Bicyclic derivative PARP inhibitor and use thereof

Abstract

A compound as represented by formula I-1, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing same, and the use thereof as a PARP-1 inhibitor in the preparation of a drug for treating related diseases. Each group in formula I-1 is as defined in the description.

Description

Bicyclic derivative PARP inhibitors and uses thereof Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a small molecule compound with PARP-1 inhibitory activity, its stereoisomers, pharmaceutically acceptable salts, solvates, cocrystals or deuterated compounds, and uses thereof in treating related diseases. Background Art

[0002] Approximately 5% of breast cancer patients are associated with germline mutations in the BRCA1 / 2 genes (3% for BRCA1 and 2% for BRCA2). Breast cancers caused by BRCA1 mutations are mostly triple-negative (70%), while BRCA2 mutations are more likely to cause estrogen receptor-positive (ER-positive) breast cancer (70%). BRCA1 / 2 genes are tumor suppressor genes that play an important role in DNA damage repair and normal cell growth. Mutations in these genes can inhibit the normal repair ability after DNA damage, causing homologous recombination deficiency (HRD). This is characterized by loss of BRCA function or mutations or loss of function in other homologous recombination-related genes, preventing double-strand breaks from being repaired by homologous recombination (HRR), ultimately leading to cancer.

[0003] Poly(ADP-ribose) polymerase (PARP) is a DNA repair enzyme that plays a key role in the DNA repair pathway. PARP is activated when DNA is damaged and broken. As a molecular sensor of DNA damage, it has the function of recognizing and binding to the site of DNA breakage, thereby activating and catalyzing the poly(ADP-ribosylation) of the receptor protein and participating in the DNA repair process. PARP plays a key role in the excision and repair of single-stranded DNA bases. In HRD tumor cells, double-stranded DNA cannot be repaired, and PARP inhibitors block single-strand repair, resulting in a "synthetic lethality" effect, leading to tumor cell death.

[0004] PARP inhibitors have a "trapping" effect on PARP proteins, causing PARP proteins bound to damaged DNA to be trapped on the DNA and unable to get off. This directly prevents other DNA repair proteins from binding, ultimately leading to cell death. Currently, a number of PARP inhibitors have been successfully developed, such as Olaparib, Rucaparib, and Niraparib. However, adverse reactions limit their ability to be used in combination with chemotherapy drugs. This may be related to the lack of selectivity of marketed PARP inhibitors for the PARP family. These side effects include intestinal toxicity caused by end-ankyropolymerase inhibition and hematotoxicity caused by PARP-2 inhibition. Therefore, it is of great clinical significance to develop highly selective PARP-1 inhibitors to reduce the related toxic side effects of non-selective PARP inhibitors.

[0005] Summary of the Invention

[0006] The object of the present invention is to provide a PARP-1 inhibitory compound, its stereoisomers or pharmaceutically acceptable salts, and its medical use. The compound of the present invention has the advantages of good activity, low toxicity and side effects, good safety, high selectivity, good pharmacokinetics, and high bioavailability.

[0007] The present invention provides compounds of the following formula I, formula I-1, or stereoisomers or pharmaceutically acceptable salts thereof:

[0008] in,

[0009] Ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from The left side of the "*" end is connected to the right side;

[0010] R1 is C 1-4 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1-3 groups selected from D, halogen, OH, CN, and NH2; in some embodiments, R1 is C 1-2 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1-3 groups selected from D, halogen, OH, CN, and NH2; in some embodiments, R1 is C 1-2 Alkyl, C 3-4Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1-3 groups selected from D, F, Cl, OH, CN, and NH2; in some embodiments, R1 is methyl, ethyl, isopropyl, cyclopropyl, or cyclobutyl, wherein the methyl, ethyl, isopropyl, cyclopropyl, or cyclobutyl is optionally substituted by 1, 2, or 3 groups selected from D, F, Cl, OH, CN, and NH2; in some embodiments, R1 is methyl, ethyl, cyclopropyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, or -CF2CF3;

[0011] In some embodiments, R1 is selected from methyl, ethyl, and the methyl, ethyl groups 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;

[0012] R2 is -CONHR A 、-NHCOR A ; In some embodiments, R2 is -CONHR A ; In some embodiments, R2 is -NHCOR A ;

