Substituted Fused Bicyclic Compounds as PARP Inhibitors and Their Use

Abstract

The present disclosure provides substituted fused bicyclic compounds and their use as PARP inhibitors. The present disclosure provides compounds represented by the following formula I, where A1, A2, A3, R1, L, Cy, and n are defined herein. The compounds of formula I of the present disclosure are PARP inhibitors and are therefore useful for treating diseases, disorders, and conditions, such as cancer, that respond to the inhibition of PARP activity. The present disclosure also relates to pharmaceutical compositions comprising the compounds of formula I and the use of the compounds of formula I in the preparation of medicaments for the treatment or prevention of diseases or conditions that respond to the inhibition of PARP activity. JPEG2024513538000058.jpg3655

Description

[Technical field]

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

[0002] Poly(ADP-ribose) polymerase (PARP) is a donor NAD + PARP is a family of proteins that transfer the negatively charged ADP-ribose group from ribosomal RNA onto target proteins. This is one of many post-transcriptional modifications. Therefore, PARP is also called ADP-ribose transferase.

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

[0004] The best-characterized member of the PARP family is PARP1, which was found to have the highest intracellular levels. PARP1 is 1014 amino acids long (NCBI accession P09874) with a total molecular weight of approximately 116 kDa. Structurally, the enzyme is composed of two major domains, including an N-terminal DNA binding domain and a catalytic domain. PARP1 is known to play important roles in many cellular functions, including gene expression, transcription, cell division, cell differentiation, cell apoptosis, and DNA damage response and repair. PARP1 is activated upon DNA damage and participates in base excision repair (BER), the main mechanism of DNA single-strand damage repair. PARP1 binds to the site of a single-strand break (SSB) and then repairs DNA via BER. In response to DNA damage, in addition to the BER repair mechanism, cells have also evolved two major repair pathways: homologous recombination (HR) and non-homologous end joining (NHEJ). PARP inhibitors have been shown to be sensitive to HR-deficient tumors, indicating that homologous recombination deficiency and PARP1 inhibition formed a pair of synthetic lethality that has been validated by clinical trials. Currently, several PARP inhibitors are approved for the treatment of breast, ovarian, pancreatic, and prostate cancers with BRCA1 / 2 mutations.

[0005] PARP2 is a 559 amino acid protein with a molecular weight of approximately 62 kDa and composed of a DNA binding domain and a catalytic domain (Ame et al., 1999 J Biol Chem 274:17860). The catalytic domain of PARP2 is very similar to that of PARP1. PARP2 has also been shown to have a similar function to PARP1, and is involved in the repair of DNA damage repair via the BER mechanism (Schreiber et al., 2002 J Biol Chem 277:23028). 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 pharmacodynamic effects of these commercially available PARP inhibitors are comparable, but the toxicity profiles are significantly different. For example, these PARP inhibitors have similar hematological toxicity, but talazoparib has similar side effects to chemotherapy drugs, such as hair loss. Talazoparib also shows more potent inhibitory activity against TNKS1 / 2 in biochemical assays than other PARP inhibitors (PARPi) (Ryan et al., 2021, J Biol Chem 296:100251). Tankyrase 1 (TNKS1) and Tankyrase 1 (TNKS2) share 83% overall sequence identity, and their catalytic domain sequences are 89% identical. They play roles in DNA repair, telomere maintenance, and Wnt / β-catenin signaling. Targeting other PARPs besides PARP1 may be the reason why PARP inhibitors cause extrinsic toxicity, such as hair loss and diarrhea. Furthermore, it has been demonstrated that inhibition of PARP2 activity can result in hematologic toxicity (Farres et al., 2013, Blood 122:44; Farres et al., 2015, Cell Death and Differentiation 22:1144). The toxicity of these PARP inhibitors limits their clinical use and combination with other targeted agents. Therefore, to improve, enhance, and expand the clinical use of PARP1 inhibitors, there is a need to explore highly selective PARP1 inhibitors with reduced toxicity, whether mechanism-related or mechanism-independent. Various PARP1 inhibitors have been disclosed, for example, in WO2011 / 006803, WO2013 / 014038, WO2021 / 013735, and WO2021 / 260092. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2011 / 006803 [Patent Document 2] International Publication No. 2013 / 014038 [Patent Document 3] International Publication No. 2021 / 013735 [Patent Document 4] International Publication No. 2021 / 260092 [Non-patent literature]

[0007] [Non-Patent Document 1] Vyas et al.,2013 Nature Communication,4,3240 / 1-3240 / 13 [Non-Patent Document 2] Ame et al.,1999 J Biol Chem 274:17860 [Non-Patent Document 3] Schreiber et al.,2002 J Biol Chem 277:23028 [Non-Patent Document 4] Ryan et al.,2021,J Biol Chem 296:100251 Summary of the Invention [Means for solving the problem]

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

[0009] The present disclosure also provides pharmaceutical compositions comprising an effective amount of a compound of Formula I, II, III, and IV for the treatment of cancer.

[0010] In certain embodiments, the pharmaceutical compositions may also include one or more pharma- ceutically acceptable carriers or diluents for the treatment of cancer.

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

[0012] The present disclosure is also directed to methods for preparing the novel compounds of Formulas I, II, III, and IV. 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 can be applied to any of the embodiments described herein.For example, the definition of the alkyl substituent in this specification applies to any of the embodiments described herein, unless the alkyl substituent is clearly defined in the embodiment.

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

[0015] As used herein, the term "alkyl" refers to alkyl itself or to a straight or branched chain radical of up to 10 carbons. Useful alkyl groups include straight or branched C 1-10 Alkyl groups, preferably C 1-6 In some embodiments, the alkyl group is C1-4 In some embodiments, alkyl is C 1-3 It is an alkyl group. Typical C 1-10 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl, and octyl groups, which may be optionally substituted.

[0016] As used herein, the term "alkenyl" refers to a straight or branched chain radical of 2 to 10 carbon atoms, unless the chain length is limited thereto, and has at least one double bond between two of the carbon atoms in the chain, preferably a C 2-6 Exemplary alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl.

[0017] As used herein, the term "alkynyl" refers to a straight or branched chain radical of 2 to 10 carbon atoms, unless the chain length is limited thereto, and has at least one triple bond between two of the carbon atoms in the chain, preferably a C 2-6 Exemplary alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl, and 2-butynyl.

[0018] Useful alkoxy groups include those described above for C 1-10 Alkyl groups, preferred C 1-6 Alkyl group or C 1-4 Included are oxygen substituted with alkyl groups such as methoxy, ethoxy, etc. The alkyl in the alkoxy group may be optionally substituted. Alkoxy group substituents include, but are not limited to, halogen, morpholino, amino (including alkylamino and dialkylamino), and carboxy (including esters thereof).

[0019] 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 hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 or R' and R" together with the N to which they are attached form an optionally substituted 4-7 membered cyclic amino group, which optionally contains one or more (such as 2, 3) additional heteroatoms selected from the group consisting of O, N, and S. Preferred amino groups include NH2, where at least one of R' and R" is C in -NR'R". 1-6 It is an alkyl.

[0020] As used herein, the term "oxo" refers to =O.

[0021] The term "aryl" as used herein by itself or as part of another group refers to a monocyclic, bicyclic, or tricyclic aromatic group containing 6 to 14 carbon atoms. Aryl may be optionally substituted by one or more substituents described herein.

[0022] 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.

[0023] 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 C3-6 Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Useful partially saturated carbocyclic groups include cyclopentenyl, cycloheptenyl, and cyclooctenyl, C 3-8 Carbocyclic groups may be optionally substituted by one or more substituents described herein.

[0024] Useful halo or halogen groups include fluoro, chloro, bromo, and iodo.

[0025] Useful acylamino (acylamide) groups include any C aryl group attached to an amino nitrogen, such as acetamino, propionamido, butanoylamido, pentanoylamido, and hexanoylamido. 1-6 Acyl (alkanoyl) and aryl substituted C 1-6 Acylamino groups, for example benzoylamide.

[0026] Useful acyl groups include C 1-6 Examples of substituted acyl groups include acyl, which may be optionally substituted by a group selected from the group consisting of halo, amino, and aryl, and amino and aryl may be optionally substituted. When acyl is substituted by halo, the number of halogen substituents may range from 1 to 5. Examples of substituted acyl include chloroacetyl and pentafluorobenzoyl. When acyl is substituted by amino, the amino group may be substituted by one or two substituents as described herein. In some embodiments, aminoacyl is -C(O)-NR R'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 hydrogen, optionally substituted C 1-4Alkyl or optionally substituted C 3-6 and cycloalkyl. As used herein, when the alkyl, cycloalkyl, aryl, and heteroaryl groups in R' and R" are substituted, the substituents are as described in any of the embodiments herein, and preferred substituents include halogen, hydroxyl, amino, and alkyl.

[0027] 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, N, and S), where the nitrogen and / or sulfur heteroatoms may be optionally oxidized, and the nitrogen may be optionally quaternized; the term also includes any bicyclic ring system in which any of the heterocyclic rings defined above are fused to a benzene ring. A heterocyclic ring 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.

[0028] 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.

[0029] As used herein, the term "heteroaryl" refers to a group having 5-14 ring atoms, preferably 5-10 ring atoms, in which 6, 10, or 14 electrons are shared in a cyclic array. The ring atoms are carbon atoms and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Heteroaryls may be optionally substituted with one or more substituents described herein.

[0030] Useful heteroaryl groups include thienyl (thiophenyl), benzo[d]isothiazol-3-yl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (furanyl), pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl (pyridinyl, including but not limited to 2-pyridyl, 3-pyridyl, and 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthaldinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolidinyl, and the like. nyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, 1,4-dihydroquinoxaline-2,3-dione, 7-amino-isocoumarin, pyrido[1,2-a]pyrimidin-4-one, tetrahydrocyclopenta[c]pyrazol-3-yl, benzoisoxazolyl, such as 1,2-benzisoxazol-3-yl, benzimidazolyl, 2-oxindolyl, thiadiazolyl, 2-oxobenzimidazolyl, imidazopyridazinyl, imidazopyridyl, triazolopyridazinyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, pyrrolopyridyl, pyrrolopyrazinyl, or triazolopyrazinyl. Where a heteroaryl group contains a nitrogen atom in a ring, such nitrogen atom may be in the form of an N-oxide, e.g., a pyridyl N-oxide, pyrazinyl N-oxide, and pyrimidinyl N-oxide.

[0031] In this disclosure, unless otherwise stated, when substituted, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, heterocycloalkoxy, alkenyl, heterocycloalkenyl, alkynyl, amino, amido, acyloxy, carboxyl, hydroxyl, mercapto, alkylthiosulfonyl, sulfonyl, sulfinyl, aminoacyl, silyl, phosphinecarboxy, phosphono, carbocyclic, heterocyclic, aryl, or heteroaryl as described in any of the embodiments herein can be selected from the group consisting of halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 1-6 Amide, C 1-6 Acyloxy, C 1-6 Alkoxy, aryloxy, alkylthio, C 1-6 Alkyl, C 1-6 Achill, C 6-10 Aryl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 It may be substituted by one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents selected from the group consisting of alkynyl, heterocyclic or heteroaryl, methylenedioxy, urea group, mercapto group, azido group, carbonyl, alkanesulfonyl, sulfamoyl, dialkylsulfamoyl, alkylsulfinyl, and the like. The substituents themselves may be optionally substituted. Preferred substituents include, but are not limited to, halogen, hydroxyl, carboxyl, amino, C 1-6 Amide, C 1-6 Acyloxy, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 acyl, and alkanesulfonyl.

[0032] In each embodiment, it is to be understood that when the substituent is a heterocyclic group, aryl, or heteroaryl, the number is typically one.

[0033] Specifically, the present disclosure provides a compound represented by formula I: [ka] or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, wherein: R1 is selected from the group consisting of optionally substituted alkyl, optionally substituted carbocyclic, optionally substituted alkenyl, and optionally substituted alkynyl; A1, A2, and A3 are each independently selected from the group consisting of N and CR2; L is selected from the group consisting of a bond and alkylene optionally substituted by R3 and / or R4; Cy is selected from the group consisting of optionally substituted heterocyclic groups, optionally substituted aryl, and optionally substituted heteroaryl; R2 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted carbocyclic groups; R3 and R4 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 R3 and R4 together with the bonded C form a ring; n is selected from the group consisting of 0, 1, and 2; When n is 1 or 2, the formula -(CH2) is shown. n - is optionally replaced by =O.

