Bicyclic derivative PARP inhibitors and their applications

Abstract

The compound shown in formula I-1, its stereoisomers, pharmaceutically acceptable salts, or pharmaceutical compositions containing them, and its use in the manufacture of a PARP-1 inhibitor for the treatment of related diseases, wherein each group shown in formula I-1 is as defined in the specification. [C1] TIFF2026521712000083.tif31156

Description

[Technical Field]

[0001] This invention belongs to the pharmaceutical field and, more particularly, to low molecular weight compounds having PARP-1 inhibitory activity, their stereoisomers, pharmaceutically acceptable salts, solvates, cocrystals or deuterides, and their uses in the treatment of related diseases. [Background technology]

[0002] Approximately 5% of breast cancer patients are associated with germline mutations in the BRCA1 / 2 genes (3% in the BRCA1 gene and 2% in the BRCA2 gene). While the majority of breast cancers caused by BRCA1 mutations are triple-negative breast cancers (70%), BRCA2 mutations are more likely to cause estrogen receptor-positive breast cancers (70%). The BRCA1 / 2 genes are tumor suppressor genes that play a crucial role in DNA damage repair and normal cell growth. Mutations in these genes suppress the normal repair capacity after DNA damage, leading to homologous recombination deficiency (HRD), i.e., loss of function in BRCA or mutations or loss of function in other homologous recombination-related genes. This prevents the repair of double-strand break DNA by homologous recombination repair (HRR), ultimately leading to cancer.

[0003] Polyadenylated ribose phosphate polymerase (PARP) is a DNA repair enzyme that plays a crucial role in the DNA repair pathway. When DNA is damaged and broken, PARP is activated and acts as a molecular sensor for DNA damage, recognizing and binding to the DNA break site. Furthermore, it activates and catalyzes the poly-ADP ribosylation of the receptor protein, thus participating in the DNA repair process. PARP plays an important role in the excision and repair process of single-strand DNA bases. In HRD tumor cells, DNA double-strand repair is not possible, and PARP inhibitors block single-strand repair, thereby creating a "synthetic lethal" effect and causing tumor cell death.

[0004] PARP inhibitors have a "trapping" effect on PARP proteins, resulting in the PARP protein binding to damaged DNA becoming trapped within the DNA, preventing other DNA repair proteins from binding as well, ultimately leading to cell death. Currently, numerous PARP inhibitors, such as olaparib, rucaparib, and niraparib, have been successfully developed, but their ability to be used in combination with chemotherapy agents is limited due to adverse reactions. This may be related to the lack of selectivity for the PARP family in commercially available PARP inhibitors, and these side effects include gastrointestinal toxicity due to tankirase inhibition and hematological toxicity due to PARP-2 inhibition. Therefore, developing highly selective PARP-1 inhibitors and mitigating the toxic side effects associated with non-selective PARP inhibitors is of clinical importance. [Overview of the project] [Problems that the invention aims to solve]

[0005] The object of the present invention is to provide PARP-1 inhibitory compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, and their pharmaceutical uses. The compounds of the present invention have advantages such as high activity, low toxic side effects, high safety, high selectivity, good pharmacokinetics, and high bioavailability. [Means for solving the problem]

[0006] The present invention provides compounds of the following formulas I and I-1, or their stereoisomers or pharmaceutically acceptable salts, [ka] Here, A is [ka] Selected from, in some embodiments, ring A is, [ka] Selected from, in some embodiments, ring A is, [ka] Selected from, in some embodiments, ring A is, [ka] Selected from, in some embodiments, ring A is, [ka] Selected from, in some embodiments, ring A is, [ka] Selected from, in some embodiments, ring A is, [ka] Selected from, [ka] The end is connected to the left side, [ka] The end is connected to the right side, R1 is C 1-4 Alkyl alkyl group, C 3-6 It is a cycloalkyl group, and the alkyl group and cycloalkyl group are optionally substituted with 1 to 3 groups selected from D, halogen, OH, CN, and NH2, and in some embodiments, R1 is C 1-2 Alkyl alkyl group, C 3-6 It is a cycloalkyl group, and the alkyl group and cycloalkyl group are optionally substituted with 1 to 3 groups selected from D, halogen, OH, CN, and NH2, and in some embodiments, R1 is C 1-2 Alkyl alkyl group, C 3-4It is a cycloalkyl group, and the alkyl group and cycloalkyl group are optionally substituted with 1 to 3 groups selected from D, F, Cl, OH, CN, and NH2. In some embodiments, R1 is a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, or a cyclobutyl group, and the methyl group, ethyl group, isopropyl group, cyclopropyl group, and cyclobutyl group are optionally substituted with 1, 2, or 3 groups selected from D, F, Cl, OH, CN, and NH2. In some embodiments, R1 is a methyl group, an ethyl group, a cyclopropyl group, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, or -CF2CF3. In some embodiments, R1 is selected from a methyl group and an ethyl group, and the methyl group and ethyl group are optionally substituted with 1, 2, or 3 groups selected from D, F, and Cl. In some embodiments, R1 is selected from -CH3, -CH2CH3, and -CHF2. R2 is -CONHR A or -NHCOR A In some embodiments, R2 is -CONHR A In some embodiments, R2 is -NHCOR A and Each R A is independently a C 3-6 cycloalkyl group or a 5- to 6-membered heteroaryl group substituted with 1 to 3 halogens. The heteroaryl group contains 1 to 3 heteroatoms selected from N, S, and O. The heteroaryl group and cycloalkyl group are optionally substituted with 1 to 3 groups selected from D, =O, C 1-4 alkyl group, C 1-4 alkoxy group, -NHC 1-4 alkyl group, -CONHC 1-4 alkyl group, -NHCOC 1-4 alkyl group, OH, CN, NH2, and C 1-4 haloalkyl group, and the cycloalkyl group has at least one =CH2, =CF2, =CHF, =CH(C1-6 Alkyl), =C(C 1-6 Substituted with alkyl)2, and in some embodiments, each R A Independently, C 3-6 A cycloalkyl group, a 5-6 membered heteroaryl group substituted with 1-3 halogens, wherein the heteroaryl group contains 1-3 heteroatoms selected from N, S, and O, and the heteroaryl group is optionally D, =O, C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHCOC 1-4 Alkyl groups, OH, CN, NH2 and C 1-4 The cycloalkyl group is substituted with 1 to 3 groups selected from haloalkyl groups, wherein the cycloalkyl group has at least one =CH2, =CF2, =CHF, =CH(C 1-6 Alkyl), =C(C 1-6 Substituted with alkyl)2, and in some embodiments, each R A These are independently 5-6 membered heteroaryl groups substituted with 1-3 halogens, C 3-6 It is a cycloalkyl group, and the heteroaryl group contains 1 to 3 heteroatoms selected from N, S, and O, and the heteroaryl group is optionally D, =O, C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHCOC 1-4 Alkyl groups, OH, CN, NH2 and C 1-4 The cycloalkyl group is substituted with 1 to 3 groups selected from haloalkyl groups, and the cycloalkyl group is substituted with at least one =CH2 or =CF2 group, and in some embodiments, each R A These are independently 5-6 membered heteroaryl groups substituted with 1-3 halogens, C 3-6 It is a cycloalkyl group, and the heteroaryl group contains 1 to 3 heteroatoms selected from N, S, and O, and the heteroaryl group is optionally D, =O, C 1-4 Alkyl groups, OH, CN, NH2 and C 1-2Substituted with 1 to 3 groups selected from haloalkyl groups, wherein the cycloalkyl group is one =CH2, =CF2, =CHF, =CH(C 1-2 Alkyl), =C(C 1-2 Substituted with alkyl)2, and in some embodiments, each R A These are independently 5-membered heteroaryl groups substituted with 1, 2, or 3 F or Cl atoms. [ka] The heteroaryl group contains one, two, or three heteroatoms selected from N, S, and O, and the heteroaryl group is optionally substituted with one, two, or three groups selected from D, =O, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH3, -CH(CH3)CH2CH3, OH, CN, and NH2, and in some embodiments, each R A These are independently 5-6 membered heteroaryl groups substituted with 1-3 halogens. [ka] The heteroaryl group contains 1 to 3 heteroatoms selected from N, S, and O, and the heteroaryl group can optionally contain D, =O, and C. 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHCOC 1-4 Alkyl groups, OH, CN, NH2 and C 1-4 Substituted with 1 to 3 groups selected from haloalkyl groups, in some embodiments, each R A The group is independently a 5-6 membered heteroaryl group substituted with 1-3 halogens, the heteroaryl group containing 1-3 heteroatoms selected from N, S, and O, and the heteroaryl group is optionally D, =O, C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHCOC 1-4Alkyl groups, OH, CN, NH2 and C 1-4 Substituted with 1 to 3 groups selected from haloalkyl groups, in some embodiments, each R A This is independently a five-membered heteroaryl group substituted with 1 to 3 halogens, wherein the heteroaryl group contains 1 to 3 heteroatoms selected from N, S, and O, and the heteroaryl group is optionally D, =O, C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHCOC 1-4 Alkyl groups, OH, CN, NH2 and C 1-4 Substituted with 1 to 3 groups selected from haloalkyl groups, in some embodiments, each R A This is independently a five-membered heteroaryl group substituted with one, two, or three halogens, wherein the heteroaryl group contains one, two, or three heteroatoms selected from N, S, and O, and the heteroaryl group is optionally D, =O, C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHCOC 1-4 Alkyl groups, OH, CN, NH2 and C 1-4 Substituted with one, two, or three groups selected from haloalkyl groups, in some embodiments, each R A In some embodiments, each R is independently a five-membered heteroaryl group substituted with 1, 2, or 3 F or Cl atoms, wherein the heteroaryl group contains 1, 2, or 3 heteroatoms selected from N, S, and O, and the heteroaryl group is optionally substituted with 1, 2, or 3 groups selected from D, =O, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH3, -CH(CH3)CH2CH3, OH, CN, and NH2, respectively. AA is independently a five-membered heteroaryl group substituted with 1, 2, or 3 F atoms, wherein the heteroaryl group contains 1, 2, or 3 heteroatoms selected from N, S, and O, and the heteroaryl group is optionally substituted with 1, 2, or 3 groups selected from D, =O, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH3, -CH(CH3)CH2CH3, OH, CN, and NH2, wherein in some embodiments, each R A This is independently a 5-membered heteroaryl group substituted with one F, the heteroaryl group containing one, two, or three heteroatoms selected from N, S, and O, and the heteroaryl group is optionally substituted with one, two, or three groups selected from D, =O, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH3, -CH(CH3)CH2CH3, OH, CN, and NH2. In some embodiments, R A Each of them operates independently. [ka] Selected from, m is 0 or 1, and in some embodiments, m is 0, and in some embodiments, m is 1. Here, the compound is [ka] isn't it.

[0007] Specifically, the first technical proposal of the present invention provides a compound represented by formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof. [ka] Here, Ring A is [ka] Selected from, R1 is C 1-4 Alkyl alkyl group, C 3-6It is a cycloalkyl group, and the alkyl group and cycloalkyl group are optionally substituted with 1 to 3 groups selected from D, halogen, OH, CN, and NH2. R2 is -CONHR A , -NHCOR A And, Each R A The group is independently a 5-6 membered heteroaryl group substituted with 1-3 halogens, the heteroaryl group containing 1-3 heteroatoms selected from N, S, and O, and the heteroaryl group is optionally D, =O, C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHCOC 1-4 Alkyl groups, OH, CN, NH2 and C 1-4 Substituted with 1 to 3 groups selected from haloalkyl groups, Here, the compound is [ka] isn't it.