[0013] Each R A Independently C 3-6 Cycloalkyl, 5-6 membered heteroaryl substituted by 1-3 halogens, the heteroaryl containing 1-3 heteroatoms selected from N, S, O, the heteroaryl, cycloalkyl is optionally substituted by 1-3 halogens selected from D, =O, C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHCOC 1-4 Alkyl, OH, CN, NH2 and C 1-4 The cycloalkyl group is substituted by at least one =CH2, =CF2, =CHF, =CH(C 1-6 alkyl), =C(C 1-6 alkyl) 2; in some embodiments, each R A Independently C 3-6 Cycloalkyl, 5-6 membered heteroaryl substituted by 1-3 halogens, said heteroaryl containing 1-3 heteroatoms selected from N, S, O, said heteroaryl optionally substituted by 1-3 heteroatoms selected from D, =O, C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -CONHC 1-4Alkyl, -NHCOC 1-4 Alkyl, OH, CN, NH2 and C 1-4 The cycloalkyl group is substituted by at least one =CH2, =CF2, =CHF, =CH(C 1-6 alkyl), =C(C 1-6 alkyl) 2; in some embodiments, each R A is independently a 5-6 membered heteroaryl group substituted by 1-3 halogens, C 3-6 Cycloalkyl, the heteroaryl contains 1-3 heteroatoms selected from N, S, O, and the heteroaryl is optionally substituted by 1-3 heteroatoms selected from D, ═O, C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHCOC 1-4 Alkyl, OH, CN, NH2 and C 1-4 The cycloalkyl group is substituted with at least one =CH2 or =CF2; in some embodiments, each R A is independently a 5-6 membered heteroaryl group substituted by 1-3 halogens, C 3-6 Cycloalkyl, the heteroaryl contains 1-3 heteroatoms selected from N, S, O, and the heteroaryl is optionally substituted by 1-3 heteroatoms selected from D, ═O, C 1-4 Alkyl, OH, CN, NH2 and C 1-2 The cycloalkyl group is substituted by 1 =CH2, =CF2, =CHF, =CH(C 1-2 alkyl), =C(C 1-2 alkyl)2; in some embodiments, each R A is independently a 5-membered heteroaryl substituted by 1, 2 or 3 F or Cl groups, The heteroaryl group contains 1, 2 or 3 heteroatoms selected from N, S, and O, and the heteroaryl group is optionally substituted by 1, 2 or 3 groups selected from D, =O, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH3, -CH(CH3)CH2CH3, OH, CN, and NH2; in some embodiments, each R A is independently a 5-6 membered heteroaryl group substituted by 1-3 halogens, The heteroaryl group contains 1-3 heteroatoms selected from N, S, and O, and the heteroaryl group is optionally substituted by 1-3 heteroatoms selected from D, ═O, C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -CONHC1-4 Alkyl, -NHCOC 1-4 Alkyl, OH, CN, NH2 and C 1-4 In some embodiments, each R A is independently a 5-6 membered heteroaryl substituted by 1-3 halogens, wherein the heteroaryl contains 1-3 heteroatoms selected from N, S, and O, and the heteroaryl is optionally substituted by 1-3 heteroatoms selected from D, ═O, C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHCOC 1-4 Alkyl, OH, CN, NH2 and C 1-4 In some embodiments, each R A is independently a 5-membered heteroaryl substituted by 1-3 halogens, the heteroaryl containing 1-3 heteroatoms selected from N, S, O, the heteroaryl being optionally substituted by 1-3 heteroatoms selected from D, ═O, C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHCOC 1-4 Alkyl, OH, CN, NH2 and C 1-4 In some embodiments, each R A is independently a 5-membered heteroaryl substituted by 1, 2 or 3 halogens, said heteroaryl containing 1, 2 or 3 heteroatoms selected from N, S, O, said heteroaryl being optionally substituted by 1, 2 or 3 heteroatoms selected from D, ═O, C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHCOC 1-4 Alkyl, OH, CN, NH2 and C 1-4 In some embodiments, each R A is independently a 5-membered heteroaryl substituted by 1, 2 or 3 F or Cl atoms, the heteroaryl containing 1, 2 or 3 heteroatoms selected from N, S, O, the heteroaryl being optionally substituted by 1, 2 or 3 groups selected from D, =O, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH3, -CH(CH3)CH2CH3, OH, CN, NH2; in some embodiments, each R Ais independently a 5-membered heteroaryl substituted with 1, 2 or 3 F, the heteroaryl containing 1, 2 or 3 heteroatoms selected from N, S, O, the heteroaryl 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; in some embodiments, each R A is independently a 5-membered heteroaryl substituted by 1 F, said heteroaryl containing 1, 2 or 3 heteroatoms selected from N, S, and O, said heteroaryl being optionally substituted by 1, 2 or 3 groups selected from D, =O, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH3, -CH(CH3)CH2CH3, OH, CN, and NH2;