[0034] In Formula I and each formula of this disclosure, unless otherwise stated, each alkyl is independently C 1-6 Alkyl, preferably C 1-4 alkyl, each alkylene being C 1-6 Alkylene, preferably C 1-3 alkylene, each alkenyl independently being C 2-6 Alkenyl, preferably C 2-4alkenyl, each alkynyl independently being C 2-6 Alkynyl, preferably C 2-4 alkynyl, each alkoxy being independently selected from the group consisting of C 1-6 Alkoxy, preferably C 1-4 Preferably, when alkyl, alkenyl, alkynyl, and alkoxy are substituted, the substituents are cyano, hydroxyl, nitro, amino (-NR ’ R ’’ The number of substituents may be 1 to 5, and R′ and R″ are preferably each independently selected from H, optionally substituted C 1-4 Alkyl or optionally substituted C 3-6 It is cycloalkyl. For example, substituted alkyl itself or as a substituent of other groups may be hydroxyalkyl, dihydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heterocyclic alkyl, aralkyl, heteroarylalkyl, haloalkyl, etc. It should be understood that when the substituent is aryl, heteroaryl, heterocyclic, cyano, nitro, and carboxyl, the number is usually 1. When the substituent is halogen, the number of the substituent can be up to 5 depending on the length of the carbon chain of the alkyl group, alkenyl group, alkynyl group, and alkoxy group, and exemplary substituents are trifluoromethyl group, pentafluoroethyl, etc.

[0035] In Formula I and each formula of the present disclosure, unless otherwise specified, the number of ring carbon atoms in each carbocyclic group is preferably 3 to 8. Preferred carbocyclic groups are 3-8 The substituents on the carbocyclic group are preferably C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4The substituents include alkoxy, halogen, hydroxyl, carboxyl, amino (-NR'R"), aryl, heterocyclic, heteroaryl, and carboxyl. The number of substituents may be 1 to 5, and R' and R" are preferably each independently selected from H, optionally substituted C 1-4 Alkyl or optionally substituted C 3-6 It is cycloalkyl. When the substituent is aryl, heteroaryl, heterocyclic group, cyano, nitro, and carboxyl, it should be understood that the number is usually 1. When the substituent is halogen, the number of the substituent can be up to 5. The aryl, heterocyclic group, and heteroaryl can be optionally substituted as described herein as a substituent of the carbocyclic group.

[0036] In Formula I and each formula of the present disclosure, unless otherwise stated, aryl is C 6-14 aryl refers to a 5- to 10-membered heteroaryl, and heterocyclic refers to a 4- to 10-membered heterocyclic group. In some embodiments, the substituents on each of the aryl, heteroaryl, and heterocyclic groups are independently selected from the group consisting of C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 and the like, wherein R′ and R″ are each independently selected from the group consisting of hydrogen, an optionally substituted C1- 10R' and R" are each independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. The number of substituents can be 1 to 5. In some embodiments, the optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclic groups are optionally substituted with C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1~4 and optionally substituted with 1 to 5 groups selected from the group consisting of alkoxy, halogen, hydroxyl, carboxyl, amino (-NR'R"), -S(O)2-NR'R", aminoacyl (-C(O)-NR'R"), and carboxyl, wherein R' and R" are preferably each independently selected from H, optionally substituted C 1-4 Alkyl or optionally substituted C 3-6 It is understood that when the substituent is an aryl, heteroaryl, heterocyclic group, cyano, nitro, or carboxyl, the number is usually 1. When the substituent is a halogen, the number of the substituent can be up to 5.

[0037] In one or more embodiments of the compound of Formula I, the aryl is preferably phenyl. The heteroaryl is a 5-10 membered heteroaryl containing one or two nitrogen atoms, including, but not limited to, pyridyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridazinyl, indolyl, pyridopyrimidinyl, indolyl, indazolyl, and benzimidazolyl. The carbocyclic group is preferably C 3-8 The heterocyclic group is preferably a 4-10 membered heterocyclic group containing O and / or N, including, but not limited to, azetidinyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrahydrofuranyl, tetrahydroisoquinolyl, and morpholinyl.

[0038] In one or more embodiments of the compound of formula I, when R2 is substituted, the substituents can be 1 to 5 groups selected from the group consisting of halogen and hydroxyl. Preferably, R2 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-3 Alkyl or optionally substituted C 1-3 More preferably, R2 is hydrogen, C 1-3 In some preferred embodiments, only one of A1, A2, and A3 is N, and the other two are independently CR2, and preferably R2 is independently H, C 1-3 In a more preferred embodiment, A3 is CH, one of A1 and A2 is N and the other is CR2, and R2 is H, C 1-3 In some embodiments, A1 is N and both A2 and A3 are CH. In some embodiments, A2 is N and both A1 and A3 are CH. In some embodiments, A1, A2, and A3 are all CR2, and each R2 is independently selected from H, C, 1-3 Preferably, A3 is CH, one of A1 and A2 is CR2, and R2 is H, C 1-3 more preferably, A2 and A3 are both CH, A1 is CR2 and R2 is C 1-3 It is alkyl or halogen.

[0039] In one or more embodiments of the compound of formula I, R is optionally substituted C 1-3 Alkyl or optionally substituted C 3-6 Preferably, when R1 is substituted, the substituents may be 1-5 groups selected from the group consisting of halogen, hydroxyl, amino (-NR'R"), and the like, where R' and R" are preferably each independently H, or C optionally substituted with 1-5 groups selected from the group consisting of hydroxyl and halogen. 1-4 Alkyl or C 3-6Preferably, R1 is C 1-3 Alkyl, halogenated C 1-3 Alkyl or C 3-4 It is cycloalkyl.

[0040] In one or more embodiments of the compound of formula I, preferably, R and R are each independently a halogen or C 1-3 It is an alkyl.

[0041] In one or more embodiments of the compound of formula I, L is a bond. In some embodiments, L is an unsubstituted alkylene, more preferably an unsubstituted C 1-3 Alkylene, preferably methylene.

[0042] In one or more embodiments of the compound of formula I, Cy is 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, optionally substituted C 3-8 Cycloalkyl, and -(CH2) m C(O)-NR a R b wherein R a and R b are independent of each other, H, C 1-4 alkyl, optionally substituted 6- to 14-membered aryl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 4- to 10-membered heterocyclic group, m is an integer from 0 to 5, preferably m is 0, and preferably R a and R bAt least one of the optionally substituted 6- to 14-membered aryl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 4- to 10-membered heterocyclic group in the definition of the Cy substituent is an 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 and R a and R b In the definition of the optionally substituted 6- to 14-membered aryl, the optionally substituted 5- to 10-membered heteroaryl, or the optionally substituted 4- to 10-membered heterocyclic group, each independently represents a halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, optionally substituted 5-10 membered heteroaryl (halogen and C 1-4 and optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, preferably 5-6 membered nitrogen and / or oxygen containing heteroaryl), -S(O)2-NR'R", -NR'R", and -C(O)-NR'R", wherein R' and R" are preferably each independently selected from H, optionally substituted C 1-4 Alkyl or optionally substituted C 3-6 More preferably, R′ and R″ are each independently H, C 1-4 Alkyl, halogenated C 1-4 Alkyl or C 3-6 In some preferred embodiments, the optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered heterocyclic group, and optionally substituted C 3-8 Cycloalkyl and R a and R bThe substituents on the optionally substituted 6- to 14-membered aryl, the optionally substituted 5- to 10-membered heteroaryl, and the optionally substituted 4- to 10-membered heterocyclic groups in the definitions of 1-4 Alkoxy and C 1-4 In some preferred embodiments, Cy is substituted by an optionally substituted 5-10 membered heteroaryl, preferably an optionally substituted 5-10 membered nitrogen-containing heteroaryl. Preferably, the 5-10 membered nitrogen-containing heteroaryl is substituted by at least -C(O)-NR'R" and optionally halogen, C 1-4 Alkoxy and C 1-4 In some embodiments, Cy is substituted with one R5 as described below. In some embodiments, Cy is a heterocyclic group optionally substituted as described above. In some particularly preferred embodiments, Cy is piperazinyl substituted with an optionally substituted pyridyl, where the pyridyl is at least substituted with -C(O)-NR'R". In other preferred embodiments, Cy is -(CH2) m C(O)-NR a R b and preferably R a and R b At least one of is a 5-10 membered heteroaryl substituted with -C(O)-NR'R".

[0043] Preferably, in the embodiments described herein, when the R' and R" are substituted, the substituents are selected from the group consisting of halogen and hydroxy. In some preferred embodiments, R' and R" are preferably each independently selected from H, C, 1-4 Alkyl, halogenated C 1-4 Alkyl or C 3-6 It is cycloalkyl.

[0044] In one or more embodiments of the compound of formula I, when L is a bond, Cy is an optionally substituted aryl or an optionally substituted heteroaryl. Preferably, the optionally substituted aryl and the optionally substituted heteroaryl are each optionally selected from the group consisting of 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogen, and -(CH2) m C(O)-NR a R b wherein R a and R b are independent of each other, H, C 1-4 m may be an alkyl, an optionally substituted 6-14 membered aryl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-10 membered heterocyclic group, and m is an integer from 0 to 5, preferably m is 0. The number of substituents may be 1 to 5. Preferably, the optionally substituted aryl and the optionally substituted heteroaryl are -(CH2) m C(O)-NR a R b At least one of the halogens, C 1-4 Alkyl and halogenated C 1-4 It may be further substituted with 1 to 3 substituents selected from the group consisting of alkyl. a and R b At least one of R is an optionally substituted 6- to 14-membered aryl, an optionally substituted 5- to 10-membered heteroaryl, or an optionally substituted 4- to 10-membered heterocyclic group. More preferably, R a and R b One of R is H and the other is an optionally substituted 5-10 membered heteroaryl. a and R b In the definition of the optionally substituted 6- to 14-membered aryl, the optionally substituted 5- to 10-membered heteroaryl, and the optionally substituted 4- to 10-membered heterocyclic group each optionally includes 1-4 Alkyl, halogenated C 1-4Alkyl, C 1-4 and optionally substituted with 1 to 5 groups selected from the group consisting of alkoxy, halogen, hydroxyl, carboxyl, amino (-NR'R"), -C(O)-NR'R", and carboxyl, wherein R' and R" are preferably each independently selected from H, optionally substituted C 1-4 Alkyl or optionally substituted C 3-6 cycloalkyl, and more preferably R′ and R″ are each independently H, C 1-4 Alkyl, halogenated C 1-4 Alkyl or C 3-6 More preferably, the 5- to 10-membered heteroaryl and 4- to 10-membered heterocyclic groups are at least substituted with -C(O)-NR'R" and are not substituted with halogen, C 1-4 Alkoxy, C 1-4 Alkyl and halogenated C 1-4 It may be further substituted with 1 to 3 substituents selected from the group consisting of alkyl.

[0045] In one or more embodiments of the compound of formula I, when L is an alkylene group, such as -CH2-, Cy is an optionally substituted 5- to 7-membered nitrogen-containing heterocyclic group. Preferably, the 5- to 7-membered nitrogen-containing heterocyclic group is covalently bonded to L through its ring nitrogen atom. More preferably, Cy is an optionally substituted piperazinyl. Preferably, the substituents on Cy are halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, optionally substituted 6- to 14-membered aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered heterocyclic groups, and optionally substituted C 3-8 cycloalkyl, optionally substituted 6- to 14-membered aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered heterocyclic group, and optionally substituted C 3-8 Each cycloalkyl is independently a halogen, C 1-4Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, optionally substituted 5-10 membered heteroaryl (halogen and C 1-4 and optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, preferably 5-6 membered heteroaryl containing nitrogen and / or oxygen, -S(O)2-NR'R", -NR'R", and -C(O)-NR'R", where R' and R" are preferably each independently selected from H, optionally substituted C 1-4 Alkyl or optionally substituted C 3-6 In some preferred embodiments, the substituents include at least -C(O)-NR'R", optionally including halogen, C 1-4 Alkoxy and C 1-4 In some preferred embodiments, Cy is substituted by an optionally substituted 5-10 membered heteroaryl, preferably an optionally substituted 5-10 membered nitrogen-containing heteroaryl, preferably the 5-10 membered nitrogen-containing heteroaryl is at least substituted by -C(O)-NR'R", halogen, C 1-4 Alkoxy and C 1-4 In some particularly preferred embodiments, Cy is piperazinyl substituted with an optionally substituted pyridyl, said pyridyl being at least substituted with -C(O)-NR'R". Preferably, in the embodiments described herein, when R' and R" are substituted, the substituents are selected from the group consisting of halogen and hydroxy. In some preferred embodiments, R' and R" are preferably each independently selected from H, C, 1-4 Alkyl, halogenated C 1-4 Alkyl or C 3-6 It is cycloalkyl.

[0046] In one or more embodiments of the compound of formula I, n is 0 or 1.

[0047] One group of preferred compounds of formula I in the present disclosure are compounds of formula II (including formula IIa and IIb): [ka] or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof; R1, A1, A2, A3, and n are as defined in formula I; R5 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; D1, D2, D3, and D4 are independently selected from the group consisting of N and CR6; R6 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.