[0008] A second technical proposal of the present invention provides the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt, Here, Ring A is [ka] Selected from, R1 is a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, or a cyclobutyl group, and the methyl group, ethyl group, isopropyl group, cyclopropyl group, or cyclobutyl group is optionally substituted with one, two, or three groups selected from D, F, Cl, OH, CN, or NH2. Each R Ais, independently, a 5-membered heteroaryl group substituted with 1, 2 or 3 F or Cl, said heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, S, O, and said heteroaryl group being optionally substituted with 1, 2 or 3 groups selected from D, =O, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH3, -CH(CH3)CH2CH3, OH, CN, NH2.

[0009] In the third technical solution of the present invention, there is provided a compound represented by formula I-1, its stereoisomer or a pharmaceutically acceptable salt.

Chemical formula

Chemical formula

[0010] A fourth technical proposal of the present invention provides the compound of formula (I-1), its stereoisomer, or a pharmaceutically acceptable salt, Here, ring A is, [ka] Selected from, R1 is C 1-2 Alkyl alkyl group, C 3-4 It is a cycloalkyl group, and the alkyl group, cycloalkyl group is optionally substituted with 1 to 3 groups selected from D, F, Cl, OH, CN, NH2, and in some specific embodiments, R1 is a methyl group, ethyl group, isopropyl group, cyclopropyl group, cyclobutyl group, and the methyl group, ethyl group, isopropyl group, cyclopropyl group, cyclobutyl group is optionally substituted with 1, 2, or 3 groups selected from D, F, Cl, OH, CN, NH2, Each R AThese are independently 5-6 membered heteroaryl groups substituted with 1-3 halogens, C 3-6 It is a cycloalkyl group, and the heteroaryl group contains 1 to 3 heteroatoms selected from N, S, and O, and the heteroaryl group is optionally D, =O, C 1-4 Alkyl groups, OH, CN, NH2 and C 1-2 Substituted with 1 to 3 groups selected from haloalkyl groups, wherein the cycloalkyl group is one =CH2, =CF2, =CHF, =CH(C 1-2 Alkyl), =C(C 1-2 Substituted with alkyl)2, in some specific embodiments, each R A These are independently 5-membered heteroaryl groups substituted with 1, 2, or 3 F or Cl atoms. [ka] The heteroaryl group contains one, two, or three heteroatoms selected from N, S, and O, and the heteroaryl group is optionally substituted with one, two, or three groups selected from D, =O, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH3, -CH(CH3)CH2CH3, OH, CN, and NH2, and in some specific embodiments, each R A These are independently 5-membered heteroaryl groups substituted with 1, 2, or 3 F or Cl atoms. [ka] The heteroaryl group contains one, two, or three heteroatoms selected from N, S, and O, and the heteroaryl group is optionally substituted with one, two, or three groups selected from D, =O, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH3, -CH(CH3)CH2CH3, OH, CN, and NH2.

[0011] A fifth technical proposal of the present invention provides the compounds of formula (I), formula (I-1), stereoisomers thereof, or pharmaceutically acceptable salts. Here, Ring A is [ka] Selected from, [ka] The end is connected to the left side, [ka] The end is connected to the right side, R1 is selected from -CH3, -CH2CH3, and -CHF2. R A Each of them operates independently. [ka] Selected from.

[0012] The sixth technical proposal of the present invention provides the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt. Ring A is [ka] Selected from, [ka] The end is connected to the left side, [ka] The end is connected to the right side, R1 is selected from -CH3, -CH2CH3, and -CHF2. R A Each of them operates independently. [ka] Selected from.

[0013] The seventh technical proposal of the present invention provides the compound of formula I-1, its stereoisomer, or a pharmaceutically acceptable salt. Ring A is [ka] Selected from, [ka] The end is connected to the left side, [ka] The end is connected to the right side, R1 is selected from -CH3, -CH2CH3, and -CHF2. m is selected from 1, R A Each of them operates independently. [ka] Selected from.

[0014] A compound described in the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is [ka] It is selected from one of these structures.

[0015] The present invention further provides a pharmaceutical composition comprising a compound described in any one of the aforementioned technical proposals, its stereoisomer or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient. The present invention further provides an application, namely, the application of a compound described in any one of the aforementioned technical proposals, its stereoisomer or pharmaceutically acceptable salt, or the aforementioned pharmaceutical composition in the manufacture of drugs for treating / preventing PARP1-mediated diseases.

[0016] The PARP1-mediated disease described in the present invention is selected from breast cancer, uterine cancer, cervical cancer, ovarian cancer, and prostate cancer.

[0017] The present invention further provides a method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the aforementioned compound, its stereoisomer or pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient and / or carrier, the therapeutically effective amount being preferably 1 to 1440 mg, and the disease being preferably breast cancer, uterine cancer, cervical cancer, ovarian cancer, and prostate cancer.

[0018] The present invention further provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound described in the present invention or a stereoisomer thereof, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In some embodiments, the mammal described in the present invention includes a human.

[0019] The “effective dose” or “therapeutic effective dose” as described in this application comprises administering a sufficient amount of the compound disclosed herein that alleviates, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms or causes of the disease, or any other desirable change in the biological system. For example, the “effective dose” for therapeutic use is the amount of the compound disclosed herein that is necessary to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective doses include 1-1440mg, 1-1400mg, 1-1300mg, 1-1200mg, 1-1000mg, 1-900mg, 1-800mg, 1-700mg, 1-600mg, 1-500mg, 1-400mg, 1-300mg, 1-250mg, 1-200mg, 1-150mg, 1-125mg, 1-100mg, 1-80mg, 1-60mg, 1-50mg, 1-40mg, 1-25mg, 1-20mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 5-500mg. 5~400mg, 5~300mg, 5~250mg, 5~200mg, 5~150mg, 5~125mg, 5~100mg, 5~90mg, 5~70mg, 5~80mg, 5~60mg, 5~50mg, 5~40mg, 5~30mg, 5~25mg, 5~20mg, 10 ~1000mg, 10~900mg, 10~800mg, 10~700mg, 10~600mg, 10~500mg, 10~450mg, 10~400mg, 10~300mg, 10~250mg, 10~200mg, 10~150mg, 10~125mg, 10~10 0mg, 10~90mg, 10~80mg, 10~70mg, 10~60mg, 10~50mg, 10~40mg, 10~30mg, 10~20mg, 20~1000mg, 20~900mg, 20~800mg, 20~700mg, 20~600mg, 20~500 mg, 20~400mg, 20~350mg, 20~300mg, 20~250mg, 20~200mg, 20~150mg, 20~125mg, 20~100mg, 20~90mg, 20~80mg, 20~70mg, 20~60mg, 20~50mg, 20~40m This includes, but is not limited to, g, 20-30 mg, 50-1000 mg, 50-900 mg, 50-800 mg, 50-700 mg, 50-600 mg, 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 50-150 mg, 50-125 mg, 50-100 mg, 100-1000 mg, 100-900 mg, 100-800 mg, 100-700 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-250 mg, and 100-200 mg.

[0020] The present invention relates to a pharmaceutical composition or pharmaceutical preparation, wherein the pharmaceutical composition or pharmaceutical preparation comprises a therapeutically effective amount of the compound described in the present invention or its stereoisomer or pharmaceutically acceptable salt, and excipients and / or carriers. The pharmaceutical composition may be in the form of a unit formulation (the amount of the active ingredient in the unit formulation is also called the "formulation specification"). In some embodiments, the pharmaceutical composition is available in doses of 1-1440 mg, 5-1000 mg, 10-800 mg, 20-600 mg, 25-500 mg, 40-200 mg, 50-100 mg, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, and 200 mg. This includes, but is not limited to, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, and 1440 mg of the compound of the present invention or its stereoisomers, solvates, deuterides, and pharmaceutically acceptable salts.

[0021] A method for treating a disease of a mammal, comprising administering to a subject a therapeutically effective amount of the compound of the present invention, its stereoisomer or a pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient and / or carrier, wherein the therapeutically effective amount is preferably 1 to 1440 mg, and the disease is preferably breast cancer, uterine cancer, cervical cancer, ovarian cancer, and prostate cancer.

[0022] A method for treating a disease of a mammal, comprising administering to a subject a daily dose of 1 to 1440 mg / day of the compound of the present invention, which is a drug, its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and / or carrier, wherein the daily dose may be a single dose or a divided dose, and in some embodiments, the daily dose is 10 to 1440 mg / day, 20 to 1440 mg / day, 25 to 1440 mg / day, 50 to 1440 mg / day, 75 to 1440 mg / day, 100 to 1440 mg / day, 200 to 1440 mg / day, 10 to 1000 mg / day, 20 to 1000 mg / day, 25 to 1000 mg / day, 50 to 1000 mg / day, 75 to 1000 mg / day, This includes, but is not limited to, 100-1000 mg / day, 200-1000 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, and 200-400 mg / day. In some embodiments, the daily dose is 1 This includes, but is not limited to, mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day, 1400 mg / day, and 1440 mg / day.

[0023] The present invention relates to a kit, which may comprise a single-dose or multi-dose composition, comprising the compound of the present invention, its stereoisomer, or a pharmaceutically acceptable salt, wherein the amount of the compound of the present invention, its stereoisomer, or a pharmaceutically acceptable salt is the same as the amount in the pharmaceutical composition.

[0024] In the present invention, the amount of the compound of the present invention, its stereoisomer, or a pharmaceutically acceptable salt is, in each case, calculated in terms of the form of the free base.

[0025] "Formulation specifications" refer to the weight of the active ingredient contained in one unit formulation, one tablet formulation, or any other unit formulation.

[0026] Synthesis pathway Methods for producing PARP-1 inhibitors are described in patent documents such as WO 2021013735A1, and those skilled in the art can produce the compounds of the present invention by combining said documents with known organic synthesis techniques, the starting materials being commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are obtained from legitimate commercial sources, including companies such as Taitan Technology, An Naiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, Wuxing Kangde and Bailingwei Technology.

[0027] Reference books and specialized texts in this field provide detailed descriptions of the synthesis of reactants that can be used to produce the compounds described herein, or, for reference, texts explaining such production methods. Specific and similar reactants can be selectively identified by indexes of known chemicals compiled by the American Chemical Society's chemical information retrieval service, and these indexes are available in many public and university libraries and online. For known chemicals not available in catalogs, production may be optionally commissioned to custom chemical synthesizers, many of which are standard chemical suppliers (e.g., the companies listed above).

[0028] term Unless otherwise specified in this invention, the terms used in this invention have the following meanings.

[0029] The carbon, hydrogen, oxygen, sulfur, nitrogen, or halogens in the groups and compounds described in the present invention all include their isotopes, that is, the carbon, hydrogen, oxygen, sulfur, nitrogen, or halogens in the groups and compounds described in the present invention may be optionally further substituted with one or more corresponding isotopes, where the isotope of carbon is, 12 C and, 13 C and, 14 It contains C, and its isotopes include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called tritium), and its isotopes include 16 O and, 17 O and,18 It contains O, and the sulfur isotopes are 32 S and, 33 S and, 34 S and, 36 It contains S, and the isotopes of nitrogen are 14 N and 15 It contains N, and the isotopes of fluorine are 19 It is F, and the isotope of chlorine is, 35 Cl and 37 It contains Cl, and the isotope of bromine is, 79 Br and 81 Includes Br.