[0014] In some embodiments, R A Each independently selected from

[0015] m is 0 or 1; in some embodiments, m is 0; in some embodiments, m is 1;

[0016] Wherein, the compound is not

[0017] Specifically, the first technical solution of the present invention provides a compound represented by Formula I, a stereoisomer or a pharmaceutically acceptable salt thereof,

[0018] in,

[0019] Ring A is selected from

[0020] R1 is C 1-4 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1-3 groups selected from D, halogen, OH, CN, and NH2;

[0021] R2 is -CONHR A 、-NHCOR A ;

[0022] Each R A is independently a 5-6 membered heteroaryl substituted by 1-3 halogens, wherein the heteroaryl contains 1-3 heteroatoms selected from N, S, and O, and the heteroaryl is optionally substituted by 1-3 heteroatoms selected from D, ═O, C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHCOC1-4 Alkyl, OH, CN, NH2 and C 1-4 haloalkyl radical substitution;

[0023] Wherein, the compound is not

[0024] The second technical solution of the present invention is that the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts,

[0025] in,

[0026] Ring A is selected from

[0027] R1 is methyl, ethyl, isopropyl, cyclopropyl, or cyclobutyl, and the methyl, ethyl, isopropyl, cyclopropyl, or cyclobutyl is optionally substituted by 1, 2, or 3 groups selected from D, F, Cl, OH, CN, or NH2;

[0028] Each R A It is independently a 5-membered heteroaryl substituted by 1, 2 or 3 F or Cl, said heteroaryl containing 1, 2 or 3 heteroatoms selected from N, S, O, said heteroaryl being optionally substituted by 1, 2 or 3 groups selected from D, =O, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH3, -CH(CH3)CH2CH3, OH, CN, NH2.

[0029] The third technical solution of the present invention is a compound represented by formula I-1, a stereoisomer or a pharmaceutically acceptable salt thereof,

[0030] in,

[0031] Ring A is selected from

[0032] R1 is C 1-4 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1-3 groups selected from D, halogen, OH, CN, and NH2;

[0033] R2 is -CONHR A 、-NHCOR A ;

[0034] Each R A Independently C 3-6 Cycloalkyl, 5-6 membered heteroaryl substituted by 1-3 halogens, said heteroaryl containing 1-3 heteroatoms selected from N, S, O, said heteroaryl optionally substituted by 1-3 heteroatoms selected from D, =O, C 1-4 Alkyl, C 1-4 Alkoxy, -NHC1-4 Alkyl, -CONHC 1-4 Alkyl, -NHCOC 1-4 Alkyl, OH, CN, NH2 and C 1-4 The cycloalkyl group is substituted by at least one =CH2, =CF2, =CHF, =CH(C 1-6 alkyl), =C(C 1-6 alkyl) 2; in some embodiments, each R A is independently a 5-6 membered heteroaryl group substituted by 1-3 halogens, C 3-6 Cycloalkyl, the heteroaryl contains 1-3 heteroatoms selected from N, S, O, and the heteroaryl is optionally substituted by 1-3 heteroatoms selected from D, ═O, C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHCOC 1-4 Alkyl, OH, CN, NH2 and C 1-4 The cycloalkyl group is substituted with at least one =CH2 or =CF2;

[0035] m is 0 or 1;

[0036] Wherein, the compound is not

[0037] The fourth technical solution of the present invention is that the compound of formula (I-1), its stereoisomers or pharmaceutically acceptable salts,

[0038] Among them, ring A is selected from

[0039] R1 is C 1-2 Alkyl, C 3-4 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with 1-3 groups selected from D, F, Cl, OH, CN, and NH2; in some specific embodiments, R1 is methyl, ethyl, isopropyl, cyclopropyl, or cyclobutyl, wherein the methyl, ethyl, isopropyl, cyclopropyl, or cyclobutyl is optionally substituted with 1, 2, or 3 groups selected from D, F, Cl, OH, CN, and NH2;