[0048] In one or more embodiments of the compounds of formula IIa and IIb, R is an optionally substituted C 1-3 Alkyl or C 3-6 Preferably, when R1 is substituted, the substituents may be 1 to 5 groups selected from the group consisting of halogen, hydroxyl, amino (-NR'R"), and the like, where R' and R" are preferably each independently selected from H, optionally substituted C 1-4 Alkyl or optionally substituted C 3-6 Preferably, R1 is C 1-3 Alkyl, halogenated C 1-3 Alkyl or C 3-4 It is cycloalkyl.

[0049] In one or more embodiments of the compounds of formula IIa and formula IIb, when R2 is substituted, the substituents can be 1 to 5 groups selected from the group consisting of halogen and hydroxyl. Preferably, R2 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-3 Alkyl or optionally substituted C 1-3 More preferably, R2 is hydrogen, C 1-3 In some preferred embodiments, only one of A1, A2, and A3 is N, and the other two are independently CR2, and preferably R2 is independently H, C 1-3 In a more preferred embodiment, A3 is CH, one of A1 and A2 is N and the other is CR2, and R2 is H, C 1-3 In some embodiments, A1 is N and both A2 and A3 are CH. In some embodiments, A2 is N and both A1 and A3 are CH. In some embodiments, A1, A2, and A3 are all CR2, and each R2 is independently selected from H, C, 1-3 Preferably, A3 is CH, one of A1 and A2 is CR2, and R2 is H, C 1-3 more preferably, A2 and A3 are both CH, A1 is CR2 and R2 is C 1-3 It is alkyl or halogen.

[0050] In one or more embodiments of the compounds of formula IIa and formula IIb, R5 is an optionally substituted phenyl or a 5-7 membered nitrogen-containing heterocyclic group, more preferably an optionally substituted phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl. Preferably, when R5 is substituted, the substituents are halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted 5-10 membered heteroaryl (e.g., halogen and C 1-4Preferably, R5 is substituted at the para position with an optionally substituted aminoacyl group. Preferably, the optionally substituted aminoacyl is -C(O)-NR'R", where R' and R" are each preferably independently selected from H, optionally substituted C(O)-NR'R", optionally substituted C(O)-NR'R", and optionally substituted C(O)-NR'R", where R' and R" are each preferably independently selected from H, ... and optionally substituted C(O)-NR'R", where R' and R" are each preferably independently selected from H, optionally substituted C(O)-NR'R", and optionally substituted C(O)-NR'R", and optionally substituted C(O)-NR'R", 1-4 Alkyl or optionally substituted C 3-6 More preferably, R′ and R″ are each independently selected from H, C 1-4 Alkyl, halogenated C 1-4 Alkyl or C 3-6 In one or more embodiments of the compounds of formula IIa and formula IIb, R5 is halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy and halogenated C 1-4 In one or more embodiments of the compounds of formula IIa and formula IIb, R5 is 1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl or 4-oxo-4H-pyrido[1,2-a]pyrimidin-8-yl, optionally substituted with 1 to 5 groups selected from the group consisting of alkoxy, and the like. 1-4 Alkyl and halogenated C 1-4 and pyridopyrimidinyl, indolyl, indazolyl, or benzimidazolyl optionally substituted with 1 to 3 groups selected from the group consisting of alkyl.

[0051] In one or more embodiments of the compounds of formula IIa and formula IIb, R5 is preferably the following group: [ka] More preferably, it is the following group: [ka] wherein B1, B2, B3, and B4 are independently selected from the group consisting of N and CR7, and R7 is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 alkoxy, and -NR'R", where R' and R" are each independently selected from the group consisting of hydrogen, optionally substituted C 1-10 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted 6- to 14-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, each independently selected from the group consisting of hydrogen, optionally substituted C 1-4 Alkyl or optionally substituted C 3-6 cycloalkyl, more preferably each independently H, C 1-4 Alkyl, halogenated C 1-4 Alkyl or C 3-6 Preferably, the B1-B4 containing group is phenyl, pyridyl, pyrimidinyl, or pyridazinyl. Preferably, R7 is H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-3 Preferably, B3 is N, B4 is CR7, B1 and B2 are CH, and R7 is H, halogen, C. 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-3 It is an alkyl.

[0052] In one or more embodiments of the compounds of formula IIa and formula IIb, D1, D2, D3, and D4 are independently selected from the group consisting of N and CR6, where R6 is preferably hydrogen, halogen, optionally substituted C 1-3 Alkyl or optionally substituted C 1-3Preferably, when R6 is substituted, the substituents may be 1 to 5 groups selected from the group consisting of halogen and hydroxyl. More preferably, R6 is hydrogen, C 1-3 In some preferred embodiments, the group comprising D1 to D4 is phenyl or pyridyl, which is selected from the group consisting of halogen and C 1-3 and optionally substituted with 1 to 3 groups selected from the group consisting of alkyl.

[0053] In one or more embodiments of the compounds of Formula IIa and Formula IIb, n is 0 or 1.

[0054] In one or more embodiments of the compound of formula IIa, R1 is selected from the group consisting of optionally substituted alkyl, optionally substituted carbocyclic, optionally substituted alkenyl, and optionally substituted alkynyl; A1, A2, and A3 are each independently selected from the group consisting of N and CR2; and R5 is [ka] wherein B1, B2, B3, and B4 are independently selected from the group consisting of N and CR7; R' is H; and R" is hydrogen, optionally substituted C 1-10 Alkyl or optionally substituted C 3-8 cycloalkyl, and R2 is selected from the group consisting of hydrogen, halogen, and the optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optionally substituted C 3-8 cycloalkyl; R7 is selected from the group consisting of hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 alkoxy, and -NR'R'', where R' and R'' are each independently selected from the group consisting of H, C 1-4 Alkyl, halogenated C 1-4 Alkyl or C 3-6cycloalkyl, n is 0, 1, or 2, and when n is 1 or 2, -(CH) n - is optionally substituted by =O. Preferably, A1, A2, and A3 are each N and CR2, and R2 is preferably hydrogen, halogen, optionally substituted C 1-3 Alkyl or optionally substituted C 1-3 More preferably, R2 is hydrogen, C 1-3 Preferably, only one of A1, A2, and A3 is N, and the other two are independently CR2, and preferably R2 is independently H, C 1-3 Preferably, A3 is CH, one of A1 and A2 is N, the other is CR2, and R2 is H, C 1-3 Preferably, A1 is N and both A2 and A3 are CH. In some embodiments, A2 is N and both A1 and A3 are CH. In some embodiments, A1, A2, and A3 are all CR2, and each R2 is independently selected from H, C, 1-3 Preferably, A3 is CH, one of A1 and A2 is CR2, and R2 is H, C 1-3 more preferably, A2 and A3 are both CH, A1 is CR2 and R2 is C 1-3 Preferably, B1, B2, B3, and B4 are each independently selected from the group consisting of N and CR7, where R7 is hydrogen, C 1-3 Alkyl, halogenated C 1-3 Preferably, B1 and B2 are both CH, B3 is N, B4 is CR7, and R7 is hydrogen, C 1-3 Alkyl, halogenated C 1-3 Preferably, R is an optionally substituted C 1-3Preferably, when R1 is substituted, the number of substituents can be 1 to 5, which can be selected from the group consisting of halogen, hydroxyl, amino-NR'R'', etc., where R' and R'' are preferably each independently H, optionally substituted C 1-4 Alkyl or optionally substituted C 3-6 Preferably, R1 is C 1-3 Alkyl or halogenated C 1-3 Preferably, R′ and R″ are each independently hydrogen, optionally substituted C 1-4 Alkyl or optionally substituted C 3-6 Preferably, when R' and R" are substituted, the number of substituents can be 1 to 5, which can be selected from the group consisting of halogen, hydroxyl, amino, etc. Preferably, R' is hydrogen and R" is hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl or C 3-6 Preferably, R7 is hydrogen, halogen, C 1-3 Alkyl or halogenated C 1-3 Preferably, n is 0 or 1.

[0055] One group of preferred compounds of formula I in the present disclosure are compounds of formula III (including formulae IIIa and IIIb): [ka] or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, wherein R1, A1, A2, A3, B1, B2, B3, and B4 are as described in any of the previous embodiments; R′ and R″ are each independently hydrogen, optionally substituted C 1-4 Alkyl or optionally substituted C 3-6 cycloalkyl; or B3 and R" form a six-membered heterocyclic group having the amide to which they are attached.

[0056] In one or more embodiments of the compounds of formula IIIa and formula IIIb, R is an optionally substituted C 1-3 Alkyl or C 3-6 Preferably, R1 is C 1-3 Alkyl, halogenated C 1-3 Alkyl or C 3-4 It is cycloalkyl.

[0057] In one or more embodiments of the compounds of formula IIIa and formula IIIb, when R2 is substituted, the substituents can be 1 to 5 groups selected from the group consisting of halogen and hydroxyl. Preferably, R2 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-3 Alkyl and optionally substituted C 1-3 More preferably, R2 is hydrogen, C 1-3 In some preferred embodiments, only one of A1, A2, and A3 is N, and the other two are independently CR2, and preferably R2 is independently H, C 1-3 In a more preferred embodiment, A3 is CH, one of A1 and A2 is N and the other is CR2, and R2 is H, C 1-3 In some embodiments, A1 is N and both A2 and A3 are CH. In some embodiments, A2 is N and both A1 and A3 are CH. In some embodiments, A1, A2, and A3 are all CR2, and each R2 is independently selected from H, C, 1-3 Preferably, A3 is CH, one of A1 and A2 is CR2, and R2 is H, C 1-3 more preferably, A2 and A3 are both CH, A1 is CR2 and R2 is C 1-3 It is alkyl or halogen.

[0058] In one or more embodiments of the compounds of Formula IIIa and Formula IIIb, B1, B2, B3, and B4 are independently selected from the group consisting of N and CR7, where R7 is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 alkoxy, and -NR'R'', where R' and R'' are each independently selected from the group consisting of hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl or C 3-6 Preferably, R7 is selected from the group consisting of hydrogen, C 1-3 In some preferred embodiments, B1 and B2 are both CH, B3 is N, and B4 is CR7, where R7 is hydrogen, C 1-3 It is alkyl, or halogen.

[0059] In one or more embodiments of the compounds of Formula IIIa and Formula IIIb, 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, halogenated C 1-3 Alkyl or C 3-6 It is cycloalkyl.

[0060] One group of preferred compounds of formula I in the present disclosure are compounds of formula IV (including formulas IVa and IVb): [ka] or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof; A1, A2, R1, R7, and R ”is as described in any of the preceding embodiments.

[0061] In one or more embodiments of the compounds of formula IVa and formula IVb, A1 and A2 are, respectively, N and CR2, where R2 is preferably hydrogen, halogen, optionally substituted C 1-3 Alkyl or optionally substituted C 1-3 More preferably, R2 is hydrogen, C 1-3 In some preferred embodiments, one of A1 and A2 is N and the other is CR2, where R2 is H, C 1-3 In some embodiments, A and A are both CR, where R is H, C, 1-3 It is alkyl, or halogen.

[0062] In one or more embodiments of the compounds of formula IVa and formula IVb, R is an optionally substituted C 1-3 Alkyl or C 3-6 Preferably, R1 is C 1-3 Alkyl, halogenated C 1-3 Alkyl or C 3-4 It is cycloalkyl.

[0063] In one or more embodiments of the compounds of formula IVa and formula IVb, R″ is hydrogen, optionally substituted C 1-3 Alkyl, optionally substituted C 3-6 Preferably, R″ is hydrogen, C 1-3 Alkyl, C 3-4 Cycloalkyl or halogenated C 1-3 It is an alkyl.

[0064] In one or more embodiments of the compounds of formula IVa and formula IVb, R7 is hydrogen, halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl.

[0065] Although R1, A1, A2, A3, L, Cy, R5, B1, B2, B3, B4, D1, D2, D3, D4, R', R", and n are described separately above, it should be understood that the described features, particularly the preferred features, may be combined in any manner to form a range of different compounds of formula I (including formulas II, III, and IV) in the present disclosure. For example, for a feature described for R2 in one formula, the feature can also be used to define the R2 group in the other formulas, if the R2 group is also present in the other formulas.

