionally substituted C 1~3 Alkoxy, and optionally substituted C 3~6 It may be 1 to 3 groups selected from the group consisting of cycloalkyl.

[0195] In one or more embodiments of the compound of Formula VIII, the D ring is selected from the following groups:

[0196] [ka] Preferably, the D ring is selected from:

[0197] [ka] and In the formula, *1 indicates the position where the D ring is bonded to the methylene; *2 indicates the position where the D ring is bonded to the pyridyl.

[0198] In one or more embodiments of the compound of Formula VIII, R 7 is hydrogen, halogen, cyano, optionally substituted C 1~3 Alkyl, optionally substituted C 1~3 Alkoxy or optionally substituted C 3~6 Cycloalkyl, preferably R 7 is hydrogen, halogen, cyano, C 1~3 Alkyl, halogenated C 1~3 Alkyl, or C 3~6 It is cycloalkyl.

[0199] In one or more embodiments of the compound of Formula VIII, Q is —C(O)—NR′R″ as described in any of the previous embodiments, where R′ and R″ are each independently hydrogen, optionally substituted C 1~10 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted heterocyclic groups, optionally substituted aryl or optionally substituted heteroaryl, preferably hydrogen, optionally substituted C 1~4 Alkyl, optionally substituted C 3~6 In one or more embodiments, Q is a halogen, cyano, C 1~3 Alkyl, halogenated C 1~3 Alkyl, C 1~3 Alkoxy and halogenated C 1~3and 5-membered heteroaryl optionally substituted with 1 to 3 substituents selected from alkoxy, wherein the 5-membered heteroaryl is preferably pyrrolyl, pyrazolyl, imidazolyl, or triazolyl.

[0200] In one or more embodiments of the compounds of formula I, preferred compounds are those represented by formula IX, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof:

[0201] [ka] wherein the D ring and Q are as defined in formula V; 7 is as defined in formulas IV and VI; R 10 is halogen, optionally substituted C 1~3 Alkyl, or optionally substituted C 1~3 is alkoxy; R 12 is halogen, cyano, optionally substituted C 1~6 Alkyl, optionally substituted C 1~3 Alkoxy, and optionally substituted C 3~6 (cycloalkyl).

[0202] In one or more embodiments of the compound of formula IX, R 10 is halogen or C 1~3 In one or more embodiments, R 10 is a halogen, preferably F.

[0203] In one or more embodiments of the compound of formula IX, R 12 is halogen, cyano, optionally substituted C 1~3 Alkyl, or optionally substituted C 3~6 In a preferred embodiment, R 12 is a halogen, C1~3 Alkyl or halogenated C 1~3 It is an alkyl.

[0204] In one or more embodiments of the compound of formula IX, the D ring is an optionally substituted 4-7 membered monocyclic ring containing at least one N atom; preferably, the D ring is an optionally substituted piperazinyl, an optionally substituted piperidinyl, or an optionally substituted dihydropyridinyl. When the D ring is substituted, the substituents are halogen, hydroxyl, cyano, optionally substituted C 1~3 Alkyl, optionally substituted C 1~3 Alkoxy, and optionally substituted C 3~6 It may be 1 to 3 groups selected from the group consisting of cycloalkyl.

[0205] In one or more embodiments of the compound of formula IX, the D ring is selected from the following groups:

[0206] [ka] Preferably, the D ring is selected from

[0207] [ka] and; In the formula, *1 indicates the position where the D ring is bonded to the methylene, and *2 indicates the position where the D ring is bonded to the pyridyl.

[0208] In one or more embodiments of the compound of formula IX, R 7 is hydrogen, halogen, cyano, optionally substituted C 1~3 Alkyl, optionally substituted C 1~3 Alkoxy or optionally substituted C 3~6 Cycloalkyl, preferably R 7 is hydrogen, halogen, cyano, C 1~3 Alkyl, halogenated C 1~3 Alkyl, or C3~6 More preferably, R 7 is halogen or C 1~3 It is an alkyl.

[0209] In one or more embodiments of the compound of formula IX, Q is —C(O)—NR′R″ as described in any of the previous embodiments, where R′ and R″ are each independently hydrogen, optionally substituted C 1~10 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted heterocyclic groups, optionally substituted aryl or optionally substituted heteroaryl, preferably hydrogen, optionally substituted C 1~4 Alkyl, optionally substituted C 3~6 More preferably, R' is H and R'' is C optionally substituted with 1 to 5 halogens. 1~4 Alkyl, or C 3~6 It is cycloalkyl.

[0210] Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , A 1 , A 2 , A 3 , L, Cy, R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , D 1 , B 1 , B 2 , B 3 , B 4, W, Q, R' and R'' are separately described above, but it should be understood that any of the described features, particularly preferred features, can be combined to form a range of different compounds of formula I (including formulas II, III, IV, V, VI, VII, VIII and IX) in the present disclosure. For example, in some embodiments of compounds of formula I (including formulas II, III, IV, V, VI, VII, VIII, and IX) in the present disclosure.

[0211] Preferred compounds of formula I include, but are not limited to, the following: 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[3,2-c]quinolin-4(5H)-one (Example 1); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[2,3-c]quinolin-4(5H)-one (Example 2); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[3,4-c]quinolin-4(5H)-one (Example 3); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thiazolo[4,5-c]quinolin-4(5H)-one (Example 4); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[2,3-c]quinolin-4(5H)-one (Example 5); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[3,2-c]quinolin-4(5H)-one (Example 6); 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 7); 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 8); 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 9); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydro-4H-pyrrolo[2,3-c]quinolin-4-one (Example 10); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methyl-3,5-dihydro-4H-pyrrolo[2,3-c]quinolin-4-one (Example 11); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)oxazolo[4,5-c]quinolin-4(5H)-one (Example 12); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thiazolo[5,4-c]quinolin-4(5H)-one (Example 13); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)oxazolo[5,4-c]quinolin-4(5H)-one (Example 14); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)isoxazolo[3,4-c]quinolin-4(5H)-one (Example 15); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[3,2-c]quinolin-4(5H)-one (Example 16); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[3,4-c]quinolin-4(5H)-one (Example 17); 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[3,2-c]quinolin-4(5H)-one (Example 18); 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[3,4-c]quinolin-4(5H)-one (Example 19); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluorothieno[3,2-c]quinolin-4(5H)-one (Example 20); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluorothieno[3,4-c]quinolin-4(5H)-one (Example 21); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluorofuro[3,2-c]quinolin-4(5H)-one (Example 22); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-dihydro-4H-pyrrolo[3,2-c]quinolin-4-one (Example 23); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrrolo[3,2-c]quinolin-4-one (Example 24); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one (Example 25); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1-methyl-1,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one (Example 26); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)isothiazolo[4,5-c]quinolin-4(5H)-one (Example 27); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methyl-3,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one (Example 28); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)isothiazolo[5,4-c]quinolin-4(5H)-one (Example 29); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)isoxazolo[5,4-c]quinolin-4(5H)-one (Example 30); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)isothiazolo[3,4-c]quinolin-4(5H)-one (Example 31); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)isothiazolo[4,3-c]quinolin-4(5H)-one (Example 32); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)isoxazolo[4,5-c]quinolin-4(5H)-one (Example 33); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2,5-dihydro-4H-pyrrolo[3,4-c]quinolin-4-one (Example 34); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-methyl-2,5-dihydro-4H-pyrrolo[3,4-c]quinolin-4-one (Example 35); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[3,4-c]quinolin-4(5H)-one (Example 36); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)isoxazolo[4,3-c]quinolin-4(5H)-one (Example 37); 9-Fluoro-7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[2,3-c]quinolin-4(5H)-one (Example 38); 9-Fluoro-7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[3,2-c]quinolin-4(5H)-one (Example 39); 9-Fluoro-7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[2,3-c]quinolin-4(5H)-one (Example 40); 9-Fluoro-7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thiazolo[4,5-c]quinolin-4(5H)-one (Example 41); 9-Fluoro-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 42); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-furo[3,2-c]quinolin-4(5H)-one (Example 43); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-furo[3,2-c]quinolin-4(5H)-one (Example 44); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (Example 45); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (Example 46); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylisoxazolo[4,5-c]quinolin-4(5H)-one (Example 47); 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoropyrrolo[1,2-c]quinazolin-5(6H)-one (Example 48); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 49); 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one (Example 50); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 51); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 52); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoroimidazo[1,5-a]quinoxalin-4(5H)-one (Example 53); 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoroimidazo[1,5-a]quinoxalin-4(5H)-one (Example 54); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoroimidazo[1,5-a]quinoxalin-4(5H)-one (Example 55); 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoroimidazo[1,5-a]quinoxalin-4(5H)-one (Example 56); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 57); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 58); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-chloro-pyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 59); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-chloro-pyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 60); 8-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one (Example 61); 8-((4-(2-fluoro-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one (Example 62); 8-((4-(2-methyl-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one (Example 63); 8-((4-(2-fluoro-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one (Example 64); 8-((4-(2-methyl-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one (Example 65); 7-((4-(2-fluoro-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one (Example 66); 7-((4-(2-fluoro-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one (Example 67); 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one (Example 68); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-methyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one (Example 69); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one (Example 70); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methyl-3,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one (Example 71); 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoropyrazolo[1,5-c]quinazolin-5(6H)-one (Example 72); 8-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoropyrazolo[1,5-c]quinazolin-5(6H)-one (Example 73); 7-((4-(6-methylcarbamoyl-2-methylpyridin-3-yl)piperazin-1-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,4-c]quinolin-4-one (Example 74); 7-((4-(6-methylcarbamoyl-2-methylpyridin-3-yl)piperazin-1-yl)methyl)-2-methyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,4-c]quinolin-4-one (Example 75); 7-((4-(6-methylcarbamoyl-2-methylpyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-1,2,3,5-tetrahydro-4H-pyrrolo[3,4-c]quinolin-4-one (Example 76); 7-((4-(6-methylcarbamoyl-2-fluoropyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-1,2,3,5-tetrahydro-4H-pyrrolo[3,4-c]quinolin-4-one (Example 77); 7-((4-(6-methylcarbamoyl-2-methylpyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-2-methyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,4-c]quinolin-4-one (Example 78); 7-((4-(6-methylcarbamoyl-2-fluoropyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-2-methyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,4-c]quinolin-4-one (Example 79); 7-((4-(6-methylcarbamoyl-2-methylpyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one (Example 80); 7-((4-(6-methylcarbamoyl-2-fluoropyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one (Example 81); 7-((4-(6-methylcarbamoyl-2-methylpyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one (Example 82); 7-((4-(6-methylcarbamoyl-2-fluoropyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one (Example 83); 7-((4-(6-methylcarbamoyl-2-methylpyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (Example 84); 7-((4-(6-methylcarbamoyl-2-fluoropyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (Example 85); 7-((4-(6-methylcarbamoyl-2-methylpyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-1,2-dihydrofuro[2,3-c]quinolin-4(5H)-one (Example 86); 7-((4-(6-methylcarbamoyl-2-fluoropyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-1,2-dihydrofuro[2,3-c]quinolin-4(5H)-one (Example 87); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-2-methyl-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (Example 88); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-8-fluoro-2-methyl-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (Example 89), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-2-methyl-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (Example 90); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-8-fluoro-2-methyl-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (Example 91); 6-Fluoro-7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (Example 92); 6-Fluoro-7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-methyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one (Example 93); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-8-fluorooxazolo[5,4-c]quinolin-4(5H)-one (Example 94); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluorooxazolo[5,4-c]quinolin-4(5H)-one (Example 95); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methyl-6-fluoroisoxazolo[4,5-c]quinolin-4(5H)-one (Example 96); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methyl-8-fluoroisoxazolo[4,5-c]quinolin-4(5H)-one (Example 97); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)isoxazolo[4,5-c]quinolin-4(5H)-one (Example 98); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydro-4H-pyrrolo[2,3-c]quinolin-4-one (Example 99); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-1-methyl-1,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one (Example 100); 7-((4-(2-(difluoromethyl)-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one (Example 101); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-8-fluorofuro[2,3-c]quinolin-4(5H)-one (Example 102); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-methylfuro[2,3-c]quinolin-4(5H)-one (Example 103); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-8-methylfuro[2,3-c]quinolin-4(5H)-one (Example 104); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-chlorofuro[2,3-c]quinolin-4(5H)-one (Example 105); 7-((4-(2-fluoro-6-carbamoylpyridin-3-yl)piperazin-1-yl)methyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one (Example 106); 6-Fluoro-7-((4-(5-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[2,3-c]quinolin-4(5H)-one (Example 107); 6-Fluoro-7-((4-(6-(methylcarbamoyl)-2-(trifluoromethyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[2,3-c]quinolin-4(5H)-one (Example 108); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperidin-1-yl)methyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one (Example 109); 7-((4-(2-fluoro-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one (Example 110); 7-((4-(2-fluoro-6-(5-methyl-1H-imidazol-2-yl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one (Example 111); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[2,3-c]quinolin-4(5H)-one (Example 112); 7-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[2,3-c]quinolin-4(5H)-one (Example 113); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[3,2-c]quinolin-4(5H)-one (Example 114); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluorofuro[3,4-c]quinolin-4(5H)-one (Example 115); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-2-methylfuro[2,3-c]quinolin-4(5H)-one (Example 116); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2,6-difluorofuro[2,3-c]quinolin-4(5H)-one (Example 117); 7-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[3,2-c]quinolin-4(5H)-one (Example 118); 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoropyrazolo[1,5-c]quinazolin-5(6H)-one (Example 119): 8-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoropyrazolo[1,5-c]quinazolin-5(6H)-one (Example 120); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 121); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 122), 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 123); 6-Fluoro-7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperidin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 124); 7-((4-(2-fluoro-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 125); 7-((4-(2-fluoro-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 126); 7-((4-(5-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 127); 7-((4-(2-cyano-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 128); 7-((4-(2-fluoro-6-(2,2-difluoroethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 129); 7-((4-(2-fluoro-6-(1H-imidazol-5-yl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 130); 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 131); 7-((4-(2-difluoromethyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 132); 7-((4-(2-trifluoromethyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 133); (R)-6-Fluoro-3-methyl-7-((3-((6-(methylcarbamoyl)pyridin-3-yl)amino)pyrrolidin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 134); (R)-6-fluoro-7-((3-((2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)amino)pyrrolidin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 135); 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-methyl-10-fluoroimidazo[1,2-c]quinazolin-5(6H)-one (Example 136); 8-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-methyl-10-fluoroimidazo[1,2-c]quinazolin-5(6H)-one (Example 137); 8-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,7-difluoroimidazo[1,2-c]quinazolin-5(6H)-one (Example 138); 8-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2,7-difluoroimidazo[1,2-c]quinazolin-5(6H)-one (Example 139); 8-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-methyl-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one (Example 140); 8-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methyl-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one (Example 141); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluorooxazolo[4,5-c]quinolin-4(5H)-one (Example 142); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[3,4-c]quinolin-4(5H)-one (Example 143); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)isoxazolo[3,4-c]quinolin-4(5H)-one (Example 144); 7-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoroimidazo[1,5-a]quinoxalin-4(5H)-one (Example 145); (R)-7-((3-((6-(methylcarbamoyl)pyridin-3-yl)amino)pyrrolidin-1-yl)methyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one (Example 146); 6-Fluoro-7-((4-(2-fluoro-6-(2,2-difluoroethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[2,3-c]quinolin-4(5H)-one (Example 147); 6-Fluoro-7-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[2,3-c]quinolin-4(5H)-one (Example 148); 6-Fluoro-7-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[3,4-c]quinolin-4(5H)-one (Example 149); 6-Fluoro-7-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[3,2-c]quinolin-4(5H)-one (Example 150); 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 151); 6-Fluoro-3-methyl-7-((6-methylcarbamoyl-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 152); 6-Fluoro-3-methyl-7-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 153); 6-Fluoro-7-((4-(2-fluoro-4-(methylcarbamoyl)phenyl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 154); 6-Fluoro-7-((4-(2-chloro-4-(methylcarbamoyl)phenyl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 155); (R)-6-fluoro-7-((4-(2-fluoro-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 156); 6-Fluoro-3-methyl-7-((4-(8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 157); 7-((4-(6-(1H-imidazol-2-yl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 158); 6-Fluoro-7-((4-(2-fluoro-6-((methyl-d3)carbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 169); 7-((4-(2-cyclopropyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 160); 6-Fluoro-7-((4-(3-fluoro-4-(methylcarbamoyl)phenyl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 161); 6-Fluoro-7-((4-(2-methyl-4-(methylcarbamoyl)phenyl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 162); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-ethyl-6-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 163); 6-Fluoro-7-((4-(2-fluoro-6-cyanopyridin-3-yl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 164); 6-Fluoro-7-((2-fluoro-6-methylcarbamoyl-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 165); (R)-6-fluoro-7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)-3-methylpiperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 166); (R)-6-Fluoro-3-methyl-7-((8-methylcarbamoyl-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-3(4H)-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 167); 8-Fluoro-7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 168); 8-Fluoro-7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 169); 8-Fluoro-7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 170); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-dimethylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 171); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-dimethylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 172); 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-dimethylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 173); 6-chloro-7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 174); 6-chloro-7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 175); 6-chloro-7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 176); 3,9-difluoro-7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 177); 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 178); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-trifluoromethyl-6-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 179); 7-((4-(2-fluoro-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 180); 7-((4-(2-fluoro-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 181); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,8-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 182); 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,8-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 183); 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,8-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 184); 7-((4-(2-fluoro-6-((methyl-d3)carbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 185); 7-((4-(2-fluoro-6-(2,2-difluoroethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 186); 7-((4-(2-cyano-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 187); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 188); 3-Fluoro-7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 189); 3-Fluoro-7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 190); 3-Fluoro-7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 191); 3-Fluoro-7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-chloropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 192); 3-Fluoro-7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-chloropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 193); 3-Fluoro-7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-chloropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 194); 7-((4-(2-fluoro-6-cyanopyridin-3-yl)piperazin-1-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 195); (R)-7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)-3-methylpiperazin-1-yl)methyl)-3,-6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 196); 7-((2-fluoro-6-methylcarbamoyl-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 197); (R)-7-((8-methylcarbamoyl-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-3(4H)-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 198); 6-Fluoro-7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-methyl-3-chloropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 199); 6-Fluoro-7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2,3-dimethylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 200); 7-((4-(2-cyano-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-(trifluoromethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 201); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-cyano-6-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 202); 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-isopropyl-6-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 203); 6-Fluoro-7-(1-(4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)ethyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (Example 204); 7-Fluoro-8-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)imidazo[1,5-c]quinazolin-5(6H)-one (Example 205); or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof.

[0212] Some of the compounds of the present disclosure may exist as stereoisomers, including optical isomers. The present disclosure includes all stereoisomers, as well as racemic mixtures of said stereoisomers, as well as the individual enantiomers, which may be separated according to methods known to those skilled in the art.

[0213] Examples of pharma- ceutically acceptable salts include inorganic and organic acid salts, such as hydrochloride, hydrobromide, phosphate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate, and oxalate salts; and inorganic and organic base salts formed with bases, such as sodium hydroxide, tris(hydroxymethyl)aminomethane (TRIS, tromethamine), and N-methyl-glucamine.

[0214] Examples of prodrugs of the compounds of the present disclosure include simple esters of carboxylic acid-containing compounds (e.g., C, by methods known in the art). 1~4 esters of hydroxy-containing compounds (e.g., those obtained by condensation with alcohols), esters of hydroxy-containing compounds (e.g., those obtained by condensation with alcohols), 1~4 Carboxylic acid, C 3~6 diacids or their anhydrides, such as those obtained by condensation with succinic anhydride and fumaric anhydride), imines of amino-containing compounds (e.g., C by methods known in the art); 1~4 and acetals and ketals of alcohol-containing compounds, such as those obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether by methods known in the art.

