Substituted fused bicyclic compounds as PARP inhibitors and their applications

Abstract

This invention provides substituted fused bicyclic compounds as PARP inhibitors and their applications. The substituted fused bicyclic compounds of this invention have the structure shown in Formula I, wherein A1, A2, A3, R1, L, Cy, and n are as defined herein. The compounds of Formula I of this invention are PARP inhibitors and are therefore suitable for treating diseases, disorders, and conditions caused by abnormal PARP activity, such as cancer. This invention also relates to pharmaceutical compositions containing compounds of Formula I and the use of these compounds in the preparation of medicaments for treating or preventing diseases or conditions caused by abnormal PARP activity.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry. This invention relates to substituted fused bicyclic compounds and their application as therapeutically effective PARP inhibitors and anticancer drugs. Background Technology

[0002] Poly(ADP-ribose) polymerase (PARP) refers to a group of proteins whose function is to catalyze the addition of ADP-ribose to receptor proteins using NAD+ as a substrate. This is one of many ways proteins are modified after translation. Therefore, they can also be called ADP-ribose transferases.

[0003] Based on the similarity of the amino acid sequences in the catalytic regions of proteins, 17 different PARP enzymes have been identified in human cells (Vyas et al., 2013 Nature Communications, DOI: 10.1038). These PARP enzymes either catalyze the modification of a single ADP-ribose on the receptor protein or catalyze the transfer of multiple ADP-riboses to form poly(ADP-ribose) modifications. PARP family members are divided into two main subtypes based on whether the catalyzed transfer of ADP-ribose is single or multiple. The biological functions resulting from ADP-ribose modifications of receptor proteins by PARP enzymes are very broad, and many functions remain unclear.

[0004] PARP1 is the most abundant and widely studied member of the PARP family. It is a protein composed of 1014 amino acids (NCBI Accession P09874) with a molecular weight of approximately 116 kDa. Its structure includes DNA binding and catalytic regions. PARP1 is known to participate in multiple cellular functions, playing a crucial role in gene expansion, transcription, cell division, cell differentiation, apoptosis, and DNA damage response and repair mechanisms. PARP1 is activated when DNA damage occurs. Base excision repair (BER) is a major mechanism for repairing single-strand DNA damage, and PARP1 is an important component of the BER mechanism. When damage occurs, PARP1 binds to the single-strand break (SSB) site and participates in BER repair. Its activity is mainly manifested in ADP-ribose modification of histones and nucleoproteins, as well as its own ADP-ribose modification. In addition to the single-strand breakage (BER) repair mechanism, cells also employ two important DNA damage repair mechanisms: homologous recombination (HR) for repairing double-strand breaks and non-homologous recombination end joining (NHEJ). Results showed that cancer cells with defects in homologous recombination repair are sensitive to PARP1 inhibitors, indicating a synergistic effect between homologous recombination deficiency and PARP1 inhibition. This finding has been validated clinically, leading to the approval of several PARP inhibitors for the treatment of ovarian, breast, prostate, and pancreatic cancers with BRCA1 / 2 mutations.

[0005] PARP2 is a protein composed of 559 amino acids with a molecular weight of approximately 62 kDa. Its structure includes DNA-binding and catalytic regions (Ame et al., 1999 J Biol Chem 274:17860). The catalytic region of PARP2 is highly similar to that of PARP1. Studies have shown that PARP2 has similar functions to PARP1, participating in the BER mechanism for DNA damage repair (Schreiber et al., 2002 J Biol Chem 277:23028). Currently marketed PARP inhibitors, including olaparib, niraparib, talazoparib, and rucaparib, all exhibit similar inhibitory activity against PARP2, except for inhibiting PARP1. Clinical trial results show that these marketed PARP inhibitors have similar efficacy; however, their toxicities differ significantly. For example, these PARP inhibitors have similar hematological toxicities, but talazoparib has a side effect similar to chemotherapy drugs, namely hair loss. A recent study comparing the selectivity of multiple PARP inhibitors showed that talazoparib, in addition to inhibiting PARP1 and PARP2, also exhibits a high affinity for two other members of the PARP family, TNKS1 (Tankyrase 1) and TNKS2 (Tankyrase 2) (Ryan et al., 2021, J Biol Chem 296:100251). TNKS1 and TNKS2 share a high degree of amino acid sequence similarity, with 83% of their overall amino acid sequences being identical, and 89% of their catalytic regions being identical. Besides their role in DNA repair, TNKS inhibitors also play a role in maintaining telomere structure and the Wnt / β-catenin signaling pathway. Targeting these sites other than PARP1 may contribute to extramechanistic toxicity, such as hair loss and diarrhea. In addition, inhibition of PARP2 activity may also lead to hematologic toxicity (Farrés et al., 2013, Blood 122:44; Farrés et al., 2015, Cell Death and Differentiation 22:1144). These toxicities may limit the use of PARP inhibitors and their combination with other targeted therapies.

[0006] Therefore, developing highly selective PARP1 inhibitors may reduce both mechanism-related and mechanism-independent toxicities, and improve, enhance, and expand the clinical application of PARP1 inhibitors.

[0007] Several selective PARP1 inhibitors have been disclosed, such as WO2011006803, WO2013014038, WO2021013735, and WO2021260092. Summary of the Invention

[0008] This invention provides compounds with structures as shown in Formula I (including Formulas II, III, and IV), which can be used as PARP inhibitors. In particular, the compounds of this invention are selective PARP1 inhibitors relative to PARP2.

[0009] The present invention also provides a pharmaceutical composition comprising an effective amount of a compound of formula I (including formulas II, III and IV) for the treatment of cancer.

[0010] In one specific embodiment, the pharmaceutical composition may also contain one or more pharmaceutically acceptable carriers or diluents for the treatment of cancer.

[0011] In one specific embodiment, the pharmaceutical composition may also contain at least one known anticancer drug or a pharmaceutically acceptable salt of said anticancer drug for the treatment of cancer.

[0012] This invention also relates to methods for preparing novel compounds of structural formula I (including formulas II, III and IV). Detailed Implementation

[0013] It should be understood that the features of the various embodiments described herein can be combined arbitrarily to form the technical solutions described herein; the definitions of each group herein apply to any embodiment described herein, for example, the definitions of alkyl substituents herein apply to any embodiment described herein, unless the alkyl substituents have been clearly defined in the embodiment.

[0014] The term "hydrogen (H)" as used in this article includes its isotopes deuterium (D) and tritium (T).

[0015] As used in this article, "alkyl" refers to an alkyl group itself or a straight-chain or branched group with up to ten carbon atoms. Useful alkyl groups include straight-chain or branched C16 groups. 1-10 Alkyl, preferably C 1-6 Alkyl group. In some embodiments, the alkyl group is C10. 1-4 Alkyl group. Typical C 1-10 Alkyl groups include optionally substituted methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl, and octyl.

[0016] As used herein, "alkenyl" refers to a group containing 2-10 carbon atoms in a straight or branched chain, unless otherwise limited by the carbon chain length, wherein at least two carbon atoms in the chain contain a double bond; preferably C 2-6Alkenyl groups. Typical alkenyl groups include vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl.

[0017] As used herein, "alkynyl" refers to a straight or branched group containing 2-10 carbon atoms, unless otherwise limited by the carbon chain length, wherein at least two carbon atoms in the chain contain a triple bond; preferably C. 2-6 Alkynyl. Typical alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl, and 2-butynyl.

[0018] The term "alkoxy" as used in this article refers to the alkoxy group that is oxidized by the aforementioned C. 1-10 Alkyl, preferably C 1-6 Alkyl or C 1-4 Alkyl-substituted oxygen groups, such as methoxy, ethoxy, etc. The alkyl group in the alkoxy group may be optionally substituted. Substituents in the alkoxy group include, but are not limited to, halogen, morpholino, amino, and carboxyl groups (including their ester groups), wherein the amino group includes alkylamino and dialkylamino groups.

[0019] The term "amino" as used herein can be represented as –NR′R″, where R′ and R″ are each independently hydrogen and optionally substituted C. 1-10 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, preferably, R′ and R″ are each independently H and optionally substituted C. 1-4 Alkyl or optionally substituted C 3-6 Cycloalkyl; or R″ and R′ together with the N to which they are attached form an optionally substituted 4- to 7-membered cycloamino group, said cycloamino group optionally containing one or more (e.g., 2, 3) additional heteroatoms selected from O, N, and S. Preferred amino groups include NH2, and at least one of R′ and R″ is C. 1-6 Alkyl groups.

[0020] The term "oxygenation" as used in this article refers to =O.

[0021] As used herein, "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic group containing 6 to 14 carbon atoms, either as a single group or as part of another group. An aryl group may be substituted by one or more of the substituents described herein.

[0022] Useful aryl groups include C 6-14 Aryl, preferably C 6-10 Aryl. Typical C 6-14 Aryl groups include phenyl, naphthyl, phenanthryl, anthraceneyl, indyl, azulel, biphenyl, biphenylene, and fumonisinyl.

[0023] The term "carbocyclic group" as used in this article includes cycloalkyl groups and partially saturated carbocyclic groups. Useful cycloalkyl groups are C16-C ... 3-8Cycloalkyl. In some preferred embodiments, the cycloalkyl group is C10. 3-6 Cycloalkyl groups. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Useful partially saturated carbocyclic groups include cycloalkenyl groups, such as C... 3-8 Cycloalkenyl groups, such as cyclopentenyl, cycloheptenyl, and cyclooctenyl. The carbocyclic group may be substituted by one or more substituents as described herein.

[0024] Useful halogens or halogen groups include fluorine, chlorine, bromine, and iodine.

[0025] Useful acylamino groups (acylamino groups) are any C-terminal groups attached to an amino nitrogen atom. 1-6 Acyl (alkanoyl) groups, such as acetamido, acetamido, propionyl, butyryl, pentanoyl, and hexanoyl, and aryl-substituted C groups. 1-6 Acylamino groups, such as benzoylamino.

[0026] Useful acyl groups include C 1-6 An acyl group, such as an acetyl group. The acyl group may optionally be substituted with a group selected from halogens, amino groups, and aryl groups, wherein the amino and aryl groups are optionally substituted. When halogenated, the number of halogen substituents may range from 1 to 5. Examples of substituted acyl groups include chloroacetyl and pentafluorobenzoyl. When substituted with an amino group, the amino group may be substituted with one or two substituents described herein. In some embodiments, the amino acyl group is -C(O)-NR′R″, wherein R′ and R″ are each independently hydrogen, optionally substituted C 1-10 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, preferably, R′ and R″ are each independently H and optionally substituted C. 1-4 Alkyl or optionally substituted C 3-6 Cycloalkyl. In this document, when the alkyl, cycloalkyl, aryl, and heteroaryl groups in R′ and R″ are substituted, the substituents are as described in any embodiment herein, and preferred substituents include halogens, hydroxyl groups, amino groups, and alkyl groups.

[0027] As used herein, "heterocyclic group" refers to a saturated or partially saturated 3-7 membered monocyclic group, 7-10 membered bicyclic group, helical ring group, or bridged ring group, consisting of a carbon atom and 1-4 heteroatoms selected from O, N, and S, wherein the heteroatoms nitrogen and sulfur can be arbitrarily oxidized, and nitrogen can be arbitrarily quaternized. Heterocyclic groups also include fused heterocycles formed by the fusion of any heterocycle defined above with a benzene ring in the aforementioned bicyclic system. If the resulting compound is stable, the carbon or nitrogen atom of the heterocycle can be substituted. The heterocyclic group can be substituted by one or more substituents as described herein.

[0028] Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, aziridine, oxacyclobutyl, pyrrolidinyl, imidazolinyl, imidazolinyl, dihydroindolyl, isodihydroindolyl, quininecycloyl, morpholinyl, isochromyl, chromanyl, pyrazolyl, pyrazolyl, tetrahydroisoquinolinyl, tetronoyl, and tetramoyl, which may be substituted by one or more of the substituents described herein.

[0029] As used herein, "heteroaryl" refers to a group containing 5–14, preferably 5–10, ring atoms, and having 6, 10, or 14 π electrons shared in the ring system. The ring atoms in a heteroaryl group are carbon atoms and 1–3 heteroatoms selected from oxygen, nitrogen, and sulfur. A heteroaryl group may be substituted with one or more of the substituents described herein.

[0030] Useful heteroaryl groups include thienyl (phenylthio), benzo[d]isothiazolyl-3-yl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthenyl, furanyl, pyranyl, isobenzofuranyl, chromenyl, oxanthiinyl, phenoxanthiinyl, pyrroleyl, imidazolyl, pyrazolyl, pyridyl (including but not limited to 2-pyridyl, 3-pyridyl and 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indazinyl, isoindolyl, 3H-indolyl, indolyl, indazoleyl, purine, 4H-quinazinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthodinyl, quinazolinyl, terpineyl, pteridinyl, carbazoleyl, β-carboline yl, phenanthridine, acridine, naphthalene-intercalated diazoxide, phenanthridine, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazinyl, phenothiazinyl, 1,4-dihydroquinoxalin-2,3-dione, 7-aminoisocoumarin, pyridinopyrimidine-4-one, tetrahydropyridinopyrimidine, tetrahydropentamembered[c]pyrazol-3-yl, benzisoxazolyl such as 1,2-benzisoxazol-3-yl, benzimidazole, 2-hydroxyindolyl, thiadiazo, 2-oxobenzisimidazole, imidazopyridinyl, imidazopyridinyl, triazolpyridinyl, tetrahydropyridinopyrimidine, pyrazolpyrimidine, pyrrolopyrimidine, pyrrolopyridinyl, pyrrolopyrazinyl or triazololopyrazinyl. When a heteroaryl group contains a nitrogen atom in the ring, such nitrogen atom can be in the form of an N-oxide, such as pyridyl N-oxide, pyrazinyl N-oxide, and pyrimidinyl N-oxide.