[0066] Preferred compounds of formula I include, but are not limited to: 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 1), 5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 2), 5-(4-((3-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 3), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (Example 4), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 5), 5-(4-((3-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 6), 5-(4-((2,4-dioxo-3-propyl-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 7), 5-(4-((2,4-dioxo-3-(trifluoromethyl)-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 8), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (Example 9), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-methylpicolinamide (Example 10), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methyl-6-(trifluoromethyl)picolinamide (Example 11), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 12), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (Example 13), 5-(4-((3-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (Example 14), 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 15), 5-(4-((1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 16), 5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (Example 17), 5-(4-((2,4-dioxo-3-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (Example 18), 5-(4-((2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (Example 19), 5-(4-((3-(2-fluoroethyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (Example 20), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-methylpicolinamide (Example 21), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (Example 22), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methyl-6-(trifluoromethyl)picolinamide (Example 23), 5-(4-((3-ethyl-8-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (Example 24), 5-(4-((3-ethyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (Example 25), 5-(4-((3-isopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (Example 26), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpyrimidine-2-carboxamide (Example 27), 6-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylnicotinamide (Example 28), 6-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpyridazine-3-carboxamide (Example 29), 2-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpyrimidine-5-carboxamide (Example 30), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-ethyl-N-methylpicolinamide (Example 31), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoropicolinamide (Example 32), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-ethylpicolinamide (Example 33), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-isopropylpicolinamide (Example 34), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-(difluoromethyl)-N-methylpicolinamide (Example 35), 3-ethyl-7-((4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)piperazin-1-yl)methyl)quinazoline-2,4(1H,3H)-dione (Example 36), 3-ethyl-7-((4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)piperazin-1-yl)methyl)quinazoline-2,4(1H,3H)-dione (Example 37), 3-ethyl-7-((4-(4-oxo-4H-pyrido[1,2-a]pyrimidin-8-yl)piperazin-1-yl)methyl)quinazoline-2,4(1H,3H)-dione (Example 38), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N,N-dimethylpicolinamide (Example 39), 5-(3-(3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)benzamide)N-methylpicolinamide (Example 40), 5-(3-(3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)benzamide)-N-methylpicolinamide (Example 41), 5-(3-(3-isopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)benzamide)-N-methylpicolinamide (Example 42), 5-(3-(3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-5-fluorobenzamido)-N-methylpicolinamide (Example 43), 5-(3-(3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)benzamido)-6-fluoro-N-methylpicolinamide (Example 44), 5-(3-(3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)benzamide)-N-methylpicolinamide (Example 45), 6-(3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-N-(6-(methylcarbamoyl)pyridin-3-yl)picolinamide (Example 46), 5-(3-(3-propyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)benzamide)-N-methylpicolinamide (Example 47), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-4-fluoro-N-methylpicolinamide (Example 48), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylpicolinamide (Example 49), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,4-dimethylpicolinamide (Example 50), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,3-dimethylpicolinamide (Example 51), 5-(4-((3-ethyl-6-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (Example 52), 5-(4-((6-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (Example 53), 3-ethyl-7-((4-(2-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)piperazin-1-yl)methyl)quinazoline-2,4(1H,3H)-dione (Example 54), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridine-2-sulfonamide (Example 55), 5-(4-((3-ethyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (Example 56), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpyrazine-2-carboxamide (Example 57), 5-(1-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperidin-4-yl)-N,6-dimethylpicolinamide (Example 58), 5-(4-((5-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (Example 59), 5-(4-((3-ethyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (Example 60), 6-chloro-5-(4-((3-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 61), 6-chloro-5-(4-((3-ethyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 62), 6-chloro-5-(4-((5-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 63), 6-chloro-5-(4-((3-ethyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 64), 6-chloro-5-(4-((6-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 65), 6-chloro-5-(4-((3-ethyl-6-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 66), 5-(4-((3-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (Example 67), 4-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylbenzamide (Example 68), 4-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylbenzamide (Example 69), 3-chloro-4-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylbenzamide (Example 70), 4-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,3-dimethylbenzamide (Example 71), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,4,6-trimethylpicolinamide (Example 72), 4-chloro-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (Example 73), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (Example 74), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,4-dimethylpyrimidine-2-carboxamide (Example 75), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyrazine-2-carboxamide (Example 76), 6-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,5-dimethylpyridazine-3-carboxamide (Example 77), N-cyclopropyl-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-methylpicolinamide (Example 78), 6-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,5-dimethylnicotinamide (Example 79), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-isopropyl-N-methylpicolinamide (Example 80), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (Example 81), N-ethyl-5-(4-((3-ethyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-methylpicolinamide (Example 82), 6-chloro-N-ethyl-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)picolinamide (Example 83), N-ethyl-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-methylpicolinamide (Example 84), N,6-dimethyl-5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)picolinamide (Example 85), 6-chloro-N-methyl-5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)picolinamide (Example 86), 5-(4-((2,4-dioxo-3-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (Example 87), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-4-fluoro-N,6-dimethylpicolinamide (Example 88), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,3,6-trimethylpicolinamide (Example 89), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-3-fluoro-N,6-dimethylpicolinamide (Example 90), 3-chloro-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (Example 91), 6-chloro-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,3-dimethylpicolinamide (Example 92), 6-chloro-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,4-dimethylpicolinamide (Example 93), 6-Bromo-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 94), 6-Bromo-N-ethyl-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)picolinamide (Example 95), N-ethyl-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-(trifluoromethyl)picolinamide (Example 96), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-methyl-N-(trifluoromethyl)picolinamide (Example 97), 6-chloro-N-methyl-5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)picolinamide (Example 98), N,6-dimethyl-5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)picolinamide (Example 99), 6-chloro-N-ethyl-5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)picolinamide (Example 100), N-ethyl-6-methyl-5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)picolinamide (Example 101), 6-chloro-N-ethyl-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)picolinamide (Example 102), N-ethyl-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-6-methylpicolinamide (Example 103), 6-chloro-N-ethyl-5-(4-((3-ethyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)picolinamide (Example 104), 5-(4-((5-fluoro-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (Example 105), 6-chloro-5-(4-((5-fluoro-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 106), N-ethyl-5-(4-((5-fluoro-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-methylpicolinamide (Example 107), 6-chloro-N-ethyl-5-(4-((5-fluoro-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)picolinamide (Example 108), 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-6-methoxy-N-methylpicolinamide (Example 109), 7-((4-(1H-indol-6-yl)piperazin-1-yl)methyl)-3-ethylquinazoline-2,4(1H,3H)-dione (Example 110), 7-((4-(1H-indazol-6-yl)piperazin-1-yl)methyl)-3-ethylquinazoline-2,4(1H,3H)-dione (Example 111), 7-((4-(1H-indazol-5-yl)piperazin-1-yl)methyl)-3-ethylquinazoline-2,4(1H,3H)-dione (Example 112), 7-((4-(1H-benzo[d]imidazol-6-yl)piperazin-1-yl)methyl)-3-ethylquinazoline-2,4(1H,3H)-dione (Example 113), 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (Example 114), 6-chloro-5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 115), 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (Example 116), 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-methyl-N-ethylpicolinamide (Example 117), 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-ethylpicolinamide (Example 118), 5-(4-((3-ethyl-5-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (Example 119), 6-chloro-5-(4-((3-ethyl-5-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 120), N-ethyl-5-(4-((3-ethyl-5-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-methylpicolinamide (Example 121), 6-chloro-N-ethyl-5-(4-((3-ethyl-5-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)picolinamide (Example 122), 5-(4-((3-ethyl-5-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (Example 123), 6-chloro-5-(4-((3-ethyl-5-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 124), 5-(4-((5-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-ethyl-6-methylpicolinamide (Example 125), 6-chloro-5-(4-((5-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-ethylpicolinamide (Example 126), 5-(4-((5-chloro-3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (Example 127), 6-chloro-5-(4-((5-chloro-3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 128), 5-(4-((5-chloro-3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-ethyl-6-methylpicolinamide (Example 129), 6-chloro-5-(4-((5-chloro-3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-ethylpicolinamide (Example 130), 6-chloro-5-(4-((5-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-cyclopropylpicolinamide (Example 131), 6-chloro-N-cyclopropyl-5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)picolinamide (Example 132), N-ethyl-5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoropicolinamide (Example 133), 5-(4-((3-ethyl-5-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (Example 134), N-cyclopropyl-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoropicolinamide (Example 135), 5-(4-((5-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (Example 136), N-cyclopropyl-5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-methylpicolinamide (Example 137), 6-Fluoro-5-(4-((8-fluoro-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 138), 6-Fluoro-5-(4-((8-fluoro-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 139), 5-(4-((3-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (Example 140), N-cyclopropyl-5-(4-((3-ethyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoropicolinamide (Example 141), 5-(4-((3-ethyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (Example 142), 5-(4-((3-ethyl-5-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (Example 143), 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (Example 144), 4-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,3-dimethylbenzamide (Example 145), 3-chloro-4-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylbenzamide (Example 146), or a stereoisomer, a tautomer, an N-oxide, a hydrate, an isotopically substituted derivative, a solvate, or a pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof.

[0067] Some of the compounds of the present disclosure may exist as stereoisomers, including optical isomers. The present disclosure includes all stereoisomers and racemic mixtures of such stereoisomers, as well as the individual enantiomers, which may be separated according to methods known to those of ordinary skill in the art.

[0068] Examples of pharma- ceutically acceptable salts include inorganic and organic salts, such as hydrochloride, hydrobromide, phosphate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate, and oxalate salts; as well as inorganic and organic base salts formed with bases, such as sodium hydroxide, tris(hydroxymethyl)aminomethane (TRIS, tromethamine), and N-methyl-glucamine.

[0069] Examples of prodrugs of the compounds of the present disclosure include simple esters of carboxylic acid-containing compounds (e.g., obtained by condensation with a C1-C4 alcohol, according to methods known in the art), esters of hydroxy-containing compounds (e.g., obtained by condensation with a C1-C4 carboxylic acid, a C3-C6 diacid, or anhydrides thereof, such as succinic anhydride and fumaric anhydride, according to methods known in the art), imines of amino-containing compounds (e.g., obtained by condensation with a C1-C4 aldehyde or ketone, according to methods known in the art), carbamates of amino-containing compounds, such as those described in Leu, et al., (J. Med. Chem. 42:3623-3628 (1999)) and Greenwald, et al. al., (J. Med. Chem. 42:3657-3667 (1999)), as well as acetals and ketals of alcohol-containing compounds (e.g., those obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether, according to methods known in the art).

[0070] The compounds of the present disclosure may be prepared using methods known to those skilled in the art or novel methods of the present disclosure. Specifically, the compounds of the present disclosure having formula I (including formulas II, III, and IV) may be prepared as illustrated by the exemplary reaction of Scheme 1. The reaction of methyl 3-amino-5-bromopicolinate and Boc anhydride under the catalysis of DMAP and DIEA produced methyl 3-(bis(tert-butoxycarbonyl)amino)-5-bromopicolinate. The Suzuki reaction of methyl 3-(bis(tert-butoxycarbonyl)amino)-5-bromopicolinate and trimethylboroxine under the catalysis of Pd(dppf)Cl2 produced methyl 3-(bis(tert-butoxycarbonyl)amino)-5-methylpicolinate. The bromination reaction of methyl 3-(bis(tert-butoxycarbonyl)amino)-5-methylpicolinate and NBS catalyzed by BPO gave methyl 3-(bis(tert-butoxycarbonyl)amino)-5-(bromomethyl)picolinate. The reaction of methyl 3-(bis(tert-butoxycarbonyl)amino)-5-(bromomethyl)picolinate and N-methyl-5-(piperazin-1-yl)picolinamide catalyzed by DIEA gave methyl 3-(bis(tert-butoxycarbonyl)amino)-5-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)picolinate. The Boc deprotection reaction of methyl 3-(bis(tert-butoxycarbonyl)amino)-5-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)picolinate under TFA catalysis produced methyl 3-amino-5-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)picolinate. The ring closure reaction of methyl 3-amino-5-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)picolinate and ethyl isocyanate produced the target compound 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide. [ka]

[0071] Other related compounds can be prepared using similar methods. For example, replacing ethyl isocyanate with methyl isocyanate produced the target compound 5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide. Replacing ethyl isocyanate with isopropyl isocyanate produced the target compound 5-(4-((3-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide. Substitution of N-methyl-5-(piperazin-1-yl)picolinamide with 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide.

[0072] The compounds of the present disclosure can be prepared as illustrated by the exemplary reactions in Scheme 2. The thermal reaction of dimethyl 2-aminoterephthalate and ethyl isocyanate in toluene in a sealed tube produced methyl 3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate. The reduction reaction of methyl 3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate and LiAlH4 produced 3-ethyl-7-(hydroxymethyl)quinazoline-2,4(1H,3H)-dione. The chlorination reaction of 3-ethyl-7-(hydroxymethyl)quinazoline-2,4(1H,3H)-dione and SOCl2 produced 7-(chloromethyl)-3-ethylquinazoline-2,4(1H,3H)-dione. Substitution reaction of 7-(chloromethyl)-3-ethylquinazoline-2,4(1H,3H)-dione and N-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide. [ka]

[0073] Other related compounds can be prepared using similar methods. For example, replacing N-methyl-5-(piperazin-1-yl)picolinamide with 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide. Replacing dimethyl 2-aminoterephthalate with dimethyl 2-amino-5-fluoroterephthalate produced the target compound 5-(4-((3-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide. Substitution of propyl isocyanate for ethyl isocyanate produced the target compound 5-(4-((2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide.