[0215] The compounds of the present disclosure can be prepared using methods known to those skilled in the art or the novel methods of the present disclosure. Specifically, the compounds of the present disclosure having Formula I (including Formulas II, III, IV, V, VI, VII, VIII and IX) can be prepared as shown by the exemplary reaction in Scheme 1. Sodium acetate and Pd(dppf)Cl 2 Aminoester exchange and Suzuki coupling of methyl 2-bromothiophene-3-carboxylate and (2-amino-4-(methoxycarbonyl)phenyl)boronic acid catalyzed by LiAlH afforded methyl 4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylate. 4 Reduction of methyl 4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylate with SOCl afforded 7-(hydroxymethyl)thieno[3,2-c]quinolin-4(5H)-one. 2Chlorination of 7-(hydroxymethyl)thieno[3,2-c]quinolin-4(5H)-one with 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)thieno[3,2-c]quinolin-4(5H)-one.

[0216] [ka]

[0217] Other related compounds can be prepared using similar methods. For example, 2-bromothiophene-3-carboxylate methyl is replaced with 4-bromothiophene-3-carboxylate methyl to produce the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[3,4-c]quinolin-4(5H)-one. 2-bromothiophene-3-carboxylate methyl is replaced with 5-bromothiazole-4-carboxylate methyl to produce the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thiazolo[4,5-c]quinolin-4(5H)-one. Replacing 2-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. Replacing 2-bromothiophene-3-carboxylate with 3-bromofuran-2-carboxylate produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[2,3-c]quinolin-4(5H)-one. Substitution of methyl 2-bromothiophene-3-carboxylate with methyl 3-bromo-1-methyl-1H-pyrrole-2-carboxylate afforded the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methyl-3,5-dihydro-4H-pyrrolo[2,3-c]quinolin-4-one.

[0218] Compounds of the present disclosure can be prepared as shown by the exemplary reaction in Scheme 2. Pd(PPh 3 ) 4 The Heck coupling reaction of methyl furan-3-carboxylate with 1,4-dibromo-2-nitrobenzene under the catalysis of 2-(4-bromo-2-nitrophenyl)furan-3-carboxylate was carried out to give methyl 2-(4-bromo-2-nitrophenyl)furan-3-carboxylate.4 The reaction of 7-bromofuro[3,2-c]quinolin-4(5H)-one with (tributylstannyl)-methanol (Bu Cl) catalyzed by chloro(2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (XPhos Pd G2) afforded 7-bromofuro[3,2-c]quinolin-4(5H)-one. 3 SnCH 2 Stille coupling reaction with 7-(hydroxymethyl)furo[3,2-c]quinolin-4(5H)-one gave 7-(hydroxymethyl)furo[3,2-c]quinolin-4(5H)-one. 2 The reaction of 7-(chloromethyl)furo[3,2-c]quinolin-4(5H)-one with N,6-dimethyl-5-(piperazin-1-yl)picolinamide under the catalysis of DIEA and KI afforded the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[3,2-c]quinolin-4(5H)-one.

[0219] [ka]

[0220] Other related compounds can be prepared using similar methods. For example, 1,4-dibromo-2-nitrobenzene was replaced with 1-bromo-2-fluoro-4-iodo-3-nitrobenzene to produce the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluorofuro[3,2-c]quinolin-4(5H)-one. N,6-dimethyl-5-(piperazin-1-yl)picolinamide was replaced with 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide to produce the target compound 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluorofuro[3,2-c]quinolin-4(5H)-one.

[0221] Compounds of the present disclosure can be prepared as shown by the exemplary reactions in Scheme 3. Reaction of ethyl 2-(4-bromo-2-nitrobenzoyl)-3-(dimethylamino)acrylate with hydrazinium hydroxide solution produced ethyl 5-(4-bromo-2-nitrophenyl)-1H-pyrazole-4-carboxylate. Reaction of ethyl 5-(4-bromo-2-nitrophenyl)-1H-pyrazole-4-carboxylate with Fe, AcOH produced 7-bromo-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one. Reaction of 7-bromo-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one with di-tert-butyl dicarbonate ((Boc)) under the catalysis of 4-(dimethylamino)pyridine (DMAP) produced 7-bromo-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one ... di-tert-butyl dicarbonate ((Boc) 2 O) to give tert-butyl 7-bromo-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-1-carboxylate. The reaction of tert-butyl 7-bromo-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-1-carboxylate with Bu under the catalysis of XPhos Pd G2 3 SnCH 2Stille coupling with OH afforded 7-(hydroxymethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one. Reaction of 7-(hydroxymethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one with HBr afforded 7-(bromomethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one. The reaction of 7-(bromomethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one with (Boc) under the catalysis of DMAP afforded 7-(bromomethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one. 2 Reaction with O gave tert-butyl 7-(bromomethyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-1-carboxylate. Reaction of tert-butyl 7-(bromomethyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-1-carboxylate with N,6-dimethyl-5-(piperazin-1-yl)picolinamide under the catalysis of DIEA and KI gave 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. Reaction 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 with HCl afforded the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one.

[0222] [ka]

[0223] Other related compounds can be prepared using similar methods. For example, replacing hydrazinium hydroxide solution with methylhydrazine produced the target compound 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. Replacing 2-(4-bromo-2-nitrobenzoyl)-3-(dimethylamino)ethyl acrylate with 2-(4-bromo-3-fluoro-2-nitrobenzoyl)-3-(dimethylamino)ethyl acrylate produced the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one. Substitution of 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)-6-fluoro-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one.

[0224] Compounds of the present disclosure can be prepared as shown by the exemplary reaction in Scheme 4. Pd(PPh 3 )Cl 2 Suzuki coupling of (2-(ethoxycarbonyl)furan-3-yl)boronic acid with methyl 4-bromo-3-fluoro-5-nitrobenzoate catalyzed by LiAlH afforded ethyl 3-(2-fluoro-4-(methoxycarbonyl)-6-nitrophenyl)furan-2-carboxylate. Reaction of ethyl 3-(2-fluoro-4-(methoxycarbonyl)-6-nitrophenyl)furan-2-carboxylate with Fe and AcOH afforded methyl 9-fluoro-4-oxo-4,5-dihydrofuro[2,3-c]quinoline-7-carboxylate. 4Reduction of methyl 9-fluoro-4-oxo-4,5-dihydrofuro[2,3-c]quinoline-7-carboxylate with 9-fluoro-7-(hydroxymethyl)furo[2,3-c]quinolin-4(5H)-one gave 9-fluoro-7-(hydroxymethyl)furo[2,3-c]quinolin-4(5H)-one. Reaction of 9-fluoro-7-(hydroxymethyl)furo[2,3-c]quinolin-4(5H)-one with HBr gave 7-(bromomethyl)-9-fluorofuro[2,3-c]quinolin-4(5H)-one. The reaction of 7-(bromomethyl)-9-fluorofuro[2,3-c]quinolin-4(5H)-one with N,6-dimethyl-5-(piperazin-1-yl)picolinamide under the catalysis of DIEA and KI afforded the target compound 9-fluoro-7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[2,3-c]quinolin-4(5H)-one.

[0225] [ka]

[0226] Other related compounds can be prepared using similar methods. For example, replacing (2-(ethoxycarbonyl)furan-3-yl)boronic acid with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate methyl produced the target compound 9-fluoro-7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[2,3-c]quinolin-4(5H)-one.

[0227] Compounds of the present disclosure can be prepared as shown by the exemplary reaction in Scheme 5. Reaction of 4-fluoro-1H-pyrazole-5-carboxylic acid with SOCl 2The reaction of 4-fluoro-1H-pyrazole-5-carbonyl chloride with methyl 3-amino-4-fluorobenzoate under the catalysis of lithium bis(trimethylsilyl)amide (LiHMDS) gave methyl 4-fluoro-3-(4-fluoro-1H-pyrazole-5-carboxamido)benzoate. 2 CO 3 The ring closure of methyl 4-fluoro-3-(4-fluoro-1H-pyrazole-5-carboxamido)benzoate under the catalysis of LiAlH gave methyl 3-fluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxylate. 4 The reaction of 3-fluoro-7-(hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one with SOCl gave 3-fluoro-7-(hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one. 2 The reaction of 7-(chloromethyl)-3-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one with 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide under the catalysis of DIEA and KI afforded the target compound 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one.

[0228] [ka]

[0229] Other related compounds can be prepared using similar methods.For example, 4-fluoro-1H-pyrazole-5-carboxylic acid is replaced with 4-fluoro-3-methyl-1H-pyrazole-5-carboxylic acid to produce the target compound 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one.4-fluoro-1H-pyrazole-5-carboxylic acid is replaced with 1H-imidazole-5-carboxylic acid to produce the target compound 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoroimidazo[1,5-a]quinoxalin-4(5H)-one.

[0230] Compounds of the present disclosure can be prepared as shown by the exemplary reactions in Scheme 6. Reaction of 2-amino-4-bromo-3-fluorobenzonitrile with chlorosulfonyl isocyanate produced 4-amino-7-bromo-8-fluoroquinazolin-2(1H)-one. Reaction of 4-amino-7-bromo-8-fluoroquinazolin-2(1H)-one with chloroacetaldehyde under the catalysis of sodium acetate produced 8-bromo-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one. Reaction of 8-bromo-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one with Bu under the catalysis of XPhos Pd G2 produced 8-bromo-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one. 3 SnCH 2Reaction of 7-fluoro-8-(hydroxymethyl)imidazo[1,2-c]quinazolin-5(6H)-one with OH gave 7-fluoro-8-(hydroxymethyl)imidazo[1,2-c]quinazolin-5(6H)-one. Reaction of 7-fluoro-8-(hydroxymethyl)imidazo[1,2-c]quinazolin-5(6H)-one with phosphorus tribromide gave 8-(bromomethyl)-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one. The reaction of 8-(bromomethyl)-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one with N,6-dimethyl-5-(piperazin-1-yl)picolinamide under the catalysis of DIEA and KI afforded the target compound 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one.

[0231] [ka]

[0232] 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)-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one. Substitution of N,6-dimethyl-5-(piperazin-1-yl)picolinamide with N-ethyl-6-fluoro-5-(piperazin-1-yl)picolinamide produced the target compound 8-((4-(2-fluoro-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one. Substitution of N,6-dimethyl-5-(piperazin-1-yl)picolinamide with N-ethyl-6-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 8-((4-(2-methyl-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-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 8-((4-(2-fluoro-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-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 8-((4-(2-methyl-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one.

[0233] Compounds of the present disclosure can be prepared as shown by the exemplary reaction in Scheme 7. Pd(PPh 3 )Cl2 Suzuki coupling of (2-(ethoxycarbonyl)furan-3-yl)boronic acid with 1,4-dibromo-2-fluoro-3-nitrobenzene catalyzed by ethyl 3-(4-bromo-3-fluoro-2-nitrophenyl)furan-2-carboxylate was afforded. Reaction of ethyl 3-(4-bromo-3-fluoro-2-nitrophenyl)furan-2-carboxylate with Fe and AcOH afforded 7-bromo-6-fluorofuro[2,3-c]quinolin-4(5H)-one. Reaction of 7-bromo-6-fluorofuro[2,3-c]quinolin-4(5H)-one with Bu catalyzed by XPhos Pd G2 afforded 3 SnCH 2 Stille coupling with OH afforded 6-fluoro-7-(hydroxymethyl)furo[2,3-c]quinolin-4(5H)-one. Reaction of 6-fluoro-7-(hydroxymethyl)furo[2,3-c]quinolin-4(5H)-one with HBr afforded 7-(bromomethyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one. Reaction of 7-(bromomethyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one with N-ethyl-6-fluoro-5-(piperazin-1-yl)picolinamide under DIEA and KI catalysis afforded the target compound 7-((4-(2-fluoro-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one.

[0234] [ka]

[0235] Other related compounds can be prepared using similar methods. For example, N-ethyl-6-fluoro-5-(piperazin-1-yl)picolinamide is replaced with N-cyclopropyl-6-fluoro-5-(piperazin-1-yl)picolinamide to produce the target compound 7-((4-(2-fluoro-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one. Substitution of N-ethyl-6-fluoro-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)-6-fluorofuro[2,3-c]quinolin-4(5H)-one.

[0236] Compounds of the present disclosure can be prepared as shown by the exemplary reaction in Scheme 8. Reaction of 4-fluoro-1H-pyrazole-5-carboxylic acid with SOCl 2 The reaction of 4-fluoro-1H-pyrazole-5-carbonyl chloride with 3-bromo-2,6-difluoroaniline under the catalysis of lithium bis(trimethylsilyl)amide (LiHMDS) gave N-(3-bromo-2,6-difluorophenyl)-4-fluoro-1H-pyrazole-5-carboxamide. The reaction of N-(3-bromo-2,6-difluorophenyl)-4-fluoro-1H-pyrazole-5-carboxamide with K 2 CO 3 The reaction of 7-bromo-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one with Bu under the catalysis of XPhos Pd G2 was used to produce 7-bromo-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one. 3 SnCH 2Stille coupling with OH gave 3,6-difluoro-7-(hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one. Reaction of 3,6-difluoro-7-(hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one with HBr gave 7-(bromomethyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one. The reaction of 7-(bromomethyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one with N,6-dimethyl-5-(piperazin-1-yl)picolinamide under the catalysis of DIEA and KI afforded the target compound 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one.

[0237] [ka]

[0238] 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)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one. Substitution of 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)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one. Substitution of N,6-dimethyl-5-(piperazin-1-yl)picolinamide with 5-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N-methylpicolinamide produced the target compound 7-((2-(6-(methylcarbamoyl)pyridin-3-yl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one.

[0239] Compounds of the present disclosure can be prepared as shown by the exemplary reaction in Scheme 9. 4-Bromo-3-fluoro-2-nitroaniline with NaNO 2 , HCl and SnCl 2 2H 2Reaction of (4-bromo-3-fluoro-2-nitrophenyl)hydrazine with methyl 4-(dimethylamino)-3-methyl-2-oxobut-3-enoate and AcOH gave methyl 1-(4-bromo-3-fluoro-2-nitrophenyl)-4-methyl-1H-pyrazole-5-carboxylate. Reaction of methyl 1-(4-bromo-3-fluoro-2-nitrophenyl)-4-methyl-1H-pyrazole-5-carboxylate with Fe and AcOH gave 7-bromo-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one. Reaction of 7-bromo-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one with Bu under the catalysis of XPhos Pd G2 gave methyl 1-(4-bromo-3-fluoro-2-nitrophenyl)-4-methyl-1H-pyrazole-5-carboxylate. 3 SnCH 2 Reaction with OH gave 6-fluoro-7-(hydroxymethyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one. Reaction of 6-fluoro-7-(hydroxymethyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one with HBr gave 7-(bromomethyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one. 2 CO 3 and the reaction of 7-(bromomethyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one with N-(2,2-difluoroethyl)-6-fluoro-5-(piperazin-1-yl)picolinamide under the catalysis of KI afforded the target compound 7-((4-(2-fluoro-6-(2,2-difluoroethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one.

[0240] [ka]

[0241] Other related compounds can be prepared using similar methods.For example, N-(2,2-difluoroethyl)-6-fluoro-5-(piperazin-1-yl)picolinamide is replaced with 6-chloro-N-methyl-5-(piperazin-1-yl)picolinamide to produce target compound 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one. Substitution of N-(2,2-difluoroethyl)-6-fluoro-5-(piperazin-1-yl)picolinamide with 6-(difluoromethyl)-N-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 7-((4-(2-difluoromethyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one. Substitution of N-(2,2-difluoroethyl)-6-fluoro-5-(piperazin-1-yl)picolinamide with N-methyl-5-(piperazin-1-yl)-6-(trifluoromethyl)picolinamide produced the target compound 7-((4-(2-trifluoromethyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one. Substitution of N-(2,2-difluoroethyl)-6-fluoro-5-(piperazin-1-yl)picolinamide with 5-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-N,6-dimethylpicolinamide produced the target compound 7-((2-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one.

[0242] An important aspect of the present disclosure is the discovery that the compound of formula I (including formula II, III, IV, V, VI, VII, VIII and IX) is a PARP inhibitor, particularly a selective PARP1 inhibitor.Therefore, the compound of formula I (including formula II, III, IV, V, VI, VII, VIII and IX) or their stereoisomers, tautomers, N-oxides, hydrates, isotopically substituted derivatives, solvates or pharma- ceutically acceptable salts, or mixtures thereof, or their prodrugs, 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).

[0243] Cyclic nucleotide phosphodiesterases (PDEs) constitute a superfamily of enzymes that catalyze the degradation of the second messengers cyclic adenosine 3',5' monophosphate (cAMP) and cyclic guanosine 3',5' monophosphate (cGMP). PDEs mediate a variety of physiological processes, including ion channel function, muscle contraction, central nervous system (CNS) function, apoptosis, glycogenolysis, and gluconeogenesis. However, PDE dysfunction has been implicated in a variety of neurological and cardiovascular diseases, chronic obstructive pulmonary disease (COPD), and cancer development (Leroy et al., 2018 Circulation 138:2003-2006; Johnson et al., Lancet 2001,358:256-257; Lee et al., 2015 Nature 519:472-476). PDE3 inhibitors are known to increase myocardial contractility and heart rate and reduce blood pressure (Young et al., 1988 Drugs 36: 158-192). Inhibition of PDE3 has also been shown to cause myocardial lesions (myocellular necrosis with inflammatory cell infiltration) and mesenteric, splenic and pancreatic vascular lesions in rats (Zhang et al., 2002 Mol Pharmacol 62: 514-520; Aguirre et al., 2010 Toxicologic Pathology, 38: 416-428). Another important aspect of the present invention is the use of compounds of formula I (including formulas II, III, IV, V, VI, VII, VIII and IX), particularly compounds of formula I (including formulas II, III, IV, V, VI, VII, VIII and IX), wherein A 2 and / or A 3 is CR 1 and R 1 is halogen, in particular F, and / or R 9 and / or R 10 is halogen, particularly F), the selectivity for PARP1 is significantly improved and the inhibitory activity against PDE3A is significantly reduced. In particular, the compounds of formulas VII, VIII and IX (wherein R 10is halogen, especially F), has very low inhibitory activity against PDE3A. Therefore, the compounds of the present invention have low off-target side effects, low toxicity, and are more suitable for clinical use and combination with other drugs.

[0244] In the present disclosure, diseases or conditions responsive to inhibition of PARP activity (particularly PARP1 activity) include cancers, including 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 tumors, malignant melanoma, gastric cancer, colon cancer, malignant pancreatic islet tumors, malignant carcinoma, and the like. The tumor may be a solid tumor or a hematological tumor, including, but not limited to, thyroid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteosarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary tumors, 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.

[0245] Thus, the present disclosure includes a method for treating or preventing a disease or condition that responds to the inhibition of PARP activity (particularly PARP1 activity), comprising administering to a subject (particularly a mammal, more particularly a human) in need of such treatment or prevention an effective amount of a compound of formula I (including formulas II, III, IV, V, VI, VII, VIII and IX) or its stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharmaceutically acceptable salt, or mixture thereof, or prodrug thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula I (including formulas II, III, IV, V, VI, VII, VIII and IX) or its stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharmaceutically acceptable salt, or mixture thereof, or prodrug thereof. In the present disclosure, the subject includes a mammal, more particularly a human.