[0040] Each R A is independently a 5-6 membered heteroaryl group substituted by 1-3 halogens, C 3-6 Cycloalkyl, the heteroaryl contains 1-3 heteroatoms selected from N, S, O, and the heteroaryl is optionally substituted by 1-3 heteroatoms selected from D, ═O, C 1-4 Alkyl, OH, CN, NH2 and C 1-2The cycloalkyl group is substituted by 1 =CH2, =CF2, =CHF, =CH(C 1-2 alkyl), =C(C 1-2 alkyl) 2; in some embodiments, each R A is independently a 5-membered heteroaryl substituted by 1, 2 or 3 F or Cl groups, The heteroaryl group contains 1, 2 or 3 heteroatoms selected from N, S, and O, and the heteroaryl group is optionally substituted by 1, 2 or 3 groups selected from D, =O, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH3, -CH(CH3)CH2CH3, OH, CN, and NH2; in some specific embodiments, each R A is independently a 5-membered heteroaryl substituted by 1, 2 or 3 F or Cl groups, The heteroaryl group contains 1, 2 or 3 heteroatoms selected from N, S, and O, and the heteroaryl group is optionally substituted by 1, 2 or 3 groups selected from D, =O, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH3, -CH(CH3)CH2CH3, OH, CN, and NH2.

[0041] The fifth technical solution of the present invention is that the compound of formula (I) or formula (I-1), its stereoisomer or pharmaceutically acceptable salt,

[0042] in,

[0043] Ring A is selected from The left side of the "*" end is connected to the right side;

[0044] R1 is selected from -CH3, -CH2CH3, -CHF2;

[0045] R A Each independently selected from

[0046] The sixth technical solution of the present invention is that the compound of formula I, its stereoisomers or pharmaceutically acceptable salts,

[0047] Ring A is selected from The left side of the "*" end is connected to the right side;

[0048] R1 is selected from -CH3, -CH2CH3, -CHF2;

[0049] R A Each independently selected from

[0050] The seventh technical solution of the present invention is the compound of formula I-1, its stereoisomers or pharmaceutically acceptable salts,

[0051] Ring A is selected from The left side of the "*" end is connected to the right side;

[0052] R1 is selected from -CH3, -CH2CH3, -CHF2;

[0053] m is selected from 1;

[0054] R A Each independently selected from

[0055] The compound of the present invention, its stereoisomer or pharmaceutically acceptable salt, wherein the structure of the compound is selected from one of the following structures:

[0056] The present invention also provides a pharmaceutical composition comprising a compound according to any of the aforementioned technical solutions, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient. The present invention also provides a use of a compound according to any of the aforementioned technical solutions, a stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above in the preparation of a medicament for treating / preventing PARP1-mediated diseases.

[0057] The PARP1-mediated disease of the present invention is selected from breast cancer, uterine cancer, cervical cancer, ovarian cancer and prostate cancer.

[0058] The present invention also provides a method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of the aforementioned compound, its stereoisomers or pharmaceutically acceptable salts, and a pharmaceutically acceptable excipient and / or carrier, wherein the therapeutically effective amount is preferably 1-1440 mg, and the disease is preferably breast cancer, uterine cancer, cervical cancer, ovarian cancer and prostate cancer.

[0059] The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention, or a stereoisomer or pharmaceutically acceptable salt or pharmaceutical composition thereof. In some embodiments, the mammal of the present invention includes a human.

[0060] As used herein, an "effective amount" or "therapeutically effective amount" refers to the administration of a sufficient amount of a compound disclosed herein to alleviate, 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 a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective amounts include, but are not limited to, 1-1440 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1-20 mg, 5-1000 mg, 5-900 mg, 5-800 mg, 5-700 mg, 5-600 mg, 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, 10-12 5mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-60 0mg, 20-500mg, 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, 20-40mg, 20-30mg; 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg , 50-125mg, 50-100mg; 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg.

[0061] The present invention relates to a pharmaceutical composition or pharmaceutical preparation comprising a therapeutically effective amount of a compound of the present invention, or a stereoisomer or pharmaceutically acceptable salt thereof, and an excipient and / or carrier. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as the "drug strength"). In some embodiments, the pharmaceutical composition includes but is not limited to 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, 0mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1440mg of a compound of the present invention or a stereoisomer, solvate, deuterated substance, or pharmaceutically acceptable salt thereof.