[0074] Compounds of the present disclosure can be prepared as illustrated by the exemplary reaction in Scheme 3. Under the catalysis of TFA, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid was reacted with (COCl)2 and then condensed with 5-amino-N-methylpicolinamide to produce N-methyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide)picolinamide. Suzuki reaction of N-methyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)picolinamide and 7-bromo-3-methylquinazoline-2,4(1H,3H)-dione under Pd(dppf)Cl2 catalysis afforded the target compound 5-(3-(3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)benzamido)N-methylpicolinamide. [ka]

[0075] Other related compounds can be prepared using similar methods. For example, replacing 7-bromo-3-methylquinazoline-2,4(1H,3H)-dione with 7-bromo-3-ethylquinazoline-2,4(1H,3H)-dione produced the target compound 5-(3-(3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)benzamide)-N-methylpicolinamide. Replacing 7-bromo-3-methylquinazoline-2,4(1H,3H)-dione with 7-bromo-3-isopropylquinazoline-2,4(1H,3H)-dione produced the target compound 5-(3-(3-isopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)benzamide)-N-methylpicolinamide. Substitution of 7-bromo-3-methylquinazoline-2,4(1H,3H)-dione with 7-bromo-3-ethylpyrido[3,2-d]pyrimidine-2,4(1H,3H)-dione produced the target compound 5-(3-(3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)benzamide)-N-methylpicolinamide. Substitution of 7-bromo-3-methylquinazoline-2,4(1H,3H)-dione with 7-bromo-3-propylquinazoline-2,4(1H,3H)-dione produced the target compound 5-(3-(3-propyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)benzamide)-N-methylpicolinamide.

[0076] The compounds of the present disclosure can be prepared as illustrated by the exemplary reactions in Scheme 4. Bromination reaction of methyl 4-methyl-3-nitrobenzoate and NBS under the catalysis of BPO produced methyl 4-(bromomethyl)-3-nitrobenzoate. Substitution reaction of methyl 4-(bromomethyl)-3-nitrobenzoate and ethylamine under the catalysis of DIEA produced methyl 4-((ethylamino)methyl)-3-nitrobenzoate. Reduction reaction of methyl 4-((ethylamino)methyl)-3-nitrobenzoate and Fe / NH4Cl produced methyl 3-amino-4-((ethylamino)methyl)benzoate. Ring-closing reaction of methyl 3-amino-4-((ethylamino)methyl)benzoate and CDI under heating produced methyl 3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate. The reduction reaction of methyl 3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-carboxylate and LiAlH4 gave 3-ethyl-7-(hydroxymethyl)-3,4-dihydroquinazolin-2(1H)-one. The chlorination reaction of 3-ethyl-7-(hydroxymethyl)-3,4-dihydroquinazolin-2(1H)-one and SOCl2 under DMF catalysis gave 7-(chloromethyl)-3-ethyl-3,4-dihydroquinazolin-2(1H)-one. The DIEA-catalyzed displacement reaction of 7-(chloromethyl)-3-ethyl-3,4-dihydroquinazolin-2(1H)-one and N-methyl-5-(piperazin-1-yl)picolinamide afforded the target compound 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide. [ka]

[0077] Other related compounds can be prepared using similar methods. For example, replacing N-methyl-5-(piperazin-1-yl)picolinamide with 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide. Replacing N-methyl-5-(piperazin-1-yl)picolinamide with 6-chloro-N-methyl-5-(piperazin-1-yl)picolinamide produced the target compound 6-chloro-5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide. Substitution of N-methyl-5-(piperazin-1-yl)picolinamide with N,6-dimethyl-5-(piperazin-1-yl)picolinamide produced the target compound 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide.

[0078] An important aspect of the present disclosure is the discovery that the compounds of formula I (including formulas II, III, and IV) are PARP inhibitors, particularly selective PARP1 inhibitors. Thus, the compounds of formula I (including formulas II, III, and IV), or stereoisomers, tautomers, N-oxides, hydrates, isotopically substituted derivatives, solvates, or pharma- ceutically acceptable salts thereof, or mixtures thereof, or prodrugs thereof, can be used to treat various diseases or conditions that respond to inhibition of PARP activity (particularly PARP1 activity), or can be used to prepare a medicament for treating a disease or condition caused by response to inhibition of PARP activity (particularly PARP1 activity).

[0079] In the present disclosure, diseases or conditions responsive to inhibition of PARP activity (particularly PARP1 activity) include cancer. Cancer can be a solid tumor or a hematological tumor, including but not limited to liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, and pulmonary arterial cancer. The cancers include lung cancer, gastric cancer, colon cancer, malignant pancreatic islet tumors, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteosarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary cancer, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocythemia, adrenocortical carcinoma, skin cancer, and prostate cancer. Preferably, the cancer is responsive to inhibition of PARP activity.

[0080] Accordingly, the present disclosure also includes methods for the treatment or prevention of a disease or condition responsive to inhibition of PARP activity (particularly PARP1 activity), the method comprising administering to a subject (particularly a mammal, more particularly a human) in need thereof an effective amount of a compound of Formula I (Formulas II, III, and IV), or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate, or a pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula I (Formulas II, III, and IV), or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate, or a pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof.

[0081] In carrying out the treatment method, an effective amount of the pharmaceutical preparation is administered to an individual who exhibits one or more symptoms of these disorders. The pharmaceutical preparation comprises a therapeutically effective amount of a compound of formula I (including formulas II, III, and IV) formulated for oral, intravenous, topical, or local application for the treatment of cancer and other diseases. The amount is effective to improve or eliminate one or more symptoms of the disorder. An effective amount of a compound for treating a particular disease is an amount that is sufficient to improve or in some way reduce symptoms associated with the disease. Such an amount can be administered as a single dose or according to an effective regimen. Although the amount can cure the disease, it is typically administered to improve the symptoms of the disease. Typically, repeated administration is required to achieve the desired improvement of symptoms.

[0082] In another embodiment, there is provided a pharmaceutical composition comprising a compound of Formula I (including Formulas II, III, and IV) as a PARP inhibitor, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, and a pharma- ceutically acceptable carrier.

[0083] Another embodiment of the present disclosure is directed to a pharmaceutical composition effective for treating cancer, comprising a compound of formula I (including formulas II, III, and IV) as a PARP inhibitor, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharma- ceutically acceptable salt thereof and a prodrug thereof, in combination with at least one known anticancer drug or a pharma- ceutically acceptable salt thereof. In particular, the compounds herein can be combined with other anticancer drugs related to the mechanism of DNA damage and repair, including PARP inhibitors such as olaparib, niraparib, rucaparib, talazoparib, pamiparib, fluzoparib, and senaparib, HDAC inhibitors such as vorinota, romididesin, papiceta, and bayresta, and the like. The compounds herein can also be combined with other anticancer drugs related to the cell division detection site, including Chk1 / 2 inhibitors, CDK4 / 6 inhibitors such as paposinib, ATM / ATR inhibitors, Wee1 inhibitors, and the like.Other known anti-cancer drugs that may be used in the anti-cancer combination therapy include, but are not limited to, alkylating agents such as busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, and carboplatin; topoisomerase I inhibitors such as camptothecin, irinotecan, and topotecan; doxorubicin, epirubicin, aclacinomycin, mitoxantrone, elliptinium, and etoposide. topoisomerase II inhibitors such as 5-azacytidine, gemcitabine, 5-fluorouracil, capecitabine, and methotrexate; RNA / DNA antimetabolites such as 5-fluoro-2'-deoxy-uridine, fludarabine, nelarabine, ara-C, pralatrexate, pemetrexed, hydroxyurea, and thioguanine; colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, and docetaxel. any antimitotic agent; antibodies such as mAbs, 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, and MabThera; imatinib, gefitinib, erlotuzumab, Kinase inhibitors such as rotinib, osimertinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lapatinib, sorafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, ponatinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cobimetinib, axitinib, temsirolimus, idelalisib, pazopanib, torisel, and everolimus.Other known anti-cancer drugs that may be used in the anti-cancer combination therapy include tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin-2), and sipuleucel-T (a prostate cancer treatment vaccine).

[0084] In carrying out the method of the present disclosure, the compound of the present disclosure can be administered together with at least one known anti-cancer drug in a single pharmaceutical composition. Alternatively, the compound of the present disclosure can be administered separately from at least one known anti-cancer drug. In one embodiment, the compound of the present disclosure and at least one known anti-cancer drug are administered substantially simultaneously, i.e., all drugs are administered simultaneously or sequentially, provided that the compounds reach therapeutic levels in the blood at the same time. In another embodiment, the compound of the present disclosure and at least one known anti-cancer drug are administered according to individual dose schedules, provided that the compounds reach therapeutic levels in the blood.

[0085] Another embodiment of the present disclosure is directed to a bioconjugate that includes the compounds described herein and functions as a kinase inhibitor, which is effective in inhibiting tumors. The tumor-inhibiting 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.

[0086] 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, and IV), or a pharma- ceutically acceptable salt thereof, or a prodrug thereof, in combination with radiation therapy. In this embodiment, the compound of the present disclosure may be administered simultaneously with or at a different time than the radiation therapy.

[0087] Yet another embodiment of the present disclosure is directed to a pharmaceutical composition comprising a PARP inhibitor of formula I (including formulas II, III, and IV), or a pharma- ceutically acceptable salt thereof, or a prodrug thereof, effective for post-operative treatment of cancer. The present disclosure also relates to a method of treating cancer by surgically removing a tumor and then treating a mammal with a pharmaceutical composition described herein.

[0088] The pharmaceutical compositions of the present disclosure include all pharmaceutical preparations that contain the compounds of the present disclosure in an amount effective to achieve their intended purpose. Although individual needs vary, determining the optimal amount of each component in a pharmaceutical preparation is within the skill of the art. Typically, the compound or a pharma- ceutically acceptable salt thereof may be orally administered to a mammal at a dose of about 0.0025 to 50 mg per kg of body weight per day. Preferably, about 0.01 mg / kg body weight to about 10 mg / kg body weight is orally administered. If 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.

[0089] A unit oral dose may contain from about 0.01 to about 50 mg, preferably from about 0.1 to about 10 mg, of a compound of the present disclosure. The unit dose may be administered one or more times daily in one or more tablets, each containing from about 0.1 to about 50 mg, advantageously from about 0.25 to 10 mg, of a compound of the present disclosure or a solvate thereof.

[0090] In a topical formulation, the compounds of the present disclosure may be present in a concentration of approximately 0.01 to 100 mg per gram of carrier.

[0091] 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 preparation that includes a pharmaceutically acceptable carrier (including excipients and auxiliary agents), which facilitates the processing of the compound into a pharmaceutically acceptable preparation. Preferably, pharmaceutical preparations, especially oral preparations, and those used for preferred administration, such as tablets, draggers, and capsules, as well as solutions suitable for injection or oral administration, contain approximately 0.01%-99%, preferably approximately 0.25%-75% of the active compound together with excipients.

[0092] Also included within the scope of the present disclosure are non-toxic pharmaceutically acceptable salts of the compounds of the present disclosure. Acid addition salts are formed by mixing a solution of the compounds of the present disclosure with a solution of a pharmaceutically acceptable non-toxic acid, such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, etc. Base addition salts are formed by mixing a solution of the compounds of the present disclosure with a solution of a pharmaceutically acceptable non-toxic base, such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, tris(hydroxymethyl)aminomethane, N-methyl-glucamine, etc.

[0093] The pharmaceutical preparations of the present disclosure may be administered to any mammal so long as the mammal can experience the therapeutic effects of the compounds of the present disclosure. Foremost among such mammals are humans and veterinary animals, although the disclosure is not intended to be so limited.

[0094] The pharmaceutical preparations of the present disclosure can be administered by any means that achieves their intended purpose.For example, administration can be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal, or topical route.Alternatively or simultaneously, administration can be by oral route.The dosage administered will depend on the age, health, and weight of the recipient, the type of concurrent treatment, the frequency of treatment, and the nature of the desired effect.

[0095] The pharmaceutical preparations of the present disclosure are manufactured in a known manner, for example by 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.

[0096] 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 a salt thereof, such as sodium alginate. Auxiliaries are in particular flow regulators and lubricants, such as silica, talc, stearic acid or a salt thereof, 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 sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.To produce coatings that are resistant to gastric juice, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate are used.Dyes or pigments may be added to tablets or dragee coatings, for example, for identification or to characterize combinations of active compound doses.