[0031] In this document, unless otherwise stated, when substituted, the alkyl, cycloalkyl, heterocycloalkyl, alkoxy, heterocycloalkoxy, alkenyl, heterocycloalkenyl, alkynyl, amino, amide, acyloxy, carboxyl, hydroxyl, mercapto, alkylthio, sulfonyl, sulfinyl, aminoacyl, silyl, phosphonocarboxyl, phosphonyl, carbocyclic, heterocyclic, aryl, or heteroaryl groups described in any embodiment herein may be substituted by one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents selected from the following groups: halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 1-6 Acylamino, C 1-6 Acyloxy group, C 1-6 Alkoxy, aryloxy, alkylthio, C 1-6 Alkyl, C 1-6 Acyl group, C 6-10 Aryl, C 3-8 cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkyne, heterocyclic or heteroaryl, methylenedioxy, ureo, mercapto, azide, carbonyl, alkylsulfonyl, aminosulfonyl, dialkylaminosulfonyl, and alkylsulfinyl, etc. The substituent itself may also be optionally substituted. More preferably, the substituents include, but are not limited to, halogen, hydroxyl, carboxyl, amino, C... 1-6 Acylamino, C 1-6 Acyloxy group, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Acyl and alkylsulfonyl groups.

[0032] It should be understood that in the various embodiments described herein, when the substituent is a heterocyclic group, aryl group, or heteroaryl group, the number of such heterocyclic group, aryl group, or heteroaryl group is usually one.

[0033] Specifically, the present invention provides compounds of Formula I, their stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds, or pharmaceutically acceptable salts, or mixtures thereof:

[0034]

[0035] Wherein, R1 is selected from optionally substituted alkyl, optionally substituted carbocyclic, optionally substituted alkenyl, and optionally substituted alkynyl;

[0036] A1, A2, and A3 are each independently selected from N and CR2;

[0037] L is selected from bonds and optionally alkylene groups substituted with R3 and / or R4;

[0038] Cy is selected from optionally substituted heterocyclic groups, optionally substituted aryl groups, and optionally substituted heteroaryl groups;

[0039] R2 is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy and optionally substituted carbocyclic groups;

[0040] R3 and R4 are each independently selected from halogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or R3 and R4 form a ring with the connected C;

[0041] n is selected from 0, 1, and 2;

[0042] Where n is not 0, the result is -(CH2). n - can be arbitrarily replaced by a =O.

[0043] In Formula I and the various structural formulas described in this invention, unless otherwise stated, each alkyl group is independently C10. 1-6 Alkyl group, preferably C 1-4 Alkyl groups; each alkylene group is C10. 1-6 Alkylene, preferably C 1-3 Alkylene; each alkenyl group is independently C10. 2-6 Alkenyl group, preferably C 2-4 Alkenyl; each alkynyl group is independently C10. 2-6 Alkyne group, preferably C 2-4 Alkyne group; each alkoxy group is independently C10. 1-6 Alkoxy, preferably C 1-4 Alkoxy group. Preferably, when alkyl, alkenyl, alkynyl, or alkoxy groups are substituted, the substituents can be selected from cyano, hydroxy, nitro, amino (–NR′R″), aryl, heterocyclic, heteroaryl, halogen, and carboxyl groups, etc., and the number of substituents can be 1-5. R′ and R″ are preferably each independently H and optionally substituted C. 1-4 Alkyl or optionally substituted C 3-6 Cycloalkyl. For example, the substituted alkyl group itself or as a substituent for other groups can be hydroxyalkyl, dihydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heterocyclic alkyl, aralkyl, heteroarylalkyl, and haloalkyl, etc. It should be understood that when the substituent is aryl, heteroaryl, heterocyclic, cyano, nitro, or carboxyl, the number of substituents is usually one; when the substituent is, for example, a halogen, the number of substituents can be up to five halogen groups, depending on the carbon chain length of the alkyl, alkenyl, alkynyl, and alkoxy groups; exemplary examples of such substituents include trifluoromethyl and pentafluoroethyl, etc.

[0044] In Formula I and the various structural formulas described in this invention, unless otherwise specified, the number of carbon atoms in each carbocyclic group is preferably 3–8. The preferred carbocyclic group is C. 3-8 Cycloalkyl. The substituent on the carbocyclic group is preferably C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4The substituents can be alkoxy, halogen, hydroxyl, carboxyl, amino (–NR′R″), aryl, heterocyclic, heteroaryl, halogen, and carboxyl, etc., and the number of substituents can be 1-5. R′ and R″ are preferably each independently H, and optionally substituted C. 1-4 Alkyl or optionally substituted C 3-6 Cycloalkyl. It should be understood that when the substituent is aryl, heteroaryl, heterocyclic, cyano, nitro, or carboxyl, the number of substituents is usually 1; when the substituent is, for example, halogen, the number of substituents can be up to 5 halogen groups.

[0045] In Formula I and the various structural formulas described in this invention, unless otherwise stated, the aryl group generally refers to C. 6-14 Aryl and heteroaryl groups typically refer to 5–10-membered heteroaryl groups, while heterocyclic groups typically refer to 4–10-membered heterocyclic groups. The substituents on each aryl, heteroaryl, and heterocyclic group can be independently selected from C10. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogen, hydroxyl, carboxyl, amino (–NR′R″), optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, halogen, amide, aminoacyl (-C(O)-NR′R″), and carboxyl, wherein R′ and R″ are each independently hydrogen and optionally substituted C. 1-10 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, preferably, R′ and R″ are each independently H and optionally substituted C. 1-4 Alkyl or optionally substituted C 3-6 Cycloalkyl. The number of substituents can be 1–5. The optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclic groups can each be optionally selected from C1 to C5. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Substitution of alkoxy, halogen, hydroxyl, carboxyl, amino (–NR′R″), aminoacyl (-C(O)-NR′R″), halogen, and carboxyl groups, wherein R′ and R″ are preferably each independently H, and optionally substituted C 1-4 Alkyl or optionally substituted C 3-6 Cycloalkyl. It should be understood that when the substituent is aryl, heteroaryl, heterocyclic, cyano, nitro, or carboxyl, the number of substituents is usually 1; when the substituent is, for example, a halogen, the number of substituents can be up to 5 halogen groups.

[0046] In one or more embodiments of the compound of formula I, the aryl group is preferably phenyl; the heteroaryl group is a 5-10 member heteroaryl group containing one or two nitrogen atoms, including but not limited to pyridyl, pyrazinyl, pyrroloyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridazinyl, indazinyl, pyridopyrimidinyl, indolyl, indazoleyl, and benzimidazolyl; the carbocyclic group is preferably C 3-8 Cycloalkyl; the heterocyclic group is preferably a 4-10 membered heterocyclic group containing O and / or N, including but not limited to azirrobutyl, oxoheterobutyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, and morpholinyl.

[0047] In one or more embodiments of the compound of formula I, when R2 is substituted, the substituent can be 1 to 5 substituents selected from halogens and hydroxyl groups. Preferably, R2 is hydrogen, halogen, or optionally substituted C. 1-3 Alkyl or optionally substituted C 1-3 Alkoxy, and more preferably R2 is hydrogen or C. 1-3 Alkyl or halogen. In a preferred embodiment, only one of A1, A2, and A3 is N, and the other two are independently CR2. Preferably, R2 is independently H or C. 1-3 Alkyl or halogen. In a more preferred embodiment, A3 is CH, one of A1 and A2 is N and the other is CR2, wherein R2 is H or C. 1-3 Alkyl or halogen. In some embodiments, A1 is N, and A2 and A3 are both CH. In some embodiments, A2 is N, and A1 and A3 are both CH. In some embodiments, A1, A2, and A3 are all CR2, and each R2 is independently H or C. 1-3 Alkyl or halogen; preferably, A3 is CH, and one of A1 and A2 is CR2, wherein R2 is H or C. 1-3 Alkyl or halogen; more preferably, A2 and A3 are both CH, and A1 is CR2, wherein R2 is C. 1-3 Alkyl or halogen.

[0048] In one or more embodiments of the compound of formula I, R1 is an optionally substituted C 1-3 Alkyl or C 3-6 Cycloalkyl. Preferably, when R1 is substituted, the number of substituents can be 1–5, selected from halogens, hydroxyl groups, amino groups (–NR′R″), etc., wherein R′ and R″ are preferably each independently H and optionally C substituted with 1–5 substituents selected from hydroxyl and halogens. 1-4 Alkyl or C 3-6 Cycloalkyl. Preferably, R1 is C1. 1-3 Alkyl, Halogenated C 1-3 Alkyl or C 3-4 Cycloalkyl.

[0049] In one or more embodiments of the compound of formula I, R3 and R4 are preferably each independently a halogen or C. 1-3 alkyl.

[0050] In one or more embodiments of the compound of formula I, L is a bond. In some embodiments, L is an unsubstituted alkylene group, more preferably an unsubstituted C group. 1-3 Alkylene, preferably methylene.

[0051] In one or more embodiments of the compound of formula I, Cy may be substituted with 1-5 substituents, preferably 1-3 substituents, selected from: halogens, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, optionally substituted 6-14 aryl, optionally substituted 5-10 heteroaryl, optionally substituted 4-10 heterocyclic, optionally substituted C 3-8 Cycloalkyl groups and -(CH2) m -C(O)-NR a R b Substituents; wherein, R a and R b Can be independently H or C 1-4 Alkyl, optionally substituted 6-14-membered aryl, optionally substituted 5-10-membered heteroaryl, or optionally substituted 4-10-membered heterocyclic, m being an integer from 0 to 5, preferably m being 0, preferably R a and R b At least one of them is an optionally substituted 6-14 aryl group, an optionally substituted 5-10 heteroaryl group, or an optionally substituted 4-10 heterocyclic group; wherein the optionally substituted 6-14 aryl group, the optionally substituted 5-10 heteroaryl group, the optionally substituted 4-10 heterocyclic group, and the optionally substituted C group are defined as such. 3-8 cycloalkyl and R a and R b The optionally substituted 6-14 aryl, optionally substituted 5-10 heteroaryl, or optionally substituted 4-10 heterocyclic groups in the definition can each be independently substituted by 1-5 groups selected from halogens, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, optionally substituted 5-10 heteroaryl groups (e.g., optionally selected from 1-3 halogens and C) 1-4 Alkyl substituents, preferably 5-6-membered heteroaryl groups containing nitrogen and / or oxygen, -S(O)2-NR′R″, –NR′R″, and -C(O)-NR′R″, wherein R′ and R″ are preferably each independently H and optionally substituted C1-4 Alkyl or optionally substituted C 3-6 Cycloalkyl, more preferably H or C 1-4 Alkyl, Halogenated C 1-4 Alkyl and C 3-6 Cycloalkyl. In a preferred embodiment, the Cy substituent is defined as the optionally substituted 5-10-membered heteroaryl, optionally substituted 4-10-membered heterocyclic group, and optionally substituted C. 3-8 cycloalkyl and R a and R b The substituents of the optionally substituted 6-14 aryl, optionally substituted 5-10 heteroaryl, and optionally substituted 4-10 heterocyclic groups as defined herein include at least -C(O)-NR′R″, and optionally also include halogens, C 1-4 Alkoxy and C 1-4 Any one or two of the alkyl groups. In a preferred embodiment, Cy is substituted with an optionally substituted 5-10-membered heteroaryl group, preferably with an optionally substituted nitrogen-containing 5-10-membered heteroaryl group, preferably, the nitrogen-containing 5-10-membered heteroaryl group is at least substituted with -C(O)-NR′R″, and optionally also with a halogen, C 1-4 Alkoxy and C 1-4 The alkyl group is substituted with any one or two of the alkyl groups. In some embodiments, Cy is substituted with one R5 group as described below. In some embodiments, the heterocyclic group is optionally substituted as described above. In a particularly preferred embodiment, Cy is a piperazine group substituted with an optionally substituted pyridinyl group, and said pyridinyl group is at least substituted with said -C(O)-NR′R″. In other preferred embodiments, Cy is substituted with said -(CH2) m -C(O)-NR a R b Substituent substitution, preferably, the R a and R b At least one of them is a 5-10 heteroaryl group substituted with at least -C(O)-NR′R″.

[0052] Preferably, in the embodiments described herein, when R′ and R″ are substituted, the substituents are selected from halogens and hydroxyl groups. In a preferred embodiment, R′ and R″ are preferably each independently H and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl or C 3-6 Cycloalkyl.