[0246] In carrying out the treatment method, an effective amount of the pharmaceutical preparation is administered to an individual who shows one or more symptoms of these disorders. The pharmaceutical preparation comprises a therapeutically effective amount of a compound of formula I (including formulas II, III, IV, V, VI, VII, VIII and IX) formulated for oral, intravenous, local or topical 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 alleviate symptoms associated with the disease. Such an amount may be administered as a single dose or according to an effective regimen. The amount may cure the disease, but is typically administered to improve the symptoms of the disease. Typically, repeated administration is required to achieve the desired improvement of symptoms.

[0247] In another embodiment, there is provided a pharmaceutical composition comprising a compound of Formula I (including Formulas II, III, IV, V, VI, VII, VIII and IX) or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, as a PARP inhibitor.

[0248] Another embodiment of the present disclosure is directed to a pharmaceutical composition that is effective for treating or preventing cancer, comprising the compound of formula I (including formula II, III, IV, V, VI, VII, VIII and IX) as PARP inhibitor, or its stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharmaceutically acceptable salt and prodrug, in combination with at least one known anticancer drug or its pharmaceutically acceptable salt.In particular, the compound of the present disclosure can be combined with other anticancer drugs related to DNA damage and repair mechanism (such as ATM inhibitor, ATR inhibitor, Wee1 inhibitor, DNA-PK inhibitor, etc.); HDAC inhibitor (such as Volinota, Romididesin, Papiseta and Bailesta); other anticancer drugs related to cell division (including Chk1 / 2 inhibitor, CDK4 / 6 inhibitor such as Paposinib), other targeted anticancer drugs (including USP1 inhibitor, PRMT5 inhibitor, Polθ inhibitor, RAD51 inhibitor, etc.). Other known anti-cancer drugs that may be used in the anti-cancer combination therapy include alkylating agents such as busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, and carboplatin; topoisomerase I inhibitors such as camptothecin, irinotecan, and topotecan; topoisomerase I inhibitors such as doxorubicin, epirubicin, aclacinomycin, mitoxantrone, elliptinium, and etoposide. 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 mAb, 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, sacituzumab goviteca antibody-drug conjugates (ADCs) 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 anticancer drugs that may be used in the anticancer combination therapy include tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin-2), sipuleucel-T (prostate cancer treatment vaccine);

[0249] 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 agent in a single pharmaceutical composition. Alternatively, the compound of the present disclosure can be administered separately from at least one known anti-cancer agent. In one embodiment, the compound of the present disclosure and at least one known anti-cancer agent are administered substantially simultaneously, i.e., all agents 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 agent are administered according to individual dosing schedules, provided that the compounds reach therapeutic levels in blood.

[0250] Another embodiment of the present disclosure is directed to a bioconjugate for inhibiting tumors. The bioconjugate is composed of the compounds 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 compounds described herein to their target, making them effective anti-cancer agents. The bioconjugate can also enhance the anti-cancer effect of therapeutically useful antibodies, such as trastuzumab or rituximab.

[0251] Another embodiment of the present disclosure is directed to a pharmaceutical composition effective for inhibiting tumors comprising a PARP inhibitor of Formula I (including Formulas II, III, IV, V, VI, VII, VIII and IX), 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 or at different times with radiation therapy.

[0252] Yet another embodiment of the present disclosure is directed to a pharmaceutical composition comprising a PARP inhibitor of Formula I (including Formulas II, III, IV, V, VI, VII, VIII and IX), 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 the mammal with a pharmaceutical composition described herein.

[0253] The pharmaceutical compositions of the present disclosure include all pharmaceutical formulations containing the compounds of the present disclosure in an amount effective to achieve their intended purpose. Although individual needs vary, determining the optimal amount of each component in a pharmaceutical formulation 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, about 0.01 mg to about 10 mg per kg of body weight is orally administered. When a known anti-cancer agent is also administered, it is administered in an amount effective to achieve its intended purpose. The optimal amount of such known anti-cancer agents is well known to those skilled in the art.

[0254] 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. A unit dose may be administered one or more times per day, with 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.

[0255] In a topical formulation, the compounds of the present disclosure may be present in a concentration of about 0.01 to 100 mg per gram of carrier.

[0256] The compounds of the present disclosure may be administered as raw chemicals. The compounds of the present disclosure may also be administered as part of a suitable pharmaceutical formulation containing pharma- ceutically acceptable carriers (including excipients and adjuvants) that facilitate the processing of the compounds into pharma- ceutically acceptable formulations. Preferably, pharmaceutical formulations, especially oral formulations, and those used for preferred administration, such as tablets, dragees, and capsules, as well as solutions suitable for injection or oral administration, contain about 0.01%-99%, preferably about 0.25%-75%, of the active compound(s) together with the excipient(s).

[0257] Also included within the scope of the present disclosure are non-toxic pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically acceptable non-toxic base, such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, tris(hydroxymethyl)aminomethane, N-methyl-glucamine, etc.

[0258] The pharmaceutical formulations 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.

[0259] 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 depends on the age, health and weight of the recipient, the type of concurrent therapy, the frequency of treatment, and the nature of the desired effect.

[0260] The pharmaceutical preparations of the present disclosure are prepared in a known manner, for example by means of conventional mixing, granulation, dragee making, dissolving or lyophilization processes. Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliary agents as desired or necessary, thereby obtaining tablets or dragee cores.

[0261] 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 a suitable coating that is resistant to gastric juices. For this purpose, concentrated saccharide 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.For example, dyes or pigments may be added to the tablets or dragee coatings for identification or to characterize combinations of active compound doses.

[0262] Other medicaments that can be used orally include the push-fit capsule made of gelatin, and the soft sealed capsule made of gelatin and 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, stabilizers may be added.

[0263] 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 as suitable oily injection suspensions may be administered.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.

[0264] According to one aspect of the present disclosure, the compounds of the present disclosure are used in topical and parenteral formulations for the treatment of skin cancer.

[0265] 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, moisturizers, and antioxidants may also be included, and, if desired, color or fragrance additives may also be included. In addition, 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.

[0266] Creams are preferably formulated from a mixture of mineral oil, self-emulsifying beeswax, and water (mixed with a small amount of the active ingredient dissolved in the oil, such as almond oil. A typical example of such a cream is one that contains about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil, and about 1 part almond oil.

[0267] 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 about 30% by weight of almond oil and about 70% by weight of white soft paraffin.

[0268] The present disclosure also relates to the use of the compounds of the present disclosure for the manufacture of a medicament for treating a clinical condition responsive to the inhibition of the activity of PARP. The medicament can include the pharmaceutical composition described above. EXAMPLES

[0269] 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-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[3,2-c]quinolin-4(5H)-one a) Preparation of methyl 4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylate: A mixture of methyl 2-bromothiophene-3-carboxylate (170.0 mg, 0.8 mmol) and (2-amino-4-(methoxycarbonyl)phenyl)boronic acid (214.0 mg, 0.9 mmol) in DMF (15.0 mL) was treated with sodium acetate (95.0 mg, 1.2 mmol) and Pd(dppf)Cl 2 (169.0 mg, 0.2 mmol) was added under nitrogen. The mixture was stirred at 120° C. overnight under nitrogen. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=20 / 1) to give the product (76.7 mg, yellow solid, yield: 38%). MS(ESI): 260.00 [M+H] + . b) Preparation of 7-(hydroxymethyl)thieno[3,2-c]quinolin-4(5H)-one: A suspension of methyl 4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylate (75.0 mg, 0.3 mmol) in THF (8 mL) was treated with LiAlH 4 (1M in THF, 1.2 mL, 1.2 mmol) was added at 0° C. under nitrogen. The mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was then quenched with water (5 mL) and extracted with EA (15 mL×3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product (60.0 mg, crude, brown solid). MS(ESI): 232.00 [M+H] + . c) Preparation of 7-(chloromethyl)thieno[3,2-c]quinolin-4(5H)-one: To a suspension of 7-(hydroxymethyl)thieno[3,2-c]quinolin-4(5H)-one (60.0 mg, 0.3 mmol) in DCM (6 mL) was added DMF (2 drops) and thionyl chloride (123.5 mg, 1.0 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature for 15 min. After the reaction was complete, the mixture was concentrated to give the product (50.0 mg, crude, grey solid). MS(ESI): 250.00 [M+H] + . d) Preparation of 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[3,2-c]quinolin-4(5H)-one: To a solution of 7-(chloromethyl)thieno[3,2-c]quinolin-4(5H)-one (50.0 mg, 0.2 mmol), KI (3.3 mg, 0.02 mmol) and N,6-dimethyl-5-(piperazin-1-yl)picolinamide (56.0 mg, 0.24 mmol) in CH3CN (5 mL) was added DIEA (156.0 mg, 1.2 mmol) at room temperature. The resulting solution was stirred at 4°C for 1 hour at rt. 2 The mixture was stirred at 80° C. for 1.5 hours under reduced pressure. After the reaction was completed, the solvent was removed under vacuum. The residue was purified by preparative TLC (DCM / MeOH=10 / 1) to give the target compound (14.5 mg, white solid, 3-step yield: 11%). The compounds of the following Examples 2-5 were prepared using synthetic methods similar to those described in Example 1.

[0270] [Table 1] Example 6 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[3,2-c]quinolin-4(5H)-one a) Preparation of methyl 2-(4-bromo-2-nitrophenyl)furan-3-carboxylate: A solution of methyl furan-3-carboxylate (1.0 g, 8.0 mmol) in toluene (10 mL) was treated with 1,4-dibromo-2-nitrobenzene (2.7 g, 9.6 mmol) and potassium acetate (2.4 g, 24.0 mmol) and Pd(PPh 3 ) 4 (924.0 mg, 0.8 mmol) was added. The mixture was stirred under nitrogen at 110° C. overnight. After the reaction was complete, the mixture was poured into water (100 mL) and extracted with EA (20 mL×3), the organic phase was washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The residue was purified by silica gel column (PE:EA=30:1) to give the product (610 mg, yellow solid, yield: 22.6%). b) Preparation of 7-bromofuro[3,2-c]quinolin-4(5H)-one: A solution of methyl 2-(4-bromo-2-nitrophenyl)furan-3-carboxylate (610 mg, 1.8 mmol) in EtOH (10 mL) was treated with Fe (503 mg, 9.0 mmol) and NH 4 Cl (481 mg, 9.0 mmol) and H 2 A solution of 2,4-dichloromethane (5 mL) was added. The mixture was stirred at 80° C. overnight. After the reaction was complete, the mixture was filtered through diatomaceous earth. The filtrate was concentrated and the residue was purified by H 2 The mixture was diluted with O and extracted with EA, and the organic phase was washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The residue was then purified on a silica gel column (PE:EA=5:1) to give the product (270 mg, white oil, yield: 57.1%). MS(ESI): 263.96 [M+H] + . c) Preparation of 7-(hydroxymethyl)furo[3,2-c]quinolin-4(5H)-one: A solution of 7-bromofuro[3,2-c]quinolin-4(5H)-one (270 mg, 1.03 mmol) in dioxane (5 mL) was added with Bu 3 SnCH 2OH (660 mg, 2.06 mmol) and Xphos Pd G2 (78.7 mg, 0.1 mmol) were added. The mixture was stirred at 90° C. overnight under nitrogen atmosphere. After the reaction was completed, a solution of KF (1 M, 10 mL) was added at room temperature, the mixture was stirred at room temperature for 10 min, and filtered. The filtrate was extracted with EA (20 mL×3). The combined organic phase was washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The residue was triturated with a mixed solvent of PE and EA (PE:EA=1:1), and the solid was collected by filtration to give a white solid product (120 mg, grey solid, yield: 54.3%). MS(ESI): 216.25 [M+H] + . d) Preparation of 7-(chloromethyl)furo[3,2-c]quinolin-4(5H)-one: A solution of 7-(hydroxymethyl)furo[3,2-c]quinolin-4(5H)-one (100 mg, 0.46 mmol) in DCM (2 mL) was added with SOCl 2 (276 mg, 2.33 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to give the product (110 mg, crude, white solid). MS(ESI): 234.00 [M+H] + . e) Preparation of 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[3,2-c]quinolin-4(5H)-one: To a solution of 7-(chloromethyl)furo[3,2-c]quinolin-4(5H)-one (110 mg, 0.47 mmol) in acetonitrile (5 mL) was added N,6-dimethyl-5-(piperazin-1-yl)picolinamide (134 mg, 0.56 mmol), KI (7.8 mg, 0.05 mmol), and DIEA (181.9 mg, 1.41 mmol). The mixture was stirred at 80° C. for 1 h under nitrogen atmosphere. After the reaction was completed, the solvent was removed under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=10:1) to give the target compound (7.0 mg, white solid, yield: 3.5%). Example 7 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: A solution of ethyl 2-(4-bromo-2-nitrobenzoyl)-3-(dimethylamino)acrylate (1.0 g, 2.69 mmol) in acetonitrile (8 mL) was added with hydrazine hydrate (H 2 50% in O, 323 mg, 2.69 mmol) was added. The resulting mixture was stirred at 50° C. for 1 h. After the reaction was completed, 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 phase was 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 product (800 mg, yellow solid, yield: 88%). MS(ESI): 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 completed, the mixture was cooled to room temperature and filtered. The solid was dried under reduced pressure to give the product (400 mg, white solid, yield: 67.6%). MS(ESI): 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 (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 phase was washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The residue was purified by silica gel (DCM:MeOH=10:1) to give the product (500 mg, yellow solid, yield: 73%). MS(ESI): 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 Bu. 3 SnCH 2 OH (881 mg, 2.7 mmol) and Xphos Pd G2 (80 mg, 0.13 mmol, 0.1 equiv) were added at room temperature. The mixture was stirred overnight at 90° C. under nitrogen atmosphere. After the reaction was completed, a solution of KF aqueous solution (1 M, 10 mL) was added at room temperature. The mixture was stirred for 10 min at room temperature, filtered, and the filtrate was extracted with EA (50 mL×3). The combined organic phase was washed with brine and anhydrous Na 2 SO 4 The residue was triturated with a mixed solvent of PE and EA (PE:EA=1:1, 10 mL) and the solid was collected by filtration to give the product (450 mg, crude, white solid, yield: 90%). MS(ESI): 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% aq, 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 residue and the mixture was concentrated under reduced pressure to give the product (300 mg, crude, off-white solid). MS (ESI): 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 the resulting mixture was extracted with EA (40 mL x 2). The combined organic phase was washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The residue was purified by silica gel (DCM:MeOH=10:1) to give the product (131 mg, yellow solid, 33%). MS(ESI): 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 7-(bromomethyl)-1-methyl-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (13 mg, 0.34 mmol), KI (10.0 mg, 0.1 mmol) and 7-(chloromethyl)-3-ethylquinazoline-2,4(1H,3H)-dione (81 mg, 0.34 mmol) in acetonitrile (3 mL) was added DIEA (140.0 mg, 1.0 mmol) and N2 The mixture was added at room temperature under reduced pressure. The resulting suspension was stirred at 80° C. for 30 min. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was washed with acetonitrile to give the product (95.0 mg, white solid, yield: 52%). MS(ESI): 532.25 [M+H] + . h) Preparation of 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-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 solution (5 mL) with N 2 The resulting suspension was stirred at room temperature for 2 hours. After the reaction was completed, 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 compound of Example 8 was prepared using a synthetic method similar to that described for Example 7 (Scheme 3), and the compound of Example 9 was prepared using a synthetic method similar to that described for Example 1 (Scheme 1).

[0271] [Table 2] Example 10 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydro-4H-pyrrolo[2,3-c]quinolin-4-one a) Preparation of methyl 3-(2-amino-4-(hydroxymethyl)phenyl)-1H-pyrrole-2-carboxylate: Dioxane and H 2A solution of (3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (100 mg, 0.40 mmol) in a mixture of 1,2-dioxaborolan-2-yl (v / v=10 / 1, 5.5 mL) and 3-bromo-1H-pyrrole-2-methylcarboxylate (82 mg, 0.40 mmol), K 2 CO 3 (111 mg, 0.80 mmol) and Pd(dppf)Cl 2 (29 mg, 0.04 mmol) was added at room temperature. The mixture was diluted with N 2 The mixture was stirred at 100° C. under atmospheric pressure for 16 hours. After the reaction was completed, the mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure to give the product (270 mg, crude, brown solid), which was used directly in the next step without further purification. MS(ESI): 247.10 [M+H] + . b) Preparation of 7-(hydroxymethyl)-3H-pyrrolo[2,3-c]quinolin-4(5H)-one: A solution of methyl 3-(2-amino-4-(hydroxylmethyl)phenyl)-1H-pyrrole-2-carboxylate (270 mg, 1.1 mmol) in AcOH (3.0 mL) was diluted with N 2 The mixture was stirred at room temperature under atmospheric pressure for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was triturated with a mixed solvent of PE and EA (PE / EA=1 / 1, 10 mL×3) to give the product (72 mg, black solid, yield: 30%). MS(ESI): 215.10 [M+H] + . c) Preparation of 7-(bromomethyl)-3H-pyrrolo[2,3-c]quinolin-4(5H)-one: HBr(H 2 A solution of 7-(hydroxymethyl)-3H-pyrrolo[2,3-c]quinolin-4(5H)-one (64 mg, 0.3 mmol) in 48% in 2H2O (5.0 mL) was stirred at 85° C. for 3 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in MeCN (3.0 mL) and concentrated under reduced pressure to give the product (90 mg, crude, grey solid). MS(ESI): 555.50 [2M+H] + . d) Preparation of 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydro-4H-pyrrolo[2,3-c]quinolin-4-one: To a solution of 7-(bromomethyl)-3H-pyrrolo[2,3-c]quinolin-4(5H)-one (90 mg, 0.3 mmol) and N,6-dimethyl-5-(piperazin-1-yl)picolinamide (76 mg, 0.32 mmol) in MeCN (2.0 mL) was added KI (5.4 mg, 0.03 mmol) and DIEA (126 mg, 0.97 mmol). The mixture was diluted with N 2 The mixture was stirred at 80° C. for 0.5 h under reduced pressure. After the reaction was completed, the mixture was concentrated in vacuo. The residue was purified by preparative HPLC (C18, CH 3 CN / H 2 0, 30~55%) to give the target compound (16.2 mg, off-white solid, yield: 12%). The following compounds of Example 11 were prepared using a synthetic method similar to that described in Example 10, and the compounds of Examples 12-13 were prepared using a synthetic method similar to that described in Example 1 (Scheme 1).