[0097] Other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol.Push-fit capsules may contain the active compound in the form of granules, which may be mixed with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and stabilizers.In soft capsules, the active compound is preferably dissolved or suspended in a suitable liquid such as fatty oils or liquid paraffin.In addition, stabilizers may be added.

[0098] Suitable formulations for parenteral administration include aqueous solutions of active compounds, such as aqueous solutions of water-soluble salts and alkaline solutions. In addition, suspensions of active compounds may be administered as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate 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.

[0099] 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.

[0100] The topical formulations of the present disclosure are preferably formulated as oils, creams, lotions, ointments, etc., by selection of the appropriate carrier. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats, and high molecular weight alcohols (C 12The preferred carriers are those in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants, and antioxidants may also be included, as well as agents imparting color or fragrance, if desired. Additionally, transdermal penetration enhancers may be used in these topical formulations. Examples of such enhancers are found in U.S. Patents 3,989,816 and 4,444,762.

[0101] Creams are preferably formulated from mineral oil, self-emulsifying beeswax, and water in which the active ingredient is mixed with the active ingredient dissolved in a small amount of oil, such as almond oil. A typical example of such a cream is one that contains approximately 40 parts water, approximately 20 parts beeswax, approximately 40 parts mineral oil, and approximately 1 part almond oil.

[0102] Ointments can be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and allowing the mixture to cool. A typical example of such an ointment is one that contains approximately 30% by weight of almond oil and approximately 70% by weight of white soft paraffin.

[0103] The present disclosure also involves the use of the compounds of the present disclosure for the manufacture of a medicament for treating a clinical condition responsive to inhibition of the activity of PARP. The medicament can include the pharmaceutical composition described above.

[0104] 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. EXAMPLES

[0105] 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).

[0106] Example 1 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide: (a) Preparation of methyl 3-(bis(tert-butoxycarbonyl)amino)-5-bromopicolinate: To a solution of methyl 3-amino-5-bromopicolinate (3.0 g, 13.0 mmol) in THF (60 mL) was added (Boc)2O (7.1 g, 32.6 mmol), DIEA (5.1 g, 39.1 mmol), and DMAP (318.2 mg, 2.6 mmol). The resulting mixture was stirred at room temperature overnight. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with DCM (30 mL×3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (EtOAc / PE, 1-5%) to give the title compound (3.5 g, white solid, yield: 62.5%). MS(ESI,m / z):431.20[M+1] + . (b) Preparation of methyl 3-(bis(tert-butoxycarbonyl)amino)-5-methylpicolinate: To a solution of methyl 3-(bis(tert-butoxycarbonyl)amino)-5-bromopicolinate (3.0 g, 7.0 mmol) in dioxane (60 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (6.0 mL, 21.0 mmol, 3.5 M in THF), Cs2CO3 (4.6 g, 14.0 mmol), and Pd(dppf)Cl2 (768.6 mg, 1.05 mmol). The system was evacuated and backfilled with nitrogen three times. After stirring at 100 °C overnight, the mixture was filtered and the filtrate was concentrated under reduced pressure. The solvent was removed and the residue was purified by chromatography on silica gel (EtOAc / PE, 10-50%) to give the title compound (2.3 g, white solid, yield: 88.2%). MS (ESI, m / z): 367.30 [M+1] + . (c) Preparation of methyl 3-(bis(tert-butoxycarbonyl)amino)-5-bromomethyl)picolinate: A solution of methyl 3-(bis(tert-butoxycarbonyl)amino)-5-methylpicolinate (50.0 mg, 0.14 mmol), NBS (24.3 mg, 0.14 mmol), and BPO (3.3 mg, 0.01 mmol) in CCl4 (3 mL) was stirred at 100° C. overnight. LCMS showed starting material remained. To the mixture was added NBS (12.1 mg, 0.07 mmol) and stirred at 100° C. for another 6 h. After completion, the solvent was removed and the residue was purified by preparative TLC (DCM / MeOH=10:1) to give the title compound (30.0 mg, yellow solid, 49.5% yield). MS (ESI, m / z): 445.30 [M+1] + . (d) Preparation of methyl 3-(bis(tert-butoxycarbonyl)amino)-5-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)picolinate: To a mixture of methyl 3-(bis(tert-butoxycarbonyl)amino)-5-methylpicolinate (30.0 mg, 0.07 mmol) in ACN (6 mL) was added N-methyl-5-(piperazin-1-yl)picolinamide (17.5 mg, 0.08 mmol), DIEA (43.2 mg, 0.34 mmol), and KI (1.1 mg, 0.01 mmol). The mixture was stirred at 80° C. overnight. After completion, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=10:1) to give the title compound (40.0 mg crude) as a yellow solid, which was used directly in the next step without further purification. MS (ESI, m / z): 585.25 [M+1] + . (e) Preparation of methyl 3-amino-5-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)picolinate: To a solution of methyl 3-(bis(tert-butoxycarbonyl)amino)-5-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)picolinate (40.0 mg, 0.07 mmol) in DCM (5 mL) was added TFA (39.0 mg, 0.34 mmol). The resulting mixture was stirred at room temperature for 3 h. After completion, the mixture was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the title compound (30.0 mg crude) as a yellow solid, which was used directly in the next step without further purification. MS(ESI,m / z):385.15[M+1] + . (f) Preparation of 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide: To a solution of methyl 3-amino-5-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)picolinate (30.0 mg, 0.08 mmol) in toluene (10 mL), ethyl isocyanate (1 mL), TEA (1 mL) were added. The resulting solution was stirred at 120° C. overnight. After completion, the residue was diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=10:1) and the resulting impure product was slurried with EA (2 mL) to give the target compound (3.5 mg, white solid, yield: 12.3% for three steps).

[0107] The following compounds, Examples 2-11, were prepared using synthetic methods similar to those described in Example 1. [Table 3-1] [Table 3-2] [Table 3-3]

[0108] Example 12 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (a) Preparation of methyl 3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate: A mixture of dimethyl 2-aminoterephthalate (200.0 mg, 1.0 mmol), ethyl isocyanate (228.0 mg, 3.2 mmol), and triethylamine (180.0 mg, 1.6 mmol) in toluene (3.0 mL) was heated at 90° C. overnight in a sealed tube. The mixture was concentrated. Methanol (5 mL) and concentrated hydrochloric acid (3 mL) were added, and the mixture was stirred at room temperature overnight. After concentration, the residue was washed with water (20 mL) and methanol (20 mL) and dried to give the title compound (crude, 480.0 mg, white solid). MS (ESI, m / z): 249.10 [M+1] + ,247.00[M-1] - . (b) Preparation of 3-ethyl-7-(hydroxymethyl)quinazoline-2,4(1H,3H)-dione: To a suspension of lithium aluminum hydride (62.0 mg, 1.6 mmol) in THF (5 mL) was added methyl 3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (200.0 mg, 0.8 mmol) under N2 at 0° C. The mixture was warmed to room temperature and stirred for 2 h, then quenched with 1M HCl (2 mL). The mixture was concentrated and diluted with water (10 mL) to give a yellow suspension. The solid was collected by filtration, washed with water (10 mL), diethyl ether (10 mL) and dried to give the title compound (80.0 mg, yellow solid, yield: 91% for two steps). MS (ESI, m / z): 221.20 [M+1] + ,219.15[M-1] - . (c) Preparation of 7-(chloromethyl)-3-ethylquinazoline-2,4(1H,3H)-dione: To a suspension of 3-ethyl-7-(hydroxymethyl)quinazoline-2,4(1H,3H)-dione (80.0 mg, 0.2 mmol) in DCM (3 mL) was added DMF (2.4 mg, 0.03 mmol) and thionyl chloride (231.0 mg, 1.9 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature for 2 h. After completion, the mixture was concentrated to give the title compound (crude, 70.0 mg, grey solid). MS (ESI, m / z): 239.35 [M+1] + ,237.10[M-1] - . (d) Preparation of 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide: To a solution of 7-(chloromethyl)-3-ethylquinazoline-2,4(1H,3H)-dione (70.0 mg, crude from above), KI (11.0 mg, 0.1 mmol), and N-methyl-5-(piperazin-1-yl)picolinamide hydrochloride (71.0 mg, 0.3 mmol) in CH3CN (4 mL) was added DIEA (209.0 mg, 1.6 mmol) at room temperature. The resulting solution was stirred at 80° C. for 2 h. After completion, the solvent was removed under vacuum. The crude was diluted with water (10 mL) and the suspension was filtered. The filter cake was washed with methanol (10 mL) and ethyl acetate (10 mL) and dried to give the target compound (35 mg, grey powder, yield: 23% for two steps).

[0109] The following compounds, Examples 13-14, were prepared using synthetic methods similar to those described in Example 12. [Table 4]

[0110] Example 15 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (a) Preparation of methyl 4-(bromomethyl)-3-nitrobenzoate: A solution of methyl 4-methyl-3-nitrobenzoate (6.9 g, 35.4 mmol), NBS (6.3 g, 35.4 mmol), and BPO (858.0 mg, 3.5 mmol) in CCl4 (140 mL) was stirred at 100° C. for 15 h. After completion, the solvent was removed and the residue was purified by chromatography on silica gel (EtOAc / PE, 2-5%) to give the title compound (4.2 g, yellow solid, yield: 43.3%). (b) Preparation of methyl 4-((ethylamino)methyl)-3-nitrobenzoate: To a mixture of ethylamine (6.9 mL, 13.8 mmol, 2 M in THF), DIEA (1.4 g, 10.4 mmol) in THF (20 mL), methyl 4-(bromomethyl)-3-nitrobenzoate (1.9 g, 6.9 mmol in 10 mL of THF) was added at −78° C. The mixture was stirred at room temperature overnight. After completion, the solvent was removed and the residue was purified by chromatography on silica gel (EtOAc / PE, 10-20%) to give the title compound (1.2 g, yellow solid, yield: 72.7%). MS (ESI, m / z): 239.20 [M+1] + . (c) Preparation of methyl 3-amino-4-((ethylamino)methyl)benzoate: To a solution of methyl 4-((ethylamino)methyl)-3-nitrobenzoate (1.0 g, 4.2 mmol) in EtOH (30 mL) was added Fe (941.0 mg, 16.8 mmol) and NH4Cl (2.2 g, 42.0 mmol in 15 mL of H2O). The resulting mixture was stirred at room temperature for 3 h. After completion, the reaction mixture was filtered, the filter cake was washed with EtOH (50 mL), and the mixture was concentrated under reduced pressure to give a residue, which was diluted with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic phase was removed and the residue was purified by chromatography on silica gel (EtOAc / PE, 10-50%) to give the title compound (400.0 mg, yellow solid, yield: 46.0%). MS (ESI, m / z): 209.05 [M+1] + . (d) Preparation of methyl 3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate: To a suspension of methyl 3-amino-4-((ethylamino)methyl)benzoate (200.0 mg, 1.0 mmol) in CH3CN (5 mL) was added CDI (623.1 mg, 3.9 mmol) under N2. The resulting mixture was stirred at 80 °C overnight. After completion, the mixture was concentrated. The residue was purified by preparative TLC (P / E = 1 / 1) to give the title compound (40.0 mg, yellow solid, yield: 17.8%). MS (ESI, m / z): 235.00 [M+1] + . (e) Preparation of 3-ethyl-7-(hydroxymethyl)-3,4-dihydroquinazolin-2(1H)-one: To a suspension of lithium aluminum hydride (26.0 mg, 0.7 mmol) in THF (5 mL) was added methyl 3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (40.0 mg, 0.2 mmol) under N2 at 0° C. The mixture was warmed to room temperature and stirred for 2 h, then quenched with 1M HCl (1 mL). The mixture was concentrated and diluted with water (10 mL) to give a yellow suspension. The solid was collected by filtration, washed with water (10 mL), diethyl ether (10 mL), and the filtrate was removed to give the title compound (35.0 mg, yellow solid, yield: 99.0%). MS (ESI, m / z): 207.10 [M+1] + . (f) Preparation of 7-(chloromethyl)-3-ethyl-3,4-dihydroquinazolin-2(1H)-one: To a suspension of 3-ethyl-7-(hydroxymethyl)-3,4-dihydroquinazolin-2(1H)-one (35.0 mg, 0.2 mmol) in DCM (3 mL) was added DMF (1 drop) and thionyl chloride (80.9 mg, 0.7 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature for 2 h. After completion, the mixture was concentrated to give the title compound (crude, 30.0 mg, grey solid, yield: 61.2%), which was used directly in the next step. MS (ESI, m / z): 225.05 [M+1] + . (g) Preparation of 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide: To a solution of 7-(chloromethyl)-3-ethyl-3,4-dihydroquinazolin-2(1H)-one (30.0 mg, 0.13 mmol), KI (4.4 mg, 0.03 mmol), and N-methyl-5-(piperazin-1-yl)picolinamide hydrochloride (37.6 mg, 0.16 mmol) in CH3CN (4 mL) was added DIEA (86.4 mg, 0.67 mmol, 5.0 equiv) at room temperature. The resulting solution was stirred at 80° C. for 2 h. After completion, the solvent was removed under vacuum. The crude was diluted with water (10 mL) and the suspension was filtered. The filter cake was washed with methanol (10 mL) and ethyl acetate (10 mL) and dried to give the target compound (22.8 mg, yellow solid, yield: 41.7%). MS (ESI, m / z): 409.10 [M+1] + CDCl3:δ 8.96(s,1H),8.45(d,J=8.0 Hz,1H),8.36(d,J=7.9 Hz,1H),7.86(d,J=5.4 Hz,1H),7.69-7.63(m,1H),7.58(d,J=8.1 Hz,1H),7.42(s,1H),4.42-4.36(m,2H),3.99(s,2H),3.62-3.57(m,4H),3.35(d,J=4.6 Hz,3H),3.05-2.99(m,4H),2.09(dd,J=14.5,7.3 Hz,2H),1.34(t,J=7.2 Hz,3H).