[0053] In one or more embodiments of the compound of formula I, when L is a bond, Cy is an optionally substituted aryl group or an optionally substituted heteroaryl group. Preferably, the optionally substituted aryl group and the optionally substituted heteroaryl group are optionally selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4Alkoxy groups, halogens, and -(CH2) m -C(O)-NR a R b Substituents, wherein R a and R b Can be independently H or C 1-4 The substituents are alkyl, optionally substituted 6-14-membered aryl, optionally substituted 5-10-membered heteroaryl, or optionally substituted 4-10-membered heterocyclic, where m is an integer from 0 to 5, preferably m is 0. The number of substituents can be 1–5. Preferably, the optionally substituted aryl and optionally substituted heteroaryl groups are at least -(CH2). m -C(O)-NR a R b The alternative may also be selected from halogens, C 1-4 Alkyl and Halogenated C 1-4 The alkyl group is substituted with 1-3 substituents. Preferably, R a and R b At least one of them is an optionally substituted 6-14-membered aryl, an optionally substituted 5-10-membered heteroaryl, or an optionally substituted 4-10-membered heterocyclic group; more preferably, R a and R b One is H, and the other is an optional substituted 5-10 membered heteroaryl group. R a and R b The optionally substituted 6-14 aryl, optionally substituted 5-10 heteroaryl, and optionally substituted 4-10 heterocyclic groups described in the definition may each be optionally replaced by 1-5 groups selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Substitution of alkoxy, halogen, hydroxyl, carboxyl, amino (–NR′R″), -C(O)-NR′R″, halogen, and carboxyl groups, wherein R′ and R″ are preferably each independently H, and optionally substituted C 1-4 Alkyl or optionally substituted C 3-6 Cycloalkyl, more preferably H or C 1-4 Alkyl, Halogenated C 1-4 Alkyl or C 3-6 Cycloalkyl; more preferably, the 5-10 membered heteroaryl and 4-10 membered heterocyclic groups are at least substituted with one -C(O)-NR′R″, and may optionally be selected from halogens, C 1-4 Alkoxy, C 1-4 Alkyl and Halogenated C 1-4 Alkyl groups are substituted with 1-3 substituents.

[0054] 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 nitrogen-containing 5-7-membered heterocyclic group. Preferably, the nitrogen-containing 5-7-membered heterocyclic group is covalently linked to L via its cyclic nitrogen atom. More preferably, Cy is an optionally substituted piperazine group. Preferably, the substituent on Cy is selected from: halogens, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, optionally substituted 6-14 aryl, optionally substituted 5-10 heteroaryl, optionally substituted 4-10 heterocyclic and optionally substituted C 3-8 Cycloalkyl; wherein the optionally substituted 6-14 aryl, optionally substituted 5-10 heteroaryl, optionally substituted 4-10 heterocyclic, and optionally substituted C 3-8 Each cycloalkyl group can be independently separated by 1-5 groups selected from halogens, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, optionally substituted 5-10 heteroaryl groups (e.g., optionally selected from 1-3 halogens and C) 1-4 Alkyl substituents, preferably 5-6-membered heteroaryl groups containing nitrogen and / or oxygen, -S(O)2-NR′R″, –NR′R″, and -C(O)-NR′R″, wherein R′ and R″ are preferably each independently H and optionally substituted C 1-4 Alkyl or optionally substituted C 3-6 Cycloalkyl; in a preferred embodiment, the substituent includes at least -C(O)-NR′R″, and optionally also includes halogen, C 1-4 Alkoxy and C 1-4 Any one or two of the alkyl groups. In a preferred embodiment, Cy is substituted with an optionally substituted 5-10-membered heteroaryl group, preferably with an optionally substituted nitrogen-containing 5-10-membered heteroaryl group, preferably, the nitrogen-containing 5-10-membered heteroaryl group is at least substituted with -C(O)-NR′R″, and optionally also with a halogen, C 1-4 Alkoxy and C 1-4 The alkyl group is substituted with any one or two of the alkyl groups. In a particularly preferred embodiment, Cy is a piperazine group substituted with an optionally substituted pyridinyl group, and the pyridinyl group is 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 halogens and hydroxyl groups. In a preferred embodiment, R′ and R″ are preferably each independently H and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl or C 3-6 Cycloalkyl.

[0055] In one or more embodiments of the compound of formula I, n is 0 or 1.

[0056] The preferred compounds of Formula I of the present invention are represented by compounds of Formula II (including Formulas IIa and IIb) or their stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds or pharmaceutically acceptable salts, or mixtures thereof:

[0057]

[0058]

[0059] Wherein, R1, A1, A2, A3 and n are as described in Equation I;

[0060] R5 is selected from optionally substituted aryl and optionally substituted heteroaryl;

[0061] D1, D2, D3, and D4 are each independently selected from N and CR6;

[0062] R6 is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted carbocyclic, optionally substituted alkenyl, and optionally substituted alkynyl.

[0063] In one or more embodiments of the compounds shown in formulas IIa and IIb, R1 is an optionally substituted C 1-3 Alkyl or C 3-6 Cycloalkyl. Preferably, when R1 is substituted, the number of substituents can be 1-5, selected from halogens, hydroxyl groups, amino groups (–NR′R″), etc., wherein R′ and R″ are preferably each independently H, and optionally substituted C. 1-4 Alkyl or optionally substituted C 3-6 Cycloalkyl. Preferably, R1 is C1. 1-3 Alkyl, Halogenated C 1-3 Alkyl or C 3-4 Cycloalkyl.

[0064] In one or more embodiments of the compounds shown in formulas IIa and IIb, when R2 is substituted, the substituent can be 1 to 5 substituents selected from halogens and hydroxyl groups. Preferably, R2 is hydrogen, halogen, or optionally substituted C. 1-3 Alkyl or optionally substituted C 1-3 Alkoxy, and more preferably R2 is hydrogen or C. 1-3 Alkyl or halogen. In a preferred embodiment, only one of A1, A2, and A3 is N, and the other two are independently CR2. Preferably, R2 is independently H or C. 1-3 Alkyl or halogen. In a more preferred embodiment, A3 is CH, one of A1 and A2 is N and the other is CR2, wherein R2 is H or C.1-3 Alkyl or halogen. In some embodiments, A1 is N, and A2 and A3 are both CH. In some embodiments, A2 is N, and A1 and A3 are both CH. In some embodiments, A1, A2, and A3 are all CR2, and each R2 is independently H or C. 1-3 Alkyl or halogen; preferably, A3 is CH, and one of A1 and A2 is CR2, wherein R2 is H or C. 1-3 Alkyl or halogen; more preferably, A2 and A3 are both CH, and A1 is CR2, wherein R2 is C. 1-3 Alkyl or halogen.

[0065] In one or more embodiments of the compounds shown in formulas IIa and IIb, R5 is an optionally substituted phenyl or a nitrogen-containing 5-7 membered heterocyclic group, more preferably an optionally substituted phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group. Preferably, when R5 is substituted, the number of substituents can be 1-5, selected from halogens, optionally substituted alkyl groups, optionally substituted alkoxy groups, optionally substituted 5-10 membered heteroaryl groups (such as optionally 1-3 selected from halogens and C...). 1-4 The alkyl group is substituted, preferably a 5-6 membered heteroaryl group containing nitrogen and / or oxygen, -S(O)2-NR′R″, and optionally a substituted aminoacyl group. More preferably, R5 is substituted at the para position with an optionally substituted aminoacyl group. Preferably, the optionally substituted aminoacyl group is -C(O)-NR′R″, wherein R′ and R″ are preferably each independently H and optionally substituted C. 1-4 Alkyl or optionally substituted C 3-6 More preferably, R′ and R″ are each independently H and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl or C 3-6 Cycloalkyl. In one or more embodiments of the compounds shown in formulas IIa and IIb, R5 is optionally substituted 1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl or 4-oxo-4H-pyrido[1,2-a]pyrimidin-8-yl, and when substituted, the substituents may be 1-5 selected from halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy and halogenated C 1-4 Substituents such as alkoxy groups. In one or more embodiments of the compounds shown in formulas IIa and IIb, R5 is an optionally substituted pyridopyrimidinyl, indolyl, indazole, or benzimidazole group, and when substituted, the substituents may be 1-3 selected from halogens, C 1-4 Alkyl and Halogenated C 1-4 Alkyl substituents.

[0066] In one or more embodiments of the compounds shown in formulas IIa and IIb, R5 is preferably a group consisting of:

[0067]

[0068] More preferably, the following groups are preferred:

[0069]

[0070] Among them, B1, B2, B3, and B4 are each independently selected from N and CR7; R7 is selected from hydrogen, halogens, and C. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkyl group and –NR′R″; R′ and R″ are each independently selected from hydrogen, optionally substituted C 1-10 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted 6-14 aryl or optionally substituted 5-10 heteroaryl, preferably each being an independent hydrogen, optionally substituted C 1-4 Alkyl or optionally substituted C 3-6 Cycloalkyl groups, more preferably each having an independent H or C atom. 1-4 Alkyl, Halogenated C 1-4 Alkyl or C 3-6 Cycloalkyl; * indicates the position where the group is attached to other parts of the compound. Preferably, the groups containing B1-B4 are phenyl, pyridyl, pyrimidinyl, or pyridazinyl. Preferably, R7 is H, halogen, or C. 1-3 Alkyl, C 1-3 alkoxy or halogenated C 1-3 Alkyl group. Preferably, B3 is N, B4 is CR7, and B1 and B2 are CH, wherein R7 is H, a halogen, or C. 1-3 Alkyl, C 1-3 alkoxy or halogenated C 1-3 alkyl.

[0071] In one or more embodiments of the compounds shown in formulas IIa and IIb, D1, D2, D3, and D4 are each independently selected from N and CR6, wherein R6 is preferably hydrogen, halogen, or optionally substituted C. 1-3 Alkyl or optionally substituted C 1-3 Alkyl group. Preferably, when R6 is substituted, the substituent can be 1-5 substituents selected from halogens and hydroxyl groups. More preferably, R6 is hydrogen, C... 1-3 Alkyl or halogen. In some preferred embodiments, the groups containing D1-D4 are optionally composed of 1-3 groups selected from halogens and C. 1-3 Alkyl-substituted phenyl or pyridyl groups.

[0072] In one or more embodiments of the compounds shown in formulas IIa and IIb, n is 0 or 1.

[0073] In one or more embodiments of formula IIa, R1 is selected from the optionally substituted alkyl, optionally substituted carbocyclic, optionally substituted alkenyl, and optionally substituted alkynyl groups; A1, A2, and A3 are each independently selected from N and CR2; R5 is:

[0074]

[0075] B1, B2, B3, and B4 are each independently selected from N and CR7; R′ is H; R″ is selected from hydrogen, the optionally substituted C 1-10 Alkyl and optionally substituted C 3-8 cycloalkyl; R2 is selected from hydrogen, halogen, or the optionally substituted C. 1-10 Alkyl, optionally substituted C 1-10 Alkoxy and optional substituted C 3-8 Cycloalkyl; R7 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkyl groups and –NR′R″, where R′ and R″ are independently H and C, respectively. 1-4 Alkyl, Halogenated C 1-4 Alkyl or C 3-6 Cycloalkyl; n is selected from 0, 1, and 2; wherein, when n is 1 or 2, the -(CH2) n -Optionally substituted with a =O. Preferably, A1, A2, and A3 are each N and CR2, wherein R2 is preferably hydrogen, halogen, or optionally substituted C. 1-3 Alkyl or optionally substituted C 1-3 Alkoxy, and more preferably R2 is hydrogen or C. 1-3 Alkyl or halogen. Preferably, only one of A1, A2, and A3 is N, and the other two are independently CR2. Preferably, R2 is independently H or C. 1-3 Alkyl or halogen. Preferably, A3 is CH, and one of A1 and A2 is N and the other is CR2, wherein R2 is H or C. 1-3 Alkyl or halogen. Preferably, A1 is N, and A2 and A3 are both CH. In some embodiments, A2 is N, and A1 and A3 are both CH. In some embodiments, A1, A2, and A3 are all CR2, and each R2 is independently H or C. 1-3 Alkyl or halogen; preferably, A3 is CH, and one of A1 and A2 is CR2, wherein R2 is H or C. 1-3 Alkyl or halogen; more preferably, A2 and A3 are both CH, and A1 is CR2, wherein R2 is C. 1-3Alkyl or halogen. Preferably, B1, B2, B3, and B4 are each independently selected from N and CR7, wherein R7 is hydrogen, C 1-3 Alkyl, Halogenated C 1-3 Alkyl or halogen. Preferably, B1 and B2 are both CH, B3 is N, and B4 is CR7, wherein R7 is hydrogen or C. 1-3 Alkyl, Halogenated C 1-3 Alkyl or halogen. Preferably, R1 is an optionally substituted C. 1-3 Alkyl group. Preferably, when R1 is substituted, the number of substituents can be 1-5, selected from halogens, hydroxyl groups, amino groups (–NR′R″), etc., wherein R′ and R″ are preferably each independently H, and optionally substituted C. 1-4 Alkyl or optionally substituted C 3-6 Cycloalkyl. Preferably, R1 is C1. 1-3 Alkyl or halogenated C 1-3 Alkyl group. Preferably, R′ and R″ are each independently hydrogen, optionally substituted C. 1-4 Alkyl or optionally substituted C 3-6 Cycloalkyl. Preferably, when R′ and R″ are substituted, the number of substituents can be 1-5, selected from halogens, hydroxyl groups, amino groups, etc. Preferably, R′ is hydrogen; R″ is hydrogen, C 1-4 Alkyl, Halogenated C 1-4 Alkyl or C 3-6 Cycloalkyl. Preferably, R7 is hydrogen, halogen, or C. 1-3 Alkyl or halogenated C 1-3 Alkyl group. Preferably, n is 0 or 1.

[0076] The preferred compounds of Formula I of the present invention are represented by compounds of Formula III (including Formulas IIIa and IIIb) or their stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds or pharmaceutically acceptable salts, or mixtures thereof:

[0077]

[0078] Wherein, R1, A1, A2, A3, B1, B2, B3 and B4 are as described in any of the aforementioned implementation schemes;

[0079] R′ and R″ are each independently selected from hydrogen and optionally substituted C. 1-4 Alkyl or optionally substituted C 3-6 cycloalkyl; or

[0080] B3 and R″ form a 6-membered heterocyclic group with the acylamino group to which they are attached.