[0062] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and / or carrier, wherein the therapeutically effective amount is preferably 1-1440 mg. The disease is preferably breast cancer, uterine cancer, cervical cancer, ovarian cancer, and prostate cancer.

[0063] A method for treating a disease in a mammal, comprising administering a compound of the present invention, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and / or carrier to a subject at a daily dose of 1-1440 mg / day, wherein the daily dose may be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1440 mg / day, 20-1440 mg / day, 25-1440 mg / day, 50-1440 mg / day, 75-1440 mg / day, 100-1440 mg / day, 200-1440 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-10 In some embodiments, daily doses include but are not limited to 1 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 100 mg / day, 200 mg / day, 250 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 750 mg / day, 1000 mg / day, 1000 mg / day, 2000 mg / day, 2500 mg / day, 500 mg / day, 1500 mg / day, 2000 mg / day, 400 mg / day, 600 mg / day, 750 mg / day, 1000 mg / day, 2000 mg / day, 2500 mg / day, 5000 mg / day, 10000 mg / day, 20000 mg / day, 2500 mg / day, 5000 mg / day, 15000 mg / day, 20000 mg / day, 4000 mg / day, 6000 mg / day, 6000 mg / day, 7500 mg / day, 10000 mg / day, 20000 mg / day, 25000 mg / day, day, 800 mg / day, 1000 mg / day, 1200 mg / day, 1400 mg / day, 1440 mg / day.

[0064] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer or a pharmaceutically acceptable salt thereof, and the amount of the compound of the present invention or its stereoisomer or pharmaceutically acceptable salt is the same as that in the above-mentioned pharmaceutical composition.

[0065] The amount of the compound of the invention or its stereoisomer or pharmaceutically acceptable salt in the present invention is in each case calculated as the free base.

[0066] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0067] Synthesis route

[0068] Patent documents such as WO2021013735A1 describe methods for preparing PARP-1 inhibitors. Those skilled in the art can combine this document with known organic synthesis techniques to prepare the compounds of the present invention, starting with commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are obtained from legitimate commercial sources, and suppliers include companies such as Titan Technology, Anage Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and J&K Technology.

[0069] Reference books and monographs in the field detail the synthesis of reactants that can be used to prepare the compounds described herein, or provide reference to articles describing such preparations. Specific and similar reactants can be selectively identified through indexes of known chemical substances prepared by the American Chemical Society's Chemical Abstracts Service, which are available in most public and university libraries and online. Chemicals that are known but not commercially available in the catalog are optionally prepared by custom chemical synthesis facilities, with many standard chemical supply houses (e.g., those listed above) offering custom synthesis services.

[0070] the term

[0071] Unless otherwise specified in the present invention, the terms of the present invention have the following meanings:

[0072] The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, that is, the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (deuterium, also known as heavy hydrogen), tritium (T, also known as super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, an isotope of fluorine 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0073] "Halogen" herein refers to F, Cl, Br, I, or isotopes thereof.

[0074] "Halo" or "halogen-substituted" refers to substitution with one or more halogens selected from F, Cl, Br, I, or isotopes thereof. The upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be replaced by the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. When the number of halogen substituents is greater than 1, they may be the same or different halogens. Typical examples include 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, and 1 halogen substitution.

[0075] "Deuterium" refers to the isotope of hydrogen (H) and is synonymous with "D".

[0076] "Deuterated" or "deuterated compound" refers to a situation where a hydrogen atom on an alkyl, cycloalkyl, alkylene, aryl, heteroaryl, thiol, heterocycloalkyl, alkenyl, alkynyl or other group is replaced by at least one deuterium atom. The upper limit of the number of deuterated groups is equal to the sum of the number of replaceable hydrogen atoms in the substituted group. Unless otherwise specified, the number of deuterated groups is any integer between 1 and the upper limit, for example, 1-20 deuterium atoms, 1-10 deuterium atoms, 1-6 deuterium atoms, 1-3 deuterium atoms, 1-2 deuterium atoms or 1 deuterium atom.

[0077] “C x-y " group refers to a group containing x to y carbon atoms, such as "C 1-6 "Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms, and "C0" generally refers to a bond.