[0272] [Table 3] Example 14 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)oxazolo[5,4-c]quinolin-4(5H)-one

[0273] [ka] a) Preparation of 4-amino-3-hydroxy-7-(hydroxymethyl)quinolin-2(1H)-one: Dioxane (20.0 mL) and H 2 To a solution of (3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (1.6 g, 7.2 mmol) in 2HO (4.0 mL) was added ethyl 4-bromooxazole-5-carboxylate (1.8 g, 7.2 mmol), KCO3 (1.987g, 14.4mmol), Pd(dppf)Cl 2 (522 mg, 0.72 mmol) was added. The resulting mixture was stirred at 100° C. overnight under nitrogen atmosphere. The reaction mixture was slowly cooled to room temperature and concentrated under reduced pressure to give the product (1.6 g, crude, black oil). MS(ESI): 207.00[M+H] + . b) Preparation of 4-amino-7-(bromomethyl)-3-hydroxyquinolin-2(1H)-one: HBr(H 2 A solution of 4-amino-3-hydroxy-7-(hydroxymethyl)quinolin-2(1H)-one (1.6 mg, 7.2 mmol) in 48% in O, 20 mL) was stirred at 85° C. for 1 h. The reaction mixture was concentrated under reduced pressure. Acetonitrile (10 ml) was added to the residue and the mixture was concentrated under reduced pressure to give the product (1.6 g, crude, black oil). MS(ESI): 268.95[M+H] + . c) Preparation of 7-(bromomethyl)oxazolo[5,4-c]quinolin-4(5H)-one: A solution of 4-amino-7-(bromomethyl)-3-hydroxyquinolin-2(1H)-one (1.6 g, 7.2 mmol) in trimethoxymethane (20 mL) was stirred at 85° C. for 18 h. After the reaction was complete, the solvent was removed under vacuum. The residue was purified by preparative TLC (PA:EA=1:1) to give the product (180 mg, crude, white solid, yield: 10%). MS(ESI): 280.95[M+H] + . d) Preparation of 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)oxazolo[5,4-c]quinolin-4(5H)-one: CH 3To a solution of 7-(bromomethyl)oxazolo[5,4-c]quinolin-4(5H)-one (180 mg, 0.7 mmol), KI (12 mg, 0.07 mmol) and N,6-dimethyl-5-(piperazin-1-yl)picolinamide (211 mg, 0.7 mmol) in CN (6 mL) was added DIEA (251.0 mg, 1.9 mmol) at room temperature under nitrogen. The resulting suspension was stirred at 80° C. for 1 h. After the reaction was completed, the solvent was removed under vacuum. The residue was purified by preparative HPLC to give the target compound (4.2 mg, white solid, yield: 1.4%). MS(ESI): 433.15[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.14 (s, 1H), 8.96 (s, 1H), 8.39 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.48 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 3.63 (s, 2H), 2.97-2.87 (m, 4H), 2.76 (d, J = 4.6 Hz, 3H), 2.60-2.52 (m, 4H), 2.50 (s, 3H). The following compounds of Examples 15-21 were prepared using a synthetic method similar to that described in Example 1 (Scheme 1); the compound of Example 22 was prepared using a synthetic method similar to that described in Example 6 (Scheme 2).

[0274] [Table 4] Example 23 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-dihydro-4H-pyrrolo[3,2-c]quinolin-4-one

[0275] [ka] a) Preparation of N-(4-bromo-2-nitrobenzyl)formamide: A solution of (4-bromo-2-nitrophenyl)methanamine (11.5 g, 49.8 mmol) in ethyl formate (100.0 mL) was stirred at 45° C. for 16 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM / MeOH=1 / 0-200 / 1) to give the product (10.4 g, yellow solid, yield: 90%). MS(ESI): 258.95 [M+H] + . b) Preparation of 1-(4-bromo-2-nitrophenyl)-N-methylidinemethanaminium: To a solution of N-4-bromo-2-nitrophenyl)methylformamide (500.0 mg, 1.9 mmol) in THF (30.0 mL) was added Burgess reagent (689.9 mg, 2.9 mmol) at room temperature. The reaction mixture was stirred at 45° C. for 1 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EA=1 / 0-50 / 1) to give the product (130.0 mg, white solid, yield: 27%). MS(ESI): 479.00 [2M+H] + . c) Preparation of methyl 2-(4-bromo-2-nitrophenyl)-1H-pyrrole-3-carboxylate: Methyl propionate (750.2 mg, 8.9 mmol) and Ag in dioxane (42.0 mL). 2 CO 3 To a solution of (164.0 mg, 0.6 mmol), 1-(4-bromo-2-nitrophenyl)-N-methylidynemethanaminium (1.4 g, 5.9 mmol) was added at room temperature. The reaction mixture was stirred at 80° C. for 0.5 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EA=1 / 0-5 / 1) to give the product (1.5 g, yellow solid, yield: 77%). MS(ESI): 324.90 [M+H] + . d) Preparation of 7-bromo-1,5-dihydro-4H-pyrrolo[3,2-c]quinolin-4-one: To a solution of methyl 2-(4-bromo-2-nitrophenyl)-1H-pyrrole-3-carboxylate (800.0 mg, 2.4 mmol) in acetic acid (20.0 mL) was added zinc dust (1.6 g, 24.6 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was triturated with DCM (100 mL×3) to give the product (507.0 mg, white solid, yield: 78%). MS(ESI): 262.90 [M+H] + . e) Preparation of 7-(hydroxymethyl)-1,5-dihydro-4H-pyrrolo[3,2-c]quinolin-4-one: To a solution of 7-bromo-1,5-dihydro-4H-pyrrolo[3,2-c]quinolin-4-one (250.0 mg, 0.9 mmol) in dioxane (20.0 mL) was added (tributylstannyl)methanol (1.5 g, 4.5 mmol) and Xphos Pd G2 (74.8 mg, 0.1 mmol) at room temperature. The reaction mixture was stirred at 110° C. under nitrogen for 16 h. After the reaction was complete, the mixture was cooled to room temperature and quenched with a saturated aqueous solution of KF (20.0 mL). The mixture was filtered. The solid was washed with MeOH (10.0 mL) to give the product (280 mg, crude, black solid). MS(ESI): 215.05 [M+H] + . f) Preparation of 7-(bromomethyl)-1,5-dihydro-4H-pyrrolo[3,2-c]quinolin-4-one: A solution of 7-(hydroxymethyl)-1H,4H,5H-pyrrolo[3,2-c]quinolin-4-one (175.0 mg, 0.8 mmol) in THF (15.0 mL) was diluted with PBr 3 (442.2 mg, 1.6 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was quenched with ice water (5.0 mL) and NaHCO 3A saturated aqueous solution of (10.0 mL) was added to adjust pH=7-8, and then the mixture was extracted with DCM (100.0 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the product (230.0 mg, crude, yellow oil). MS(ESI): 276.90 [M+H] + . g) Preparation of 7-((4-(2-methyl-6-(methylcarbamoyl)quinolin-3-yl)piperazin-1-yl)methyl)-1,5-dihydro-4H-pyrrolo[3,2-c]quinolin-4-one: To a solution of 7-(bromomethyl)-1,5-dihydro-4H-pyrrolo[3,2-c]quinolin-4-one (230.0 mg, 0.8 mmol) in MeCN (10.0 mL) was added N,6-dimethyl-5-(piperazin-1-yl)pyridine-2-carboxamide (291.6 mg, 1.2 mmol) and potassium carbonate (573.5 mg, 4.1 mmol) at room temperature. The reaction mixture was stirred at 80° C. for 16 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated. The residue was purified by preparative HPLC (C18, MeCN / H 2 O=0%-27%, 0.1% HCOOH) to give the title compound (42.4 mg, yellow solid, 10% yield). MS(ESI): 431.20[M+H] + . 1 H NMR (400MHz, CD 3 OD):δ8.12 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 1.3 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.45 (dd, J = 8.2, 1.5 Hz, 1H), 7.26 (d, J = 3.0 Hz, 1H), 6.84 (d, J = 3.0 Hz, 1H), 4.54 (s, 2H), 3.68-3.55 (m, 2H), 3.51- 3.38 (m, 4H), 3.16-3.04 (m, 2H), 2.93 (s, 3H), 2.59 (s, 3H). Example 24 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrrolo[3,2-c]quinolin-4-one

[0276] [ka] The compound of Example 24 was prepared using a synthetic method similar to that described in Example 23. MS(ESI): 449.20[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.18 (s, 1H), 8.43-8.36 (m, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.53 (dd, J = 10.6, 8.1 Hz, 1H), 7.36 (s, 1H), 7.21 - 7.08 (m, 2H), 6.54 (d, J = 2.9 Hz, 1H), 4.11 (s, 3H), 3.56 (s, 2H), 3.22-3.12 (m, 4H), 2.72 (d, J = 4.8 Hz, 3H), 2.58-2.49 (m, 4H). Example 25 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one

[0277] [ka] a) Preparation of (2-amino-4-(bromomethyl)phenyl)boronic acid: A solution of (3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (0.5 g) in HBr (48% aq, 10 mL) was stirred at 85° C. for 1 h. The reaction mixture was concentrated under reduced pressure. Acetonitrile (5 ml) was added to the residue and the mixture was concentrated under reduced pressure three times to give the product (350 mg, crude, orange solid). MS(ESI): 232.05[M+H] + . b) Preparation of (2-amino-4-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)phenyl)boronic acid: To a solution of (2-amino-4-(bromomethyl)phenyl)boronic acid (1.0 g, crude) in acetonitrile (50 mL) was added N,6-dimethyl-5-(piperazin-1-yl)picolinamide (1.0 g, 4.4 mmol), KI (72 mg, 0.4 mmol) and DIEA (1.6 g, 13.1 mmol) at room temperature under nitrogen. The resulting mixture was stirred at 80° C. for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give the product (0.2 g, white solid, 14% yield). MS(ESI): 384.00[M+H] + . c) Preparation of methyl 5-(2-amino-4-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)phenyl)-1H-imidazole-4-carboxylate: In a mixture of dioxane (10 mL) and H 2 To a solution of methyl 5-bromo-1H-imidazole-4-carboxylate (100 mg, 0.5 mmol) in 20O (1 mL), (2-amino-4-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)phenyl)boronic acid (187.7 mg, 0.5 mmol), K 2 CO 3 (258.0mg, 1.2mmol), Pd(dppf)Cl 2 (72.6 mg, 0.1 mmol) was added at room temperature. The reaction mixture was heated to 100° C. and N 2The mixture was stirred under reduced pressure for 18 hours. After the reaction was completed, the mixture was diluted with water (5 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC ((DCM / MeOH = 10 / 1) to give the product (30.0 mg, black solid). MS (ESI): 464.20 [M+H] + . d) Preparation of 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one: A solution of methyl 5-(2-amino-4-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)phenyl)-1H-imidazole-4-carboxylate (30.0 mg) in AcOH (10 mL) was stirred at 80° C. for 3 h under nitrogen. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, CH 3 CN / H 2 HO, 10-40%, 0.1% HCOOH) to give the target compound (12.5 mg, white solid, 2-step yield: 6%). MS(ESI): 432.20[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 13.52 (s, 1H), 11.52 (s, 1H), 8.43 - 8.33 (m, 1H), 8.19 (s, 1H), 7.97 (s, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.21 (d, J = 8.3 Hz, 1H), 3.60 (s, 2H), 2.98 - 2.87 (m, 4H), 2.76 (d, J = 4.9 Hz, 3H), 2.61 - 2.52 (m, 4H), 2.46 (s, 3H). Example 26 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1-methyl-1,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one

[0278] [ka] a) Preparation of 5-(4-(4-bromo-3-nitrobenzyl)piperazin-1-yl)-N,6-dimethylpicolinamide: CH 3 To a solution of 1-bromo-4-(bromomethyl)-2-nitrobenzene (2.0 g), KI (113 mg, 0.7 mmol) and N,6-dimethyl-5-(piperazin-1-yl)picolinamide (1.6 g, 6.8 mmol) in CN (30 mL) was added DIEA (5.3 g, 40.8 mmol) at room temperature. The resulting solution was stirred at 80 °C for 2 h. The mixture was quenched with water (50 mL) and extracted with DCM (50 mL × 3). 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 (SiO 2 , petroleum ether:ethyl acetate=10 / 1 to 1 / 1) to give the product (1.1 g, yellow solid). MS(ESI): 450.30[M+H] + . b) Preparation of 5-(4-(3-amino-4-bromobenzyl)piperazin-1-yl)-N,6-dimethylpicolinamide: EtOH (10 mL) and H 2 To a solution of 5-(4-(4-bromo-3-nitrobenzyl)piperazin-1-yl)-N,6-dimethylpicolinamide (1.0 g, 2.1 mmol) in 2HO (10 mL) was added NH 4 Cl (1.1 g, 21.0 mmol) and zinc dust (683 mg, 10.5 mmol) were added at room temperature. The reaction mixture was cooled to room temperature and cooled to 37° C. 2The mixture was stirred at room temperature under reduced pressure for 16 hours. The mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column (DCM / MeOH = 100 / 1 to 20 / 1) to give the product (470 mg, yellow solid, yield: 50%). MS (ESI): 420.05 [M+H] + . c) Preparation of methyl 5-(2-amino-4-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)phenyl)-1-methyl-1H-imidazole-4-carboxylate: To a solution of methyl 1-methyl-5-(trimethylstannyl)-1H-imidazole-4-carboxylate (220 mg, 0.7 mmol) in dioxane (10 mL), 5-(4-(3-amino-4-bromobenzyl)piperazin-1-yl)-N,6-dimethylpicolinamide (302 mg, 0.7 mmol) and Pd(dppf)Cl 2 (73 mg, 0.1 mmol) was added at room temperature. The reaction mixture was heated to 100° C. and N 2 The mixture was stirred under reduced pressure for 16 hours. The mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to give the product (40 mg, grey solid). MS (ESI): 478.25 [M+H] + . d) Preparation of 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1-methyl-1,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one: A solution of methyl 5-(2-amino-4-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)phenyl)-1-methyl-1H-imidazole-4-carboxylate (40 mg) in AcOH is diluted with N 2 The mixture was stirred at 80° C. for 3 hours under reduced pressure. After the reaction was completed, the mixture was concentrated. The residue was purified by preparative HPLC (C18, CH 3 CN / H 2HO, 10-40%, 0.1% HCOOH) to give the target compound (7.5 mg, white solid, 2-step yield: 2%). MS(ESI): 446.15[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.46 (s, 1H), 8.40 - 8.36 (m, 1H), 8.24 (s, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.44 (d, J = 8 Hz, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.21 (dd, J = 8.2, 1.6 Hz, 1H), 4.12 (s, 3H), 3.60 (s, 2H), 2.98 - 2.86 (m, 4H), 2.76 (d, J = 4.8 Hz, 3H), 2.59 - 2.50 (m, 4H), 2.46 (s, 3H). The following compounds of Examples 27-29 were prepared using synthetic methods similar to those described in Example 1 (Scheme 1).

[0279] [Table 5] Example 30 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)isoxazolo[5,4-c]quinolin-4(5H)-one Dioxane (4.0 mL) and H 2 To a solution of (2-amino-4-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)phenyl)boronic acid (64 mg, 0.2 mmol) in 2HO (1.0 mL), ethyl 4-bromooxazole-5-carboxylate (45 mg, 0.2 mmol), K 2 CO 3 (70 mg, 0.5 mmol) and Pd(dppf)Cl 2 (15 mg, 0.02 mmol) was dissolved in N 2The mixture was added at room temperature under atmospheric pressure. The resulting mixture was stirred at 100° C. overnight. The mixture was slowly cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the target compound (6.6 mg, gray solid). The following compounds of Examples 31-37 and 39 were prepared using synthetic methods similar to those described in Example 1 (Scheme 1); the compound of Example 38 was prepared using synthetic methods similar to those described in Example 40 (Scheme 4).

[0280] [Table 6] Example 40 9-Fluoro-7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[2,3-c]quinolin-4(5H)-one a) Preparation of ethyl 3-(2-fluoro-4-(methoxycarbonyl)-6-nitrophenyl)furan-2-carboxylate: THF (10 mL) and H 2 To a solution of methyl 4-bromo-3-fluoro-5-nitrobenzoate (500.0 mg, 1.8 mmol) in 2 mL of HO was added (2-(ethoxycarbonyl)furan-3-yl)boronic acid (398.5 mg, 2.1 mmol), Pd(PPh 3 ) 2 Cl 2 (126.3 mg, 0.2 mmol) and K 2 CO 3 (496.8 mg, 3.6 mmol) was added. The mixture was degassed, purged with nitrogen for 2 min, and stirred under nitrogen at 85 °C for 16 h. After the reaction was completed, the mixture was quenched with water (30 mL) and 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 preparative TLC (PE / EA = 40 / 1 to 10 / 1) to give the product (450.0 mg, yellow solid, yield: 74%). b) Preparation of methyl 9-fluoro-4-oxo-4,5-dihydrofuro[2,3-c]quinoline-7-carboxylate: To a solution of ethyl 3-(2-fluoro-4-(methoxycarbonyl)-6-nitrophenyl)furan-2-carboxylate (450.0 mg, 1.3 mmol) in AcOH (20 mL), iron powder (375.2 mg, 6.7 mmol) was added. The resulting mixture was stirred at 80° C. for 2 h. After the reaction was completed, 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 product (400.0 mg, crude, brown solid). MS(ESI): 262.05 [M+H] + . c) Preparation of 9-fluoro-7-(hydroxymethyl)furo[2,3-c]quinolin-4(5H)-one: A solution of methyl 9-fluoro-4-oxo-4,5-dihydrofuro[2,3-c]quinoline-7-carboxylate (400 mg) in THF (5 mL) was treated with LiAlH 4 (1M in THF, 3.1 mL, 3.1 mmol) was added at 0° C. under nitrogen. The resulting mixture was stirred at 0° C. for 20 min and then warmed to room temperature. After stirring for 2 h, the mixture was quenched with ice water (20 mL) and the pH value was adjusted to 3 with 1M aqueous HCl. The resulting mixture was extracted with EA (30 mL×3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product (150.0 mg, yellow solid, two-step yield: 48%). MS(ESI): 234.00 [M+H] + . d) Preparation of 7-(bromomethyl)-9-fluorofuro[2,3-c]quinolin-4(5H)-one: A solution of 9-fluoro-7-(hydroxymethyl)furo[2,3-c]quinolin-4(5H)-one (150 mg, 0.6 mmol) in HBr (48% in water, 10 mL) was stirred at 80° C. for 2 h. After the reaction was complete, the mixture was concentrated to give the product (150.0 mg, crude, yellow solid). MS(ESI): 297.90 [M+H] + . e) Preparation of 9-fluoro-7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[2,3-c]quinolin-4(5H)-one: CH 3 To a solution of 7-(bromomethyl)-9-fluorofuro[2,3-c]quinolin-4(5H)-one (75.0 mg, crude from above), KI (16.6 mg, 0.1 mmol) and N,6-dimethyl-5-(piperazin-1-yl)picolinamide (93.2 mg, 0.4 mmol) in CN (10 mL) was added DIEA (196.7 mg, 1.5 mmol) at room temperature. The resulting suspension was stirred at 80° C. for 2 h. After the reaction was completed, the solvent was removed under vacuum. The residue was purified by preparative TLC (DCM / MeOH=15 / 1) to give the target compound (34.0 mg, white powder, two-step yield: 16%). The following compound of Example 41 was prepared using a synthetic method similar to that described in Example 1 (Scheme 1); compounds of Examples 42 and 45-46 were prepared using a synthetic method similar to that described in Example 7 (Scheme 3); compounds of Examples 43-44 were prepared using a synthetic method similar to that described in Example 6 (Scheme 2).