[0081] In one or more embodiments of the compounds shown in formulas IIIa and IIIb, R1 is an optionally substituted C 1-3 Alkyl or C3-6 cycloalkyl; preferably, R1 is C 1-3 Alkyl, Halogenated C 1-3 Alkyl or C 3-4 Cycloalkyl.

[0082] In one or more embodiments of the compounds shown in formulas IIIa and IIIb, when R2 is substituted, the substituent can be 1 to 5 substituents selected from halogens and hydroxyl groups. Preferably, R2 is hydrogen, halogen, or optionally substituted C. 1-3 Alkyl or optionally substituted C 1-3 Alkoxy, and more preferably R2 is hydrogen or C. 1-3 Alkyl or halogen. In a preferred embodiment, only one of A1, A2, and A3 is N, and the other two are independently CR2. Preferably, R2 is independently H or C. 1-3 Alkyl or halogen. In a more preferred embodiment, A3 is CH, one of A1 and A2 is N and the other is CR2, wherein R2 is H or C. 1-3 Alkyl or halogen. In some embodiments, A1 is N, and A2 and A3 are both CH. In some embodiments, A2 is N, and A1 and A3 are both CH. In some embodiments, A1, A2, and A3 are all CR2, and each R2 is independently H or C. 1-3 Alkyl or halogen; preferably, A3 is CH, and one of A1 and A2 is CR2, wherein R2 is H or C. 1-3 Alkyl or halogen; more preferably, A2 and A3 are both CH, and A1 is CR2, wherein R2 is C. 1-3 Alkyl or halogen.

[0083] In one or more embodiments of the compounds shown in formulas IIIa and IIIb, B1, B2, B3, and B4 are each independently selected from N and CR7, wherein R7 is preferably hydrogen, halogen, or C. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkyl groups and –NR′R″, where R′ and R″ are independently H and C, respectively. 1-4 Alkyl, Halogenated C 1-4 Alkyl or C 3-6 Cycloalkyl groups. Preferably, each of the R7 groups is independently hydrogen or C. 1-3 Alkyl or halogen. In a preferred embodiment, B1 and B2 are both CH, B3 is N, and B4 is CR7, wherein R7 is hydrogen or C. 1-3 Alkyl or halogen.

[0084] In one or more embodiments of the compounds shown in formulas IIIa and IIIb, R′ and R″ are each independently hydrogen, optionally substituted C 1-3Alkyl or optionally substituted C 3-6 Cycloalkyl; preferably, R′ is hydrogen, R″ is hydrogen, C 1-3 Alkyl, Halogenated C 1-3 Alkyl or C 3-6 Cycloalkyl.

[0085] The preferred compounds of Formula I of the present invention are represented by compounds of Formula IV (IVa and IVb), or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds, or pharmaceutically acceptable salts, or mixtures thereof, or prodrugs thereof:

[0086]

[0087] Wherein, A1, A2, R1, R7 and R″ are as described in any of the aforementioned implementation schemes.

[0088] In one or more embodiments of the compounds shown in formulas IVa and IVb, A1 and A2 are each N and CR2, wherein R2 is preferably hydrogen, halogen, or optionally substituted C. 1-3 Alkyl or optionally substituted C 1-3 Alkoxy, and more preferably R2 is hydrogen or C. 1-3 Alkyl or halogen. In a preferred embodiment, one of A1 and A2 is N and the other is CR2, wherein R2 is H or C. 1-3 Alkyl or halogen. In some embodiments, both A1 and A2 are CR2, wherein R2 is H or C. 1-3 Alkyl or halogen.

[0089] In one or more embodiments of the compounds shown in formulas IVa and IVb, R1 is an optionally substituted C 1-3 Alkyl or C 3-6 Cycloalkyl, preferably, R1 is C 1-3 Alkyl, Halogenated C 1-3 Alkyl or C 3-4 Cycloalkyl.

[0090] In one or more embodiments of the compounds shown in formulas IVa and IVb, R″ is hydrogen, optionally substituted C 1-3 Alkyl or optionally substituted C 3-6 Cycloalkyl, preferably, R″ is hydrogen, C 1-3 Alkyl or halogenated C 1-3 alkyl.

[0091] In one or more embodiments of the compounds shown in formulas IVa and IVb, R7 is each independently hydrogen, halogen, C 1-3 Alkyl or halogenated C 1-3 alkyl.

[0092] It should be understood that although the foregoing describes R1, A1, A2, A3, L, Cy, R5, B1, B2, B3, B4, D1, D2, D3, D4, R′, R″, and n in Formula I (including Formulas II, III, and IV), the described features, especially the preferred features, can be arbitrarily combined to form the range of different Formula I (including Formulas II, III, and IV) compounds of the present invention. For example, the feature described for R2 in one structural formula can also be used to define the R2 group in other structural formulas when the R2 group is also present in other structural formulas.

[0093] Preferred compound examples of Formula I include, but are not limited to:

[0094] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide (Example 1);

[0095] 5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide (Example 2);

[0096] 5-(4-((3-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide (Example 3);

[0097] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridinecarboxamide (Example 4);

[0098] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide (Example 5);

[0099] 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-methylpyridinecarboxamide (Example 6);

[0100] 5-(4-((2,4-dioxo-3-propyl-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide (Example 7);

[0101] 5-(4-((2,4-dioxo-3-(trifluoromethyl)-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide (Example 8);

[0102] 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-methylpyridinecarboxamide (Example 9);

[0103] 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-methylpyridinecarboxamide (Example 10);

[0104] 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)pyridinecarboxamide (Example 11);

[0105] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide (Example 12);

[0106] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridinecarboxamide (Example 13);

[0107] 5-(4-((3-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridinecarboxamide (Example 14);

[0108] 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide (Example 15);

[0109] 5-(4-((1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide (Example 16);

[0110] 5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridinecarboxamide (Example 17);

[0111] 5-(4-((2,4-dioxo-3-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridinecarboxamide (Example 18);

[0112] 5-(4-((2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridinecarboxamide (Example 19);

[0113] 5-(4-((3-(2-fluoroethyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridinecarboxamide (Example 20);

[0114] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-methylpyridinecarboxamide (Example 21);

[0115] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridinecarboxamide (Example 22);

[0116] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methyl-6-(trifluoromethyl)pyridinecarboxamide (Example 23);

[0117] 5-(4-((3-ethyl-8-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridinecarboxamide (Example 24);

[0118] 5-(4-((3-ethyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridinecarboxamide (Example 25);

[0119] 5-(4-((3-isopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridinecarboxamide (Example 26);

[0120] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpyrimidine-2-carboxamide (Example 27);

[0121] 6-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylnicotinamide (Example 28);

[0122] 6-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpyridazin-3-carboxamide (Example 29);

[0123] 2-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpyrimidine-5-carboxamide (Example 30);

[0124] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-ethyl-N-methylpyridinecarboxamide (Example 31);

[0125] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoropyridinecarboxamide (Example 32);

[0126] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-ethylpyridinecarboxamide (Example 33);

[0127] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-isopropylpyridinecarboxamide (Example 34);

[0128] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-(difluoromethyl)-N-methylpyridinecarboxamide (Example 35);

[0129] 3-Ethyl-7-((4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)piperazin-1-yl)methyl)quinazolin-2,4(1H,3H)-dione (Example 36);

[0130] 3-Ethyl-7-((4-(1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)piperazin-1-yl)methyl)quinazolin-2,4(1H,3H)-dione (Example 37);

[0131] 3-Ethyl-7-((4-(4-oxo-4H-pyrido[1,2-a]pyrimidin-8-yl)piperazin-1-yl)methyl)quinazolin-2,4(1H,3H)-dione (Example 38);

[0132] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N,N-dimethylpyridinecarboxamide (Example 39);

[0133] 5-(3-(3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)benzamido)N-methylpyridinecarboxamide (Example 40);

[0134] 5-(3-(3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)benzamido)-N-methylpyridinecarboxamide (Example 41);

[0135] 5-(3-(3-isopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)benzamido)-N-methylpyridinecarboxamide (Example 42);

[0136] 5-(3-(3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-5-fluorobenzamido)-N-methylpyridinecarboxamide (Example 43);

[0137] 5-(3-(3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)benzamido)-6-fluoro-N-methylpyridinecarboxamide (Example 44);

[0138] 5-(3-(3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)benzamido)-N-methylpyridinecarboxamide (Example 45);

[0139] 6-(3-Ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-N-(6-(methylcarbamoyl)pyridin-3-yl)pyridinecarboxamide (Example 46);

[0140] 5-(3-(3-propyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)benzamido)-N-methylpyridinecarboxamide (Example 47);

[0141] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-4-fluoro-N-methylpyridinecarboxamide (Example 48);

[0142] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylpyridinecarboxamide (Example 49);

[0143] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,4-dimethylpyridinecarboxamide (Example 50);

[0144] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,3-dimethylpyridinecarboxamide (Example 51);

[0145] 5-(4-((3-ethyl-6-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridinecarboxamide (Example 52);

[0146] 5-(4-((3-ethyl-6-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridinecarboxamide (Example 53);

[0147] 3-Ethyl-7-((4-(2-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)piperazin-1-yl)methyl)quinazolin-2,4(1H,3H)-dione (Example 54);

[0148] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridine-2-methanesulfonamide (Example 55);

[0149] 5-(4-((3-ethyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridinecarboxamide (Example 56);

[0150] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpyrazine-2-carboxamide (Example 57);

[0151] 5-(1-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperidin-4-yl)-N,6-dimethylpyridineamide (Example 58);

[0152] 5-(4-((5-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridinecarboxamide (Example 59);

[0153] 5-(4-((3-ethyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridinecarboxamide (Example 60);

[0154] 5-(4-((3-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-methylpyridinecarboxamide (Example 61);

[0155] 5-(4-((3-ethyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-methylpyridinecarboxamide (Example 62);

[0156] 5-(4-((3-ethyl-5-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-methylpyridinecarboxamide (Example 63);

[0157] 5-(4-((3-ethyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-methylpyridinecarboxamide (Example 64);

[0158] 5-(4-((3-ethyl-6-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-methylpyridinecarboxamide (Example 65);

[0159] 5-(4-((3-ethyl-6-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-methylpyridinecarboxamide (Example 66);

[0160] 5-(4-((3-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridinecarboxamide (Example 67);

[0161] 4-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylbenzamide (Example 68);

[0162] 4-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylbenzamide (Example 69);

[0163] 4-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-3-chloro-N-methylbenzamide (Example 70);

[0164] 4-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-3-methyl-N-methylbenzamide (Example 71);

[0165] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,4,6-trimethylpyridinecarboxamide (Example 72);

[0166] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-4-chloro-N,6-dimethylpyridinecarboxamide (Example 73);

[0167] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridinecarboxamide (Example 74);

[0168] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,4-dimethylpyrimidin-2-carboxamide (Example 75);

[0169] 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);

[0170] 6-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,5-dimethylpyridazin-3-carboxamide (Example 77);

[0171] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-6-methyl-N-cyclopropylpyridinecarboxamide (Example 78);

[0172] 6-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,5-dimethylnicotinamide (Example 79);

[0173] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-6-isopropyl-N-methylpyridinecarboxamide (Example 80);

[0174] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridinecarboxamide (Example 81);

[0175] 5-(4-((3-ethyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-6-methyl-N-ethylpyridinecarboxamide (Example 82);

[0176] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-ethylpyridinecarboxamide (Example 83);

[0177] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-6-methyl-N-ethylpyridinecarboxamide (Example 84);

[0178] 5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridinecarboxamide (Example 85);

[0179] 5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-methylpyridinecarboxamide (Example 86);

[0180] 5-(4-((2,4-dioxo-3-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridinecarboxamide (Example 87);

[0181] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-4-fluoro-N,6-dimethylpyridinecarboxamide (Example 88);

[0182] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,3,6-trimethylpyridinecarboxamide (Example 89);

[0183] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-3-fluoro-N,6-dimethylpyridinecarboxamide (Example 90);

[0184] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-3-chloro-N,6-dimethylpyridinecarboxamide (Example 91);

[0185] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N,3-dimethylpyridinecarboxamide (Example 92);

[0186] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N,4-dimethylpyridinecarboxamide (Example 93);

[0187] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-methylpyridinecarboxamide (Example 94);

[0188] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-ethylpyridinecarboxamide (Example 95);

[0189] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-trifluoromethyl-N-ethylpyridinecarboxamide (Example 96);

[0190] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-methyl-N-trifluoromethylpyridinecarboxamide (Example 97);

[0191] 5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-methylpyridinecarboxamide (Example 98);

[0192] 5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridinecarboxamide (Example 99);

[0193] 5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-ethylpyridinecarboxamide (Example 100);

[0194] 5-(4-((3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-methyl-N-ethylpyridinecarboxamide (Example 101);

[0195] 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-ethylpyridinecarboxamide (Example 102);

[0196] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-6-methyl-N-ethylpyridinecarboxamide (Example 103);

[0197] 5-(4-((3-ethyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-ethylpyridinecarboxamide (Example 104);

[0198] 5-(4-((3-methyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridinecarboxamide (Example 105);

[0199] 5-(4-((3-methyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-methylpyridinecarboxamide (Example 106);

[0200] 5-(4-((3-methyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-methyl-N-ethylpyridinecarboxamide (Example 107);