[0078] "Alkyl" refers to a monovalent straight-chain or branched saturated aliphatic hydrocarbon group. Typically, it is an alkyl group having 1 to 20 carbon atoms, or an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 6 carbon atoms, or an alkyl group having 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like. The alkyl group may be further substituted with a substituent.

[0079] "Alkylene" refers to a divalent straight-chain or branched saturated alkyl group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, and the like.

[0080] "Haloalkyl" refers to a situation where one or more hydrogen atoms in an alkyl group are replaced by one or more halogen atoms (such as fluorine, chlorine, bromine, iodine, or their isotopes). The upper limit of the number of halogen substituents is equal to the sum of the number of replaceable hydrogen atoms in the alkyl group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. Typically, an alkyl group is substituted with 1-5 halogens, or 1-3 halogens, or 1-2 halogens, or 1 halogen. When the number of halogen substituents is greater than 1, they can be the same or different halogens. Specific examples include, but are not limited to, -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, etc.

[0081] "Alkoxy" or "alkyloxy" refers to an -O-alkyl group. For example, -OC 1-8 Alkyl, -OC 1-6 Alkyl, -OC 1-4 Alkyl or -OC 1-2 Specific non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy, and cyclobutyloxy, and the like; the alkoxy groups may be optionally substituted with substituents.

[0082] "Haloalkoxy" refers to an -O-haloalkyl group. For example, -O-haloC 1-8 Alkyl, -O-halogenated C 1-6 Alkyl, -O-halogenated C 1-4 Alkyl or -O-halogenated C 1-2 Alkyl; the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be substituted by the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit, preferably 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, or 1 halogen substitution; when the number of halogen substituents is greater than 1, they may be the same or different halogen substitutions; non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.

[0083] "Alkenyl" refers to a straight or branched chain hydrocarbon group containing at least one carbon-carbon double bond (C=C), typically containing 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, and further such as 2 to 4 carbon atoms, examples of which include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-4-butenyl, 2-methyl-5-butenyl, 2-methyl-6-butenyl, 2-methyl-7-butenyl, 2-methyl-8-butenyl, 2-methyl-9-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3 ... -methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group may be optionally further substituted with a substituent.

[0084] "Alkynyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon triple bond (C≡C), typically containing 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, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, and 4-decynyl. The alkynyl group may be optionally substituted with a substituent.

[0085] "Cycloalkyl" refers to a saturated or partially unsaturated, non-aromatic carbocyclic hydrocarbon group containing no ring heteroatoms. Cycloalkyl can be monocyclic, bicyclic or polycyclic. Bicyclic or polycyclic rings can be cyclic, spirocyclic, bridged or a combination thereof. Bicyclic or polycyclic rings can include one or more aromatic rings, but the ring system as a whole does not have aromaticity, and the connection point is on the non-aromatic ring. Usually, the cycloalkyl group contains 3 to 20 carbon atoms, further contains 3-8 carbon atoms, and further contains 3-6 carbon atoms; when it is a monocyclic cycloalkyl group, it contains 3-15 carbon atoms, or 3-10 carbon atoms, or 3-8 carbon atoms, or 3-6 carbon atoms; when it is a bicyclic or polycyclic cycloalkyl group, it contains 5-12 carbon atoms, or 5-11 carbon atoms, or 6-10 carbon atoms; non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, butenyl, cyclopentenyl, cyclohexenyl, The cycloalkyl group may be optionally substituted with a substituent.

[0086] "Aryl" refers to a carbocyclic ring having aromaticity and not containing heteroatoms, including monocyclic aryl and condensed ring aryl. It generally contains 6 to 14 carbon atoms, and further contains 6 to 10 carbon atoms. Non-limiting examples include phenyl, naphthyl, anthracenyl, and phenanthrenyl. Aryl can optionally be substituted with a substituent.

[0087] "Heteroaromatic ring" or "heteroaryl" unless otherwise specified refers to a ring containing 1 to 4 heteroatoms selected from N, O or S and their oxidation states and having aromatic properties, which may be monocyclic, bicyclic or polycyclic, and the bicyclic or polycyclic rings may be bridged, parallel, spirocyclic or combinations thereof; when bicyclic or polycyclic, it may be a fusion of a heteroaryl and an aryl, or a fusion of a heteroaryl and a heteroaryl, wherein either the heteroaryl or the aryl may be a connection site. Non-limiting examples include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, purinyl, The heteroaryl group may be optionally substituted by a substituent.