[0030] In this specification, "halogen" refers to F, Cl, Br, I, or their isotopes.

[0031] "Halogenation" or "halogen substitution" refers to substitution with one or more elements selected from F, Cl, Br, I, or their isotopes, where the upper limit of the number of halogen substituents is equal to the sum of the substitutable hydrogens of the group being substituted, and unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit, and if the number of halogen substituents is greater than 1, they may be substituted with the same or different halogens. Typically, this includes cases of 1 to 5 halogen substitutions, 1 to 3 halogen substitutions, 1 to 2 halogen substitutions, and 1 halogen substitution.

[0032] "Deuterium" refers to the isotope of hydrogen (H), and has the same meaning as "D".

[0033] "Deuterated" or "deuterated" refers to a case in which a hydrogen atom in a group such as an alkyl group, cycloalkyl group, alkylene group, aryl group, heteroaryl group, mercapto group, heterocycloalkyl group, alkenyl group, or alkynyl group is substituted with at least one deuterium atom. The upper limit of the number of deuterated groups is equal to the sum of the number of substituted hydrogens in the group being substituted. Unless otherwise specified, the number of deuterated groups is any integer between 1 and the upper limit, for example, 1 to 20 deuterium substitutions, 1 to 10 deuterium substitutions, 1 to 6 deuterium substitutions, 1 to 3 deuterium substitutions, 1 to 2 deuterium substitutions, or 1 deuterium substitution.

[0034] "C x-y A "group" refers to a group containing x to y carbon atoms, for example, "C 1-6 An "alkyl group" refers to an alkyl group containing 1 to 6 carbon atoms, and "C0" usually refers to a bond.

[0035] "Alkyl group" refers to a monovalent linear or branched saturated aliphatic hydrocarbon group. Typically, it is an alkyl group having 1 to 20 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, neobutyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group, etc., and the alkyl group may be further substituted with substituents.

[0036] "Alkylene group" refers to a divalent linear and branched saturated alkyl group. Examples of alkylene groups include, but are not limited to, methylene and ethylene groups.

[0037] A "halogenated alkyl group" refers to a group in which one or more hydrogen atoms in an alkyl group are substituted with one or more halogen atoms (e.g., fluorine, chlorine, bromine, iodine, or their isotopes), and the upper limit of the number of halogen substituents is equal to the sum of the substitutable hydrogen atoms in the alkyl group, and unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. Typically, an alkyl group is substituted with 1 to 5 halogens, or 1 to 3 halogens, or 1 halogen, and when the number of halogen substituents is greater than 1, they may be substituted with the same or different halogens, and specific examples include, but are not limited to, -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, etc.

[0038] "Alkoxy group" or "alkyloxy group" refers to an -O-alkyl group. For example, -OC 1-8 alkyl group, -OC 1-6 alkyl group, -OC 1-4 Alkyl alkyl group or -OC 1-2 It is an alkyl group. Specific non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropoxy, and cyclobutoxy groups, and the alkoxy group may be optionally substituted with a substituent.

[0039] "Halogenated alkoxy group" refers to -O-halogenated alkyl group. For example, -O-haloC 1-8 Alkyl, -O-halo C 1-6 Alkyl, -O-halo C 1-4 Alkyl or -O-haloC 1-2The alkyl group is such that the upper limit of the number of halogen substituents is equal to the sum of the substituted hydrogens of the group being substituted, and unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit, preferably 1 to 5 halogen substitutions, 1 to 3 halogen substitutions, 1 to 2 halogen substitutions, or 1 halogen substitution, and when the number of halogen substituents is greater than 1, they may be substituted with the same or different halogens, and non-restrictive examples include monofluoromethoxy groups, difluoromethoxy groups, trifluoromethoxy groups, difluoroethyloxy groups, etc.

[0040] An "alkenyl group" refers to a straight-chain or branched-chain hydrocarbon group containing at least one carbon-carbon double bond (C=C), and typically contains 2 to 18 carbon atoms, for example, 2 to 8 carbon atoms, for example, 2 to 6 carbon atoms, and for example, 2 to 4 carbon atoms. Examples include vinyl group, allyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-methyl-1-butenyl group, 2-methyl-1-butenyl group, and 2-methyl-3-butenyl group. The alkenyl groups include, but are not limited to, 1-hexenyl groups, 2-hexenyl groups, 3-hexenyl groups, 4-hexenyl groups, 5-hexenyl groups, 1-methyl-1-pentenyl groups, 2-methyl-1-pentenyl groups, 1-heptenyl groups, 2-heptenyl groups, 3-heptenyl groups, 4-heptenyl groups, 1-octenyl groups, 3-octenyl groups, 1-nonenyl groups, 3-nonenyl groups, 1-decenyl groups, 4-decenyl groups, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, and the alkenyl groups may be further optionally substituted with substituents.

[0041] An "alkynyl group" refers to a linear or branched hydrocarbon group containing at least one carbon-carbon triple bond (C≡C), and typically contains 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, and further containing 2 to 4 carbon atoms. Examples include ethynyl group, 1-propynyl group, 2-propynyl group, butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 4-pentyl group, 3-pentyl group, 1-methyl-2-butynyl group, 2-hexynyl group, 3-hexynyl group, 2-heptynyl group, 3-heptynyl group, 4-heptynyl group, 3-octinyl group, 3-noninyl group, and 4-decynyl group, but is not limited to these. The alkynyl group may be optionally substituted with substituents.

[0042] A "cycloalkyl group" refers to a saturated or partially unsaturated, non-aromatic carbocyclic hydrocarbon group that does not contain a cycloheteratoon. A cycloalkyl group may be monocyclic, dicyclic, or polycyclic, and the dicyclic or polycyclic group may be in the form of parallel rings, spirocyclic rings, bridging rings, or combinations thereof. The dicyclic or polycyclic group may contain one or more aromatic rings, but the entire ring system is not aromatic, and the linking site is located on a non-aromatic ring. Typically, a cycloalkyl group contains 3 to 20 carbon atoms, further 3 to 8 carbon atoms, and even further 3 to 6 carbon atoms. If it is a monocyclic cycloalkyl group, it contains 3 to 15 carbon atoms, or 3 to 10 carbon atoms, or 3 to 8 carbon atoms, or 3 to 6 carbon atoms. If it is a bicyclic or polycyclic cycloalkyl group, it contains 5 to 12 carbon atoms, or 5 to 11 carbon atoms, or 6 to 10 carbon atoms. Non-limiting examples include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, butenyl group, cyclopentenyl group, cyclohexenyl group. [ka] The cycloalkyl groups may be optionally substituted with substituents.

[0043] An "aryl group" refers to an aromatic, heteroatom-free carbon ring, and includes monocyclic and fused aryl groups. Typically, it contains 6 to 14 carbon atoms, and further contains 6 to 10 carbon atoms. Non-limiting examples include phenyl, naphthyl, anthryl, and phenanthryl groups, and the aryl group may be optionally substituted with substituents.

[0044] Unless otherwise specified, a "hetero-aromatic ring" or "heteroaryl group" refers to an aromatic ring containing N, O, or S and 1 to 4 heteroatoms selected from their oxidation states, which may be monocyclic, dicyclic, or polycyclic. The dicyclic or polycyclic ring may be a bridging ring, a parallel ring, a spiro-ring, or a combination thereof. In the case of a dicyclic or polycyclic ring, it may be a condensation of a heteroaryl group and an aryl group, or a condensation of two heteroaryl groups, where both the heteroaryl group and the aryl group can be linking sites. Unrestricted examples include furyl group, thienyl group, pyrrolyl group, oxazolyl group, thiazolyl group, imidazolyl group, pyrazolyl group, pyridyl group, pyrimidinyl group, pyridadinyl group, pyrazinyl group, indolyl group, prinyl group, [ka] The heteroaryl group may be optionally substituted with a substituent.

[0045] A "heterocyclo" or "heterocyclo group" refers to a saturated or unsaturated aromatic or non-aromatic ring containing 1 to 4 heteroatoms selected from N, O, or S and their oxidation states, including heteroaryl groups and heterocycloalkyl groups. Heterocyclos include monocyclic heterocyclos, bridging bicyclic heterocyclos, condensed bicyclic heterocyclos, spiro-dicyclic heterocyclos, or combinations thereof. They are typically 3- to 12-membered heterocyclos, 5- to 12-membered heterocyclos, or 5- to 7-membered heterocyclos. The heterocyclo group may be linked to a heteroatom or carbon atom, and non-limiting examples include oxyranyl group, azacyclopropyl group, oxetanyl group, azetidinyl group, 1,3-dioxolanyl group, 1,4-dioxolanyl group, 1,3-dioxanyl group, piperazinyl group, azacycloheptyl group, pyridyl group, furyl group, thienyl group, pyranyl group, N-alkylpyrrolyl group, pyrimidinyl group, pyrazyl group, pyrazolyl group, pyridadinyl group, imidazolyl group, piperidinyl group, piperidyl group, morpholinyl group, thiomorpholinyl group, 1,3-dithianyl group, dihy Drofuryl group, dihydropyranyl group, dithiolanyl group, tetrahydrofuranyl group, tetrahydropyrrolyl group, tetrahydroimidazolyl group, oxazolyl group, dihydrooxazolyl group, tetrahydrooxazolyl group, tetrahydrothiazolyl group, tetrahydropyranyl group, benzimidazolyl group, benzopyridyl group, pyrrolopyridyl group, benzodihydrofuryl group, azabicyclo[3.2.1]octyl group, azabicyclo[5.2.0]nonyl group, oxatricyclo[5.3.1.1]dodecyl group, azaadamantyl group and oxapiro[3.3]heptyl group, [ka] The heterocyclo group may be optionally substituted with substituents.

[0046] Unless otherwise specified, "substitution" or "substituent" means that any substitution occurs at a chemically acceptable position and that the number of substituents satisfies the laws of chemical bonding. An example substituent is C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6Alkynyl group, C 3-8 Heteroalkyl groups, C 5-12 Aryl group, 5-12 membered heteroaryl group, hydroxyl group, C 1-6 Alkoxy group, C 5-12 Aryloxy group, thiol group, C 1-6 Alkylthio group, cyano group, halogen, C 1-6 Alkylthiocarbonyl group, C 1-6 Alkylcarbamoyl group, N-carbamoyl group, nitro group, silyl group, sulfinyl group, sulfoxide, halo C 1-6 Alkyl, halo C 1-6 Alkoxy group, amino group, phosphonic acid, -CO2(C 1-6 Alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl), -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2,-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 Alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 Alkyl)2,-HC(=O)NH(C 1-6 Alkyl), -NHC(=O)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2,-SO2NH(C 1-6 Alkyl), -SO2NH2, -SO2C 1-6 This includes, but is not limited to, alkyl groups.

[0047] "Optionally" or "optionally" means that the event or environment described thereafter may occur, but does not necessarily occur, and the description includes both cases where the event or environment occurs and cases where it does not. For example, "an alkyl group that is optionally substituted with F" means that the alkyl group may be substituted with F, but does not necessarily have to be substituted with F, and indicates that this includes cases where the alkyl group is substituted with F and cases where the alkyl group is not substituted with F.

[0048] "Pharmacologically acceptable salt" refers to a salt obtained by a reaction in which the compound of the present invention maintains the biological efficacy and properties of the free acid or free base, and by a reaction in which the free acid is reacted with a non-toxic inorganic base or organic base, or with a non-toxic inorganic acid or organic acid.