[0201] 5-(4-((3-methyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-ethylpyridinecarboxamide (Example 108);

[0202] 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-methylpyridinecarboxamide (Example 109);

[0203] 7-((4-(1H-indol-6-yl)piperazin-1-yl)methyl)-3-ethylquinazoline-2,4(1H,3H)-dione (Example 110);

[0204] 7-((4-(1H-indazol-6-yl)piperazin-1-yl)methyl)-3-ethylquinazoline-2,4(1H,3H)-dione (Example 111);

[0205] 7-((4-(1H-indazol-5-yl)piperazin-1-yl)methyl)-3-ethylquinazoline-2,4(1H,3H)-dione (Example 112);

[0206] 7-((4-(1H-benzo[d]imidazol-6-yl)piperazin-1-yl)methyl)-3-ethylquinazoline-2,4(1H,3H)-dione (Example 113);

[0207] 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridinecarboxamide (Example 114);

[0208] 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-methylpyridinecarboxamide (Example 115);

[0209] 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridinecarboxamide (Example 116);

[0210] 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-methyl-N-ethylpyridinecarboxamide (Example 117);

[0211] 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-ethylpyridinecarboxamide (Example 118);

[0212] 5-(4-((3-ethyl-5-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridinecarboxamide (Example 119);

[0213] 5-(4-((3-ethyl-5-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-methylpyridinecarboxamide (Example 120);

[0214] 5-(4-((3-ethyl-5-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-methyl-N-ethylpyridinecarboxamide (Example 121);

[0215] 5-(4-((3-ethyl-5-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-ethylpyridinecarboxamide (Example 122);

[0216] 5-(4-((3-ethyl-5-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridineamide (Example 123);

[0217] 5-(4-((3-ethyl-5-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-methylpyridineamide (Example 124);

[0218] 5-(4-((5-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-ethyl-6-methylpyridineamide (Example 125);

[0219] 5-(4-((5-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-ethylpyridineamide (Example 126);

[0220] 5-(4-((5-chloro-3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridineamide (Example 127);

[0221] 5-(4-((5-chloro-3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-methylpyridineamide (Example 128);

[0222] 5-(4-((5-chloro-3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-ethyl-6-methylpyridineamide (Example 129);

[0223] 5-(4-((5-chloro-3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-ethylpyridineamide (Example 130);

[0224] 5-(4-((5-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-cyclopropylpyridineamide (Example 131);

[0225] 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-cyclopropylpyridineamide (Example 132);

[0226] 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-ethylpyridineamide (Example 133);

[0227] 5-(4-((3-ethyl-5-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridineamide (Example 134);

[0228] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-cyclopropylpyridineamide (Example 135);

[0229] 5-(4-((5-chloro-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridineamide (Example 136);

[0230] 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-methyl-N-cyclopropylpyridineamide (Example 137);

[0231] 5-(4-((8-fluoro-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridineamide (Example 138);

[0232] 5-(4-((8-fluoro-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridineamide (Example 139);

[0233] 5-(4-((3-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridineamide (Example 140);

[0234] 5-(4-((3-ethyl-5-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-cyclopropylpyridineamide (Example 141);

[0235] 5-(4-((3-ethyl-5-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridineamide (Example 142);

[0236] 5-(4-((3-ethyl-5-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridineamide (Example 143);

[0237] 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpyridineamide (Example 144);

[0238] 4-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N,3-dimethylbenzamide (Example 145);

[0239] 4-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-3-chloro-N-methylbenzamide (Example 146);

[0240] Or its stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds or pharmaceutically acceptable salts, or mixtures thereof.

[0241] Some of the compounds of this invention may exist as stereoisomers, including optical isomers. This invention includes all stereoisomers and racemic mixtures of such stereoisomers, as well as individual enantiomers that can be isolated according to methods well known to those skilled in the art.

[0242] Examples of medicinal salts include inorganic and organic acid salts, such as hydrochloride, hydrobromide, phosphate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate, and oxalate; as well as inorganic and organic base salts formed with bases such as sodium hydroxyl, tris(hydroxymethyl)aminomethane (TRIS, tromethamine), and N-methylglucosamine.

[0243] Examples of prodrugs of the compounds of the present invention include simple esters of compounds containing carboxylic acids (e.g., esters obtained by condensation with C1-C4 alcohols according to methods known in the art); esters of compounds containing hydroxyl groups (e.g., esters obtained by condensation with C1-C4 carboxylic acids, C3-C6 diacids, or their anhydrides such as succinic anhydride and fumaric anhydride according to methods known in the art); imines of compounds containing amino groups (e.g., imines obtained by condensation with C1-C4 aldehydes or ketones according to methods known in the art); carbamates of compounds containing amino groups, such as those esters described by Leu et al. (J.Med.Chem.42:3623-3628 (1999)) and Greenwald et al. (J.Med.Chem.42:3657-3667 (1999)); and aldol acetals or ketal acetals of compounds containing alcohols (e.g., those acetals obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).

[0244] The compounds of this invention can be prepared using methods known to those skilled in the art or novel methods of this invention. Specifically, the compounds of this invention having formula I (including formulas II, III, and IV) can be prepared as shown in the reaction examples of reaction scheme 1. Methyl 3-amino-5-bromopyridinecarboxylate reacts with Boc anhydride under the catalysis of DMAP and DIEA to give the product methyl 3-(bis(tert-butoxycarbonyl)amino)-5-bromopyridinecarboxylate. Methyl 3-(bis(tert-butoxycarbonyl)amino)-5-bromopyridinecarboxylate undergoes a Suzuki coupling reaction with trimethylcyclotriboroxane under the catalysis of Pd(dppf)Cl2 to give the product methyl 3-(bis(tert-butoxycarbonyl)amino)-5-methylpyridinecarboxylate. Methyl 3-(bis(tert-butoxycarbonyl)amino)-5-methylpyridinecarboxylate reacts with NBS in the presence of BPO (benzoyl peroxide) to give methyl 3-(bis(tert-butoxycarbonyl)amino)-5-(bromomethyl)pyridinecarboxylate. Methyl 3-(bis(tert-butoxycarbonyl)amino)-5-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyridinecarboxamide reacts with N-methyl-5-(piperazin-1-yl)pyridinecarboxamide in the presence of DIEA to give methyl 3-(bis(tert-butoxycarbonyl)amino)-5-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyridinecarboxylate. Methyl 3-(bis(tert-butoxycarbonyl)amino)-5-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyridinecarboxylate undergoes a deBoc reaction under TFA catalysis to give methyl 3-amino-5-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyridinecarboxylate. Methyl 3-amino-5-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyridinecarboxylate then undergoes a cyclization reaction with ethyl isocyanate to give the target compound 5-(4-((3-ethyl-2,4-oxo-1,2,3,4-tetrahydropyridino[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide.

[0245] Reaction Scheme 1

[0246]

[0247] Other related compounds can be prepared using similar methods. For example, replacing ethyl isocyanate with methyl isocyanate yields 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-methylpyridinecarboxamide. Replacing ethyl isocyanate with isopropyl isocyanate yields 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-methylpyridinecarboxamide. By replacing N-methyl-5-(piperazin-1-yl)pyridinecarboxamide with 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridinecarboxamide, the target compound 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyridino[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridinecarboxamide can be prepared.

[0248] The compounds of this invention can be prepared as shown in the reaction examples of reaction scheme 2. Dimethyl 2-aminoterephthalate, ethyl isocyanate, and triethylamine are reacted in toluene in a sealed tube under heating to give the product methyl 3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid. The methyl 3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid is then subjected to lithium aluminum hydride catalytic reduction of the ester group to give the product 3-ethyl-7-(hydroxymethyl)quinazoline-2,4(1H,3H)-dione. 3-ethyl-7-(hydroxymethyl)quinazoline-2,4(1H,3H)-dione undergoes a chlorination reaction with thionyl chloride to give the product 7-(chloromethyl)-3-ethylquinazoline-2,4(1H,3H)-dione. 7-(chloromethyl)-3-ethylquinazoline-2,4(1H,3H)-dione reacts with N-methyl-5-(piperazin-1-yl)pyridinecarboxamide in the presence of N,N-diisopropylethylamine to give the target compound 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide.

[0249] Reaction Scheme 2

[0250]

[0251] Other related compounds can be prepared using similar methods. For example, replacing N-methyl-5-(piperazin-1-yl)pyridinecarboxamide with 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridinecarboxamide yields the target compound 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridinecarboxamide. Replacing dimethyl 2-amino-5-fluoroterephthalate with dimethyl 2-amino-5-fluoroterephthalate yields the target compound 5-(4-((3-ethyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridinecarboxamide. By replacing ethyl isocyanate with propyl isocyanate, the target compound 5-(4-((2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridinecarboxamide can be prepared.

[0252] The compounds of the present invention can be prepared as shown in the reaction examples of reaction scheme 3. 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoic acid is first reacted with oxalyl chloride, and then condensed with 5-amino-N-methylpyridine carboxamide under TEA catalysis to give the product N-methyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoamido)pyridine carboxamide. N-methyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzamido)pyridinecarboxamide and 7-bromo-3-methylquinazoline-2,4(1H,3H)-dione undergo a Suzuki coupling reaction catalyzed by Pd(dppf)Cl2 to give the target compound 5-(3-(3-methyl-2,4-dioxa-1,2,3,4-tetrahydroquinazoline-7-yl)benzamido)N-methyl-pyridinecarboxamide.

[0253] Reaction scheme 3

[0254]

[0255] Other related compounds can be prepared using similar methods. For example, replacing 7-bromo-3-ethylquinazoline-2,4(1H,3H)-dione with 7-bromo-3-methylquinazoline-2,4(1H,3H)-dione yields the target compound 5-(3-(3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-yl)benzamido)-N-methylpyridinecarboxamide; replacing 7-bromo-3-isopropylquinazoline-2,4(1H,3H)-dione with 7-bromo-3-methylquinazoline-2,4(1H,3H)-dione yields the target compound 5-(3-(3-isopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-yl)benzamido)-N-methylpyridinecarboxamide; using 7-bromo-3-... The target compound 5-(3-(3-(3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)benzamido)-N-methylpyridinecarboxamide can be prepared by substituting 7-ethylpyridino[3,2-d]pyrimidin-7-yl)benzamido)-N-methylpyridinecarboxamide with the substitution of 7-bromo-3-propylquinazolin-2,4(1H,3H)-dione.

[0256] The compounds of this invention can be prepared as shown in the reaction examples of reaction scheme 4. Methyl 4-methyl-3-nitrobenzene reacts with NBS under BPO catalysis to undergo bromination, yielding methyl 4-(bromomethyl)-3-nitrobenzene. Methyl 4-(bromomethyl)-3-nitrobenzene reacts with ethylamine under DIEA catalysis to yield methyl 4-((ethylamino)methyl)-3-nitrobenzene. Methyl 4-((ethylamino)methyl)-3-nitrobenzene undergoes reduction under Fe / NH4Cl conditions to yield methyl 3-amino-4-((ethylamino)methyl)benzoate. Methyl 3-amino-4-((ethylamino)methyl)benzoate reacts with CDI under heating conditions to yield methyl 3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid. Methyl 3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid reacts with LiAlH4 to give the product 3-ethyl-7-(hydroxymethyl)-3,4-dihydroquinazoline-2(1H)-one. 3-ethyl-7-(hydroxymethyl)-3,4-dihydroquinazoline-2(1H)-one then undergoes a chlorination reaction with SOCl2 under DMF catalysis to give the product 7-(chloromethyl)-3-ethyl-3,4-dihydroquinazoline-2(1H)-one. 7-(chloromethyl)-3-ethyl-3,4-dihydroquinazoline-2(1H)-one reacted with N-methyl-5-(piperazin-1-yl)pyridinecarboxamide under the catalysis of DIEA to give the target compound 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide.

[0257] Reaction scheme 4

[0258]

[0259] Other related compounds can be prepared using similar methods. For example, replacing N-methyl-5-(piperazin-1-yl)pyridinecarboxamide with 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridinecarboxamide yields the target compound 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridinecarboxamide; replacing N-methyl-5-(piperazin-1-yl)pyridinecarboxamide with 6-chloro-N-methyl-5-(piperazin-1-yl)pyridinecarboxamide yields the target compound. 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)piperazin-1-yl)-6-chloro-N-methylpyridinecarboxamide; the target compound 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridinecarboxamide can be prepared by replacing N-methyl-5-(piperazin-1-yl)pyridinecarboxamide.

[0260] An important aspect of this invention is the discovery that compounds of formula I (including formulas II, III, and IV) are PARP inhibitors, particularly selective inhibitors of PARP1. Therefore, compounds of formula I (including formulas II, III, and IV), or their stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds, or pharmaceutically acceptable salts, mixtures thereof, or prodrugs thereof, can be used to treat a variety of diseases or conditions caused by abnormal PARP activity (especially abnormal PARP1 activity), or to prepare medicaments for treating diseases or conditions caused by abnormal PARP activity (especially abnormal PARP1 activity).

[0261] In this invention, the diseases or conditions caused by abnormal PARP activity (especially abnormal PARP1 activity) include cancer. Cancer can be a solid tumor or a hematologic malignancy, including but not limited to liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, non-small cell lung cancer, small cell lung cancer, gastric cancer, and colon cancer. Colorectal cancer, malignant pancreatic islet tumors, malignant carcinoid cancers, choriocarcinoma, mycosis fungoides, head and neck cancer, osteosarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary neoplasms, 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 cancers are associated with abnormal PARP activity.