[0281] [Table 7] Example 47 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylisoxazolo[4,5-c]quinolin-4(5H)-one

[0282] [ka] a) Preparation of 7-(hydroxymethyl)-3-methylisoxazolo[4,5-c]quinolin-4(5H)-one: To a solution of (3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (500.0 mg, 2.0 mmol) in dioxane (5 mL), ethyl 5-chloro-3-methylisoxazole-4-carboxylate (378.0 mg, 2.0 mmol), K 2 CO 3 (553mg, 4.0mmol), Pd(dppf)Cl 2 (145 mg, 0.2 mmol) was added. The resulting mixture was stirred at 100° C. overnight under nitrogen atmosphere. The reaction mixture was slowly cooled to room temperature and concentrated under reduced pressure to give the product (350.0 mg, crude, white solid), which was used in the next step without further purification. MS(ESI): 231.05[M+H] + . b) Preparation of 7-(bromomethyl)-3-methylisoxazolo[4,5-c]quinolin-4(5H)-one: A solution of 7-(bromomethyl)-3-methylisoxazolo[4,5-c]quinolin-4(5H)-one (350.0 mg, crude) in HBr (48% aq, 6 mL) was stirred at 85° C. for 1 h. The reaction mixture was concentrated under reduced pressure. Acetonitrile (3 mL) was added to the residue and the mixture was concentrated under reduced pressure to give the product (150.0 mg, crude, orange solid). MS (ESI): 294.95 [M+H] + . c) Preparation of 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylisoxazolo[4,5-c]quinolin-4(5H)-one: To a solution of 7-(bromomethyl)-3-methylisoxazolo[4,5-c]quinolin-4(5H)-one (324.0 mg, crude), KI (45.0 mg) and N,6-dimethyl-5-(piperazin-1-yl)picolinamide (297.0 mg, 1.0 mmol) in acetonitrile (6 mL) was added DIEA (387.0 mg, 3.0 mmol) at room temperature under nitrogen. The resulting mixture was stirred at 80° C. for 4 hours. After the reaction was completed, the solvent was removed under vacuum. The residue was purified by preparative HPLC to give the target compound (4.2 mg, white solid, 3-step yield: 1%). MS(ESI): 447.25[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.88 (s, 1H), 8.43 (d, J = 5.3 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.48 (d, J = 6.8 Hz, 2H), 7.33 (d, J = 8.1 Hz, 1H), 3.67 (s, 2H), 2.99 - 2.93 (m, 4H), 2.80 (d, J = 4.8 Hz, 3H), 2.64-2.57 (m, 4H), 2.56 (s, 3H), 2.49 (s, 3H). Example 48 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoropyrrolo[1,2-c]quinazolin-5(6H)-one

[0283] [ka] a) Preparation of tert-butyl 2-(4-bromo-3-fluoro-2-nitrophenyl)-1H-pyrrole-1-carboxylate: Toluene (20 mL) and H 2A solution of 1,4-dibromo-2-fluoro-3-nitrobenzene (1.0 g, 3.4 mmol) in 20O (4 mL) was treated with (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid (745.9 mg, 3.5 mmol), Pd(PPh3)4 (389.2 mg, 0.3 mmol) and Na 2 CO 3 (1.3 g, 11.8 mmol) was added. The mixture was degassed and purged with nitrogen for 2 min. The tube was sealed and the mixture was stirred at 85 °C for 16 h. After the reaction was complete, the mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with DCM (50 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 silica gel (EtOAc / PE, 1-10%) to give the product (1.2 g, yellow oil, yield: 92.2%). b) Preparation of 8-bromo-7-fluoropyrrolo[1,2-c]quinazolin-5(6H)-one: To a solution of tert-butyl 2-(4-bromo-3-fluoro-2-nitrophenyl)-1H-pyrrole-1-carboxylate (1.2 g, 3.2 mmol) in AcOH (50 mL) was added iron powder (905 mg, 16.2 mmol). The resulting mixture was stirred at 80 °C for 3 h. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with DCM (30 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 silica gel column (EtOAc / PE, 5-20%) to give the product (165 mg, yellow solid, yield: 18.9%). MS(ESI): 280.95 [M+H] + . c) Preparation of 7-fluoro-8-(hydroxymethyl)pyrrolo[1,2-c]quinazolin-5(6H)-one: To a solution of 8-bromo-7-fluoropyrrolo[1,2-c]quinazolin-5(6H)-one (105 mg, 0.38 mmol) in dioxane (5 mL) was added (tributylstannyl)methanol (181 mg, 0.56 mmol) and Xphos Pd G2 (44 mg, 0.06 mmol) at room temperature. The mixture was stirred overnight at 90° C. under nitrogen atmosphere. After the reaction was complete, a solution of KF (1 M aq., 10 mL) was added at room temperature and the mixture was stirred at the same temperature for 0.5 h, filtered and the filtrate was extracted with EA (50 mL×3). The combined organic phase was washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The residue was purified by silica gel column (EtOAc / PE, 10-50%) to give the product (65 mg, white solid, yield: 74.9%). MS(ESI): 233.00 [M+H] + . d) Preparation of 8-(chloromethyl)-7-fluoropyrrolo[1,2-c]quinazolin-5(6H)-one: A solution of 7-fluoro-8-(hydroxymethyl)pyrrolo[1,2-c]quinazolin-5(6H)-one (57.0 mg, 0.25 mmol) in DCM (5 mL) was diluted with SOCl 2 (58.1 mg, 0.49 mmol) and DMF (2 drops) were added. The mixture was stirred at 80° C. for 2 h. After the reaction was completed, the mixture was concentrated to give the product (55.3 mg, crude, yellow solid). MS(ESI): 251.00 [M+H] + . e) Preparation of 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoropyrrolo[1,2-c]quinazolin-5(6H)-one: CH 3 To a solution of 8-(bromomethyl)-7-fluoropyrrolo[1,2-c]quinazolin-5(6H)-one (20.0 mg), KI (1.3 mg, 0.01 mmol) and N,6-dimethyl-5-(piperazin-1-yl)picolinamide (22.5 mg, 0.10 mmol) in CN (5 mL) was added K 2 CO3 (44.2 mg, 0.32 mmol) was added at room temperature. The resulting suspension was stirred at 80° C. for 16 h. After the reaction was completed, the solvent was removed under vacuum. The residue was purified by preparative TLC (DCM / MeOH=10 / 1) to give the target compound (7.2 mg, white solid, yield: 19.5%). MS(ESI): 449.20[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.54 (s, 1H), 8.38 (d, J = 4.5 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.61 (s, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.20 (t, J = 7.0 Hz, 1H), 7.01 (s, 1H), 6.67 (d, J = 3.4 Hz, 1H), 3.64 (s, 2H), 2.93 - 2.88 (m, 4H), 2.75 (d, J = 4.4 Hz, 3H), 2.59 - 2.55 (m, 4H), 2.44 (s, 3H). Example 49 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one a) Preparation of 4-fluoro-1H-pyrazole-5-carbonyl chloride: SOCl 2 A suspension of 4-fluoro-1H-pyrazole-5-carboxylic acid (175.0 mg, 1.35 mmol, 1.0 equiv) in hexanes (5 mL) was stirred under nitrogen at 80° C. for 2 h. The mixture was concentrated in vacuo to give the product (160 mg, crude, white solid). b) Preparation of methyl 4-fluoro-3-(4-fluoro-1H-pyrazole-5-carboxamido)benzoate: To a solution of 4-fluoro-1H-methyl 3-amino-4-fluorobenzoate (218 mg, 1.3 mmol) in THF (3 mL) was added LiHMDS (1.0 M in THF, 3.2 mL) under nitrogen at 0° C. The mixture was stirred at 0° C. for 15 min, then a solution of 4-fluoro-1H-pyrazole-5-carbonyl chloride (160.0 mg, 1.1 mmol, in 2 mL of THF) was added dropwise and the mixture was stirred at 0° C. for 0.5 h. After the reaction was complete, water (10 mL) was added to quench the LiHMDS and the mixture was extracted with EA (5 mL×3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH=20 / 1) to give the product (110 mg, white solid, yield: 36%). MS(ESI): 282.00 [M+H] + . c) Preparation of methyl 3-fluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxylate: To a solution of methyl 4-fluoro-3-(4-fluoro-1H-pyrazole-5-carboxamido)benzoate (100 mg, 0.4 mmol) in DMSO (10 mL), 2 CO 3 (194 mg, 1.4 mmol) was added at room temperature under nitrogen. The mixture was stirred at 120° C. overnight in a sealed tube. After the reaction was completed, water (20 mL) was added and the mixture was extracted with EA (10 mL×3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to give the product (85 mg, white solid, 91% yield). MS(ESI): 262.05 [M+H] + . d) Preparation of 3-fluoro-7-(hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one: THF (3 mL) and H 2 To a solution of methyl 3-fluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxylate (85 mg, 0.33 mmol) in 20HO (1 mL) was added LiAlH 4(1.0M in THF, 1.3 mL) was added under nitrogen at 0° C. The mixture was stirred at 0° C. for 10 min, the mixture was quenched with water (3 mL) and 1M aqueous NaOH (1 mL) was added. The resulting mixture was stirred at room temperature for 15 min. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was washed with (MeOH / EA=2 / 3) to give the product (70 mg, white solid, yield: 92%). MS(ESI): 234.00 [M+H] + . e) Preparation of 7-(chloromethyl)-3-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one: A suspension of 3-fluoro-7-(hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (50 mg, 0.22 mmol) in DCM (3 mL) was diluted with DMF (1.0 mg, 0.01 mmol) and SOCl 2 (153 mg, 1.3 mmol) was added under nitrogen at 0° C. The mixture was stirred at 0° C. for 10 min and the mixture was concentrated in vacuo to give the product (54.0 mg, crude, yellow solid). MS(ESI): 252.20 [M+H] + . f) Preparation of 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one: To a solution of 8-(chloromethyl)-10-fluoropyrrolo[1,2-c]quinazolin-5(6H)-one (54 mg, 0.2 mmol) in acetonitrile (5 mL) was added KI (3.6 mg, 0.02 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (52 mg, 0.2 mmol) and K 2 CO 3 (146.2 mg, 1.1 mmol) was added at room temperature under nitrogen. The mixture was stirred at 80° C. for 2 h. Water (10 mL) was added to the mixture and extracted with EA (5 mL×3). The organic phase was concentrated and the residue was purified by preparative TLC (DCM / MeOH=20 / 1) to give the target compound (20.8 mg, white solid, two-step yield: 21%). Example 50 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one a) Preparation of 4-amino-7-bromo-8-fluoroquinazolin-2(1H)-one: A mixture of 2-amino-4-bromo-3-fluorobenzonitrile (800 mg, 3.72 mmol) and chlorosulfonyl isocyanate (632 mg, 4.48 mmol) in DCM (5 mL) was stirred at room temperature for 3 h. The reaction was concentrated under reduced pressure. The residue was treated with saturated NaHCO 3 Aqueous solution (10 mL) was added and the resulting mixture was stirred at 100° C. for 1 h. The reaction was cooled to room temperature and filtered. The solid was washed with water (10 mL) and dried to give the product (780 mg, off-white solid, yield: 79%). MS(ESI): 257.96 [M+H] + . b) Preparation of 8-bromo-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one: To a solution of 4-amino-7-bromo-8-fluoroquinazolin-2(1H)-one (190 mg, 0.74 mmol) in DMF (5 mL) was added 2-chloroacetaldehyde (287 mg, 3.68 mmol) and sodium acetate (151 mg, 1.84 mmol). The mixture was stirred at 100° C. for 3 h. The reaction was cooled to room temperature and filtered. The solid was washed with water (5 mL) and dried to give the product (95 mg, grey solid, yield: 46%). MS(ESI): 281.96 [M+H] + . c) Preparation of 7-fluoro-8-(hydroxymethyl)imidazo[1,2-c]quinazolin-5(6H)-one: A solution of 8-bromo-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one (90 mg, 0.32 mmol) in dioxane (5 mL) was treated with Bu 3 SnCH 2 OH (123 mg, 0.38 mmol) and Xphos Pd G2 (25 mg, 0.03 mmol) were added at room temperature. The mixture was cooled to 37° C. 2 Atmosphere, 90 °C overnight. After the reaction was completed, a solution of KF (1M aq, 5 mL) was added at room temperature, the mixture was stirred at room temperature for 10 min, filtered, and the filtrate was extracted with EA (50 mL x 3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 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 product (61 mg, white solid, yield: 81%). MS(ESI): 234.06 [M+H] + . d) Preparation of 8-(bromomethyl)-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one: A solution of 7-fluoro-8-(hydroxymethyl)imidazo[1,2-c]quinazolin-5(6H)-one (90 mg, 0.38 mmol) in DCM (5 mL) was added with PBr 3 (514 mg, 1.9 mmol) 2 The mixture was added at 0° C. under reduced pressure. The mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was then concentrated under reduced pressure, the residue triturated with DCM (5 mL) and the solid collected by filtration to give the product (65 mg, white solid, 65% yield). MS(ESI): 295.90 [M+H] + . e) Preparation of 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one: CH 3 To a solution of 8-(bromomethyl)-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one (30 mg, 0.17 mmol), KI (3.0 mg, 0.015 mmol) and N,6-dimethyl-5-(piperazin-1-yl)picolinamide (46.1 mg, 0.18 mmol) in CN (10 mL) was added DIEA (97.1 mg, 0.75 mmol) at room temperature. The resulting solution was stirred at 80° C. for 2 h. After the reaction was completed, the solvent was removed under vacuum. The residue was purified by preparative TLC (DCM:MeOH=10:1) to give the target compound (36.8 mg, white solid, yield: 80%). The following compounds of Examples 51-60 were prepared using a synthetic method similar to that described in Example 49 (Scheme 5); the compounds of Examples 61-65 were prepared using a synthetic method similar to that described in Example 50 (Scheme 6).

[0284] [Table 8-1]

[0285] [Table 8-2] Example 66 7-((4-(2-fluoro-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one a) Preparation of ethyl 3-(4-bromo-3-fluoro-2-nitrophenyl)furan-2-carboxylate: To a solution of 1,4-dibromo-2-fluoro-3-nitrobenzene (12.5 g, 42.09 mmol) in DMF (125 mL) was added (2-(ethoxycarbonyl)furan-3-yl)boronic acid (7.74 g, 42.09 mmol), Pd(dppf)Cl 2 Dichloromethane complex (3.43 g, 4.21 mmol) and Cs 2 CO 3 (41.2 g, 126.26 mmol) was added. The mixture was stirred at 100° C. for 3 hours. Water (150 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (100 mL×3). The organic phase was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by flash silica chromatography (elution gradient 0-5% ethyl acetate in petroleum ether) to give the product (7.16 g, yellow oil, yield: 48%). MS(ESI): 357.90 [MH] + . b) Preparation of 7-bromo-6-fluorofuro[2,3-c]quinolin-4(5H)-one: To a solution of ethyl 3-(4-bromo-3-fluoro-2-nitrophenyl)furan-2-carboxylate (5.4 g, 15.08 mmol) in AcOH (100 mL), Fe powder (4.2 g, 75.39 mmol) was added. The resulting mixture was stirred at 80 °C for 3 h. After the reaction was complete, the reaction mixture was concentrated and purified by flash silica chromatography (elution gradient of 0-5% methanol in dichloromethane) to give the product (3.07 g, yellow solid, 72% yield). MS(ESI): 281.95 [MH] + . c) Preparation of 6-fluoro-7-(hydroxymethyl)furo[2,3-c]quinolin-4(5H)-one: To a solution of 7-bromo-6-fluorofuro[2,3-c]quinolin-4(5H)-one (3.07 g, 10.89 mmol) in dioxane (60 mL), (tributylstannyl)methanol (5.24 g, 16.33 mmol) and Xphos Pd G2 (857.6 mg, 1.09 mmol) were added at room temperature. The mixture was stirred at 100° C. for 3 hours. After the reaction was completed, the reaction mixture was filtered. The filter cake was washed with DMF, and the DMF phase was concentrated and washed with dichloromethane to give the product (1.2 g, white solid, 47% yield). MS(ESI): 234.05 [MH] + . d) Preparation of 7-(bromomethyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one: To a solution of 6-fluoro-7-(hydroxymethyl)furo[2,3-c]quinolin-4(5H)-one (1.2 g, 5.15 mmol) in DCM (50 mL) was added phosphorus tribromide (2.8 g, 10.30 mmol). The mixture was stirred at room temperature for 16 h. After the reaction was complete, the mixture was concentrated to give the product (1.4 g, crude, white solid, 92% yield), which was used in the next step without further purification. MS(ESI): 295.85[MH] + . e) Preparation of 7-((4-(2-fluoro-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one: To a solution of 7-(bromomethyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one (52.7 mg, 0.18 mmol), KI (3.0 mg, 0.02 mmol) and N-ethyl-6-fluoro-5-(piperazin-1-yl)picolinamide (45.0 mg, 0.18 mmol) in acetonitrile (20 mL) was added K 2 CO 3 (73.9 mg, 0.54 mmol) was added at room temperature. The resulting mixture was stirred at 80° C. for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filter cake was purified by preparative HPLC to give the target compound (35.2 mg, white solid, 42% yield). The following compounds of Examples 67 and 68 were prepared using a synthetic method similar to that described in Example 66 (Scheme 7); compounds of Examples 69-71 were prepared using a synthetic method similar to that described in Example 1 (Scheme 1); compounds of Examples 72-73 were prepared using a synthetic method similar to that described in Example 48; compounds of Examples 74-87 were prepared using a synthetic method similar to that described in Example 40 (Scheme 4).

[0286] [Table 9-1]

[0287] [Table 9-2] Example 88 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-2-methyl-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one a) Preparation of (3-amino-4-bromo-2-fluorophenyl)methanol: To a solution of (4-bromo-2-fluoro-3-nitrophenyl)methanol (1.6 g, 7.2 mmol) in AcOH (25 mL) was added iron powder (1.2 g, 21.6 mmol) at room temperature. The mixture was cooled to 37° C. with 5% CO.sub.2O.sub.3. 2 The mixture was stirred at 85° C. under atmospheric pressure for 1 h. The mixture was slowly cooled to room temperature. Water (50 mL) was added and the mixture was extracted with EA (50 mL×2). The combined organic phase was washed with saturated NaHCO 3 Washed with aqueous solution and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was triturated with a mixed solvent of PE and EA (PE / EA=20:1, 10 mL) to give the product (900 mg, orange solid, yield: 56%). MS(ESI): 219.90[M+H] + . b) Preparation of (3-amino-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol: A solution of (3-amino-4-bromo-2-fluorophenyl)methanol (730 mg, 3.3 mmol) in dioxane (10 mL) was treated with bis(pinacolato)diboron (1.1 g, 4.0 mmol), KOAc (980 mg, 10.0 mmol) and Pd(dppf)Cl. 2 (239 mg, 0.3 mmol) 2 The resulting mixture was stirred at 100° C. overnight. After the reaction was completed, the mixture was cooled to room temperature. Water (50 mL) was added to the resulting mixture and extracted with EA (50 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 silica gel column (PE / EA=3 / 1) to give the product (0.6 g, yellow oil, yield: 68%). MS(ESI): 267.85[M+H] + . c) Preparation of methyl 3-(2-amino-3-fluoro-4-(hydroxymethyl)phenyl)-1-methyl-1H-pyrazole-4-carboxylate: Dioxane (5.0 mL) and H 2To a solution of (3-amino-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (0.4 g, 1.4 mmol) in 2H2O (1.0 ml), methyl 3-bromo-1-methyl-1H-pyrazole-4-carboxylate (284 mg, 1.4 mmol), K 2 CO 3 (0.6 g, 4.2 mmol) and Pd(dppf)Cl 2 (80 mg, 0.1 mmol) 2 The mixture was added at room temperature under atmospheric pressure. 2 The mixture was stirred under atmosphere at 100° C. overnight. The mixture was slowly cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give the product (0.4 g, crude, brown solid). d) Preparation of 6-fluoro-7-(hydroxymethyl)-2-methyl-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one: A solution of ethyl 3-(2-amino-3-fluoro-4-(hydroxymethyl)phenyl)-1-methyl-1H-pyrazole-4-carboxylate (0.4 g, 1.4 mmol) in AcOH (5 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was triturated three times with PE:EA=1:1 (5 mL) to give the product (0.4 g, crude, brown solid). MS(ESI): 248.00 [M+H] + . e) Preparation of 7-(bromomethyl)-6-fluoro-2-methyl-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one: HBr (H 2 A solution of 6-fluoro-7-(hydroxymethyl)-2-methyl-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (0.4 g, 1.6 mmol) in 48% in 2H2O (18 mL) was stirred at 85° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give the product (0.4 g, crude, brown solid). MS(ESI): 309.90 [M+H] + . f) Preparation of 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-2-methyl-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one: To a solution of 7-(bromomethyl)-6-fluoro-2-methyl-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (0.1 g, 0.4 mmol), KI (7.0 mg, 0.04 mmol) and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (165 mg, 1.3 mmol), DIEA (81 mg, 0.6 mmol) was added to N 2 The mixture was added at room temperature under reduced pressure. The resulting mixture was stirred at 80° C. for 1 h. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC to give the target compound (10.0 mg, white solid, 4-step yield: 5.0%). The following compounds of Examples 89-100 were prepared using a synthetic method similar to that described in Example 1 (Scheme 1); compounds of Examples 101-118 were prepared using a synthetic method similar to that described in Example 66 (Scheme 7); compounds of Examples 119-120 were prepared using a synthetic method similar to that described in Example 48.