[0049] "Pharmaceutical composition" means one or more of the compounds herein or their stereoisomers, solvates, pharmaceutically acceptable salts or cocrystals, or mixtures with other components, wherein the other components include physiologically / pharmaceutically acceptable carriers and / or excipients.

[0050] A "carrier" refers to a system that does not cause significant irritation to the living body, does not cause the loss of the biological activity and properties of the administered compound, alters the method of drug administration to the human body and its distribution within the body, controls the rate of drug release, and delivers the drug to the target organ. Non-limited examples include microcapsules and microspheres, nanoparticles, and liposomes.

[0051] "Excipients" are substances that are not therapeutic agents themselves, but are added to pharmaceutical compositions as diluents, excipients, adhesives and / or mediators to improve their treatment and preservation properties, or to allow or facilitate the formation of a dosage form for administration. As is known to those skilled in the art, medicinal excipients can provide a variety of functions and may be described as wetting agents, buffers, suspension aids, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents and sweeteners. Examples of medicinal excipients include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropylmethylcellulose, hydroxypropylcellulose, microcrystalline cellulose and cross-linked carboxymethylcellulose (e.g., sodium cross-linked carboxymethylcellulose); (4) tragacanth gum powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, goa oil, olive oil, corn oil, and (10) Glycols, such as propylene glycol, (11) Polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol, (12) Esters, such as ethyl oleate and ethyl laurate, (13) Agar, (14) Buffers, such as magnesium hydroxide and aluminum hydroxide, (15) Alginic acid, (16) Water for endotoxin testing, (17) Isotonic saline solution, (18) Ringer's solution; (19) Ethanol, (20) pH buffer solution, (21) Polyesters, polycarbonates, and / or polyanhydrides, and (22) Other non-toxic and suitable substances used in pharmaceutical formulations.

[0052] The term "isomer" includes "stereoisomers" and "tautomers." "Stereoisomers" refer to isomers that arise from differences in stereochemistry, where atoms or groups of atoms in a molecule are linked in the same order. Stereoiomers include cis-trans isomers, optical isomers, and conformational isomers. "Tautomers" are compounds that can interconvert through a reversible chemical reaction called tautomerization, typically resulting from the simultaneous movement of hydrogen atoms and π bonds (double or triple bonds), leading to the conversion of one functional group to the other. Examples include the following pairs of compounds: aldehydes / ketones / enols and imines / enamines.

[0053] A "solvate" refers to a substance formed when the compound or salt thereof of the present invention forms intermolecular non-covalent bonds with a stoichiometric or non-stoichiometric solvent. When the solvent is water, it becomes a hydrate.

[0054] A "cocrystal" refers to a crystalline body formed when an active pharmaceutical ingredient (API) and a cocrystal compound (CCF) are bonded together by hydrogen bonds or other non-covalent bonds, where the pure states of the API and CCF are both solids at room temperature, and a fixed stoichiometric ratio exists between each component. Cocrystals are multi-component crystalline bodies, including not only binary cocrystals formed between two neutral solids, but also multi-component cocrystals formed between a neutral solid and a salt or solvate. [Modes for carrying out the invention]

[0055] The technical aspects of the present invention will be described in detail below, along with examples, but the scope of protection of the present invention includes, but is not limited to, those examples. The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift (δ) is given in units of 10⁻⁶ (ppm). NMR measurements are performed using nuclear magnetometers (Bruker Avance III 400 and Bruker Avance 300), with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS). MS measurements were performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI)). HPLC measurements were performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM). For thin-layer chromatography, silica gel plates of Yantai Huanghai HSGF254 or Qingdao GF254 were used. The size of the silica gel plates used for thin-layer chromatography (TLC) was 0.15 mm to 0.20 mm, and the size used for the separation and purification of products by chromatography was 0.4 mm to 0.5 mm. Column chromatography typically uses silica gel of 200-300 mesh size from Yantai Huanghai as the support material.

[0056] Explanation of abbreviations: DIPEA: N,N-diisopropylethylamine HATU:2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate DMF: N,N-dimethylcarboxamide DCM: Dichloromethane Example 1 [ka]

[0057] Step 1: Compound 1A (synthesized according to patent US2022009901A1) (3.39 g, 10 mmol) was dissolved in tetrahydrofuran (100 mL) and water (10 mL), lithium hydroxide (400 mg, 10 mmol) was added, and the mixture was stirred at room temperature for 2 hours to allow the reaction to proceed. The solvent was removed by distillation under reduced pressure to obtain a white powdery solid 1B (3.38 g, 100%), which was used directly in the next step without purification. LC-MS (ESI): m / z = 324.2 [MH] - .

[0058] Step 2: Compound 1B (324 mg, 1 mmol) and Compound 1C (115 mg, 1 mmol, synthesized according to patent WO2022 / 212538Al) were dissolved in DMF (5 mL), HATU (380 mg, 1 mmol) was added, and the reaction was allowed to proceed at room temperature for 16 hours. The reaction system was poured into water (50 mL), and a large amount of solid product precipitated. This was filtered by suction and dried to obtain crude compound 1D (450 mg). LC-MS (ESI): m / z = 421.4 [MH] -

[0059] Step 3: 450 mg of the crude compound 1D was dissolved in a mixed solvent of DCM / TFA = 10 / 1 and stirred at room temperature for 16 hours. The reaction system was concentrated to obtain trifluoroacetate (360 mg) of the crude compound 1E. LC-MS (ESI): m / z = 323.4[M+H] +

[0060] Step 4: The trifluoroacetate salt of the crude product of compound 1E (180 mg) and compound 1F (143 mg, 0.5 mmol, synthesized according to patent WO2021 / 260092Al) were dissolved in acetonitrile (10 mL), DIPEA (1 mL) was added, and the reaction system was heated to 65°C and reacted for 16 hours. The reaction system was concentrated and then separated by column chromatography (petroleum ether:ethyl acetate (v:v) = 1:2) to obtain compound 1 (77 mg, 29%).

[0061] LC-MS (ESI): m / z = 527.2[M+H] + 1 H NMR (400MHz,DMSO-d6) δ 12.42 (s,1H),9.82 (s,1H),7.93 - 7.88 (m,1H),7.86 - 7.82 (m,1H),7.63 - 7.53 (m,2H),7.33 - 7.27 (m,1H),3.71 (s,5H),3.25 - 3.17 (m,4H),2.86 - 2.78 (m,2H),2.65 - 2.57 (m,4H),1.25 - 1.19 (m,3H). Example 2 [ka]

[0062] Step 1: Compound 2A (synthesized according to patent US2022009901A1) (1.3 g, 4.96 mmol) was dissolved in a mixed solution of anhydrous ethanol (26 mL) and water (2 mL). Ammonium chloride solid (3.18 g, 59.47 mmol) and zinc powder (3.24 g, 49.6 mmol) were added sequentially while stirring at room temperature. After all additions were made, the mixture was allowed to react at room temperature for 90 minutes, and the reaction was monitored by LC-MS. After the reaction was complete, saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was filtered over diatomaceous earth. The filter cake was washed with ethyl acetate (100 mL). Ethyl acetate (100 mL) was added to the filtrate to separate the aqueous phase. The organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and filtered to obtain the target compound 2B (1.30 g, yield: 99.21%). LCMS m / z = 265.2[M+H] + 1 H NMR (400MHz,DMSO-d6) δ 10.96 (s,1H),7.16 (s,1H),6.88 - 6.84 (m,1H),6.63 - 6.61 (m,1H),5.01 - 4.98 (m,1H),4.87 - 4.80 (m,1H),4.39 - 4.40 (m,2H).

[0063] Step 2: Compound 2B (1.0 g, 3.79 mmol) was dissolved in tetrahydrofuran (20 mL). While stirring at room temperature, 25% (w / w) aqueous sodium hydroxide solution (5 mL) was added to the reaction mixture. After adding the solution, the mixture was heated and reacted at 50°C for 2 hours. The reaction was monitored by TLC (ethyl acetate:petroleum ether (v:v) = 3:2). After the reaction was complete, ethyl acetate (40 mL) and water (20 mL) were added to the reaction mixture to separate the organic phase. The pH of the aqueous phase was adjusted to 6 with hydrochloric acid (6 mol / L hydrochloric acid), after which a large amount of solid precipitated. The mixture was filtered, and the filtered cake was dried to obtain the target compound 2C (0.7 g, yield: 75.64%). LCMS m / z=245.2[M+H] + 1 H NMR (400MHz,DMSO-d6) δ 12.97 (s,1H),7.73 - 7.70 (m,1H),7.46 - 7.42 (m,1H),7.19 - 6.93 (m,1H),5.52 - 5.49 (m,1H),4.69 - 4.67 (m,2H). 19 F NMR (400MHz,DMSO-d6) δ -122.41(s),-123.46(s).

[0064] Step 3: Compound 2C (488 mg, 2.0 mmol) was dissolved in dichloromethane (20 mL), cooled to 0°C, and triphenylphosphine (1.57 g, 6.0 mmol) and carbon tetrabromide (1.98 g, 6.0 mmol) were added sequentially. After the additions were complete, the ice bath was removed, and the mixture was allowed to rise naturally to room temperature. The mixture was stirred at this temperature for 2 hours, and the reaction was monitored by LC-MS. Immediately after the reaction was complete, the mixture was concentrated and purified by column chromatography (eluent, PE:EA (v:v) = 5:1 to 1:1) to obtain the target compound 2D (530 mg, yield: 86.32%). LC-MS (ESI): m / z=307.2,309.2[M+H] + .

[0065] Step 4: The trifluoroacetate salt of the crude compound 1E (180 mg) and compound 2D (154 mg, 0.5 mmol) were dissolved in acetonitrile (10 mL), DIPEA (1 mL) was added, and the reaction system was heated to 65°C and reacted for 16 hours. The reaction system was concentrated and then separated by column chromatography (petroleum ether:ethyl acetate (v:v) = 1:2) to obtain compound 2 (80 mg, 29%).

[0066] LC-MS (ESI): m / z = 549.2[M+H] + 1H NMR (400MHz,DMSO-d6) δ 13.00 (s,1H),9.82 (s,1H),7.94 - 7.88 (m,1H),7.86 - 7.81 (m,1H),7.75 - 7.69 (m,1H),7.63 - 7.56 (m,1H),7.46 - 7.39 (m,1H),7.22 - 6.91 (m,1H),3.76 (s,2H),3.72 (s,3H),3.25 - 3.17 (m,4H),2.65 - 2.59 (m,4H). Example 3 [ka]

[0067] Step 1: Compound 1B (3.01 g, 9.24 mmol) was added to the reaction flask and dissolved in DMF (30 ml). Then DIPEA (21 ml, 121.6 mmol) and HATU (5.6 g, 14.73 mmol) were added, and the mixture was stirred at room temperature for 20 minutes. Finally, compound 3A (1.4 g, 9.24 mmol) (synthesized according to patent WO2020249664A1) was added, and the mixture was reacted at room temperature for 1 hour. After monitoring the completion of the reaction by TLC, the compound was purified by silica gel column chromatography (PE:EA(v:v)=2:1) ​​to obtain compound 3B (1.1 g, yield: 28.20%). LC-MS(ESI): m / z = 423.7[M+H] + .