[0262] Therefore, the present invention provides a method for treating or preventing diseases or conditions caused by abnormal PARP activity (especially abnormal PARP1 activity), the method comprising administering to a desired subject (especially mammals, more specifically humans) an effective amount of a compound of formula I (including formulas II, III and IV) or its stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds or pharmaceutically acceptable salts, or mixtures thereof, or its prodrugs, or a pharmaceutical composition containing an effective amount of a compound of formula I (including formulas II, III and IV) or its stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds or pharmaceutically acceptable salts, or mixtures thereof, or its prodrugs.

[0263] In implementing the treatment method of the present invention, an effective amount of a pharmaceutical preparation is administered to a patient with one or more of these symptoms. The pharmaceutical preparation contains an effective therapeutic concentration of a compound of formula I (including formulas II, III, and IV), formulated for oral, intravenous, topical, or external administration, for the treatment of cancer and other diseases. The dosage is the amount of medicine that effectively improves or eliminates one or more symptoms. For the treatment of a specific disease, an effective amount is an amount sufficient to improve or alleviate, in some way, the symptoms associated with the disease. Such a dosage may be administered as a single dose or may be administered according to an effective treatment regimen. The dosage may cure the disease, but administration is usually intended to improve the symptoms of the disease. Repeated administration is generally required to achieve the desired symptom improvement.

[0264] In another embodiment, a pharmaceutical composition is provided comprising a PARP inhibitor of formula I (including formulas II, III and IV) or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, or comprising a pharmaceutically acceptable carrier.

[0265] Another embodiment of the present invention relates to a pharmaceutical composition capable of effectively treating cancer, comprising a PARP inhibitor of formula I (including formulas II, III, and IV), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, in combination with at least one known anticancer drug or a pharmaceutically acceptable salt thereof. In particular, this includes combination with other anticancer drugs associated with DNA damage and repair mechanisms, such as PARP inhibitors olaparib, niraprib, rucaparib, talazoparib, pamiparib, fluzoparib, and senaparib; HDAC inhibitors vorinostat, romidesin, pabistat, and belistat, etc. It also includes combination with other anticancer drugs associated with cell division checkpoints, including Chk1 / 2 inhibitors, CDK4 / 6 inhibitors such as palbociclib, ATM / ATR inhibitors, Wee1 inhibitors, etc. Other known anticancer drugs that can be used in combination therapy include, but are not limited to, alkylating agents such as busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, and carboplatin; topoisomerase I inhibitors such as camptothecin, irinotecan, and topotecan; topoisomerase II inhibitors such as doxorubicin, epirubicin, aclarubicin, mitoxantrone, methyl hydroxyrosine, and mentholtoporp; RNA / DNA Antimetabolites such as 5-azacytidine, gemcitabine, 5-fluorouracil, and methotrexate; DNA antimetabolites such as 5-fluoro-2′-deoxyuridine, fludarabine, nelarabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea, and thioguanine; antimitotic agents such as colchicine, vincristine, vinorelbine, paclitaxel, ixaprilone, cabazitaxel, and docetaxel; antibodies such as monoclonal antibodies, panitumumab, nazotocin, nivolumab, pembrolizumab, etc. Ramucirumab, Bevacizumab, Pertuzumab, Trastuzumab, Cetuximab, Obinutuzumab, Ofamumab, Rituximab, Alemtuzumab, Tiimumab, Tosimomab, Bentuximab, Daremumab, Erotozumab, T-DM1, Ofatumumab, Dinutuximab, Blinatumomab, Ipilimumab, Avastin, Herceptin, and Rituximab; kinase inhibitors such as Imatinib, Genomicon. Fertrinib, Erlotinib, Ostinib, Afatinib, Ceritinib, Alectinib, Crizotinib, Erlotinib, Lapatinib, Sorafenib, Regorafenib, Vemurafenib, Dabrafenib, Aflibercept, Sunitinib, Nilotinib, Dasatinib, Bosutinib, Pramipinib, Ibrutinib, Cabozantinib, Lenvatinib, Vandetanib, Trametinib, Carbitinib, Axitinib, Tessiromoxetine, Idelalisib, Pazopanib, Tetracycline, and Everolimus.Other known anticancer drugs that can be used in combination therapy include tamoxifen, letrozole, fulvestrant, mitoxantridine, octreotide, retinoid, arsenic, zoledronic acid, bortezomib, carfilzomib, Ixazomib, vemodega, sondega, denosumab, thalidomide, lenalidomide, venetoclax, Aldesleukin (recombinant human interleukin-2), and Sipueucel-T (prostate cancer treatment vaccine).

[0266] In carrying out the method of the present invention, the compound of the present invention may be administered together with at least one known anticancer drug as a single pharmaceutical composition. Alternatively, the compound of the present invention may be administered separately from at least one known anticancer drug. In one embodiment, the compound of the present invention and at least one known anticancer drug are administered approximately simultaneously, i.e., all drugs are administered simultaneously or sequentially, as long as the compound simultaneously reaches therapeutic concentrations in the blood. In another embodiment, the compound of the present invention and at least one known anticancer drug are administered according to their respective dosage regimens, as long as the compound reaches therapeutic concentrations in the blood.

[0267] Another embodiment of the invention is a biocoupler, consisting of the said compound, that effectively inhibits tumors as a kinase inhibitor. This tumor-inhibiting biocoupler comprises the said compound with at least one known therapeutically active antibody, such as Herceptin or Rituxan, or a growth factor, such as EGF or FGF, or a cytokine, such as interleukin-2 or 4, or any molecule capable of binding to the cell surface. The antibody, along with other molecules, can deliver the compound to its target site, making it an effective anticancer drug. This biocoupler can also enhance the anticancer effects of therapeutically active antibodies, such as Herceptin or Rituxan.

[0268] Another embodiment of the invention relates to a pharmaceutical composition capable of effectively inhibiting tumors, comprising a PARP inhibitor of formula I (including formulas II, III, and IV), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, for combination therapy with radiotherapy. In this embodiment, the compound of the invention and radiotherapy may be administered at the same time or at different times.

[0269] Another embodiment of the invention relates to a pharmaceutical composition effective for postoperative treatment of cancer, comprising a PARP inhibitor of formula I (including formulas II, III, and IV), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof. The invention also relates to a treatment method involving surgical removal of a tumor followed by treatment of cancer in a mammal with the pharmaceutical composition of the invention.

[0270] The pharmaceutical compositions of the present invention comprise pharmaceutical formulations in which the contents of all the compounds of the present invention effectively achieve their intended objectives. Although individual needs vary, those skilled in the art can determine the optimal dosage of each component of the pharmaceutical formulation. Generally, the compounds, or their available salicies, are administered orally to mammals daily at a dosage of about 0.0025 to 50 mg / kg body weight. However, it is preferable to administer orally at a dosage of about 0.01 to 10 mg / kg. If a known anticancer drug is also administered, its dosage should effectively achieve its intended purpose. The optimal dosages of these known anticancer drugs are well known to those skilled in the art.

[0271] A single oral dose may comprise about 0.01 to 50 mg, preferably about 0.1 to 10 mg, of the compound of the present invention. A single dose may be administered once or multiple times daily as one or more tablets, each tablet containing about 0.1 to 50 mg, preferably about 0.25 to 10 mg, of the compound of the present invention or a solvate thereof.

[0272] In topical formulations, the concentration of the compounds of the present invention can be from about 0.01 to 100 mg per gram of carrier.

[0273] The compounds of the present invention can be administered as unprocessed pharmaceutical products. They can also be administered as part of a suitable pharmaceutical formulation containing a pharmaceutically acceptable carrier (including excipients and adjuvants). These pharmaceutically acceptable carriers facilitate the processing of the compounds into pharmaceutically acceptable formulations. Preferred pharmaceutical formulations, particularly those for oral administration and preferred routes of administration such as tablets, lozenges, and capsules, as well as solutions suitable for injection or oral administration, contain about 0.01% to 99%, preferably from about 0.25% to 75%, of the active compound and excipients.

[0274] The scope of this invention also includes non-toxic, pharmaceutically acceptable salts of the compounds of this invention. Acid addition salts are formed by mixing a solution of a non-toxic, pharmaceutically acceptable acid with a solution of the compound of this invention. Examples of the acids include 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 a non-toxic, pharmaceutically acceptable base with a solution of the compound of this invention. Examples of the bases include sodium hydroxide, potassium hydroxide, hydrocholine, sodium carbonate, tris(hydroxymethyl)aminomethane, N-methylglucosamine, etc.

[0275] The pharmaceutical formulations of this invention can be administered to any mammal, provided they achieve the therapeutic effects of the compounds of this invention. Humans and veterinary animals are most important among these mammals, although this invention is not intended to be so limited.

[0276] The pharmaceutical formulation of this invention can be administered via any route to achieve its intended purpose. For example, it can be administered via parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, intracranial, nasal, or topical routes. Alternatively or concurrently, it can be administered orally. The dosage of the drug will be determined based on the patient's age, health and weight, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic benefit.

[0277] The pharmaceutical formulations of the present invention can be manufactured using known methods. For example, they can be manufactured by conventional mixing, granulation, tableting, dissolving, or freeze-drying processes. When manufacturing oral formulations, solid excipients and active compounds can be combined and the mixture can be selectively ground. If necessary or required, an appropriate amount of excipients can be added, and the granular mixture can be processed to obtain tablets or tablet cores.

[0278] Suitable excipients, especially fillers, include sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations and / or calcium phosphates, such as tricalcium phosphate or dicalcium phosphate; and binders, such as starch pastes including corn starch, wheat starch, rice starch, potato starch, gelatin, astragalus gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. If desired, disintegrants, such as the starches mentioned above, as well as carboxymethyl starch, croscarmellose, agar, or alginate or its salts, such as sodium alginate, may be added. Adjuvants, especially flow conditioners and lubricants, include silica, talc, stearic acid or its salts, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. If desired, a suitable coating that resists gastric juices can be provided to the tablet core. For this purpose, a concentrated sugar solution can be applied. This solution may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solution, and suitable organic solvents or solvent mixtures. To prepare a gastric juice-resistant coating, a suitable cellulose solution, such as cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate, can be used. Dyes or pigments may be added to the coating of the tablet or tablet core, for example, for identification or to characterize the dosage of the active ingredient.

[0279] Other orally edible pharmaceutical formulations include compressible capsules made of gelatin, and sealed soft capsules made of gelatin and plasticizers such as glycerin or sorbitol. The compressible capsule may contain an active compound in particulate form, 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 oils or liquid paraffin, in which stabilizers may be added.

[0280] Suitable formulations for parenteral administration include aqueous solutions of the active compound, such as solutions of water-soluble salts and alkaline solutions. Additionally, oily injectable suspensions of the appropriate active compound can be administered. Suitable lipophilic solvents or carriers include oils such as sesame oils, synthetic fatty acid esters such as ethyl oleate or triglycerides or polyethylene glycol 400, or hydrogenated castor oil, or cyclodextrin. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, and / or dextran. Suspension stabilizers may also be included.

[0281] According to one aspect of the invention, the compounds of the invention are formulated for external and parenteral use and are used to treat skin cancer.

[0282] The topical formulations of this invention can be formulated into oils, creams, emulsions, ointments, etc., using a preferred suitable carrier. Suitable carriers include plant or mineral oils, white mineral oil (white paraffin), branched-chain fatty acids or oils, animal fats, and high molecular weight alcohols (greater than C10). 12 Preferred carriers are those in which the active ingredient can dissolve. Emulsifiers, stabilizers, moisturizers, and antioxidants may also be included, as well as agents that impart color or fragrance if desired. Furthermore, these topical formulations may contain transdermal penetration enhancers. Examples of such enhancers can be found in U.S. Patent Nos. 3,989,816 and 4,444,762.

[0283] Creams are preferably formulated with a mixture of mineral oil, self-emulsifying beeswax, and water, mixed with an active ingredient dissolved in a small amount of oil, such as almond oil. A typical example of a cream includes approximately 40 parts water, 20 parts beeswax, 40 parts mineral oil, and 1 part almond oil.

[0284] Ointments can be formulated by mixing a plant oil containing active ingredients, such as almond oil, with warm paraffin wax, and then allowing the mixture to cool. A typical example of an ointment consists of approximately 30% by weight almond oil and 70% by weight white paraffin wax.

[0285] This invention also relates to the preparation of medicaments for treating clinical conditions that are effective in inhibiting PARP using the compounds of this invention. These medicaments may include the aforementioned pharmaceutical compositions.

[0286] The following examples are illustrative and not intended to limit the methods and formulations of the present invention. Other appropriate modifications and improvements to various conditions and parameters that will be apparent to those skilled in the art and that are commonly encountered in clinical treatment are all within the spirit and scope of the present invention.

[0287] Example

[0288] General instructions

[0289] All reagents used were commercially available, and solvents were dried and purified according to standard methods. Mass spectrometry samples were analyzed using a single quadrupole mass spectrometer (Platform II, Agilent 6110) with electrospray ionization. Recordings were performed at 300 MHz or 400 MHz using a Brücker Ascend 400 NMR spectrometer. 1 1H NMR spectra, chemical shifts were recorded in ppm starting from the low field with TMS as the internal standard (0.00 ppm), and coupling constant J values ​​were in Hz.