[0088] "Heterocycle" or "heterocyclyl" 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, and includes heteroaryl and heterocycloalkyl. Heterocycles include monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic heterocycles, and bicyclic spiro heterocycles, or combinations thereof. Heterocycles are typically 3- to 12-membered heterocycles, 5- to 12-membered heterocycles, or 5- to 7-membered heterocycles. The heterocyclic group may be attached to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, piperazinyl, azepanyl, pyridinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl , dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl, The heterocyclic ring may be optionally substituted with a substituent.

[0089] "Substitution" or "substituent" unless otherwise specified refers to any substitution at a position permitted by chemical theory, and the number of substituents complies with the chemical bond rules. Exemplary substituents include but are not limited to: C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Heteroalkyl, C 5-12 Aryl, 5-12 membered heteroaryl, hydroxyl, C 1-6 Alkoxy, C 5-12 Aryloxy, thiol, C 1-6 Alkylthio, cyano, halogen, C 1-6 Alkylthiocarbonyl, C 1-6 Alkylcarbamoyl, N-carbamoyl, nitro, silyl, sulfinyl, sulfonyl, sulfoxide, halo 1-6 Alkyl, halogenated C 1-6 Alkoxy, amino, 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 Alkyl, etc.

[0090] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0091] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that retain the biological effectiveness and properties of the free acids or free bases, and the free acids are reacted with non-toxic inorganic or organic bases, or the free bases are reacted with non-toxic inorganic or organic acids.

[0092] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or stereoisomers, solvates, pharmaceutically acceptable salts or cocrystals thereof, with other ingredients, wherein the other ingredients include physiologically / pharmaceutically acceptable carriers and / or excipients.

[0093] "Carrier" refers to a system that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug and deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0094] An "excipient" is a substance that is not itself a therapeutic agent but serves as a diluent, adjuvant, binder, and / or vehicle that is added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate the formation of a compound or pharmaceutical composition into a unit dosage form for administration. As known to those skilled in the art, pharmaceutical excipients can serve a variety of functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and sweeteners. Examples of pharmaceutical excipients include, but are not limited to: (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, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, and cross-linked carboxymethylcellulose (e.g., cross-linked sodium carboxymethylcellulose); (4) tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn starch, and maltodextrin. oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, 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) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solutions; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other non-toxic compatible substances used in pharmaceutical preparations.

[0095] "Isomers" include "stereoisomers" and "tautomers". "Stereoisomers" refer to isomers produced by the same order of connection of atoms or atomic groups in molecules, but different ways of arrangement in space. Stereoisomers include cis-trans isomers, optical isomers, and conformational isomers. "Tautomers" refer to the transformation of one functional group into another functional group that can be converted into each other through a reversible chemical reaction called tautomerization, usually caused by the concomitant migration of hydrogen atoms and π bonds (double bonds or triple bonds). For example, the following pairs of compounds: aldehyde / ketone-enol, imine-enamine.

[0096] "Solvate" refers to a substance formed by a compound of the present invention or a salt thereof and a stoichiometric or non-stoichiometric amount of a solvent bound to the compound or salt thereof by non-covalent forces between the molecules. When the solvent is water, the solvate is a hydrate.

[0097] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate. DETAILED DESCRIPTION

[0098] The technical solution of the present invention is described in detail below in conjunction with the examples, but the scope of protection of the present invention includes but is not limited to this. The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10-6 (ppm). NMR measurements are performed using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometer, and the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS);

[0099] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0100] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0101] Thin layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.20 mm, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm.

[0102] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0103] Brief description:

[0104] DIPEA: N,N-diisopropylethylamine

[0105] HATU: 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0106] DMF: N,N-dimethylformamide

[0107] DCM: dichloromethane

[0108] Example 1

[0109] Step 1: Compound 1A (synthesized according to patent US2022009901 A1) (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 reaction was stirred at room temperature for 2 h. The solvent was removed by distillation under reduced pressure to obtain a white powdery solid 1B (3.38 g, 100%), which was directly used in the next step without purification.

[0110] LC-MS (ESI): m / z = 324.2 [MH] - .