[0068] Step 2: Compound 3B (1.1 g, 2.60 mmol) was added to the reaction flask, dissolved in DCM (30 ml), and then trifluoroacetic acid (10 ml) was added. The mixture was reacted at room temperature for 1 hour. After monitoring the completion of the reaction by TLC, the mixture was concentrated under reduced pressure, the residue was washed twice with PE:EA (v:v) = 10:1 (100 ml x 2), and the residue was dried to obtain the crude product, trifluoroacetic acid salt of compound 3C (800 mg), which was then carried out directly to the next step. LC-MS(ESI): m / z = 323.3[M+H] + .

[0069] Step 3: The trifluoroacetate of compound 3C (400 mg, 1.24 mmol), 2D (380 mg, 1.24 mmol), and DIPEA (0.9 ml, 5.0 mmol) were added to the reaction flask, dissolved in ACN (20 ml), and reacted at 70°C for 2 hours. After monitoring the completion of the reaction by TLC, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH(v:v)=10:1) to obtain compound 3 (142 mg, yield: 20.88%).

[0070] 1 H NMR (400MHz,DMSO-d6) δ 9.91 (s,1H),7.91 (d,1H),7.71 (d,1H),7.64 - 7.56 (m,1H),7.48 - 7.46 (m,1H),7.43 - 7.39 (m,1H),7.20 - 6.94 (m,1H),3.76 (s,2H),3.71 (s,3H),3.25 - 3.20 (m,4H),2.65 - 2.61 (m,4H). LC-MS(ESI): m / z = 549.1[M+H] + . Example 4 [ka]

[0071] Step 1: The trifluoroacetate of compound 3C (400 mg, 1.24 mmol), 1F (350 mg, 1.24 mmol), and DIPEA (0.9 ml, 5.0 mmol) were added to a reaction flask, dissolved in acetonitrile (20 ml), and reacted at 70°C for 2 hours. After monitoring the completion of the reaction by TLC, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH(v:v)=10:1) to obtain compound 4 (57 mg, yield: 8.73%).

[0072] 1H NMR (400MHz,DMSO-d6) δ 9.91 (s,1H),7.92 - 7.90 (m,1H),7.64 - 7.51 (m,2H),7.48 - 7.45 (m,1H),7.31 - 7.27 (m,1H),3.74 - 3.68 (m,5H),3.24 - 3.18 (m,4H),2.85 - 2.80 (m,2H),2.64 - 2.58 (m,4H),1.24 -1.20 (m,3H). LC-MS(ESI): m / z = 527.2[M+H] + . Example 5 [ka]

[0073] Step 1: A 100 mL round-bottom flask was taken, and methyl 1-methyl-1H-pyrazole-4-carboxylate (5.2 g, 30 mmol) and AgF2 (17.5 g, 120 mmol) were added sequentially, followed by the addition of acetonitrile (40 mL). The mixture was reacted overnight at room temperature under N2 protection. The mixture was filtered through diatomaceous earth, the filtrate was washed with ethyl acetate, and the filtrate was concentrated. The resulting residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 10:1) to obtain the target compound 5A (3.9 g, 82.3%). LC-MS (ESI): m / z = 159.2[M+H] + .

[0074] Step 2: Compound 5A (1 g, 6.3 mmol) was weighed out and dissolved in tetrahydrofuran (20 mL). 2 M lithium hydroxide solution (4 mL) was added while stirring, and the mixture was reacted overnight at room temperature. When complete conversion of the starting material was detected by LC-MS, the pH was adjusted to 5-6 with 1 M hydrochloric acid, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was recrystallized (petroleum ether:ethyl acetate (v:v) = 4:1) to obtain the target compound 5B (624 mg, 68.1%). LC-MS (ESI): m / z = 143.2 [MH] - .

[0075] Step 3: Weigh out compound 5B (144 mg, 1 mmol), place it in a 25 mL round-bottom flask, add thionyl chloride (5 mL), reflux at 60°C for 2 hours, and concentrate to obtain the target compound 5C (142 mg, crude product), which was used directly in the next step reaction without further purification.

[0076] Step 4: Compound 5D (4 g, 21 mmol) was dissolved in dichloromethane (50 mL), pyridine (2.5 mL, 32 mmol) and acetyl chloride (1.7 mL, 23 mmol) were added at room temperature, and after monitoring for the disappearance of the starting materials by TLC, the system was concentrated and beaten with ethyl acetate / petroleum ether (v:v) = 1 / 15 (160 mL) to obtain compound 5E (4 g, 90%). LC-MS (ESI): m / z = 233.1 [M + H] +

[0077] Step 5: 5E (4g, 17 mmol), N-Boc-piperazine (3.8g, 21 mmol), Pd 2( dba)3 (1.6g, 1.7 mmol), RuPhos (1.4g, 3.2 mmol), and t-BuOK (4.8g, 43 mmol) were added to a round-bottom flask, 100 mL of 1,4-dioxane was added, the mixture was purged with nitrogen gas, and the temperature was raised to reflux, with stirring overnight. After cooling to room temperature, silica gel was added, the mixture was concentrated, and separated by column chromatography (PE:EA(v:v) = 5:1~1:3) to obtain compound 5F (1.1g, 19%). LC-MS (ESI): m / z = 338.1[M+H] +

[0078] Step 6: Compound 5F (800 mg, 2.4 mmol) was dissolved in TFA / DCM = 1:4 (20 mL), and the mixture was reacted at room temperature until the starting material disappeared. The system was then concentrated directly to obtain the trifluoroacetate salt of the crude compound 5G (744 mg), and the process proceeded directly to the next step. LC-MS (ESI): m / z = 238.2[M+H] +

[0079] Step 7: Crude compound 5G (744 mg) and 2D (675 mg, 2.2 mmol) were dissolved in 30 mL of acetonitrile, 6 mL of DIPEA was added, the temperature was raised to 60°C, the reaction was carried out for 2 hours, and after cooling to room temperature, most of the acetonitrile was concentrated to dry, and the compound was separated by reverse-phase column chromatography (water / acetonitrile (v:v) = 1:1) to obtain compound 5H (320 mg, 27%, 2 steps). LC-MS (ESI): m / z = 464.1 [M + H] +

[0080] Step 8: Compound 5H (320 mg, 0.76 mmol) was dissolved in 12 mL of a mixed solvent of concentrated hydrochloric acid / ethanol = 2:1, heated to 70°C, and reacted for 1 hour. After cooling to room temperature, the system was immediately concentrated to dry to obtain the crude hydrochloride product of compound 5I (410 mg), and the process proceeded directly to the next step. LC-MS (ESI): m / z = 422.2[M+H] +

[0081] Step 9: Crude 5I (410 mg) was dispersed in dichloromethane (10 mL), pyridine (2 mL) was added, and while stirring, a dichloromethane solution of 5C (142 mg, crude) (5 mL) was added dropwise, and the reaction was allowed to proceed at room temperature for 2 hours. The mixture was concentrated, and the resulting residue was separated by silica gel column chromatography (dichloromethane:methanol (v:v) = 20:1) to obtain compound 5 (147 mg, 35.3%, 2 steps).

[0082] 1H NMR (400MHz,DMSO-d6) δ 12.99 (s,1H),10.40 (s,1H),8.17 - 8.14 (m,1H),7.96 - 7.91 (m,1H),7.74 - 7.70 (m,1H),7.57 - 7.52 (m,1H),7.45 - 7.40 (m,1H),7.23 - 6.91 (m,1H),3.74 (s,2H),3.72 (s,3H),3.07 - 3.00 (m,4H),2.64 - 2.56 (m,4H). LC-MS (ESI): m / z = 549.2[M+H] + . Example 6 [ka]

[0083] Step 1: Compound 6A (10 g, 61 mmol) was dissolved in THF (200 mL), 5 g (60%) sodium hydride was added at 0°C, and the mixture was stirred for 30 minutes. Iodomethane (6 mL, 96 mmol) was added, the mixture was slowly heated to room temperature, and the reaction was allowed to proceed for 2 hours. Then, saturated ammonium chloride aqueous solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was collected, concentrated, and separated by column chromatography (PE:EA = 20:1 to 5:1) to obtain compound 6B (6.01 g, 56%). 1 H NMR (400MHz, CDCl3) δ 7.23 - 7.21 (m,1H),3.77 - 3.75 (m,3H).

[0084] Step 2: Compound 6B (3.42 g, 19 mmol) was dissolved in THF (50 mL) and cooled to -78°C. n-butyllithium (11.5 mL, 2.5 M in hexane) was added and the mixture was stirred at -78°C for 15 min. DMF (3 mL, 39 mmol) was added and the mixture was reacted at -78°C for 1 hour. Ethyl acetate and water were added to the system to quench it, and then the mixture was extracted with ethyl acetate. The organic phase was collected and concentrated, and then separated by column chromatography (PE:EA = 15:1 to 2:1) to obtain compound 6C (840 mg, 35%). LC-MS (ESI): m / z = 129.1[M+H] + .

[0085] Step 3: Compound 6C (400 mg, 2.8 mmol) was dissolved in a 0.375 M KMnO4 solution, the temperature was raised to 75°C, and the reaction was allowed to proceed for 1 hour. After cooling to room temperature, a 10% KOH aqueous solution was added to adjust the system to basicity, and a solid appeared in the system. The solution was filtered, the filtrate was taken, and hydrochloric acid was added to adjust the pH to 2. The solution was extracted three times with ethyl acetate / methanol = 10 / 1 system (200 mL), and the resulting organic phase was concentrated to obtain the crude product of compound 6D (300 mg). LC-MS (ESI): m / z = 145.1 [M+H] + .

[0086] Step 4: 20 mL of dichloromethane and 10 mL of thionyl chloride were added to the crude compound 6D, and the system was heated to 50°C under a nitrogen atmosphere and reacted for 1 hour. After cooling to room temperature, the mixture was concentrated until no solvent remained to obtain the target compound 6E, which was used directly in the next step.

[0087] Step 5: Crude compound 5G (1.6 g) and 1F (1.2 g, 4.2 mmol) were dissolved in 50 mL of acetonitrile, 6 mL of DIPEA was added, the temperature was raised to 60°C, and the reaction was allowed to proceed for 2 hours. The mixture was concentrated to remove the solvent, water (20 mL) was added, the mixture was shaken thoroughly, and then filtered. After drying the filtered cake, the target compound 6F (768 mg) was obtained. LC-MS (ESI): m / z = 443.2[M+H] + .

[0088] Step 6: Compound 6F (768 mg, 1.73 mmol) was dissolved in 12 mL of a mixed solvent of concentrated hydrochloric acid / ethanol = 2:1, heated to 70°C, and reacted for 1 hour. Slowly added saturated sodium bicarbonate solution dropwise until no more bubbles were produced, filtered, washed the filter cake with water, and dried to obtain the target compound 6G (577 mg, 83.8%). LC-MS (ESI): m / z = 401.2[M+H] + .

[0089] Step 7: 6G (577 mg, 1.44 mmol) was dispersed in dichloromethane (20 mL), pyridine (4 mL) was added, and while stirring, a 5 mL solution of 6E (142 mg, crude) in dichloromethane was added dropwise, and the mixture was reacted at room temperature for 2 hours. The mixture was concentrated, and the resulting residue was separated by silica gel column chromatography (dichloromethane:methanol (v:v) = 20:1) to obtain compound 6 (174 mg, 22.9%).