[0288] [Table 10-1]

[0289] [Table 10-2]

[0290] [Table 10-3]

[0291] [Table 10-4] Example 121 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one a) Preparation of 4-fluoro-1H-pyrazole-5-carbonyl chloride: SOCl 2 A solution of 4-fluoro-1H-pyrazole-5-carboxylic acid (1.1 g, 8.5 mmol) in (12 mL) was stirred for 2 hours at 80° C. After the reaction was completed, the mixture was concentrated under reduced pressure to give the product (1.0 g, white solid, yield: 83%). b) Preparation of N-(3-bromo-2,6-difluorophenyl)-4-fluoro-1H-pyrazole-5-carboxamide: To a solution of 3-bromo-2,6-difluoroaniline (1.5 g, 7.4 mmol) in THF (15 mL) was added LiHMDS (1 M in THF, 20.2 mL, 20.2 mmol) under nitrogen at 0° C. The mixture was stirred at 0° C. for 30 min and 4-fluoro-1H-pyrazole-5-carbonyl chloride (1.0 g, 6.7 mmol, 1.0 equiv) in THF (10 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min and warmed to room temperature for 1.5 h. The mixture was quenched with water (20 mL) and extracted with EA (20 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column (PE / EA=5 / 1) to give the product (1.5 g, yellow solid, yield: 72%). MS: 319.95 [M+H] + , 321.95[M+H+2] + . c) Preparation of 7-bromo-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one: To a solution of N-(3-bromo-2,6-difluorophenyl)-4-fluoro-1H-pyrazole-5-carboxamide (1.5 g, 4.7 mmol) in DMSO (15 mL), 2 CO 3(2.6 g, 18.7 mmol, 4.0 equiv) was added under nitrogen. The mixture was stirred at 100° C. overnight. The mixture was cooled to room temperature. The mixture was quenched with water (20 mL) and extracted with EA (20 mL×3). The organic phase was then concentrated under reduced pressure. The residue was purified by flash chromatography (C18, water / acetonitrile=55 / 45) to give the title compound as a white solid, which was used directly in the next step without further purification. MS(ESI): 300.00 [M+H] + , 302.00 [M+H+2] + . d) Preparation of 3,6-difluoro-7-(hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one: A solution of 7-bromo-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (1.2 g, 4.0 mmol) in dry dioxane (12 mL) was added with Xphos Pd GC. 2 (314.7 mg, 0.4 mmol) and (tributylstannyl)methanol (3.9 g, 12 mmol) were added under nitrogen. The mixture was stirred at 80° C. for 4 h. The mixture was cooled to room temperature and aqueous KF solution (1 M, 24 mL) was added. The resulting mixture was filtered and the filtrate was extracted with EA (20 mL×3). The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column (DCM / MeOH=1 / 0-100 / 1-80 / 1-50 / 1) to give the product (260.0 mg, white solid, 2-step yield: 22%). MS(ESI): 252.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.94 (s, 1H), 8.20 (d, J = 3.8 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 5.44 (t, J = 5.8 Hz, 1H), 4.61 (d, J = 5.5Hz, 2H). e) Preparation of 7-(bromomethyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one: A solution of 3,6-difluoro-7-(hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (200.0 mg, 0.8 mmol) in HBr (48% in water, 20 mL) was stirred at 80° C. under nitrogen for 2 h. The mixture was concentrated under reduced pressure to give the product (261.0 mg, white solid, yield: 96%). MS(ESI): 313.95 [M+H] + , 315.95 [M+H+2] + . f) Preparation of 7-((4-(2-methyl-6-(methylcarbamoyl)quinoxal-3-yl)piperazin-1-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one: To a solution of 7-(bromomethyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (53.0 mg, 0.2 mmol) in acetonitrile (5 mL) was added KI (3.4 mg, 0.02 mmol), N,6-dimethyl-5-(piperazin-1-yl)picolinamide hydrochloride (47.0 mg, 0.2 mmol), DIEA (129.0 mg, 1.0 mmol) under nitrogen at room temperature. The mixture was stirred at 80° C. for 4 h. The mixture was concentrated. The residue was purified by preparative TLC (DCM / MeOH=10 / 1) to give the crude product. The crude product was purified by preparative HPLC (water / acetonitrile=42 / 58%, 0.1% HCOOH) to give the title compound (48.8 mg, white solid, yield: 62%). The compounds of Examples 121-128 were prepared using synthetic methods similar to those described in Example 121 (Scheme 8).

[0292] [Table 11] Example 129 7-((4-(2-fluoro-6-(2,2-difluoroethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one a) Preparation of (4-bromo-3-fluoro-2-nitrophenyl)hydrazine: A solution of 4-bromo-3-fluoro-2-nitroaniline (5.0 g, 21.3 mmol) in concentrated hydrochloric acid (36% in water, 50 mL) was added with H 2 NaNO in O (50 ml) 2 A solution of SnCl (14.4 g, 64.0 mmol) was added dropwise at −10° C. The mixture was stirred at −10° C. for 1 h. The mixture was cooled to −30° C. and diluted with SnCl in concentrated hydrochloric acid (36% in water, 50 ml). 2 2H 2 A solution of 2H2O (1.6 g, 23.4 mmol) was added dropwise. The mixture was stirred at -30°C for 1 h. After the reaction was complete, the mixture was poured into water (200 mL) and diluted with NaHCO 3 The pH of the solution was adjusted to 7-8 with the solid. The resulting mixture was extracted with EA (100 mL×3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the product (4.3 g, crude, yellow solid, yield: 81%). b) Preparation of methyl 1-(4-bromo-3-fluoro-2-nitrophenyl)-4-methyl-1H-pyrazole-5-carboxylate: To a solution of (4-bromo-3-fluoro-2-nitrophenyl)hydrazine (1.0 g, 4.0 mmol) in acetic acid (10 mL) was added a solution of methyl 4-(dimethylamino)-3-methyl-2-oxobut-3-enoate (0.82 g, 4.8 mmol) in acetic acid (10 mL) dropwise at room temperature. The mixture was stirred at 80° C. overnight. After the reaction was completed, the mixture was poured into ice water (100 mL) and extracted with EA (100 mL×3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel (PE:EA=15:1) to give the product (0.83 g, yellow solid, yield: 58%). 1 H NMR (400MHz, DMSO-d 6 ):δ8.16-8.14(m,1H),7.78(s,1H),7.61-7.59(m,1H),3.71(s,3H),2.25(s,3H). c) Preparation of 7-bromo-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one: To a solution of methyl 1-(4-bromo-3-fluoro-2-nitrophenyl)-4-methyl-1H-pyrazole-5-carboxylate (0.83 g, 2.3 mmol) in acetic acid (10 mL), Fe powder (0.65 g, 11.6 mmol) was added at room temperature. The mixture was stirred at 80° C. overnight. After the reaction was completed, the mixture was filtered, the filtrate was diluted with water (50 mL) and ethyl acetate (5 mL), and then the solid was collected by filtration to give the product (370 mg, off-white solid, yield: 55%). MS(ESI): 295.90 [M+H] + , 293.85 [MH] - . 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.90 (br, 1H), 7.91 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.50-7.46 (m, 1H), 2.38 (s, 3H). d) Preparation of 6-fluoro-7-(hydroxymethyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one: To a solution of 7-bromo-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (5.0 g, 16.9 mmol) in dioxane (100 mL) was added tributylstannylmethanol (10.9 g, 33.9 mmol) and Xphos Pd G2 (1.3 g, 1.7 mmol) at room temperature. The mixture was stirred at 90° C. under nitrogen atmosphere for 16 h. After the reaction was completed, a solution of KF (1 M, 100 mL) was added at room temperature. The mixture was stirred at the same temperature for 10 min and filtered. The filtrate was extracted with EA (200 mL×3). The combined organic phase was washed with brine (200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was triturated with a mixture of PE / EA (v / v=1:1) and the solid was collected by filtration to give the title compound (2.8 g, grey solid, yield: 67%). MS(ESI): 248.05 [M+H] + , 246.00 [MH] - . e) Preparation of 7-(bromomethyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one: HBr (30 mL, H 2 A solution of 6-fluoro-7-(hydroxymethyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (2.8 g, 11.3 mmol) in 2H 2 O (48%) was stirred at 80° C. for 2 h. After the reaction was complete, the reaction was concentrated under reduced pressure to give the product (2.7 g, crude, yellow solid). MS(ESI): 309.90[M+H] + , 311.90[M+H+2] + . f) Preparation of 7-((4-(2-fluoro-6-(2,2-difluoroethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one: CH 3 To a solution of 7-(bromomethyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (193.8 mg crude, 0.63 mmol), KI (8.7 mg, 0.05 mmol) and N-(2,2-difluoroethyl)-6-fluoro-5-(piperazin-1-yl)picolinamide (150.0 mg, 0.52 mmol) in CN (20 mL) was added K 2 CO 3 (359.5 mg, 2.61 mmol, 5.0 equiv) was added at room temperature. The resulting mixture was stirred at 80° C. for 3 h. After the reaction was completed, the reaction mixture was filtered. The solid was purified by preparative HPLC (C18, 5-50% acetonitrile in water, 0.1% HCOOH) to give the target compound (21.8 mg, white solid, yield: 8.1%). The compounds of Examples 130-135, 151-167, and 203-204 were prepared using a synthetic method similar to that described in Example 129 (Scheme 9); the compounds of Examples 136-141 were prepared using a synthetic method similar to that described in Example 50 (Scheme 6); the compounds of Examples 142-144 and 149 were prepared using a synthetic method similar to that described in Example 1 (Scheme 1); the compound of Example 145 was prepared using a synthetic method similar to that described in Example 49 (Scheme 5); the compounds of Examples 146-148 were prepared using a synthetic method similar to that described in Example 66 (Scheme 7), the compound of Example 150 was prepared using a synthetic method similar to that described in Example 6 (Scheme 2), the compounds of Examples 168-202 were prepared using a synthetic method similar to that described in Example 121 (Scheme 8), and the compound of Example 205 was prepared using a synthetic method similar to that described in Example 48.

[0293] [Table 12-1]

[0294] [Table 12-2]

[0295] [Table 12-3]

[0296] [Table 12-4]

[0297] [Table 12-5]

[0298] [Table 12-6]

[0299] [Table 12-7]

[0300] [Table 12-8]

[0301] [Table 12-9] Example 206 PARP1 and PARP2 chemiluminescence assays A solution of recombinant poly(ADP-ribose) polymerase 1 and 2 (PARP1 and PARP2) (40 ng enzyme / well) was mixed with each compound to be tested. The solution was added to a 96-well plate coated with histone mixture and incubated at room temperature for 1 hour, then 0.3 ng / mL streptavidin-HRP (50 μL) 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 that can be measured using a chemiluminescence reader. The inhibition rate of the tested compound against PARP 1 / 2 enzyme activity was calculated according to the following formula:

[0302]

number

[0303] [Table 13-1]

[0304] [Table 13-2] Most of the tested compounds have a potent and selective inhibitory effect on the PARP1 enzyme compared to the PARP2 enzyme. Example 207 Growth inhibition assay against BRCA-mutated human breast cancer MDA-MB-436 cell line Cells were cultured in complete medium (DMEM medium + 10% FBS + insulin + glutathione). When the confluence reached about 80%, the cells were digested and gently dispensed from the bottom of the dish with a 1 mL pipette. The cell suspension was collected and centrifuged at 500 rpm for 3 minutes. The supernatant was discarded and the cell pellet was resuspended in complete medium. The cells were seeded in culture dishes at an appropriate ratio and then incubated at 37°C with 5% CO 2 The cells were cultured in a 5% CO incubator. The assay was performed when the cells were in optimal condition and had reached 80% confluence. Exponentially growing cells were harvested, centrifuged, and the culture supernatant was removed. The cells were resuspended in fresh complete medium and counted. The resuspended cells were seeded at 3000 / well in a 96-well plate and incubated at 37°C in 5% CO 2 Incubated overnight in an incubator. Compounds were prepared as follows: 1000x diluted tested compound solutions were prepared by adding 5μL of 1000x compound solution to 120μL of medium to 40x test compound solution (25x dilution). Solutions were mixed by shaking. 0.1% DMSO was used as a control. The next day, the 96-well plate inoculated with cells was removed from the incubator and the culture supernatant was removed. Then, 195 uL / well and 5 μL / well of the above-mentioned 40× test compound solution were added to the 96-well plate, respectively. Finally, the plate was incubated at 37° C. in 5% CO 2The plates were incubated in an incubator for 7 days. The medium containing the compounds was replaced on the 4th day. After 7 days, 20 μL of CCK-8 was added to each well, gently shaken, and then cultured for 4 hours. After incubation, the plates were shaken for 5 minutes. The absorbance values ​​at wavelengths of 450 nm or 650 nm were recorded respectively using a multi-function readout instrument (OD=absorbance value at 450 nm-absorbance value at 650 nm). Data was analyzed by the software GraphPad Prism 6.0. The inhibitory activity of the compounds against cell proliferation was plotted using cell viability versus compound concentration as the coordinate. Cell viability %=(OD 化合物 -OD バックグラウンド ) / (OD DMSO -OD バックグラウンド ) x 100. I.C. 50 Values ​​were fitted by a sigmoidal dose-response curve equation: Y=100 / (1+10^(logC-logIC 50 )) and C was the compound concentration. Table 2 shows the inhibitory effect data (IC 50 ) are summarized.

[0305] [Table 14-1]

[0306] [Table 14-2]

[0307] The tested compounds have good inhibitory effects on the proliferation of BRCA-mutated human breast cancer cells MDA-MB-436. Example 208 Inhibitory effect of compounds on PDE3A A multi-stage format PDE3A fluorescence polarization (FP) assay was performed using black round-bottom 384-well plates (Corning, 4514). Test compounds were serially diluted from stock solutions to 11 concentrations with 3-fold dilution factors using DMSO. 50 nl of compound dilutions were mixed with 5 μl of reaction buffer (10 mM Tris-HCl, pH 7.2, 10 mM MgCl2, 0.05% NaN3, 0.1% phosphate-free BSA) containing 0.2 μM FAM-cAMP (BPS, 60200) and 2 nM PDE3A (Sino Biological, 11908-H20B1) enzyme and incubated at 25°C for 60 minutes. Then, 15 μl of binder mix (Molecular Devices, R8124) was added to each well and the plate was incubated at 25°C for 60 minutes. The plate was loaded into a BMG PHERAstar FSX and the fluorescence polarization (FP) values ​​were read with the following settings: Ex: 485 nm and Em: 520 nm. Emission intensity with polarizer parallel.

[0308]

number

[0309]

number

[0310]

number

[0311] [Table 15] The compounds of the present disclosure have low inhibitory effects on PDE3A, and some compounds have IC 50 >30μM.

[0312] Although the disclosure has been described in its entirety herein, those skilled in the art will appreciate that the same disclosure can be practiced within a broad and equivalent range of conditions, formulations and other parameters without affecting the scope of the disclosure or any of its embodiments. All patents, patent applications, and publications cited herein are hereby fully incorporated by reference in their entirety.

Claims

1. Compounds of Formula I: 【Chemistry 1】 or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharmaceutically acceptable salt, or prodrug thereof, or mixtures thereof, wherein: A １ , A ２ and A ３ are each independently N and CR １ Selected from: 【Chemistry 2】 The Z ring represented by is an optionally substituted 5-membered heteroaryl group, an optionally substituted 5-membered carbocyclic group, or an optionally substituted 5-membered heterocyclic group, wherein * indicates the position at which the Z ring is attached to the remainder of the compound, and the dashed line indicates the presence of optional unsaturated bond(s), wherein when said Z ring is an optionally substituted 5-membered heteroaryl group, Z １ , Z ２ and Z ３ are each independently CR ２ , N.R. ３ , O, N or S, and Z ４ and Z ５ are each independently C or N, where Z ４ and Z ５ is not N and the Z ring is an optionally substituted 5-membered carbocyclic group or an optionally substituted 5-membered heterocyclic group, Z １ , Z ２ and Z ３ are each independently CR ２ R ２ ', C.R. ２ , N.R. ３ , O or S, and Z ４ and Z ５ are each independently C, CH, or N; and Z ５ If N, then Z １ , Z ２ and Z ３ At least one of is N or Z ５ is N and Z １ , Z ２ and Z ３ All of this is CR ２ Or CR ２ R ２ ', then A １ is CR １ and L is a bond and R ４ and / or R ５ alkylene optionally substituted by Cy is selected from the group consisting of optionally substituted heterocyclic groups, optionally substituted aryl, and optionally substituted heteroaryl; R １ is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted carbocyclic groups; R ２ and R ２ each ' is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R ３ is selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl; R ４ and R ５ are each independently selected from the group consisting of halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or R ４ and R ５ forms a ring together with the attached C).