[0290] Example 1

[0291] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide

[0292] (a) Methyl 3-(bis(tert-butoxycarbonyl)amino)-5-bromopyridinecarboxylate: Methyl 3-amino-5-bromopyridinecarboxylate (3.0 g, 13.0 mmol, 1.0 eq), (Boc)₂O (7.1 g, 32.6 mmol), DIEA (5.1 g, 39.1 mmol), and DMAP (318.2 mg, 2.6 mmol) were dissolved in THF (60 mL). The resulting mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, the crude product was diluted with water (30 mL), and extracted with DCM (30 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc / PE, 1–5%) to give the product (3.5 g, white solid, yield: 62.5%). MS (ESI, m / z): 431.20 [M+1] + .

[0293] (b) Methyl 3-(bis(tert-butoxycarbonyl)amino)-5-methylpyridinecarboxylate: Methyl 3-(bis(tert-butoxycarbonyl)amino)-5-bromopyridinecarboxylate (3.0 g, 7.0 mmol), trimethylcycloboroxane (6.0 mL, 21.0 mmol, 3.5 M THF solution), Cs₂CO₃ (4.6 g, 14.0 mmol), and Pd(dppf)Cl₂ (768.6 g, 1.05 mmol) were dissolved in dioxane (60 mL). The reaction mixture was degassed and purged three times with nitrogen, and stirred overnight at 100 °C. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc / PE, 10-50%) to give the product (2.3 g, white solid, yield: 88.2%). MS (ESI, m / z): 367.30 [M+1] + .

[0294] (c) Methyl 3-(bis(tert-butoxycarbonyl)amino)-5-(bromomethyl)pyridinecarboxylate: Methyl 3-(bis(tert-butoxycarbonyl)amino)-5-methylpyridinecarboxylate (50.0 mg, 0.14 mmol), NBS (24.3 mg, 0.14 mmol), and BPO (3.3 mg, 0.01 mmol) were dissolved in CCl4 (3 mL) and stirred overnight at 100 °C. Since there was excess starting material, NBS (12.1 mg, 0.07 mmol) was added and the mixture was stirred at 100 °C for 6 hours. After the reaction was complete, the solvent was removed, and the crude product was purified by preparative thin-layer chromatography (DCM / MeOH = 10:1) to give the product (30.0 mg, yellow solid, yield: 49.5%). MS (ESI, m / z): 445.30 [M+1] + .

[0295] (d) Methyl 3-(bis(tert-butoxycarbonyl)amino)-5-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyridinecarboxylate: methyl 3-(bis(tert-butoxycarbonyl)amino)-5-(bromomethyl)pyridinecarboxylate (30.0 mg, 0.07 mmol), N-methyl-5-(piperazin-1-yl)pyridinecarboxamide (17.5 mg, 0.08 mmol), DIEA (43.2 mg, 0.34 mmol), and KI (1.1 mg, 0.01 mmol) were dissolved in acetonitrile (6 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (DCM / MeOH = 10:1) to obtain the product (40.0 mg crude product), which could be used directly in the next reaction without further purification. MS(ESI, m / z): 585.25 [M+1] + .

[0296] (e) Methyl 3-amino-5-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyridinecarboxylate: Methyl 3-(bis(tert-butoxycarbonyl)amino)-5-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyridinecarboxylate (40.0 mg, 0.07 mmol) and TFA (39.0 mg, 0.34 mmol) were dissolved in DCM (5 mL). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The target product (30.0 mg, yellow solid, crude) was obtained. It was used directly in the next reaction without purification. MS (ESI, m / z): 385.15 [M+1] + .

[0297] (f) 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyridino[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide: Methyl 3-amino-5-((4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyridinecarboxylate (30.0 mg, 0.08 mmol), ethyl isocyanate (1 mL), and TEA (1 mL) were dissolved in toluene (10 mL). The reaction mixture was stirred overnight at 120 °C. After the reaction was complete, the reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, and then concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (DCM / MeOH = 10:1) to obtain the crude product, and then slurried with EA (2 mL) to obtain the target compound (3.5 mg, white solid, yield: 12.3%).

[0298] The compounds of Examples 2-11 were prepared using a similar method. The results are shown below.

[0299]

[0300]

[0301] Example 12

[0302] 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide

[0303] (a) Methyl 3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid: 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) were mixed in a sealed tube with toluene (3 mL) and heated to 90 °C overnight. After the reaction was complete, the reaction solution was concentrated. Methanol (5 mL) and concentrated hydrochloric acid (3 mL) were added to the residue, and the mixture was stirred overnight at room temperature. After concentrating the reaction solution, the residue was washed successively with water (20 mL) and methanol (20 mL), and dried to obtain the crude target product (480.0 mg, white solid). MS (ESI, m / z): 249.10 [M+1] + 247.00 [M-1] - .

[0304] (b) 3-Ethyl-7-(hydroxymethyl)quinazoline-2,4(1H,3H)-dione: Under nitrogen protection, lithium aluminum hydride (62.0 mg, 1.6 mmol) was added to a tetrahydrofuran (5 mL) solution of methyl 3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid (200.0 mg, 0.8 mmol). The reaction mixture was brought to room temperature and stirred for 2 hours, then quenched with 1N hydrochloric acid (2 mL). The concentrated mixture was diluted with water (10 mL) to give a yellow floating solid. The solid was filtered, washed successively with water (10 mL) and diethyl ether (10 mL), and dried to give the target product (80.0 mg, 2-step yield: 91%, yellow solid). MS (ESI, m / z): 221.20 [M+1] + 219.15 [M-1] - .

[0305] (c) 7-(chloromethyl)-3-ethylquinazoline-2,4(1H,3H)-dione: 3-ethyl-7-(hydroxymethyl)quinazoline-2,4(1H,3H)-dione (80.0 mg, 0.2 mmol) was dissolved in dichloromethane (3 mL), and N,N-dimethylformamide (2.4 mg, 0.03 mmol) was added. Thionyl chloride (231.0 mg, 1.9 mmol) was added dropwise at 0 °C. The reaction mixture was allowed to return to room temperature and reacted for 2 hours. After the reaction was complete, the reaction mixture was concentrated to obtain the crude target product (70.0 mg). MS (ESI, m / z): 239.35 [M+1] + 237.10 [M-1] - .

[0306] (d) 5-(4-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide: At room temperature, 7-(chloromethyl)-3-ethylquinazoline-2,4(1H,3H)-dione (70.0 mg, crude), potassium iodide (11.0 mg, 0.1 mmol), and N-methyl-5-(piperazin-1-yl)pyridineline hydrochloride (71.0 mg, 0.3 mmol) were dissolved in acetonitrile (4 mL). N,N-diisopropylethylamine (209.0 mg, 1.6 mmol) was added, and the reaction mixture was heated to 80 °C for 2 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The crude product was diluted with water (10 mL) and filtered as a solid. The filter cake was washed with methanol (10 mL) and ethyl acetate (10 mL) to obtain the target product (35 mg, 2-step yield: 23%, gray powder).

[0307] The compounds of Examples 13-14 were prepared using a method similar to that of Example 12. The results are shown below.

[0308]

[0309] Example 15

[0310] 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide

[0311] (a) Methyl 4-(bromomethyl)-3-nitrobenzene: Methyl 4-methyl-3-nitrobenzene (6.9 g, 35.4 mmol), NBS (6.3 g, 35.4 mmol), and BPO (858.0 mg, 3.5 mmol) were dissolved in CCl4 (140 mL) and heated to 100 °C for 15 hours. After the reaction was complete, the solvent was removed, and the crude product was purified by silica gel column chromatography (EtOAc / PE, 2-5%) to obtain the target product (4.2 g, yield: 43.3%, yellow solid).

[0312] (b) Methyl 4-((ethylamino)methyl)-3-nitrobenzene: Ethylamine (6.9 mL, 13.8 mmol, 2 M in THF) and DIEA (1.4 g, 10.4 mmol) were dissolved in THF (20 mL). Methyl 4-(bromomethyl)-3-nitrobenzene (1.9 g, 6.9 mmol) was added to the above solution at -78 °C, and the reaction mixture was allowed to rise naturally to room temperature and stirred overnight. After the reaction was complete, the solvent was removed, and the crude product was purified by silica gel column chromatography (EtOAc / PE, 10-20%) to obtain the target product (1.2 g, yield: 72.7%, yellow solid). MS (ESI, m / z): 239.20 [M+1] + .

[0313] (c) Methyl 3-amino-4-((ethylamino)methyl)benzoate: Methyl 4-((ethylamino)methyl)-3-nitrobenzene (1.0 g, 4.2 mmol) was dissolved in ethanol (30 mL), followed by the addition of iron powder (Fe, 941.0 mg, 16.8 mmol) and NH4Cl (2.2 g, 42.0 mmol). The reaction was carried out at room temperature for 3 hours. After the reaction was complete, the reaction solution was filtered, the filter cake was washed with ethanol (50 mL), the filtrates were combined and the solvent was removed under reduced pressure, the crude product was diluted with water (50 mL), and extracted with DCM (50 mL × 3). The organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (EtOAc / PE, 10-50%) to obtain the target product (400 mg, yield: 46.0%, yellow solid). MS (ESI, m / z): 209.05 [M+1] + .

[0314] (d) Methyl 3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid: Methyl 3-amino-4-((ethylamino)methyl)benzoate (200.0 mg, 1.0 mmol) was dissolved in ethyl acetate (5 mL). Under nitrogen protection, N,N'-carbonyldiimidazole (CDI, 623.1 mg, 3.9 mmol) was added to the above solution. The reaction mixture was stirred overnight at 80 °C. After the reaction was complete, the reaction mixture was concentrated, and the crude product was purified by preparative thin-layer chromatography (EtOAc / PE, 1 / 1) to give the target compound (40 mg, yield: 17.8%, yellow solid). MS (ESI, m / z): 235.00 [M+1] + .

[0315] (e) 3-Ethyl-7-(hydroxymethyl)-3,4-dihydroquinazoline-2(1H)-one: Methyl 3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid (40.0 mg, 0.2 mmol) was dissolved in THF (5 mL). LiAlH4 (26.0 mg, 0.7 mmol) was added to the solution under nitrogen protection at 0 °C. The reaction mixture was allowed to return to room temperature and reacted for 2 hours, then quenched with 1 M HCl (1 mL). The reaction mixture was concentrated and diluted with water (10 mL) to obtain a yellow precipitate. The precipitate was then filtered, and the filter cake was washed first with water (10 mL) and then with diethyl ether (10 mL). After drying, the target compound (35 mg, yield: 99.0%, yellow solid) was obtained. MS (ESI, m / z): 207.10 [M+1] + .

[0316] (f) 7-(chloromethyl)-3-ethyl-3,4-dihydroquinazoline-2(1H)-one: 3-ethyl-7-(hydroxymethyl)-3,4-dihydroquinazoline-2(1H)-one (35.0 mg, 0.2 mmol) was dissolved in DCM (3 mL), and DMF (1 drop) was added at 0 °C, followed by SOCl2 (80.9 mg, 0.7 mmol). The reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated to give the crude target compound (30.0 mg, yield: 61.2%, gray solid). MS (ESI, m / z): 225.05 [M+1] + It can be used directly in the next reaction.

[0317] (g) 5-(4-((3-ethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide: 7-(chloromethyl)-3-ethyl-3,4-dihydroquinazoline-2(1H)-one (30.0 mg, 0.13 mmol), KI (4.4 mg, 0.03 mmol), and N-methyl-5-(piperazin-1-yl)pyridinecarboxamide hydrochloride (37.6 mg, 0.16 mmol) were dissolved in acetonitrile, and then DIEA (86.4 mg, 0.67 mmol) was added. The reaction was carried out at 80 °C for 2 hours. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was diluted with water (10 mL) and then filtered to obtain a solid precipitate. The filter cake was washed with methanol (10 mL) and ethyl acetate (10 mL), and dried to give the target compound (22.8 mg, yield: 41.7%, yellow solid). MS (ESI, m / z): 409.10 [M+1] + . CDCl3: δ8.96(s,1H),8.45(d,J=8.0Hz,1H),8.36(d,J=7.9Hz,1H),7.86(d,J=5.4Hz,1H),7.69–7.63(m,1H),7.58(d,J=8.1Hz,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=4.6Hz,3H) ,3.05–2.99(m,4H),2.09(dd,J=14.5,7.3Hz,2H),1.34(t,J=7.2Hz,3H).

[0318] The compounds of Examples 16-39 were prepared using a method similar to that of Example 12. The results are shown below.

[0319]

[0320]

[0321]

[0322] Example 40

[0323] 5-(3-(3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)benzamido)N-methylpyridinecarboxamide

[0324] (a) N-Methyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzamido)pyridinecarboxamide: To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzoic acid (1.8 g, 7.15 mmol) in DCM (20 mL), oxalyl chloride (2.7 g, 21.45 mmol) and DMF (2 drops) were added. The reaction mixture was stirred at room temperature for 30 minutes. The solvent was removed by rotary evaporation, and the residue was dissolved in DCM (10 mL) for later use. At low temperature, Et3N (0.9 g, 8.94 mmol) was added to a solution of 5-amino-N-methylpyridinecarboxamide (0.9 g, 5.96 mmol) in DCM (20 mL), followed by the addition of the solution prepared above. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solvent was removed by rotary evaporation, and the crude product was purified by column chromatography (ethyl acetate-petroleum ether: 0-50%) to give the product (1.3 g, yield: 48%, white solid). MS (ESI, m / z): 381.90 [M+1] + .