[0090] LC-MS (ESI): m / z = 527.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 11.59 - 10.27 (m,2H),7.97 - 7.90 (m,1H),7.63 - 7.55 (m,1H),7.55 - 7.48 (m,1H),7.29 - 7.20 (m,1H),6.94 - 6.88 (m,1H),3.99 (s,3H),3.69 (s,2H),3.08 - 3.00 (m,4H),2.86 - 2.76 (m,2H),2.62 - 2.54 (m,4H),1.25 - 1.15 (m,3H).

[0091] Example 7 [ka]

[0092] Step 1: Compound 7A (1 g, 5.46 mmol) was dissolved in a mixed solvent of dichloromethane (20 mL) and trifluoroacetic acid (5 mL), and the reaction was stirred at room temperature for 4 hours. The reaction system was concentrated to obtain trifluoroacetic acid salt (800 mg) of the crude compound 7B. LC-MS (ESI): m / z = 84.3 [M + H] +

[0093] Step 2: The trifluoroacetate salt of the crude compound 7B (700 mg, 5.46 mmol) and compound 1B (1.8 g, 1 mmol) were dissolved in DMF (30 mL), HATU (2.28 g, 6 mmol) was added, and the mixture was reacted at room temperature for 16 hours. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (50 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and extracted by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain compound 7C (1.5 g, 65.7%). LC-MS (ESI): m / z = 391.4[M+H] +

[0094] Step 3: Compound 7C (300 mg, 0.77 mmol) was dissolved in a mixed solvent of dichloromethane (6 mL) and trifluoroacetic acid (1.5 mL), and the reaction was stirred at room temperature for 4 hours. The reaction system was concentrated to obtain the trifluoroacetic acid salt (250 mg) of the crude product of compound 7D. LC-MS (ESI): m / z = 291.1[M+H] +

[0095] Step 4: The trifluoroacetate salt of the crude compound 7D (250 mg) and compound 2D (212 mg, 0.69 mmol) were dissolved in acetonitrile (10 mL), DIPEA (298 mg, 2.31 mmol) was added, and the reaction system was heated to 50°C and reacted for 16 hours. The reaction system was concentrated and then separated by column chromatography (dichloromethane:methanol (v:v) = 20:1) to obtain compound 7 (30 mg, 8.4%).

[0096] LC-MS (ESI): m / z = 517.2[M+H] + 1HNMR (400MHz,DMSO-d6) δ 13.00 (s,1H),8.73-8.71 (m,1H),7.84-7.82 (m,1H),7.73-7.71 (m,1H),7.58-7.54 (m,1H),7.44-7.40(m,1H),7.21-6.94 (m,1H),5.07-4.61 (m,2H),4.44-4.34 (m,1H),3.75 (s,2H),3.19-3.17 (m,4H),2.99-2.81 (m,4H),2.65-2.63 (m,4H) Example 8 [ka]

[0097] Step 1: 8A (0.5 g, 1.53 mmol, synthesized according to WO2023056039A1), 7B (0.25 g, 3.06 mmol), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.87 g, 2.29 mmol), and diisopropylethylamine (0.59 g, 4.56 mmol) were dissolved in DMF (8 mL) and reacted at room temperature for 2 hours. After the reaction was complete, the mixture was rotated dry and purified by normal phase (petroleum ether:ethyl acetate (v:v) = 4:1) to obtain product 8B (0.3 g, 50%). LC-MS (ESI): m / z=336.2[M-56+H] + .

[0098] Step 2: 8B (0.25 g, 0.64 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1.53 g, 13.42 mmol) was added, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the mixture was directly rotated to obtain crude product 8C (0.18 g, crude). LC-MS (ESI): m / z = 292.2[M+H] + .

[0099] Step 3: Compound 8C (0.15 g, 0.51 mmol), Compound 1F (0.16 g, 0.56 mmol) and diisopropylethylamine (0.33 g, 2.55 mmol) were dissolved in acetonitrile (8 mL) and reacted at 55 °C for 3 hours. After completion of the reaction, it was concentrated to dryness and directly rotary dried, and preparative HPLC was performed. Method Instrument: waters 2767 preparative liquid, chromatography column: SunFire@Prep C18 (19 mm×150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5% ammonium acetate), gradient: 10% - 50% acetonitrile gradient, Compound 8 (50 mg, 19%) was obtained.

[0100] LC-MS (ESI): m / z = 496.2 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 8.80 (d, 1H), 7.85 (d, 1H), 7.64 - 7.57 (m, 1H), 7.53 (d, 1H), 7.30 - 7.23 (m, 1H), 4.85 - 4.77 (m, 2H), 4.64 - 4.55 (m, 1H), 4.44 - 4.33 (m, 1H), 3.91 (d, 1H), 3.84 - 3.78 (m, 1H), 3.70 (d, 1H), 3.44 - 3.34 (m, 1H), 2.97 - 2.86 (m, 4H), 2.85 - 2.77 (m, 3H), 1.24 - 1.19 (m, 6H). Example 9

Chemical Structure

[0101] Step 1: Compound 9A (200 mg, 0.74 mmol, synthesized according to Patent US20220009901A1), 7D (215 mg, 0.74 mmol) and DIPEA (0.4 ml, 2.22 mmol) were added to a reaction flask and dissolved in acetonitrile (5 ml), and reacted at 50 °C for 2 hours. After monitoring the completion of the reaction by TLC, it was cooled to room temperature, filtered, the filter cake was washed once with acetonitrile (5 ml), then washed once with ethyl acetate (10 ml), the filter cake was collected and dried to obtain Compound 9 (140 mg, yield 39.44%).

[0102] LC-MS (ESI): m / z = 481.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.42 (s, 1H), 8.74 - 8.67 (m, 1H), 7.85 - 7.80 (m, 1H), 7.58 - 7.49 (m, 2H), 7.32 - 7.25 (m, 1H), 4.83 - 4.78 (m, 2H), 4.44 - 4.33 (m, 1H), 3.70 (s, 2H), 3.20 - 3.13 (m, 4H), 2.94 - 2.84 (m, 4H), 2.62 - 2.55 (m, 4H), 2.41 (s, 3H). Example 10

Chemical Structure

[0103] Step 1: The trifluoroacetate of the crude product of Compound 7D (300 mg) and Compound 1F (250 mg, 0.88 mmol) were dissolved in acetonitrile (10 mL), DIPEA (1 mL) was added, the reaction system was heated to 50 °C and reacted for 2 h. The reaction system was concentrated and then separated by column chromatography (DCM:MeOH (v:v) = 15:1) to obtain Compound 10 (105 mg, 24.14%).

[0104] LC-MS (ESI): m / z = 495.4 [M+H] + 1 H NMR (400MHz,DMSO-d6) δ 12.43 (s,1H),8.73 - 8.71 (m,1H),8.03 - 7.77 (m,1H),7.70 - 7.45 (m,2H),7.31 - 7.27 (m,1H),5.14 - 4.75 (m,2H),4.42 - 4.36 (m,1H),3.71 (s,2H),3.16 - 3.18 (m,4H),2.88 - 2.94 (m,4H),2.824 - 2.79(m,2H),2.60 - 2.58 (m,4H),1.24 - 1.20(m,3H). Example 11 [ka]

[0105] Step 1: 8A (0.15 g, 0.46 mmol) (synthesized according to WO2023056039A1), 11A (0.077 g, 0.64 mmol) (synthesized according to WO2023025324A1), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.26 g, 0.69 mmol), and diisopropylethylamine (0.18 g, 1.38 mmol) were dissolved in N,N-diisopropylethylamine (8 mL) and reacted at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, rotated dry, stirred, and purified by normal phase (petroleum ether:ethyl acetate = 4:1) to obtain product 11B (0.18 g, 91.6%). LC-MS (ESI): m / z=372.0[M-56+H] + .

[0106] Step 2: Dissolve 11B (0.040 g, 0.094 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (0.77 g, 6.71 mmol), and react at room temperature for 1 hour. After the reaction was complete, the mixture was directly rotated to obtain crude product 11C (0.027 g, crude). LC-MS (ESI): m / z = 328.2[M+H]+ .

[0107] Step 3: 11C (0.027 g, 0.082 mmol), 1F (0.028 g, 0.098 mmol), and diisopropylethylamine (0.042 g, 0.33 mmol) were dissolved in acetonitrile (5 mL) and reacted at 50°C for 3 hours. After the reaction was complete, the mixture was concentrated to dry and purified by preparative HPLC. Method and instrumentation: waters 2767 preparative liquid, chromatography column: SunFire@Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5% ammonium acetate), gradient: 10% to 50% acetonitrile gradient, compound 11 (11 mg, 25%) was obtained.

[0108] LC-MS (ESI): m / z = 532.7[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.96 (d,1H),7.86 (d,1H),7.66 - 7.58 (m,1H),7.53 (d,1H),7.31 - 7.23 (m,1H),4.64 - 4.47 (m,2H),3.91 (d,1H),3.85 - 3.79 (m,1H),3.70 (d,1H),3.44 - 3.36(m,1H),3.00 - 2.88 (m,4H),2.85 - 2.78 (m,3H),1.23 (d,3H),1.21 - 1.19 (m,3H). Example 12 [ka]

[0109] Step 1: Compound 1B (950 mg, 2.86 mmol) was dissolved in DMF (10 mL), and then HATU (1.53 g, 4.03 mmol), diisopropylethylamine (2 mL), and compound 11A (400 mg, 3.36 mmol) were added sequentially. After all additions were made, the mixture was reacted at room temperature for 16 hours. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (50 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was beaten with a mixed solvent of ethyl acetate petroleum ether (EA: petroleum ether = 1:2), filtered, and dried to obtain the target compound 12A (826 mg, 56.98%). LC-MS (ESI): m / z = 427.2[M+H] + .

[0110] Step 2: Compound 12A (213 mg, 0.5 mmol) was weighed out and placed in dichloromethane (5 mL), then trifluoroacetic acid (1 mL) was added. After adding the trifluoroacetic acid, the mixture was stirred at room temperature for 2 hours. The dichloromethane and excess trifluoroacetic acid were concentrated under reduced pressure to obtain the trifluoroacetic acid salt of compound 12B (160 mg), which was then used directly in the reaction of the next step. LC-MS (ESI): m / z = 327.1[M+H] + .

[0111] Step 3: Weigh out 160 mg of the trifluoroacetate salt of compound 12B, dissolve it in 20 mL of acetonitrile, and add 2 mL of diisopropylethylamine and compound 9A (140 mg, 0.5 mmol). After adding the compounds, heat to 65°C and allow to react for 3 hours. Once the reaction is complete, directly heat filter the mixture, wash the filtered cake with acetonitrile, and dry it to obtain the target compound 12 (160 mg, 62.01%).

[0112] LC-MS (ESI): m / z = 517.2[M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.99 - 8.97 (m, 1H), 7.85 - 7.83 (m, 1H), 7.62 - 7.44 (m, 2H), 7.39 - 7.15 (m, 1H), 4.56 - 4.50 (m, 1H), 3.70 (s, 2H), 3.18 - 3.16 (m, 4H), 3.01 - 2.81 (m, 4H), 2.60 - 2.61 (m, 4H), 2.42 (s, 3H). Example 13

Chem.

[0113] Step 1: The trifluoroacetate (250 mg) of the crude product of compound 12B and compound 1F (142 mg, 0.5 mmol) were dissolved in acetonitrile (10 mL), DIPEA (322 mg, 2.5 mmol) was added, the reaction system was heated to 65 °C, and reacted for 2 h. After concentrating the reaction system, it was separated by column chromatography (dichloromethane:methanol (v:v) = 20:1) to obtain compound 13 (140 mg, 52.8%).