2. R １ is hydrogen, halogen, optionally substituted C １～３ Alkyl or optionally substituted C １～３ alkoxy; preferably, R １ is hydrogen, halogen or C １～３ alkyl, preferably A １ and A ３ At least one of the following is CR １ and R １ is a halogen, such as fluoro; or A ２ and A ３ At least one of the following is CR １ and R １ is a halogen, or A ２ and A ３ Both are CR １ and R １ At least one of the groups is halogen; or A ３ is CR １ and R １ is a halogen; or A １ , A ２ and A ３ All of these are CR １ wherein each R １ are independently hydrogen, halogen or C １～３ alkyl; or A １ and A ３ At least one of the following is CR １ wherein R １ is halogen, and preferably at least A ３ is CR １ and R １ is a halogen such as fluoro; or A １ is CR １ and A ２ and A ３ are both CH; or A １ is CH, and A ２ is CR １ and A ３ is CH; or A １ and A ２ Both of A and B are CH. ３ is CR １ wherein R １ is halogen or C １～３ is alkyl; and / or The Z ring is: 【Transformation 3】 Preferably, 【Chemistry 4】 More preferably, 【Transformation 5】 where * indicates the position where the Z ring is attached to the remainder of the compound; R ２ is hydrogen, halogen, cyano, optionally substituted C １～６ Alkyl, optionally substituted C １～３ Alkoxy and optionally substituted C ３～６ Cycloalkyl, preferably hydrogen, halogen and optionally substituted C １～３ alkyl; R ２ ' is hydrogen, halogen, cyano, optionally substituted C １～６ Alkyl, optionally substituted C １～３ Alkoxy and optionally substituted C ３～６ Cycloalkyl, preferably hydrogen, halogen and optionally substituted C １～３ alkyl; R ３ is hydrogen, optionally substituted alkyl and optionally substituted cycloalkyl, preferably hydrogen and optionally substituted C １～３ and / or L is C １～３ alkylene; and / or Cy is a 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 group and optionally substituted C ３～８ a 5- to 7-membered nitrogen-containing heterocyclic group optionally substituted with 1 to 5 substituents selected from the group consisting of cycloalkyl, wherein said 6- to 14-membered aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclic group and C ３～８ Each cycloalkyl is independently selected from halogen, C １～４ Alkyl, C １～４ Alkoxy, halogenated C １～４ Alkyl, halogenated C １～４ and optionally substituted with 1 to 5 substituents selected from the group consisting of alkoxy, —NR′R″, —C(O)—NR′R″ and carboxyl, wherein said R′ and R″ are each preferably independently H, optionally substituted C １～１０ Alkyl, optionally substituted C ３～８ cycloalkyl, optionally substituted 3- to 6-membered heterocyclic group, optionally substituted aryl or optionally substituted heteroaryl, preferably R′ and R″ are each, preferably independently, H, optionally substituted C １～４ Alkyl, optionally substituted C ３～８ cycloalkyl or an optionally substituted 3- to 6-membered heterocyclic group; preferably 6- to 14-membered aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclic group and C ３～８ The substituents on the cycloalkyl include at least —C(O)—NR′R″ and optionally halogen, C １～４ Alkyl and halogenated C １～４ alkyl; Preferably, Cy is substituted with an optionally substituted 5- to 10-membered heteroaryl, preferably an optionally substituted 5- to 10-membered nitrogen-containing heteroaryl, preferably the 5- to 10-membered heteroaryl or the 5- to 10-membered nitrogen-containing heteroaryl is substituted with at least —C(O)—NR′R″ and is substituted with halogen, C １～４ Alkyl and halogenated C １～４ optionally substituted with one or two substituents selected from the group consisting of alkyl, more preferably -C(O)-NR'R'' is in the para position; Preferably, the compound of claim 1, wherein Cy is piperazinyl or dihydropyridinyl substituted by optionally substituted pyridyl, said pyridyl being substituted with at least -C(O)-NR'R'', and Cy is covalently bonded to L through its ring nitrogen atom, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharmaceutically acceptable salt, or prodrug thereof, or a mixture thereof.

3. The compound of formula I is represented by formula Ia, Ib, Ic, or Id shown below: 【Transformation 6】 (In the formula: A 1 , A 2 and A 3 are each independently selected from N and CR 1 ; R 1 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted carbocyclic groups; 【Transformation 7】 wherein the Z ring is an optionally substituted 5-membered heteroaryl group, an optionally substituted 5-membered carbocyclic group, or an optionally substituted 5-membered heterocyclic group, * indicates the position where the Z ring is attached to the remainder of the compound, and a dashed line indicates the presence of optional unsaturated bond(s), wherein when the Z ring is an optionally substituted 5-membered heteroaryl group, Z 1 , Z 2 , and Z 3 are each independently CR 2 , NR 3 , O, N, or S, Z 4 and Z 5 are each independently C or N, where Z 4 and Z 5 are not both N, and when the Z ring is an optionally substituted 5-membered carbocyclic group or an optionally substituted 5-membered heterocyclic group, Z 1 , Z 2 , and Z 3 are each independently CR 2 R 2 ′, CR 2 , NR 3 , O or S, and Z 4 and Z 5 are each independently C, CH or N; L is selected from a bond and alkylene optionally substituted with R 4 and / or R 5 ; Cy is selected from the group consisting of optionally substituted heterocyclic groups, optionally substituted aryl, and optionally substituted heteroaryl, or The compound of formula I is represented by formula IIa, IIb, IIc, or IId: 【Transformation 8】 (In the formula: A 1 , A 2 and A 3 are each independently selected from N and CR 1 ; R 1 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted carbocyclic groups; 【Chemistry 9】 wherein the Z ring is an optionally substituted 5-membered heteroaryl group, an optionally substituted 5-membered carbocyclic group, or an optionally substituted 5-membered heterocyclic group, * indicates the position where the Z ring is attached to the remainder of the compound, and a dashed line indicates the presence of optional unsaturated bond(s), wherein when the Z ring is an optionally substituted 5-membered heteroaryl group, Z 1 , Z 2 , and Z 3 are each independently CR 2 , NR 3 , O, N, or S, Z 4 and Z 5 are each independently C or N, where Z 4 and Z 5 are not both N, and when the Z ring is an optionally substituted 5-membered carbocyclic group or an optionally substituted 5-membered heterocyclic group, Z 1 , Z 2 , and Z 3 are each independently CR 2 R 2 ′, CR 2 , NR 3 , O or S, and Z 4 and Z 5 are each independently C, CH or N; R ６ is selected from optionally substituted aryl and optionally substituted heteroaryl), the compound of claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharmaceutically acceptable salt thereof, or prodrug thereof, or mixtures thereof.

4. R ６ is an optionally substituted 6- to 14-membered aryl or an optionally substituted 5- to 10-membered heteroaryl, and the optionally substituted 6- to 14-membered aryl and the optionally substituted 5- to 10-membered heteroaryl are each independently selected from halogen, C １～４ Alkyl, C １～４ Alkoxy, halogenated C １～４ Alkyl, halogenated C １～４ and optionally substituted by 1 to 5 substituents selected from the group consisting of alkoxy, —NR′R″, —C(O)—NR′R″ and carboxyl; wherein said R′ and R″ are each preferably independently H, optionally substituted C １～１０ Alkyl, optionally substituted C ３～８ cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl or optionally substituted heteroaryl; preferably, R′ and R″ are each, preferably independently, H, optionally substituted C １～４ Alkyl, optionally substituted C ３～６ cycloalkyl or an optionally substituted 3- to 6-membered heterocyclic group; preferably, R ６ The substituents include at least —C(O)—NR′R″ and halogen, C １～４ Alkyl and halogenated C １～４ alkyl; preferably R ６ is an optionally substituted 5- to 10-membered heteroaryl, preferably an optionally substituted 5- to 10-membered nitrogen-containing heteroaryl, and preferably said 5- to 10-membered heteroaryl or 5- to 10-membered nitrogen-containing heteroaryl is substituted with at least —C(O)—NR′R″ and is substituted with halogen, C １～４ Alkyl or halogenated C １～４ optionally substituted with 1 or 2 substituents selected from the group consisting of alkyl; Preferably, R ６ is the following group: 【Chemistry 10】 (In the formula, B １ , B ２ , B ３ and B ４ are independently N and CR ７ R ７ are selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted carbocyclic, optionally substituted alkenyl, and optionally substituted alkynyl; wherein R′ and R″ are each independently hydrogen, optionally substituted C １～１０ Alkyl, optionally substituted C ３～８ cycloalkyl, optionally substituted heterocyclic group, optionally substituted aryl or optionally substituted heteroaryl, and preferably R′ and R″ are each independently hydrogen, optionally substituted C １～４ Alkyl, optionally substituted C ３～６ cycloalkyl or an optionally substituted 3- to 6-membered heterocyclic group; * indicates the position at which the group is attached to the remainder of the compound, preferably B １ , B ２ , B ３ and B ４ The group containing R is phenyl, pyridyl, pyrimidinyl or pyridazinyl, preferably R ７ is H, halogen, C １～３ Alkyl, C １～３ Alkoxy or halogenated C １～３ alkyl; preferably, B ３ is N and B ４ is CR ７ and B １ and B ２ and both of R are CH ７ is H, halogen, C １～３ Alkyl, C １～３ Alkoxy or halogenated C １～３ alkyl; 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 4. The compound of claim 3, wherein R is alkyl, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharmaceutically acceptable salt thereof, or prodrug thereof, or a mixture thereof.

5. The compounds of formula I are represented by formula IIIa, IIIb, IIIc, or IIId, shown below: 【Chemistry 11】 (In the formula: 【Chemistry 12】 wherein the Z ring is an optionally substituted 5-membered heteroaryl group, an optionally substituted 5-membered carbocyclic group, or an optionally substituted 5-membered heterocyclic group, * indicates the position where the Z ring is attached to the remainder of the compound, and a dashed line indicates the presence of optional unsaturated bond(s), wherein when the Z ring is an optionally substituted 5-membered heteroaryl group, Z 1 , Z 2 , and Z 3 are each independently CR 2 , NR 3 , O, N, or S, Z 4 and Z 5 are each independently C or N, where Z 4 and Z 5 are not both N, and when the Z ring is an optionally substituted 5-membered carbocyclic group or an optionally substituted 5-membered heterocyclic group, Z 1 , Z 2 , and Z 3 are each independently CR 2 R 2 ′, CR 2 , NR 3 , O or S, and Z 4 and Z 5 are each independently C, CH or N; A 1 , A 2 and A 3 are each independently selected from N and CR 1 ; R 1 is selected from the group consisting of 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 the group consisting of N and CR 7 ; R 7 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; R' and R'' are each independently hydrogen, optionally substituted C 1-10 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocyclic group, optionally substituted aryl or optionally substituted heteroaryl, preferably R' and R'' are each independently hydrogen, optionally substituted C 1-4 alkyl, optionally substituted C 3-6 cycloalkyl or optionally substituted 3-6 membered heterocyclic group), or a compound according to claim 4, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharmaceutically acceptable salt thereof, or a prodrug thereof, or a mixture thereof.

6. The compounds of formula I are represented by formula IVa, IVb, IVc, or IVd, shown below: 【Chemistry 13】 (In the formula: 【Chemistry 14】 wherein the Z ring is an optionally substituted 5-membered heteroaryl group, an optionally substituted 5-membered carbocyclic group, or an optionally substituted 5-membered heterocyclic group, * indicates the position where the Z ring is attached to the remainder of the compound, and a dashed line indicates the presence of optional unsaturated bond(s), wherein when the Z ring is an optionally substituted 5-membered heteroaryl group, Z 1 , Z 2 , and Z 3 are each independently CR 2 , NR 3 , O, N, or S, Z 4 and Z 5 are each independently C or N, where Z 4 and Z 5 are not both N, and when the Z ring is an optionally substituted 5-membered carbocyclic group or an optionally substituted 5-membered heterocyclic group, Z 1 , Z 2 , and Z 3 are each independently CR 2 R 2 ′, CR 2 , NR 3 , O or S, and Z 4 and Z 5 are each independently C, CH or N; R" is preferably independently H, optionally substituted C1-10 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted 3-6 membered heterocyclic group, optionally substituted aryl or optionally substituted heteroaryl, preferably R" is preferably independently H, optionally substituted C1-4 alkyl, optionally substituted C3-8 cycloalkyl or optionally substituted 3-6 membered heterocyclic group; R 7 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; R ８ , R ９ , and R １０ are independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted carbocyclic groups; Preferably, R8, R9, and R10 are each independently hydrogen, halogen, or C1-3 alkyl, or optionally substituted C1-3 alkoxy; preferably, R8, R9, and R10 are each independently hydrogen, halogen, or C1-3 alkyl; preferably, R8 is halogen or C1-3 alkyl, and R9 and R10 are both H; or R8 is H, R9 is halogen or C1-3 alkyl, and R10 is H; or R8 and R9 are both H, and R10 is halogen or C1-3 alkyl; Preferably, R ９ and R １０ wherein at least one of is a halogen), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharmaceutically acceptable salt thereof, or a prodrug thereof, or a mixture thereof.

7. The compounds of formula I are represented by formula Va, Vb, Vc, or Vd shown below: 【Chemistry 15】 (In the formula: Z 1 , Z 2 and Z 3 are each independently CR 2 , NR 3 , O, N or S; R 8 , R 9 , and R 10 are independently 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 the group consisting of N and CR 7 ; R 7 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; Ring D is an optionally substituted 4-12 membered N-containing heterocyclic group, wherein said N-containing heterocyclic group containing at least one N atom is selected from a 4-12 membered monocyclic group, a 5-12 membered spirocyclic group, and said N-containing heterocyclic group may also contain 1-4 heteroatoms selected from N, O or S, and may optionally be further substituted with one or more R'''; W is a bond, O, or —NR′—; Q is an optionally substituted aminoacyl (—C(O)—NR′R″) or an optionally substituted heteroaryl; R′ and R″ are each independently hydrogen, optionally substituted C １～１０ selected from alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl; R''' is halogen, hydroxyl, cyano, or C １～６ alkyl, wherein C １～６ wherein the alkyl is optionally further substituted with one or more substituents selected from hydroxyl, halogen, or cyano, or any two R''' can form a 3- to 8-membered ring), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharmaceutically acceptable salt thereof, or prodrug thereof, or a mixture thereof.

8. The compounds of formula I are represented by formula VIa, VIb, or VIc, shown below: 【Chemistry 16】 (In the formula: Z 1 , Z 2 and Z 3 are each independently CR 2 , NR 3 , O, N or S; R 7 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; Q is an optionally substituted aminoacyl (—C(O)—NR′R″) or an optionally substituted heteroaryl; R ７ ' is hydrogen, halogen, cyano, optionally substituted C １～３ Alkyl, optionally substituted C １～３ Alkoxy, or optionally substituted C ３～６ is cycloalkyl; R ９ and R １０ are each independently hydrogen, halogen, optionally substituted C １～３ alkyl, or optionally substituted C １～３ is alkoxy, and R ９ and R １０ at least one of is not hydrogen; D １ is N or CR １１ and R １１ is H, halogen, cyano, hydroxyl, optionally substituted C １～３ alkyl, or optionally substituted C １～３ 8. The compound of claim 7, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharmaceutically acceptable salt thereof, or prodrug thereof, or a mixture thereof.

9. The Z ring is: 【Chemistry 17】 (In the formula, R ２ is hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted C １～３ Alkoxy and optionally substituted C ３～６ Cycloalkyl, preferably hydrogen, halogen, cyano, optionally substituted C １～３ Alkyl and optionally substituted C ３～６ cycloalkyl; R ２ ' is hydrogen, halogen, cyano, optionally substituted C １～６ Alkyl, optionally substituted C １～３ Alkoxy and optionally substituted C ３～６ Cycloalkyl, preferably hydrogen, halogen, cyano, optionally substituted C １～３ Alkyl or C ３～６ cycloalkyl; and wherein R ２ and R ２ At least one of the groups ' is a non-hydrogen substituent, and preferably the non-hydrogen substituent is halogen, cyano, C １～３ Alkyl or C ３～６ cycloalkyl; and in Formulas IVa-IVd and Va-Vd, R ８ , R ９ and R １０ One of the groups is a halogen or C １～３ alkyl, and the other two are hydrogen; and in Formulas VIa to VId, R ９ and R １０ One of the groups is a halogen or C １～３ alkyl and the other is hydrogen), or The Z ring is: [Chemistry 18] (In the formula, R ２ ' is a halogen, cyano, optionally substituted C １～６ Alkyl, optionally substituted C １～３ Alkoxy, and optionally substituted C ３～６ Cycloalkyl, preferably halogen, cyano, and optionally substituted C １～３ alkyl, and optionally substituted C3-6 cycloalkyl; in Formulas IVa-IVd and Va-Vd, R ８ is H and R ９ and R １０ One of the groups is halogen or C １～３ alkyl and the other is hydrogen; in Formulas VIa to VId, R ９ and R １０ One of the groups is halogen or C １～３ and the other is hydrogen), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharmaceutically acceptable salt thereof, or prodrug thereof, or a mixture thereof.

10. In formula VIa, Z １ , Z ２ and Z ３ One of them is O and the other two are CR １ wherein R １ is hydrogen, halogen and C １～３ alkyl; preferably, Z １ is O and Z ２ and Z ３ are both CH; preferably, R ９ is halogen, optionally substituted C １～３ Alkyl or optionally substituted C １～３ is a non-hydrogen substituent such as alkoxy, preferably halogen, more preferably F; １０ is hydrogen, halogen or C １～３ alkyl, preferably hydrogen; D １ is N or CH; R ７ But hydrogen, C １～３ Alkyl, halogenated C １～３ Alkyl, halogen, cyano or C ３～６ cycloalkyl, preferably hydrogen or halogen; preferably Q is —C(O)—NR′R″ or pyrrolyl, halogen and C １～３ alkyl, wherein R′ and R″ are each independently hydrogen, C １～４ Alkyl, C ３～６ selected from cycloalkyl or 3 to 6 heterocyclic groups; or In formula VIa, Z １ , Z ２ and Z ３ One of them is O and the other two are CR １ and preferably Z １ is O and Z ２ and Z ３ are both CH; １ is hydrogen, halogen and C １～３ alkyl; R １０ is halogen, optionally substituted C １～３ Alkyl or optionally substituted C １～３ is a non-hydrogen substituent such as alkoxy, preferably halogen, more preferably F; ９ is hydrogen, halogen or C １～３ alkyl, preferably hydrogen; D １ is N or CH; R ７ But hydrogen, C １～３ Alkyl, halogenated C １～３ Alkyl, halogen, cyano or C ３～６ Cycloalkyl, preferably hydrogen, halogen, C １～３ Alkyl or halogenated C １～３ alkyl; R ７ ' is hydrogen, C １～３ Alkyl, halogenated C1-3 alkyl, halogen, cyano or C ３～６ cycloalkyl, preferably hydrogen or halogen; Q is —C(O)—NR′R″ or pyrrolyl, halogen and C １～３ alkyl, wherein R′ and R″ are each independently hydrogen, C １～４ Alkyl, C ３～６ cycloalkyl or 3 to 6 heterocyclic groups; preferably, R ９ is H and R １０ is F and R ７ is methyl, and D １ is N and R ７ ' is H and Q is -C(O)-NH(CH ３ ) or —C(O)—NH(CD ３ ) and a compound in which R ９ is H and R １０ is F and R ７ is F and D １ is N and R ７ ' is H and Q is -C(O)-NH(CH ３ ) or —C(O)—NH(CD ３ 9. The compound of claim 8, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharmaceutically acceptable salt thereof, or prodrug thereof, or a mixture thereof, wherein the compound is not included in Formula VIa.

11. The compound of formula I is represented by formula VII shown below: 【Chemistry 19】 (In the formula: R ９ and R １０ are each independently hydrogen, halogen, optionally substituted C １～３ alkyl, or optionally substituted C １～３ is alkoxy, and R ９ and R １０ at least one of is not hydrogen; L is selected from a bond and alkylene optionally substituted with R 4 and / or R 5 ; R 4 and R 5 are each independently selected from the group consisting of halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or R 4 and R 5 together with the C to which they are attached form a ring; Cy is selected from the group consisting of optionally substituted heterocyclic groups, optionally substituted aryl, and optionally substituted heteroaryl; R １２ and R １３ are each independently hydrogen, halogen, cyano, optionally substituted C １～６ Alkyl, optionally substituted C １～３ Alkoxy, and optionally substituted C ３～６ cycloalkyl; R １２ and R １３ wherein at least one of is not hydrogen), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharmaceutically acceptable salt thereof, or prodrug thereof, or a mixture thereof.