[0111] The following compounds, Examples 16-39, were prepared using synthetic methods similar to those described in Example 12. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7]

[0112] Example 40 5-(3-(3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)benzamide)N-methylpicolinamide (a) Preparation of N-methyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)picolinamide: To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (1.8 g, 7.15 mmol) in DCM (20 mL) was added oxalyl chloride (2.7 g, 21.45 mmol) and DMF (2 drops). The mixture was stirred at room temperature for 30 min. The solvent was evaporated and the residue was dissolved in DCM (10 mL) for use. To a cooled solution of 5-amino-N-methylpicolinamide (0.9 g, 5.96 mmol) in DCM (20 mL) was added Et3N (0.9 g, 8.94 mmol) and the above solution dropwise. The mixture was stirred at room temperature for 1 h. After completion, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography (ethyl acetate in petroleum ether, 0-50%) to give the title compound (1.3 g, white solid, yield: 48%). MS (ESI, m / z): 381.90 [M+1] + . (b) Preparation of 5-(3-(3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)benzamido) N-methylpicolinamide: To a solution of N-methyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)picolinamide (452.0 mg, 1.2 mmol) in DMF (4 mL) and HO (1 mL) was added 7-bromo-3-methylquinazoline-2,4(1H,3H)-dione (250.0 mg, 1.0 mmol), cesium carbonate (965.0 mg, 3.0 mmol), Pd(dppf)Cl2 (74.0 mg, 0.1 mmol). The system was evacuated and backfilled with nitrogen three times and stirred at 100 °C overnight. After completion, the mixture was filtered and the cake was washed with MeOH (10 mL) and DMF (10 mL). The solid was collected and dissolved in DMSO (10 mL). The insolubles were filtered and the filtrate was dried to give the target compound (120.0 mg, white solid, yield: 28%).

[0113] The following compounds, Examples 41-47, were prepared using synthetic methods similar to those described in Example 40. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4]

[0114] The following compounds, Examples 48-113, were prepared using synthetic methods similar to those described in Example 12. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7] [Table 7-8] [Table 7-9] [Table 7-10] [Table 7-11] [Table 7-12] [Table 7-13] [Table 7-14]

[0115] The following compounds, Examples 114-122, were prepared using synthetic methods similar to those described in Example 15. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6]

[0116] Example 147 PARP1 and PARP2 chemiluminescence assays Solutions of recombinant poly ADP ribotransferase 1 and 2 (PARP1 and PARP2) (40 ng enzyme / well) are mixed with the compounds to be tested, respectively. They are then added to the 96-well plate coated with histone mixture and incubated at room temperature for 1 hour. 50 μL of 0.3 ng / mL streptavidin-HRP is then added to each well. The plate is incubated at room temperature for 30 minutes. Finally, the plate is treated with streptavidin-HRP, followed by the addition of ELISA ECL substrate to generate chemiluminescence, which can later be measured using a chemiluminescence reader. The inhibition rate of the compound against PARP1 / 2 enzyme activity was calculated according to the following formula:

number

[0117] I C 50 Values ​​are obtained by fitting a sigmoidal dose-response curve equation using XL Fit software. The curve equation is Y=100 / (1+10^(logC-logIC 50 )) and C is the compound concentration.

[0118] Table 1 shows PARP1 and PARP2 enzyme activity (IC 50 ) and +++++ is IC 50 ≦1nM, ++++ indicates 1 <IC 50 ≦10 nM, +++ indicates 10 nM <IC 50 ≦100nM, ++ indicates 100nM <IC 50 ≦1 μM, + indicates IC50 >1μM. [Table 1-1] [Table 1-2]

[0119] Most of the compounds herein have selective inhibitory effects on PARP1 enzyme activity.

[0120] Example 148 Determination of inhibition of the disclosed compounds against 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 cultured in a 5% CO2 incubator at 37°C. The assay was performed when the cells were in optimal condition and reached 80% confluence. The cells were harvested in logarithmic growth phase using a 1 mL pipette gently and then centrifuged at 500 rpm for 3 minutes. After removing the supernatant, the cells were resuspended by using refresh medium and then the cells were counted. The cells were seeded at 3000 / well in a 96-well plate and incubated overnight in a 5% CO2 incubator at 37°C. On the second day, cells were treated with 8 serially diluted doses of compounds at 1000x final concentration in 100% DMSO. Compounds were prepared as follows: 1000x diluted test compound solution to 40x test compound solution by adding 5μL of 1000x compound solution to 120μL of medium (25x dilution). The solutions were mixed by shaking. DMSO was used as a control.

[0121] After removing the plate from the incubator, the medium was removed from the wells in the plate. Then, 195uL of fresh medium per well was added to the 96-well plate. 5μL of 40× test compound solution per well was added to the 96-well plate. Finally, the plate was incubated in a 5% CO2 incubator at 37°C for 7 days. The medium containing the compound was replaced once on the 4th day. After 7 days, 20μL of CCK-8 was added to each well, gently shaken, and then cultured for 4 hours. The plate was shaken for 5 minutes after incubation. Using a multi-function readout instrument, the absorbance values ​​at 450nm and 650nm wavelengths were recorded respectively (OD=absorbance value 450nm-absorbance value 650nm).

[0122] The data were analyzed by the software GraphPad Prism 6.0. The inhibitory activity of the compounds against cell proliferation was plotted using cell viability against 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 ​​are expressed as a function of the sigmoidal dose-response curve equation: Y=100 / (1+10^(logC-logIC 50 )), where C was the compound concentration.

[0123] Table 2 shows the inhibitory effect data (IC 50 ) and ++++ is 1 <IC 50 ≦10 nM, +++ indicates 10 nM <IC 50 ≦100nM, ++ indicates 100nM <IC 50 ≦1 μM, + indicates IC 50 >1μM. [Table 2-1] [Table 2-2]

[0124] The compounds herein have good inhibitory effects on the proliferation of human breast cancer cells MDA-MB-436 carrying BRCA mutations.

[0125] Although the present disclosure has now been fully described, those skilled in the art will appreciate that the same may be practiced within a wide equivalent range of conditions, formulations, and other parameters without affecting the scope of the present disclosure or any of its embodiments. All patents, patent applications, and publications cited herein are hereby fully incorporated by reference in their entirety.

Claims

1. A compound of formula I, 【Chemistry 1】 or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt, or a mixture thereof, or a prodrug thereof, wherein: R １ is selected from the group consisting of optionally substituted alkyl, optionally substituted carbocyclic, optionally substituted alkenyl, and optionally substituted alkynyl; A １ , A ２ , and A ３ each independently represents N and CR ２ is selected from the group consisting of L is R ３ and / or R ４ and alkylene, optionally substituted by Cy is selected from the group consisting of optionally substituted heterocyclic groups, optionally substituted aryl, and optionally substituted heteroaryl; R ２ is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted carbocyclic groups; R ３ and R ４ 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 ３ and R ４ forms a ring together with the bonded C, n is selected from the group consisting of 0, 1, and 2; When n is 1 or 2, -(CH ２ ) ｎ A compound of formula I, wherein - is optionally replaced by =O, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or a pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof.

2. R １ is optionally substituted with 1 to 5 groups selected from the group consisting of halogen, hydroxyl, and -NR'R" １－３ Alkyl or C ３－６ cycloalkyl, where R′ and R″ are each independently H or optionally substituted with 1 to 5 groups selected from the group consisting of hydroxyl and halogen. １－４ Alkyl or C ３－６ is cycloalkyl, Preferably, R １ But, C １－３ Alkyl, halogenated C １－３ Alkyl, or C ３－４ 2. The compound of claim 1, wherein R is cycloalkyl, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt, or a mixture thereof, or a prodrug thereof.

3. R ３ and R ４ are each independently a halogen or C １－３ alkyl or L is a bond or unsubstituted alkylene, preferably unsubstituted C １－３ or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt, or a mixture thereof, or a prodrug thereof.

4. R ２ is optionally substituted with 1 to 5 groups selected from the group consisting of hydrogen, halogen, or halogen and hydroxyl; １－３ Alkyl or C １－３ Alkoxy, preferably R ２ is hydrogen, C １－３ 2. The compound of claim 1, wherein R is an alkyl, alkyl, or halogen, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt, or a mixture thereof, or a prodrug thereof.

5. A １ , A ２ , and A ３ Only one of the two is N, and the other two are independently CR ２ and preferably, R ２ are independent, H, C １－３ alkyl, or halogen; or A ３ is CH, and A １ and A ２ One of the two is N and the other is CR ２ and R ２ But, H, C １－３ alkyl, or halogen; or A １ is N and A ２ and A ３ are both CH, or A ２ is N and A １ and A ３ are both CH, or A １ , A ２ , and A ３ All of this is CR ２ and each R ２ are independent, H, C １－３ alkyl, or halogen; or A ３ is CH, and A １ and A ２ One of them is CR ２ and R ２ But, H, C １－３ alkyl, or halogen; or A ２ and A ３ are both CH, and A １ But, CR ２ and R ２ But, C １－３ 2. The compound of claim 1, wherein R is an alkyl or halogen, 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.

6. Cy is 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, optionally substituted C ３－８ Cycloalkyl, and -(CH ２ ) ｍ C(O)-NR ａ R ｂ and is substituted with 1 to 5 groups selected from the group consisting of: R ａ and R ｂ are each independently H, C １－４ alkyl, optionally substituted 6- to 14-membered aryl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 4- to 10-membered heterocyclic group, preferably R ａ and R ｂ at least one of is an optionally substituted 6- to 14-membered aryl, an optionally substituted 5- to 10-membered heteroaryl, or an optionally substituted 4- to 10-membered heterocyclic group; m is an integer from 0 to 5, preferably m is 0; The optionally substituted 6- to 14-membered aryl, the optionally substituted 5- to 10-membered heteroaryl, the optionally substituted 4- to 10-membered heterocyclic group, and the optionally substituted C ３－８ Each cycloalkyl is independently halogen, C １－４ Alkyl, C １－４ Alkoxy, halogenated C １－４ Alkyl, halogenated C １－４ Alkoxy, -S(O) ２ Optionally substituted by 1 to 5 groups selected from the group consisting of -NR'R", -NR'R", -C(O)-NR'R", and optionally substituted 5- to 10-membered heteroaryl, preferably the optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered heterocyclic group, and optionally substituted C(O)-NR'R", as defined in the definition of Cy. ３－８ Cycloalkyl, and R ａ and R ｂ The substituents on the optionally substituted 6- to 14-membered aryl, the optionally substituted 5- to 10-membered heteroaryl, and the optionally substituted 4- to 10-membered heterocyclic groups in the definitions of １－４ Alkoxy, and C １－４ further comprising any one or two of alkyl; R′ and R″ are each independently H, optionally substituted C １－４ Alkyl, or optionally substituted C ３－６ cycloalkyl, preferably R′ and R″ are each independently H, C １－４ Alkyl, halogenated C １－４ Alkyl, or C ３－６ is cycloalkyl, Preferably, Cy is substituted by a 5-10 membered heteroaryl, preferably by at least -C(O)-NR'R'', and is substituted by halogen, C １－４ Alkoxy, and C １－４ or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt, or mixture thereof, or a prodrug thereof.

7. Cy is selected from the group consisting of ５ is replaced by 【Chemistry 2】 In the formula, B １ , B ２ , B ３ , and B ４ are independently N and CR ７ R ７ But hydrogen, halogen, C １－４ Alkyl, C １－４ Alkoxy, halogenated C １－４ Alkyl, halogenated C １－４ alkoxy, and -NR'R", where R' and R" are each independently selected from the group consisting of hydrogen, optionally substituted C １－４ Alkyl, optionally substituted C ３－６ cycloalkyl, and * indicates the position at which the group is attached to the remainder of the compound, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt, or a mixture thereof, or a prodrug thereof.