[0114] LC-MS (ESI): m / z = 531.3 [M + H] + 1 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.90 - 8.88 (m, 1H), 7.84 - 7.82 (m, 1H), 7.57 - 7.53 (m, 2H), 7.31 - 7.27 (m, 1H), 4.56 - 4.50 (m, 1H), 3.70 (s, 2H), 3.18 (s, 4H), 2.95 - 2.90 (m, 4H), 2.84 - 2.79 (m, 2H), 2.59 (s, 4H), 1.23 - 1.20 (m, 3H) Example 15

Chem.

[0115] <Step 1: Compound 1B (170 mg, 0.51 mmol), 3-(difluoromethylene)cyclobutylaminetrifluoroacetate (180 mg, 0.76 mmol, synthesized according to patent WO2023025324A1), and DIPEA (0.9 ml, 5.10 mmol) were added to a reaction flask, dissolved in DMF (10 ml), and HATU (230 mg, 0.61 mmol) was added. The mixture was reacted at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, the mixture was diluted with water (50 ml). The mixture was then extracted twice with ethyl acetate (40 ml x 2), the organic phases were combined, dried, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 15A (180 mg, yield: 84.51%). LC-MS(ESI): m / z = 419.1[M+H] + .

[0116] Step 2: Compound 15A (180 mg, 0.43 mmol) was added to the reaction flask, dissolved in DCM (10 ml), and then trifluoroacetic acid (1 ml) was added. The mixture was reacted at room temperature for 3 hours. After monitoring the completion of the reaction by TLC, the mixture was concentrated under reduced pressure to obtain compound 15B (200 mg, trifluoroacetate, proceeded directly to the next step). LC-MS(ESI): m / z = 319.1[M+H] + .

[0117] Step 3: Compound 15B (200 mg, 0.46 mmol) and Compound 2D (140 mg, 0.46 mmol) were added to a reaction flask, dissolved in acetonitrile (10 ml), and then DIPEA (0.4 ml, 2.30 mmol) was added. The mixture was reacted at 80°C for 3 hours. After monitoring the completion of the reaction by TLC, the mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by C18 column chromatography (A / B = 0.1% AcONH4in H2O / ACN, B: 10%~60%) to obtain Compound 15 (52 mg, yield: 20.80%).

[0118] 1H NMR (400MHz,DMSO-d6) δ 8.65 - 8.55 (m,1H),7.87 - 7.78 (m,1H),7.74 - 7.65 (m,1H),7.61 - 7.50 (m,1H),7.44 - 7.34 (m,1H),7.20 - 6.90 (m,1H),4.36 - 4.25 (m,1H),3.74 (s,2H),3.19 - 3.15 (m,4H),2.92 - 2.82 (m,2H),2.75 - 2.66 (m,2H),2.64 - 2.57(m,4H),1.50 (s,6H). LC-MS(ESI): m / z = 545.4[M+H] + . Example 16 [ka]

[0119] Step 1: 8C (0.15 g, 0.51 mmol), 2D (0.17 g, 0.56 mmol) and N,N-diisopropylethylamine (0.2 g, 1.53 mmol) were dissolved in acetonitrile (8 mL), and the reaction was carried out at 55°C for 3 hours. After the reaction was complete, the mixture was directly rotated-dried and purified by HPLC. Method and instrumentation: waters 2767 preparative solution, chromatography column: SunFire@Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5% ammonium acetate), gradient: 10% to 50% acetonitrile gradient, compound 16 (70 mg, 26%) was obtained.

[0120] LC-MS (ESI): m / z = 518.3 [M + H] + . 1H NMR (400MHz,Chloroform-d) δ 10.00 (s,1H),8.00 (d,1H),7.78 (d,1H),7.69 (d,1H),7.43 (s,1H),7.23 - 7.16 (m,1H),7.07 - 6.74 (m,1H),4.92-4.86 (m,2H),4.60 - 4.41 (m,2H),4.11 - 3.78 (m,3H),3.55 (s,1H),3.23 - 3.08 (m,2H),2.99 (s,1H),2.81-2.66 (m,2H),1.29 (d,3H). Example 17 [ka]

[0121] Step 1: Compound 8A (150 mg, 0.46 mmol), 3-(difluoromethylene)cyclobutylaminetrifluoroacetate (160 mg, 0.69 mmol, synthesized according to patent WO 2023025324A1), and DIPEA (0.8 ml, 4.60 mmol) were added to a reaction flask, dissolved in DMF (10 ml), and HATU (210 mg, 0.55 mmol) was added. The mixture was reacted at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, the mixture was diluted with water (50 ml). The mixture was then extracted twice with ethyl acetate (40 ml x 2), the organic phases were combined, dried, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 17A (80 mg). LC-MS(ESI): m / z = 364.1[M-56+H] + .

[0122] Step 2: Compound 17A (80 mg, 0.19 mmol) was added to the reaction flask, dissolved in DCM (5 ml), and trifluoroacetic acid (0.5 ml) was added. The mixture was reacted at room temperature for 3 hours. After monitoring the completion of the reaction by TLC, the mixture was concentrated under reduced pressure to obtain compound 15B (100 mg, trifluoroacetate, proceeded directly to the next step). LC-MS(ESI): m / z = 320.3[M+H]+ .

[0123] Step 3: Compound 17B (100 mg, 0.23 mmol) and compound 1F (65 mg, 0.23 mmol) were added to a reaction flask, dissolved in acetonitrile (10 ml), and then DIPEA (0.2 ml, 1.15 mmol) was added. The mixture was reacted at 80°C for 3 hours. After monitoring the completion of the reaction by TLC, the mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by C18 column chromatography (A / B = 0.1% AcONH4in H2O / ACN, B: 10%~60%) to obtain compound 17 (5 mg, yield: 4.17%).

[0124] 1 H NMR (400MHz,DMSO-d6) δ 12.40 (s,1H),8.72 - 8.67 (m,1H),7.86 - 7.82 (m,1H),7.64 - 7.50 (m,2H),7.29 - 7.23 (m,1H),4.63 - 4.56 (m,1H),4.34 - 4.27 (m,1H),3.94 - 3.88 (m,1H),3.84 - 3.79 (m,1H),3.73 - 3.67 (m,1H),3.42 - 3.37 (m,1H),2.90 - 2.78 (m,5H),2.76 - 2.69 (m,2H),1.50 (s,6H),1.23 - 1.17 (m,6H). LC-MS(ESI): m / z = 524.3[M+H] + . Example 18 [ka]

[0125] Step 1: Compound 8C (0.15 g, 0.51 mmol), Compound 9A (0.14 g, 0.51 mmol), and diisopropylethylamine (0.26 g, 2.04 mmol) were dissolved in acetonitrile (5 mL) and reacted at 70°C for 16 hours. After the reaction was complete, the mixture was concentrated to dry, directly rotated-dried, and HPLC preparative extraction was performed. Method and equipment: waters 2767 preparative liquid, chromatography column: SunFire@Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5% ammonium acetate), gradient: 10% to 50% acetonitrile gradient, Compound 18 (0.12 g, yield: 48.40%) was obtained.

[0126] LC-MS (ESI): m / z = 482.4[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.80 (d,1H),7.85 (d,1H),7.65 - 7.57 (m,1H),7.49 (d,1H),7.29 - 7.22 (m,1H),4.84 - 4.77 (m,2H),4.62 - 4.57 (m,1H),4.41 - 4.36 (m,1H),3.91 (d,1H),3.83 - 3.80 (m,1H),3.70 (d,1H),3.43 - 3.36 (m,1H),2.92 - 2.81(m,5H),2.41 (s,3H),1.20 (d,3H).

[0127] Biological tests 1. Experiment to test the enzyme activity of PARP1 Enzyme activity inhibition experiments against PARP1 / 2 by compounds were tested using the fission product (FP) method. A substrate tracer fluorescent probe (from Aisip Bio) was prepared in reaction buffer (50 mM Tris (pH 8.0), 10 mM MgCl2, 150 mM NaCl, 0.001% Triox-100). PARP1 / 2 (BPS, Cat#80501 / 80502) was added to the reaction buffer and gently mixed. The final concentrations of PARP1 / 2 and the fluorescent probe in the reaction mixture were 5 / 10 nM and 2.5 nM, respectively. The positive control, Olaparib, was initially at a concentration of 1 μM, then diluted 3-fold to a concentration of 10. Using an acoustic dispenser (Echo 655), 0.1 μL of the compound in 100% DMSO was transferred to a 384-well plate (Corning, 4514), centrifuged at 1000 rpm for 1 minute, 5 μL of PARP enzyme solution was transferred to the 384-well plate, centrifuged at 1000 rpm for 1 minute, incubated at 25°C for 10 minutes, 5 μL of substrate solution was transferred to the 384-well plate, centrifuged at 1000 rpm for 1 minute, incubated at 25°C for 60 minutes, and finally, the mP signal values ​​of FP (ex / em: 485 nm / 520 nm) were read using the fluorescence polarization module of a BMG PHERAstar FSX. Subsequently, four-parameter curve fitting by nonlinear regression was performed using GraphPad Prism8 software to obtain the IC50 value. The inhibition rate was calculated based on Equation 1, where RLUsample is the reading from the compound well, RLUmax is the reading from the solvent control well, and RLUmin is the reading from the control well without PARP1 / 2 enzyme. Curve fitting was performed using GraphPad Prism software with four parameters (log(inhibitor) vs. response -- Variable slope), and IC was calculated. 50 The value was calculated. Inhibition%=(1-(RLUsample-RLUmin) / (RLUmax-RLUmin))×100% (Formula 1)

[0128] [Table 1]

[0129] Conclusion: The compounds of the present invention, for example, the example compounds, have a significant inhibitory effect on PARP-1 enzyme activity in vitro.

[0130] 2. DLD-1 cell activity test experiment DLD-1 (150 cells / well / 100 μL) (ATCC, CCL-221) and DLD-1 BRCA2 KO (1500 cells / well / 100 μL) (from AISIP Bio) were inoculated into 96-well plates (Greiner, 655090) at appropriate cell densities and cultured overnight in a 37°C cell incubator. The test compounds were diluted with the corresponding medium and added to the well plates, incubated for 7 days, and on day 4, the medium was replaced with fresh medium and the same concentration of the compound was added. The CellTiter-Glo reagent (CTG, Vazyme, DD1101-03) and culture plates were removed and allowed to return to room temperature. 60 μL of CTG reagent was added to the cells, and the cells were shaken for 2 minutes to lyse them completely. After standing at room temperature for 30 minutes, the fluorescence signal values ​​were read using a microplate reader (PHERAstar FSX). The culture medium wells were set up as the negative control and the DMSO wells as the positive control. The inhibitory activity percentage of the compound was standardized using the readings from the negative and positive controls. The formula for calculating the inhibition rate is as follows: Inhibition rate (%) = (Fluorescence value of positive control group - Fluorescence value of experimental group) / (Fluorescence value of positive control group - Fluorescence value of negative control group) * 100% (Equation 2)

[0131] [Table 2]

[0132] Conclusion: The compounds of the present invention, for example, the example compounds, have good inhibitory activity.