12. The compound of formula I is represented by formula VIII shown below: 【Chemistry 20】 (In the formula: R ９ and R １０ are each independently hydrogen, halogen, optionally substituted C １～３ alkyl, or optionally substituted C １～３ is alkoxy, and R ９ and R １０ at least one of is not hydrogen; R 12 and R 13 are each independently selected from hydrogen, halogen, cyano, optionally substituted C 1-6 alkyl, optionally substituted C 1-3 alkoxy, and optionally substituted C 3-6 cycloalkyl, wherein at least one of R 12 and R 13 is not hydrogen; Ring D is an optionally substituted 4-12 membered N-containing heterocyclic group, wherein said N-containing heterocyclic group containing at least one N atom is selected from a 4-12 membered monocyclic group, a 5-12 membered spirocyclic group, and said N-containing heterocyclic group may also contain 1-4 heteroatoms selected from N, O or S, and may optionally be further substituted with one or more R'''; Q is an optionally substituted aminoacyl (—C(O)—NR′R″) or an optionally substituted heteroaryl; R' and R'' are each independently selected from hydrogen, optionally substituted C1-10 alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl; R 7 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted carbocyclic group, optionally substituted alkenyl and optionally substituted alkynyl), 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 a mixture thereof.

13. R １２ and R １３ each independently represents a halogen, a cyano, an optionally substituted C １～３ Alkyl or optionally substituted C ３～６ cycloalkyl; preferably, R １２ is hydrogen and R １３ is halogen, cyano, optionally substituted C １～３ Alkyl or optionally substituted C ３～６ cycloalkyl; more preferably, R １２ is halogen, cyano, optionally substituted C １～３ Alkyl or optionally substituted C ３～６ is cycloalkyl, and R １３ is hydrogen; preferably, R １２ is halogen, cyano, optionally substituted C １～３ Alkyl or optionally substituted C ３～６ is cycloalkyl, and R １３ is hydrogen; more preferably, R １２ But halogen, C １～３ Alkyl, halogenated C １～３ alkyl; and R １３ is hydrogen; R ９ is hydrogen, and R １０ is halogen or C １～３ alkyl; preferably, R ９ is halogen or C １～３ alkyl, and R １０ is hydrogen; more preferably, R ９ is hydrogen, and R １０ is a halogen; or R ９ is a halogen, and R １０ is hydrogen; The D ring is an optionally substituted 4- to 7-membered monocyclic ring containing at least one N atom; preferably, the D ring is an optionally substituted piperazinyl, an optionally substituted piperidinyl, or an optionally substituted dihydropyridinyl; when the D ring is substituted, the substituents are selected from halogen, hydroxyl, cyano, optionally substituted C １～３ Alkyl, optionally substituted C １～３ Alkoxy, and optionally substituted C ３～６ cycloalkyl; R ７ is hydrogen, halogen, cyano, optionally substituted C １～３ Alkyl, optionally substituted C １～３ Alkoxy, or optionally substituted C ３～６ cycloalkyl, preferably R ７ But hydrogen, halogen, cyano, C １～３ Alkyl, halogenated C １～３ Alkyl, or C ３～６ is cycloalkyl; Q is —C(O)—NR′R″, where R′ and R″ are each independently hydrogen, optionally substituted C １～１０ Alkyl, optionally substituted C ３～８ Cycloalkyl, optionally substituted heterocyclic group, optionally substituted aryl or optionally substituted heteroaryl, preferably hydrogen, optionally substituted C １～４ Alkyl, optionally substituted C ３～６ cycloalkyl or an optionally substituted 3- to 6-membered heterocyclic group; preferably, Q is halogen, cyano, C １～３ Alkyl, halogenated C １～３ Alkyl, C １～３ Alkoxy and halogenated C １～３ 12. The compound of claim 11, wherein the 5-membered heteroaryl is a 5-membered heteroaryl optionally substituted by 1 to 3 substituents selected from alkoxy, wherein the 5-membered heteroaryl is preferably pyrrolyl, pyrazolyl, imidazolyl or triazolyl, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharmaceutically acceptable salt thereof, or a prodrug thereof, or a mixture thereof.

14. The compound of formula I is represented by formula IX shown below: 【Chemistry 21】 (In the formula: Ring D is an optionally substituted 4-12 membered N-containing heterocyclic group, wherein said N-containing heterocyclic group containing at least one N atom is selected from a 4-12 membered monocyclic group, a 5-12 membered spirocyclic group, and said N-containing heterocyclic group may also contain 1-4 heteroatoms selected from N, O or S, and may optionally be further substituted with one or more R'''; Q is an optionally substituted aminoacyl (—C(O)—NR′R″) or an optionally substituted heteroaryl; R' and R'' are each independently selected from hydrogen, optionally substituted C1-10 alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl; R 7 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; R １０ is halogen, optionally substituted C １～３ alkyl, or optionally substituted C １～３ is alkoxy; R １２ is halogen, cyano, optionally substituted C １～６ Alkyl, optionally substituted C １～３ Alkoxy, and optionally substituted C ３～６ 9. The compound of claim 8, wherein R is 1 or 2, and R is 2 or 3, or R is 3 or 4, or R is 4 or 5, or R is 5 or 6, or R is 6 or 7, or R is 7 or 8, or R is 8 or 9, or R is 9 or 10, or R is 10 or 11, or R is 11 or 12, or R is 13 or 14, or R is 15 or 16, or R is 17 or 18, or R is 19 or 20, or R is 19 or 21, or

15. R １０ is halogen or C １～３ alkyl; preferably, R １０ is halogen, preferably F; R １２ is halogen, cyano, optionally substituted C １～３ alkyl, or optionally substituted C ３～６ cycloalkyl; preferably, R １２ But halogen, C １～３ Alkyl, halogenated C １～３ is alkyl; The D ring is an optionally substituted 4- to 7-membered monocyclic ring containing at least one N atom; preferably, the D ring is an optionally substituted piperazinyl, an optionally substituted piperidinyl, or an optionally substituted dihydropyridinyl, and when the D ring is substituted, the substituents are selected from halogen, hydroxyl, cyano, optionally substituted C １～３ Alkyl, optionally substituted C １～３ Alkoxy and optionally substituted C ３～６ cycloalkyl; or The D ring is 【Chemistry 22】 (wherein *1 indicates the position where the D ring is bonded to the methylene; *2 indicates the position where the D ring is bonded to the pyridyl); R ７ is hydrogen, halogen, cyano, optionally substituted C １～３ Alkyl, optionally substituted C １～３ Alkoxy, or optionally substituted C ３～６ cycloalkyl, preferably R ７ But hydrogen, halogen, cyano, C １～３ Alkyl, halogenated C １～３ Alkyl, or C ３～６ is cycloalkyl; Q is —C(O)—NR′R″, where R′ and R″ are each independently hydrogen, optionally substituted C １～１０ Alkyl, optionally substituted C ３～８ Cycloalkyl, optionally substituted heterocyclic group, optionally substituted aryl or optionally substituted heteroaryl, preferably hydrogen, optionally substituted C １～４ Alkyl, optionally substituted C ３～６ 15. The compound of claim 14, which is cycloalkyl, or an optionally substituted 3- to 6-membered heterocyclic group, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharmaceutically acceptable salt thereof, or a prodrug thereof, or a mixture thereof.

16. The compound is selected from the group consisting of: 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[3,2-c]quinolin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[2,3-c]quinolin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[3,4-c]quinolin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thiazolo[4,5-c]quinolin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[2,3-c]quinolin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[3,2-c]quinolin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one; 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; 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; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydro-4H-pyrrolo[2,3-c]quinolin-4-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methyl-3,5-dihydro-4H-pyrrolo[2,3-c]quinolin-4-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)oxazolo[4,5-c]quinolin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thiazolo[5,4-c]quinolin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)oxazolo[5,4-c]quinolin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)isoxazolo[3,4-c]quinolin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[3,2-c]quinolin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[3,4-c]quinolin-4(5H)-one; 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[3,2-c]quinolin-4(5H)-one; 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[3,4-c]quinolin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluorothieno[3,2-c]quinolin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluorothieno[3,4-c]quinolin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluorofuro[3,2-c]quinolin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-dihydro-4H-pyrrolo[3,2-c]quinolin-4-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrrolo[3,2-c]quinolin-4-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1-methyl-1,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)isothiazolo[4,5-c]quinolin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methyl-3,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)isothiazolo[5,4-c]quinolin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)isoxazolo[5,4-c]quinolin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)isothiazolo[3,4-c]quinolin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)isothiazolo[4,3-c]quinolin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)isoxazolo[4,5-c]quinolin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2,5-dihydro-4H-pyrrolo[3,4-c]quinolin-4-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-methyl-2,5-dihydro-4H-pyrrolo[3,4-c]quinolin-4-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[3,4-c]quinolin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)isoxazolo[4,3-c]quinolin-4(5H)-one; 9-fluoro-7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[2,3-c]quinolin-4(5H)-one; 9-fluoro-7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thieno[3,2-c]quinolin-4(5H)-one; 9-fluoro-7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[2,3-c]quinolin-4(5H)-one; 9-fluoro-7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)thiazolo[4,5-c]quinolin-4(5H)-one; 9-fluoro-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; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-furo[3,2-c]quinolin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-furo[3,2-c]quinolin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylisoxazolo[4,5-c]quinolin-4(5H)-one; 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoropyrrolo[1,2-c]quinazolin-5(6H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one; 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one: 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoroimidazo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoroimidazo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoroimidazo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoroimidazo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-chloro-pyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-chloro-pyrazolo[1,5-a]quinoxalin-4(5H)-one; 8-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one; 8-((4-(2-fluoro-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one; 8-((4-(2-methyl-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one; 8-((4-(2-fluoro-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one; 8-((4-(2-methyl-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one; 7-((4-(2-fluoro-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one; 7-((4-(2-fluoro-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one; 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-methyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methyl-3,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one; 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoropyrazolo[1,5-c]quinazolin-5(6H)-one; 8-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoropyrazolo[1,5-c]quinazolin-5(6H)-one; 7-((4-(6-methylcarbamoyl-2-methylpyridin-3-yl)piperazin-1-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,4-c]quinolin-4-one; 7-((4-(6-methylcarbamoyl-2-methylpyridin-3-yl)piperazin-1-yl)methyl)-2-methyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,4-c]quinolin-4-one; 7-((4-(6-methylcarbamoyl-2-methylpyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-1,2,3,5-tetrahydro-4H-pyrrolo[3,4-c]quinolin-4-one; 7-((4-(6-methylcarbamoyl-2-fluoropyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-1,2,3,5-tetrahydro-4H-pyrrolo[3,4-c]quinolin-4-one; 7-((4-(6-methylcarbamoyl-2-methylpyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-2-methyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,4-c]quinolin-4-one; 7-((4-(6-methylcarbamoyl-2-fluoropyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-2-methyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,4-c]quinolin-4-one; 7-((4-(6-methylcarbamoyl-2-methylpyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one; 7-((4-(6-methylcarbamoyl-2-fluoropyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one; 7-((4-(6-methylcarbamoyl-2-methylpyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one; 7-((4-(6-methylcarbamoyl-2-fluoropyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one; 7-((4-(6-methylcarbamoyl-2-methylpyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one; 7-((4-(6-methylcarbamoyl-2-fluoropyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one; 7-((4-(6-methylcarbamoyl-2-methylpyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-1,2-dihydrofuro[2,3-c]quinolin-4(5H)-one, 7-((4-(6-methylcarbamoyl-2-fluoropyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-1,2-dihydrofuro[2,3-c]quinolin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-2-methyl-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-8-fluoro-2-methyl-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-2-methyl-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-8-fluoro-2-methyl-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one; 6-fluoro-7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one; 6-fluoro-7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-methyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-8-fluorooxazolo[5,4-c]quinolin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluorooxazolo[5,4-c]quinolin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methyl-6-fluoroisoxazolo[4,5-c]quinolin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methyl-8-fluoroisoxazolo[4,5-c]quinolin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)isoxazolo[4,5-c]quinolin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,5-dihydro-4H-pyrrolo[2,3-c]quinolin-4-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-1-methyl-1,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one; 7-((4-(2-(difluoromethyl)-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-8-fluorofuro[2,3-c]quinolin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-methylfuro[2,3-c]quinolin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-8-methylfuro[2,3-c]quinolin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-chlorofuro[2,3-c]quinolin-4(5H)-one; 7-((4-(2-fluoro-6-carbamoylpyridin-3-yl)piperazin-1-yl)methyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one; 6-fluoro-7-((4-(5-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[2,3-c]quinolin-4(5H)-one; 6-fluoro-7-((4-(6-(methylcarbamoyl)-2-(trifluoromethyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[2,3-c]quinolin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperidin-1-yl)methyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one; 7-((4-(2-fluoro-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one; 7-((4-(2-fluoro-6-(5-methyl-1H-imidazol-2-yl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[2,3-c]quinolin-4(5H)-one; 7-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[2,3-c]quinolin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[3,2-c]quinolin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluorofuro[3,4-c]quinolin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-2-methylfuro[2,3-c]quinolin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2,6-difluorofuro[2,3-c]quinolin-4(5H)-one; 7-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[3,2-c]quinolin-4(5H)-one; 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-7-fluoropyrazolo[1,5-c]quinazolin-5(6H)-one; 8-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-9-fluoropyrazolo[1,5-c]quinazolin-5(6H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one; 6-fluoro-7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperidin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-fluoro-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-fluoro-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(5-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-cyano-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-fluoro-6-(2,2-difluoroethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-fluoro-6-(1H-imidazol-5-yl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-difluoromethyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-trifluoromethyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; (R)-6-fluoro-3-methyl-7-((3-((6-(methylcarbamoyl)pyridin-3-yl)amino)pyrrolidin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one; (R)-6-fluoro-7-((3-((2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)amino)pyrrolidin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 8-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-methyl-10-fluoroimidazo[1,2-c]quinazolin-5(6H)-one; 8-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-methyl-10-fluoroimidazo[1,2-c]quinazolin-5(6H)-one; 8-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,7-difluoroimidazo[1,2-c]quinazolin-5(6H)-one; 8-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2,7-difluoroimidazo[1,2-c]quinazolin-5(6H)-one; 8-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-methyl-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one; 8-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methyl-7-fluoroimidazo[1,2-c]quinazolin-5(6H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluorooxazolo[4,5-c]quinolin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[3,4-c]quinolin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)isoxazolo[3,4-c]quinolin-4(5H)-one; 7-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoroimidazo[1,5-a]quinoxalin-4(5H)-one; (R)-7-((3-((6-(methylcarbamoyl)pyridin-3-yl)amino)pyrrolidin-1-yl)methyl)-6-fluorofuro[2,3-c]quinolin-4(5H)-one; 6-fluoro-7-((4-(2-fluoro-6-(2,2-difluoroethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[2,3-c]quinolin-4(5H)-one; 6-fluoro-7-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[2,3-c]quinolin-4(5H)-one; 6-fluoro-7-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[3,4-c]quinolin-4(5H)-one; 6-fluoro-7-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)furo[3,2-c]quinolin-4(5H)-one; 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 6-fluoro-3-methyl-7-((6-methylcarbamoyl-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one; 6-fluoro-3-methyl-7-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one; 6-fluoro-7-((4-(2-fluoro-4-(methylcarbamoyl)phenyl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 6-fluoro-7-((4-(2-chloro-4-(methylcarbamoyl)phenyl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; (R)-6-fluoro-7-((4-(2-fluoro-6-((tetrahydrofuran-3-yl)carbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 6-fluoro-3-methyl-7-((4-(8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(6-(1H-imidazol-2-yl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 6-fluoro-7-((4-(2-fluoro-6-((methyl-d3)carbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-cyclopropyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 6-fluoro-7-((4-(3-fluoro-4-(methylcarbamoyl)phenyl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 6-fluoro-7-((4-(2-methyl-4-(methylcarbamoyl)phenyl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-ethyl-6-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one; 6-fluoro-7-((4-(2-fluoro-6-cyanopyridin-3-yl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 6-fluoro-7-((2-fluoro-6-methylcarbamoyl-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; (R)-6-fluoro-7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)-3-methylpiperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; (R)-6-fluoro-3-methyl-7-((8-methylcarbamoyl-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-3(4H)-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one; 8-fluoro-7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 8-fluoro-7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 8-fluoro-7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-dimethylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-dimethylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-dimethylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 6-chloro-7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 6-chloro-7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 6-chloro-7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 3,9-difluoro-7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-trifluoromethyl-6-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-fluoro-6-(ethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-fluoro-6-(cyclopropylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,8-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,8-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,8-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-fluoro-6-((methyl-d3)carbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-fluoro-6-(2,2-difluoroethylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-cyano-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one; 3-fluoro-7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 3-fluoro-7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 3-fluoro-7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 3-fluoro-7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-chloropyrazolo[1,5-a]quinoxalin-4(5H)-one; 3-fluoro-7-((4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-chloropyrazolo[1,5-a]quinoxalin-4(5H)-one; 3-fluoro-7-((4-(2-chloro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-chloropyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-fluoro-6-cyanopyridin-3-yl)piperazin-1-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one; (R)-7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)-3-methylpiperazin-1-yl)methyl)-3,-6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((2-fluoro-6-methylcarbamoyl-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one; (R)-7-((8-methylcarbamoyl-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazin-3(4H)-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one; 6-fluoro-7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2-methyl-3-chloropyrazolo[1,5-a]quinoxalin-4(5H)-one; 6-fluoro-7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-2,3-dimethylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-cyano-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-6-fluoro-3-(trifluoromethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-cyano-6-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-isopropyl-6-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one; 6-fluoro-7-(1-(4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)ethyl)-3-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one; 7-fluoro-8-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)imidazo[1,5-c]quinazolin-5(6H)-one; or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharmaceutically acceptable salt thereof, or prodrug thereof, or a mixture thereof.

17. 20. Use of a compound according to any one of claims 1 to 16, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharmaceutically acceptable salt thereof, or a prodrug thereof, or a mixture thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition responsive to the inhibition of PARP activity; Preferably, the disease or condition is cancer; preferably, the cancer is liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer (such as small cell lung cancer), Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain tumor, selected from 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 tumors, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocythemia, adrenocortical carcinoma, skin cancer, or prostate cancer; Preferably, the medicament further comprises at least one known anticancer drug or a pharmaceutically acceptable salt thereof, and preferably, the 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, and 5-fluorouracil. , capecitabine, methotrexate, 5-fluoro-2'-deoxy-uridine, fludarabine, nelarabine, ara-C, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, mAb, panitumumab, necitumumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, Ibritumomab, tositumomab, brentuximab, daratumumab, elotuzumab, T-DM1, ofatumumab, 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, osimertinib, afatinib, cefotaxime, Litinib, alectinib, crizotinib, erlotinib, rafenib, sorafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, ponatinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cobimetinib, axitinib, temsirolimus, idelalisib, pazopanib, torisel, everolimus, tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib,selected from the group consisting of carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin-2), sipuleucel-T (prostate cancer therapeutic vaccine); Preferably, the agent is used in combination with radiotherapy.

18. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharmaceutically acceptable salt thereof, or a prodrug thereof, or a mixture thereof, and a pharmaceutically acceptable carrier.

19. The composition further comprises at least one known anticancer drug or a pharmaceutically acceptable salt thereof, and preferably, the at least one known anticancer drug is selected from the group consisting of 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, and the like. ru, capecitabine, methotrexate, 5-fluoro-2'-deoxy-uridine, fludarabine, nelarabine, ara-C, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, mAb, panitumumab, necitumumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab , ibritumomab, tositumomab, brentuximab, daratumumab, elotuzumab, T-DM1, ofatumumab, dinutuximab, blinatumomab, ipilimumab, Avastin, Herceptin, MabTera, imatinib, gefitinib, erlotinib, ostinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lapatinib, solutinib, rafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, platinib, brutinib, and cabozantinib ib, 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, venetoclax, aldesleukin (recombinant human interleukin-2), sipuleucel-T (prostate cancer treatment vaccine),The pharmaceutical composition according to claim 18.

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