8. The compound of formula I is represented by formulae IIa and IIb shown below: 【Chemistry 3】 During the ceremony, R １ , A １ , A ２ , A ３ and n is as defined in claim 1; R ５ is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl, or from the groups disclosed below. 【Chemistry 4】 wherein 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, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, and -NR'R"; R' and R" are each independently selected from the group consisting of hydrogen, optionally substituted C 1-10 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted 6-14 membered aryl, and optionally substituted 5-10 membered heteroaryl; and * indicates the position at which the group is attached to the remainder of the compound; D １ , D ２ , D ３ , and D ４ are independently N and CR ６ is selected from the group consisting of R ６ 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, preferably R ６ is hydrogen, halogen, optionally substituted C １－３ Alkyl, or optionally substituted C １－３ 2. The compound of claim 1, which is alkoxy, 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.

9. R １ But, C １－３ Alkyl, halogenated C １－３ Alkyl or C ３－４ is cycloalkyl, A １ , A ２ , and A ３ each independently represents N and CR ２ is selected from the group consisting of R ２ is hydrogen, C １－３ Alkyl, C １－３ alkoxy or halogen; R ５ is phenyl, pyridyl, pyrimidinyl, or pyridazinyl substituted at the para position with an optionally substituted aminoacyl group, or R ５ is optionally substituted 1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl or 4-oxo-4H-pyrido[1,2-a]pyrimidin-8-yl, or R ５ is an optionally substituted pyridopyrimidinyl, indolyl, indazolyl, or benzimidazolyl; D １ , D ２ , D ３ , and D ４ are independently N and CR ６ R ６ is hydrogen, C １－３ Alkyl, halogenated C １－３ alkyl or halogen; 9. The compound of claim 8, wherein n is 0 or 1, 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.

10. The compound of formula I is represented by formulae IIIa and IIIb shown below: 【Chemistry 5】 During the ceremony, R １ , A １ , A ２ , and A ３ is as defined in claim 1, B １ , B ２ , B ３ , and B ４ is independently selected from the group consisting of N and CR 7 , where R 7 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, and -NR'R"; R′ and R″ are each independently hydrogen, optionally substituted C １－４ Alkyl, optionally substituted C ３－６ cycloalkyl, or C 1-4 alkyl or C 3-6 cycloalkyl, each independently optionally substituted with 1 to 5 groups selected from the group consisting of H, or hydroxyl and halogen; B ３ and R″ form a 6-membered heterocyclic group having an amide to which they are attached, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically substituted derivative, or pharma- ceutically acceptable salt, or a mixture thereof, or a prodrug thereof.

11. The compound of formula I is represented by formulas IVa and IVb shown below: 【Chemistry 6】 During the ceremony, R １ , A １ , and A ２ is as defined in claim 1, each R" is independently C 1-4 alkyl or C 3-6 cycloalkyl optionally substituted with 1 to 5 groups selected from the group consisting of H, hydroxyl and halogen; R ７ But hydrogen, halogen, C １－４ Alkyl, C １－４ Alkoxy, halogenated C １－４ Alkyl, halogenated C １－４ Alkoxy, and -NR'R", where R' and R" are each independently hydrogen, C １－４ Alkyl, halogenated C １－４ Alkyl, or C ３－６ 2. The compound of claim 1, wherein the compound is selected from the group consisting of cycloalkyl, 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.

12. The compound is 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, 5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, 5-(4-((3-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, 5-(4-((3-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, 5-(4-((2,4-dioxo-3-propyl-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, 5-(4-((2,4-dioxo-3-(trifluoromethyl)-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-methylpicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methyl-6-(trifluoromethyl)picolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide, 5-(4-((3-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide, 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, 5-(4-((1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, 5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide, 5-(4-((2,4-dioxo-3-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide, 5-(4-((2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide, 5-(4-((3-(2-fluoroethyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-methylpicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methyl-6-(trifluoromethyl)picolinamide, 5-(4-((3-ethyl-8-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide, 5-(4-((3-ethyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide, 5-(4-((3-isopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpyrimidine-2-carboxamide, 6-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylnicotinamide, 6-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpyridazine-3-carboxamide, 2-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpyrimidine-5-carboxamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-ethyl-N-methylpicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoropicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-ethylpicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-isopropylpicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-(difluoromethyl)-N-methylpicolinamide, 3-ethyl-7-((4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)piperazin-1-yl)methyl)quinazoline-2,4(1H,3H)-dione, 3-ethyl-7-((4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)piperazin-1-yl)methyl)quinazoline-2,4(1H,3H)-dione, 3-ethyl-7-((4-(4-oxo-4H-pyrido[1,2-a]pyrimidin-8-yl)piperazin-1-yl)methyl)quinazoline-2,4(1H,3H)-dione, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N,N-dimethylpicolinamide, 5-(3-(3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)benzamide)N-methylpicolinamide, 5-(3-(3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)benzamido)-N-methylpicolinamide, 5-(3-(3-isopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)benzamido)-N-methylpicolinamide, 5-(3-(3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-5-fluorobenzamido)-N-methylpicolinamide, 5-(3-(3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)benzamido)-6-fluoro-N-methylpicolinamide, 5-(3-(3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)benzamido)-N-methylpicolinamide, 6-(3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-N-(6-(methylcarbamoyl)pyridin-3-yl)picolinamide, 5-(3-(3-propyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)benzamido)-N-methylpicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-4-fluoro-N-methylpicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylpicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,4-dimethylpicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,3-dimethylpicolinamide, 5-(4-((3-ethyl-6-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide, 5-(4-((6-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide, 3-ethyl-7-((4-(2-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)piperazin-1-yl)methyl)quinazoline-2,4(1H,3H)-dione, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridine-2-sulfonamide, 5-(4-((3-ethyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpyrazine-2-carboxamide, 5-(1-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperidin-4-yl)-N,6-dimethylpicolinamide, 5-(4-((5-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide, 5-(4-((3-ethyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide, 6-chloro-5-(4-((3-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, 6-chloro-5-(4-((3-ethyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, 6-chloro-5-(4-((5-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, 6-chloro-5-(4-((3-ethyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, 6-chloro-5-(4-((6-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, 6-chloro-5-(4-((3-ethyl-6-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, 5-(4-((3-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide, 4-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylbenzamide, 4-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylbenzamide, 3-chloro-4-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylbenzamide, 4-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,3-dimethylbenzamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,4,6-trimethylpicolinamide, 4-chloro-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,4-dimethylpyrimidine-2-carboxamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyrazine-2-carboxamide, 6-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,5-dimethylpyridazine-3-carboxamide, N-cyclopropyl-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-methylpicolinamide, 6-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,5-dimethylnicotinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-isopropyl-N-methylpicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide, N-ethyl-5-(4-((3-ethyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-methylpicolinamide, 6-chloro-N-ethyl-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)picolinamide, N-ethyl-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-methylpicolinamide, N,6-dimethyl-5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)picolinamide, 6-chloro-N-methyl-5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)picolinamide, 5-(4-((2,4-dioxo-3-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-4-fluoro-N,6-dimethylpicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,3,6-trimethylpicolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-3-fluoro-N,6-dimethylpicolinamide, 3-chloro-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide, 6-chloro-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,3-dimethylpicolinamide, 6-chloro-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,4-dimethylpicolinamide, 6-bromo-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, 6-bromo-N-ethyl-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)picolinamide, N-ethyl-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-(trifluoromethyl)picolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-methyl-N-(trifluoromethyl)picolinamide, 6-chloro-N-methyl-5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)picolinamide, N,6-dimethyl-5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)picolinamide, 6-chloro-N-ethyl-5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)picolinamide, N-ethyl-6-methyl-5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)picolinamide, 6-chloro-N-ethyl-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)picolinamide, N-ethyl-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-6-methylpicolinamide, 6-chloro-N-ethyl-5-(4-((3-ethyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)picolinamide, 5-(4-((5-fluoro-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide, 6-chloro-5-(4-((5-fluoro-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, N-ethyl-5-(4-((5-fluoro-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-methylpicolinamide, 6-chloro-N-ethyl-5-(4-((5-fluoro-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)picolinamide, 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-6-methoxy-N-methylpicolinamide, 7-((4-(1H-indol-6-yl)piperazin-1-yl)methyl)-3-ethylquinazoline-2,4(1H,3H)-dione, 7-((4-(1H-indazol-6-yl)piperazin-1-yl)methyl)-3-ethylquinazoline-2,4(1H,3H)-dione, 7-((4-(1H-indazol-5-yl)piperazin-1-yl)methyl)-3-ethylquinazoline-2,4(1H,3H)-dione, 7-((4-(1H-benzo[d]imidazol-6-yl)piperazin-1-yl)methyl)-3-ethylquinazoline-2,4(1H,3H)-dione, 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide, 6-chloro-5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide, 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-methyl-N-ethylpicolinamide, 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-ethylpicolinamide, 5-(4-((3-ethyl-5-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide, 6-chloro-5-(4-((3-ethyl-5-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, N-ethyl-5-(4-((3-ethyl-5-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-methylpicolinamide, 6-chloro-N-ethyl-5-(4-((3-ethyl-5-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)picolinamide, 5-(4-((3-ethyl-5-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide, 6-chloro-5-(4-((3-ethyl-5-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, 5-(4-((5-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-ethyl-6-methylpicolinamide, 6-chloro-5-(4-((5-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-ethylpicolinamide, 5-(4-((5-chloro-3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide, 6-chloro-5-(4-((5-chloro-3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, 5-(4-((5-chloro-3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-ethyl-6-methylpicolinamide, 6-chloro-5-(4-((5-chloro-3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-ethylpicolinamide, 6-chloro-5-(4-((5-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-cyclopropylpicolinamide, 6-chloro-N-cyclopropyl-5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)picolinamide, N-ethyl-5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoropicolinamide, 5-(4-((3-ethyl-5-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide, N-cyclopropyl-5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoropicolinamide, 5-(4-((5-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide, N-cyclopropyl-5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-methylpicolinamide, 6-fluoro-5-(4-((8-fluoro-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, 6-fluoro-5-(4-((8-fluoro-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, 5-(4-((3-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide, N-cyclopropyl-5-(4-((3-ethyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoropicolinamide, 5-(4-((3-ethyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide, 5-(4-((3-ethyl-5-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide, 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide, 4-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,3-dimethylbenzamide, 3-chloro-4-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylbenzamide, or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate, or a pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof.

13. 13. A pharmaceutical composition for the treatment or prevention of a disease or condition responsive to the inhibition of PARP activity, comprising a compound according to any one of claims 1 to 12, 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.

14. The pharmaceutical composition described in claim 13, wherein the disease or condition is cancer.

15. The cancer is selected from the group consisting of liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic granulocytic leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, gastric cancer, colon cancer, and malignant pancreatic insulinoma.

15. The pharmaceutical composition of claim 14, wherein the cancer is selected from the group consisting of mycosis fungoides, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteosarcoma, pancreatic cancer, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary cancer, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, essential thrombocythemia, adrenocortical carcinoma, skin cancer, and prostate cancer.

16. The pharmaceutical composition further comprises at least one known anticancer drug or a pharma- ceutically 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, 5-fluorouracil, and carbamazepine. Pecitabine, 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, ibuprofen, Britumomab, tositumomab, brentuximab, daratumumab, elotuzumab, T-DM1, ofatumumab, dinutuximab, blinatumomab, ipilimumab, Avastin, Herceptin, MabThera, imatinib, gefitinib, erlotinib, ostinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lapatinib, solutinib, rafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, platinib, brutinib, cabozantinib, selected from the group consisting of 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), and sipuleucel-T (prostate cancer treatment vaccine);The pharmaceutical composition according to claim 13.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate, or a pharma- ceutically acceptable salt thereof, or a mixture thereof, and a pharma- ceutically acceptable carrier.

18. The composition further comprises at least one known anticancer drug or a pharma- ceutically 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, and gemcitabine. Tabine, 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, off Atumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab, daratumumab, elotuzumab, T-DM1, ofatumumab, dinutuximab, blinatumomab, ipilimumab, Avastin, Herceptin, MabThera, imatinib, gefitinib, erlotinib, ostinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lapatinib, solutinib, rafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasati Nib, bosutinib, platinib, brutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cavitinib, axitinib, temsirolimus, idelalisib, pazopanib, everolimus, tamoxifen, letrozole, fulvestrant, mitoguanhydrazone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin-2),The pharmaceutical composition according to claim 17, wherein the compound is selected from the group consisting of sipuleucel-T (prostate cancer therapeutic vaccine).

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