[0133] 3. PARP selectivity experiment A549WT, A549 PARP1 KO, and A549 PARP2 KO cell lines were inoculated into 384-well plates at 2500 / 40 μL / well and incubated overnight at 37°C in 5% CO2. The following day, 40 nL of serially diluted compound was added and incubated at 37°C in 5% CO2 for 1 hour. Each well was stimulated with 5 μL of H2O2, for 5 minutes if the final concentration of A549WT and A549 PARP2 KO was 200 μM, and for 45 minutes if the final concentration of A549 PARP1 KO was 20 mM. After stimulation, the supernatant was discarded, 40 μL of pre-cooled methanol was added, and the cells were fixed in a refrigerator at 4°C for 20 minutes. The cells were washed twice with PBS, 20 μL of blocking solution was added, and the cells were blocked for 1 hour. The primary antibody mixture (pADPr Antibody (10H): sc-56198 antibody added to blocking solution and diluted 1:500) was added and incubated overnight at 4°C. Washed three times with PBST, and the secondary antibody mixture (Goat anti-Mouse IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor) was added. TM The 488 antibody was added to the blocking solution (diluted 1:500) and incubated at room temperature for 1 hour. The samples were washed three times with PBST, 20 μL of DAPI solution (diluted 1:5000) was added, incubated at room temperature for 10 minutes, and then scanned.

[0134] Data analysis methods Assay stability was tested using DMSO and talazoparib data. H=Ave(DMSO), L=Ave(Talazoparib 5μM), SD(H)=STDEV(DMSO), SD(L)=STDEVTalazoparib 5μM), CV%(H)=100*(SD_H / Ave_H), CV%(L)=100*(SD_L / Ave_L), Z'=1-3*(SD_H+SD_L) / (Ave_H-Ave_L), Inhibition%=(Ave_H-Sample) / (Ave_H-Ave_L)*100 IC of compounds based on nonlinear regression equations 50The fitted function was: Y = bottom + (top - bottom) / (1 + 10^((LogIC50 - X) * Hil gradient)). X: concentration of the compound, Y: inhibition rate in percent. The top and bottom are both stabilization segments with the Y axis as the unit. The Hill gradient describes the slope of the curve.

[0135] [Table 3]

[0136] Conclusion: The compounds of the present invention, particularly the example compounds, for example, compound 2, have good selectivity for PARP1.

[0137] 4. Pharmacokinetic studies in rats 4.1 Test animals: Male SD rats, approximately 220g, 6-8 weeks old, 6 rats / compound. Purchased from Chengdu Dashuo Laboratory Animals Co., Ltd.

[0138] 4.2 Study Design: On the day of the study, 12 SD rats were randomly divided into groups according to their body weight. They were fasted for 12-14 hours without water restriction one day before administration, and fed 4 hours after administration.

[0139] [Table 4]

[0140] Before and after administration, 0.15 ml of blood was collected from the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood collection times for both the intravenous and intragastric administration groups were 0, 5, 15, 30 min, 1, 2, 4, 6, 8, and 24 h. Brain tissue was removed 24 hours after administration, the blood remaining on the surface of the brain tissue was washed with cold saline, wiped dry, and then homogenized. Before analysis, all samples were stored at -80°C, and quantitative analysis was performed on the samples by LC-MS / MS.

[0141] [Table 5]

[0142] Conclusion: The compounds of the present invention, for example, Example Compounds 2 and 8, exhibit good in vivo pharmacokinetic characteristics in rats.

[0143] 5. Pharmacokinetic studies in mice 5.1 Test animals: Male Balb / c mice, 20-25g, 12 mice / compound. Purchased from Chengdu Dashuo Laboratory Animals Co., Ltd.

[0144] 5.2 Study Design: On the day of the study, Balb / c mice were randomly divided into groups according to body weight. They were fasted for 12-14 hours without water restriction one day before administration, and fed 4 hours after administration.

[0145] Before and after administration, 0.06 mL of blood was collected from the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 min to collect plasma. Blood collection times for both the intravenous and intragastric administration groups were 0, 5, 15, 30 min, 1, 2, 4, 6, 8, and 24 h. Brain tissue was removed at 30 min, 2, and 24 h after compound administration, respectively. After removing the compound and brain tissue at 24 h, the blood remaining on the surface of the brain tissue was washed with cold saline, wiped dry, and then homogenized. Before analysis and detection, all samples were stored at -80°C, and quantitative analysis was performed on the samples by LC-MS / MS.

[0146] Conclusion: The compounds of the present invention, for example, the example compounds, exhibit good in vivo pharmacokinetic characteristics in mice.

[0147] 6. Pharmacokinetic studies in Beagle dogs 6.1 Test animals: Male Beagle dogs, approximately 8-11 kg, 6 dogs / compound, purchased from Beijing Mas Biotechnology Co., Ltd.

[0148] 6.2 Test Method: On the day of the test, Beagle dogs were randomly divided into groups according to their weight. They were fasted for 12-14 hours without water restriction one day before administration, and fed 4 hours after administration.

[0149] 1 ml of blood was collected from the jugular vein or limb vein before and after administration and placed in an EDTAK2 centrifuge tube. The plasma was collected by centrifugation at 5000 rpm at 4°C for 10 minutes. The blood collection times for both the venous and forced oral groups were 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, and 48 h. Before analysis, all samples were stored at -80°C and quantitative analysis was performed on the samples by LC-MS / MS.

[0150] Conclusion: The compounds of the present invention, for example, the example compounds, exhibit good in vivo pharmacokinetic characteristics in dogs.

[0151] 7. Pharmacokinetic studies in monkeys 7.1 Test animals: Male cynomolgus macaques, 3-5 kg, 3-6 years old, 4 animals / compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0152] 7.2 Test Method: On the day of the test, the monkeys were randomly divided into groups according to their weight. They were fasted for 14-18 hours without water restriction one day before administration, and fed 4 hours after administration.

[0153] 1.0 mL of blood was collected from the limb veins before and after administration and placed in an EDTAK2 centrifuge tube. The centrifuge was 5000 rpm at 4°C for 10 minutes to collect the plasma. Blood collection times for the venous group were 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, and 48 h. Before analysis, all samples were stored at -80°C and quantitative analysis was performed on the samples by LC-MS / MS.

[0154] Conclusion: The compounds of the present invention, for example, the example compounds, exhibit good in vivo pharmacokinetic characteristics in monkeys.

Claims

1. Compounds shown in formula I-1, formula I, their stereoisomers, or pharmaceutically acceptable salts, 【Chemistry 1】 Here, Ring A is, 【Chemistry 2】 Selected from, R １ C １－４ alkyl group, C ３－６ The alkyl group is a cycloalkyl group, and the alkyl group and cycloalkyl group can be optionally D, halogen, OH, CN, or NH. ２ Substituted with 1 to 3 groups selected from, R ２ is, -CONHR Ａ ,-NHCOR Ａ And, Each R Ａ is independently a C ３－６ cycloalkyl group, a 5- to 6-membered heteroaryl group substituted with 1 to 3 halogen atoms, the heteroaryl group contains 1 to 3 heteroatoms selected from N, S, O, and the heteroaryl group and cycloalkyl group are optionally substituted with 1 to 3 groups selected from D, =O, C １－４ alkyl group, C １－４ alkoxy group, -NH C １－４ alkyl group, -CONH C １－４ alkyl group, -NHCO C １－４ alkyl group, OH, CN, NH ２ and C １－４ haloalkyl group, and the cycloalkyl group is substituted with at least one =CH ２ , =CF ２ , =CHF, =CH(C １－６ alkyl), =C(C １－６ alkyl) ２ and is substituted with m is either 0 or 1. Here, the compound is 【Transformation 3】 Not a compound, its stereoisomer, or a pharmaceutically acceptable salt.

2. Ring A is, 【Chemistry 4】 Selected from, R １ C １－２ alkyl group, C ３－４ The alkyl group is a cycloalkyl group, and the alkyl group and cycloalkyl group can be optionally D, F, Cl, OH, CN, NH ２ Substituted with 1 to 3 groups selected from, preferably R １ These are methyl groups, ethyl groups, isopropyl groups, cyclopropyl groups, and cyclobutyl groups, and the methyl groups, ethyl groups, isopropyl groups, cyclopropyl groups, and cyclobutyl groups can be optionally D, F, Cl, OH, CN, and NH. ２ Replaced by one, two, or three groups selected from, Each R Ａ Independently, C ３－６ A cycloalkyl group, a 5-6 membered heteroaryl group substituted with 1-3 halogens, wherein the heteroaryl group contains 1-3 heteroatoms selected from N, S, and O, and the heteroaryl group is optionally D, =O, C １－４ Alkyl, OH, CN, NH ２ and C １－２ The cycloalkyl group is substituted with one to three groups selected from haloalkyl groups, and the cycloalkyl group has one =CH group. ２ , = CF ２ , =CHF, =CH(C １－２ Alkyl), = C (C １－２ Alkyl) ２ Replaced by, preferably, each R Ａ These are independently five-membered heteroaryl groups substituted with one, two, or three F or Cl atoms. 【Transformation 5】 The heteroaryl group contains one, two, or three heteroatoms selected from N, S, and O, and the heteroaryl group can optionally be D, =O, -CH ３ ien-CH ２ CH ３ ien-CH ２ CH ２ CH ３ , -CH(CH ３ )CH ３ , -CH(CH ３ )CH ２ CH ３ OH, CN, NH ２ A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, substituted with one, two, or three groups selected from the above.

3. Ring A is, 【Transformation 6】 Selected from, 【Transformation 7】 The end is connected to the left side, 【Transformation 8】 The end is connected to the right side, R １ is, -CH ３ ien-CH ２ CH ３ ,-CHF ２ Selected from, R Ａ Each of them operates independently. 【Chemistry 9】 A compound according to claim 1 or 2, a stereoisomer thereof, or a pharmaceutically acceptable salt, selected from among.

4. Ring A is, 【Chemistry 10】 Selected from, 【Chemistry 11】 The end is connected to the left side, 【Chemistry 12】 The end is connected to the right side, R １ is, -CH ３ ien-CH ２ CH ３ ,-CHF ２ Selected from, R Ａ Each of them operates independently. 【Chemistry 13】 A compound of formula I according to claim 1 or 2, a stereoisomer thereof, or a pharmaceutically acceptable salt, selected from among the following.

5. Ring A is, 【Chemistry 14】 Selected from, 【Chemistry 15】 The end is connected to the left side, 【Chemistry 16】 The end is connected to the right side, R １ is, -CH ３ ien-CH ２ CH ３ ,-CHF ２ Selected from, m is selected from 1, R Ａ Each of them operates independently. 【Chemistry 17】 A compound of formula I-1 according to claim 1 or 2, a stereoisomer thereof, or a pharmaceutically acceptable salt, selected from among the following.

6. A compound shown in formula I-1, formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound is [Chemistry 18] 【Chemistry 19】 A compound shown in formula I-1, formula I, its stereoisomer, or a pharmaceutically acceptable salt, selected from one of the following structures.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

8. Uses of the compound described in any one of claims 1 to 6, or its stereoisomer or pharmaceutically acceptable salt, or the composition described in claim 7, in the manufacture of a drug for treating / preventing PARP1-mediated diseases.

9. The use according to claim 8, wherein the PARP1-mediated disease is selected from breast cancer, uterine cancer, cervical cancer, ovarian cancer, and prostate cancer.

10. A pharmaceutical composition or pharmaceutical preparation comprising 1 to 1440 mg of a compound according to any one of claims 1 to 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

11. A method for treating a disease of a mammal, comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is preferably 1 to 1440 mg, and the disease is preferably breast cancer, uterine cancer, cervical cancer, ovarian cancer, or prostate cancer.

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