[0325] (b) 5-(3-(3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-yl)benzamido)N-methylpyridinecarboxamide: N-methyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzamido)pyridinecarboxamide (452.0 mg, 1.2 mmol), 7-bromo-3-methylquinazoline-2,4(1H,3H)-dione (250.0 mg, 1.0 mmol), Pd(dppf)Cl2 (74.0 mg, 0.1 mmol), and cesium carbonate (965.0 mg, 3.0 mmol) were dissolved in DMF (4 mL) and water (1 mL). The reaction system was purged with nitrogen three times, and then reacted overnight at 100 °C. After the reaction was complete, the reaction solution was filtered, and the filter cake was washed with methanol (10 mL). The filter cake was collected and dissolved in DMSO (10 mL), filtered to remove insoluble matter, and then the solvent was removed to obtain the target compound (120.0 mg, yield: 28%, white solid).

[0326] The compounds of Examples 41-47 were prepared using a method similar to that of Example 40. The results are shown below.

[0327]

[0328]

[0329] The compounds of Examples 48-113 were prepared using a method similar to that of Example 12. The results are shown below.

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337] The compounds of Examples 114-146 were prepared using a method similar to that of Example 15. The results are shown below.

[0338]

[0339]

[0340]

[0341]

[0342] Example 147

[0343] The inhibitory effect of the compounds of this invention on the activities of PARP1 and PARP2 enzymes was determined using a chemiluminescence detection method.

[0344] Diluted buffer containing recombinant poly(ADP-ribotransferases) 1 and 2 (PARP1 and PARP2) (40 ng enzyme / well) and the test compound were added to 96-well plates coated with recombinant proteins and incubated at room temperature for 1 hour. Then, 50 μL of 0.3 ng / mL horseradish peroxidase streptavidin (HRP) was added to each well, and the plates were incubated at room temperature for 30 minutes. Finally, the corresponding substrates were added, and the plates were read using an EnviSion instrument. Chemiluminescence signals were recorded, and the inhibition rates of the test compounds on PAPP1 and PARP2 enzyme activities were calculated using the following formula.

[0345]

[0346] Note: The negative control well reading is the reading of the well with only enzyme diluent (without enzyme and test compound), indicating 0% enzyme activity; the positive control well reading is the reading of the well with 1% DMSO (without test compound), indicating 100% enzyme activity; X is the reading of the well with the test compound.

[0347] Table 1 summarizes the inhibitory effects (IC50) of the compounds of this invention on PARP1 and PARP2 enzyme activities. 50 ). Where, +++++ represents IC.50 ≤1nM; ++++ represents 1 <IC 50 ≤10nM; +++ means 10nM <IC 50 ≤100nM; ++ indicates 100nM <IC 50 ≤1μM; + indicates IC 50 >1μM.

[0348] Table 1

[0349]

[0350]

[0351] Most of the compounds in this invention selectively inhibit PARP1 enzyme activity.

[0352] Example 148

[0353] The inhibitory effect of the compound of this invention on human breast cancer cells MDA-MB-436 was determined using the CCK-8 assay.

[0354] After cell resuscitation, cells were cultured and passaged in complete medium (DMEM medium + 10% FBS + insulin + glutathione). When cell confluence reached approximately 80%, cells were gently aspirated from the bottom of the culture dish using a 1 mL pipette, and the cell suspension was collected and centrifuged at 500 rpm for 3 min. The supernatant was discarded, and the cells were resuspended in complete medium. The cells were then seeded into culture dishes at an appropriate ratio and incubated statically at 37°C in a 5% CO2 incubator. Cells were passaged until they reached good growth and approximately 80% confluence and were ready for experimental use. Cells in the logarithmic growth phase were gently aspirated from the well using a 1 mL pipette, centrifuged at 500 rpm for 3 min, and the supernatant was discarded. The cells were resuspended in fresh medium, dispersed into single cells, and counted. Cells were seeded at a density of 3000 cells per well into 96-well cell culture plates (the first column was empty) and incubated overnight at 37°C in a 5% CO2 incubator. The following day, the stock solution of the compound was serially diluted with DMSO at a 1:3 ratio to obtain eight concentrations. 5 μL of each concentration was added to 120 μL of culture medium (25-fold dilution). A DMSO control well was also prepared. Cells were removed from the CO2 incubator, and the old culture medium in the wells was discarded. 195 μL of fresh culture medium was added to each well, followed by 5 μL of the corresponding concentration of the compound diluted in the medium. The culture plate was then incubated at 37°C in a 5% CO2 incubator for 7 days, with the medium changed on day 4. After 7 days, 20 μL of CCK-8 was added to each well, and the plate was shaken and incubated for another 4 hours. After shaking for 5 minutes, the absorbance values ​​at 450 nm and 650 nm wavelengths were read using a multi-channel absorbance meter (OD value = absorbance). 450nm -Absorbance 650nm ).

[0355] Data were analyzed using GraphPad Prism 6.0 software. The inhibitory activity of the compound on cell proliferation was plotted on a coordinate system of cell viability and compound concentration. Cell viability % = (OD) / (Cell viability % = 0.05%) ... 化合物 -OD 背景 ) / (OD DMSO -OD 背景 )×100. IC 50 The value was fitted with an S-shaped dose-response curve equation, which is: Y = 100 / (1 + 10^(LogC - LogIC)) 50 C is the concentration of the compound.

[0356] Table 2 summarizes the data on the inhibitory effects of the compounds on the growth of human breast cancer cells MDA-MB-436 (IC50). 50 ). Where ++++ represents 1 <IC 50 ≤10nM; +++ means 10nM <IC 50 ≤100nM; ++ indicates 100nM <IC 50 ≤1μM; + indicates IC 50 >1μM.

[0357] Table 2

[0358]

[0359]

[0360] The compound of this invention has an inhibitory effect on the growth of MDA-MB-436 cells with BRCA mutation.

[0361] While the invention has been fully described, those skilled in the art will understand that the same practices can be carried out under broad and equivalent conditions, formulations, and other parameters without affecting the scope of the invention or any embodiments thereof. All patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety.

Claims

1. A compound of the following Formula IIa: ###0001### IIa or a tautomer thereof, or a pharmaceutically acceptable salt thereof. wherein: R1is C1-C6alkyl or C3-C6cycloalkyl, wherein R 1-3 C1-C6alkyl or C3-C6cycloalkyl 3-6 C1-C6alkyl or C3-C6cycloalkyl ′ and R" are each independently H, C1-C6alkyl or C3-C6cycloalkyl, wherein R 1-4 C1-C6alkyl or C3-C6cycloalkyl 3-6 C1-C6alkyl or C3-C6cycloalkyl A3 is CH, one of A1 and A2 is N, the other is CR2, wherein R2 is H, C 1-3 alkyl or halogen; or A1, A2 and A3 are CR2, each R2 is independently H, C 1-3 alkyl or halogen; or A1, A2 and A3 are CR2, each R2 is independently H, C R5 is: ###0002### B1, B2, B3and B4are each independently selected from N and CR7; R7is selected from hydrogen, halo, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy and -NR ′ R"; R ′ and R" are each independently selected from hydrogen, C 1-4 alkyl, haloC 1-4 alkyl or C 3-6 cycloalkyl; * indicates the position of attachment of the group to the rest of the compound; n is 1; wherein the -(CH2) n - is optionally substituted with one =0.

2. The compound of claim 1, or a tautomer, or a pharmaceutically acceptable salt thereof, wherein R1 is C 1-3 alkyl, C 1-3 alkyl, or C 3-4 cycloalkyl.

3. The compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt, wherein R2 is hydrogen, C 1-3 alkyl or halogen.

4. The compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein: ###0003### A1 is N, A2 and A3 are both CH; or A2 is N, A1 and A3 are both CH; or A1 is CH, A2 and A3 are both N.

5. The compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R5 is: ###0004### The group containing B1-B4 is phenyl, pyridyl, pyrimidyl or pyridazyl. A3 is CH, one of A1 and A2 is CR2, wherein R2 is H, C 1-3 alkyl or halogen; or A2and A3are both CH, and A1is CR2, wherein R2is C 1-3 alkyl or halogen.

9. The compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein, the compound has the following structure of Formulae Ilia or Illb: ###0005### Ilia Illb wherein B1, B2, B3and B4are each independently selected from N and CR7; R7is selected from hydrogen, halo, C 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy and -NR ′ R"; R ′ and R" are each independently selected from hydrogen, C 1-4 alkyl, haloC 1-4 alkyl or C 3-6 cycloalkyl; * indicates the position of the group at which it is attached to the remainder of the compound.

6. The compound of claim 1, or a tautomer, or a pharmaceutically acceptable salt thereof, wherein, wherein: R1 is as defined in claim 1 or 2; A1, A2 and A3 are as defined in claim 1 or 4; B1, B2, B3 and B4 are as defined in claim 1, 6 or 7.

7. The compound of claim 1, or a tautomer, or a pharmaceutically acceptable salt thereof, wherein, B3 is N, B4 is CR7, B1 and B2 are CH, wherein R7 is H, halogen, C 1-3 alkyl, C 1-3 alkoxy or halogenated C 1-3 alkyl.

8. The compound of claim 1, or a tautomer, or a pharmaceutically acceptable salt thereof, wherein, R7is H, halogen, C 1-3 alkyl, C 1-3 alkoxy or halogenated C 1-3 alkyl. The compound has the following structure of Formula IVa or IVb: ###0006### IVa IVb R1is C 1-3 alkyl, haloC 1-3 alkyl or C 3-4 cycloalkyl; R5is aminoacyl substituted phenyl, pyridyl, pyrimidyl or pyridazyl; or R5is pyridopyrimidyl, indolyl, indazolyl or benzimidazolyl. 1-4 alkyl substituted 1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl or 4-oxo-4H-pyrido[1,2- a]pyrimidin-8-yl; or R5is pyridopyrimidyl, indolyl, indazolyl or benzimidazolyl.

10. The compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein wherein: R1 is as defined in claim 1 or 2; A1 and A2 are as defined in claim 1 or 4.

12. A compound selected from the group consisting of: ###0007### or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

13. Use of a compound of any one of claims 1 to 12, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease or disorder caused by abnormal PARP activity. The disease or disorder is cancer. The cancer is hepatocarcinoma, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myelocytic leukemia, primary brain carcinoma, non-small cell lung cancer, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, urogenital tumor disease, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocytopenia, adrenal cortex cancer, skin cancer and prostate cancer. R ′ and R" are each independently selected from hydrogen, C 1-4 alkyl, haloC 1-4 alkyl or C 3-6 cycloalkyl.

11. The compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein The medicament further comprises at least one known anticancer drug, or a pharmaceutically acceptable salt of the anticancer drug. ​ ​ ​ R7is hydrogen, halogen, C 1-4 alkyl and haloC 1-4 alkyl; R" is H, C 1-4 alkyl, haloC 1-4 alkyl or C 3-6 cycloalkyl. ​ ​ ​ 14. The use according to claim 13, characterized in that, ​ 15. The use according to claim 14, characterized in that, ​ 16. The use of claim 13, wherein, ​ 17. The use according to claim 16, characterized in that, The anticancer drug is selected from one or more of the following: vorinostat, romidepsin, panobinostat, belinostat, palbociclib, busulfan, mafosfamide, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mytomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, elliptinium acetate, mitopodozide, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxyuridine, fludarabine, nelarabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, trastuzumab, panitumumab, inotuzumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab, daratumumab, erlotinib, T-DM1, Ofatumumab, Dinutuximab, Blinatumomab, Ipilimumab, Avastin, Herceptin, Mabthera, imatinib, gefitinib, erlotinib, osimertinib, afatinib, icotinib, elacridar, crizotinib, erlotinib, lapatinib, sorafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, pralsetinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cabozantinib, axitinib, temsirolimus, idelalisib, pazopanib, talimogene laherparepvec, everolimus, tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, white arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin, and sipuleucel-T.

18. The use of claim 13, wherein, The drug is used in combination with radiation therapy.

19. A pharmaceutical composition comprising a compound of any one of claims 1-12, or a tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition of claim 19, wherein The pharmaceutical composition further comprises at least one known anticancer drug, or a pharmaceutically acceptable salt of the anticancer drug.

21. The pharmaceutical composition of claim 20, wherein The at least one known anticancer drug is selected from the group consisting of vorinostat, romidepsin, panobinostat, belinostat, palbociclib, busulfan, mafosfamide, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mytomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, elliptinium acetate, mitopodozide, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxyuridine, fludarabine, nelarabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, Ado-trastuzumab emtansine, Panitumumab, Nectinumomab, Nivolumab, Pembrolizumab, Ramucirumab, Bevacizumab, Pertuzumab, Trastuzumab, Cetuximab, Obinutuzumab, Ofatumumab, Dinutuximab, Blinatumomab, Ipilimumab, Avastin, Herceptin, Mabthera, Imatinib, Gefitinib, Erlotinib, Osimertinib, Afatinib, Sunitinib, Erlotinib, Lapatinib, Sorafenib, Regorafenib, Vemurafenib, Dabrafenib, Aflibercept, Sunitinib, Nilotinib, Dasatinib, Bosutinib, Pralsetinib, Ibrutinib, Cabozantinib, Lenvatinib, Vandetanib, Trametinib, Cabozantinib, Axitinib, Temsirolimus, Idelalisib, Pazopanib, Talizumab, Everolimus, Tamoxifen, Letrozole, Fulvestrant, Mitoguazone, Octreotide, Retinoic acid, Arsenic trioxide, Zoledronic acid, Bortezomib, Carfilzomib, Ixazomib, Vismodegib, Sonidegib, Denosumab, Thalidomide, Lenalidomide, Venetoclax, Aldesleukin and Sipueucel-T.

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