[0111] Step 2: Compound 1B (324 mg, 1 mmol) and compound 1C (115 mg, 1 mmol; synthesized according to patent WO 2022 / 212538A1) were dissolved in DMF (5 mL), and HATU (380 mg, 1 mmol) was added. The reaction was allowed to react at room temperature for 16 h. The reaction system was poured into water (50 mL), and a large amount of product solid precipitated. The product was filtered and dried to obtain crude compound 1D (450 mg).

[0112] LC-MS (ESI): m / z = 421.4 [MH] -

[0113] Step 3: Dissolve 450 mg of crude compound 1D in a mixed solvent of DCM / TFA = 10 / 1, stir and react at room temperature for 16 h. Concentrate the reaction system to obtain the trifluoroacetic acid salt of crude compound 1E (360 mg).

[0114] LC-MS (ESI): m / z = 323.4 [M+H] +

[0115] Step 4: The crude trifluoroacetic acid salt of compound 1E (180 mg) and compound 1F (143 mg, 0.5 mmol; synthesized according to patent WO 2021 / 260092 Al) were dissolved in acetonitrile (10 mL), and DIPEA (1 mL) was added. The reaction system was heated to 65°C and reacted for 16 hours. The reaction system was concentrated and separated by column chromatography (petroleum ether:ethyl acetate (v:v) = 1:2) to obtain compound 1 (77 mg, 29%).

[0116] LC-MS (ESI): m / z = 527.2 [M+H] +

[0117] 1 H NMR(400MHz,DMSO-d6)δ12.42(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).

[0118] Example 2

[0119] The first step: Compound 2A (synthesized according to patent US2022009901 A1) (1.3 g, 4.96 mmol) was dissolved in a mixed solution of anhydrous ethanol (26 mL) and water (2 mL), and ammonium chloride solid (3.18 g, 59.47 mmol) and zinc powder (3.24 g, 49.6 mmol) were added sequentially under stirring at room temperature. After the addition was completed, the reaction was reacted at room temperature for 90 minutes, and the reaction was monitored by LCMS. After the reaction was completed, saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (100 mL). Ethyl acetate (100 mL) was added to the filtrate, the aqueous phase was separated, and 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%).

[0120] LCMS m / z=265.2[M+H] +

[0121] 1H NMR (400MHz, DMSO-d6) δ10.96(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).

[0122] Step 2: Compound 2B (1.0 g, 3.79 mmol) was dissolved in tetrahydrofuran (20 mL). 25% (w / w) aqueous sodium hydroxide solution (5 mL) was added to the reaction solution with stirring at room temperature. After the addition was complete, the mixture was heated at 50°C for 2 h. 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 solution, and the organic phase was separated. The aqueous phase was adjusted to pH 6 with hydrochloric acid (6 mol / L hydrochloric acid) to precipitate a large amount of solid, which was filtered and the filter cake was dried to obtain the target compound 2C (0.7 g, yield: 75.64%).

[0123] LCMS m / z=245.2[M+H] +

[0124] 1 H NMR (400MHz, DMSO-d6) δ12.97(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).

[0125] 19 F NMR(400MHz,DMSO-d6)δ-122.41(s),-123.46(s).

[0126] Step 3: Compound 2C (488 mg, 2.0 mmol) was dissolved in dichloromethane (20 mL) and cooled to 0°C. Triphenylphosphine (1.57 g, 6.0 mmol) and carbon tetrabromide (1.98 g, 6.0 mmol) were added sequentially. After the addition was complete, the ice bath was removed, and the mixture was naturally warmed to room temperature and stirred at this temperature for 2 h. The reaction was monitored by LCMS. After completion of the reaction, it was directly 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%).

[0127] LC-MS(ESI):m / z=307.2,309.2[M+H] + .

[0128] Step 4: The crude trifluoroacetic acid salt of 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 for 16 h. The reaction system was concentrated and separated by column chromatography (petroleum ether:ethyl acetate (v:v) = 1:2) to obtain compound 2 (80 mg, 29%).

[0129] LC-MS (ESI): m / z = 549.2 [M+H] +

[0130] 1 H NMR(400MHz,DMSO-d6)δ13.00(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).

[0131] Example 3

[0132] Step 1: Compound 1B (3.01 g, 9.24 mmol) was added to a reaction flask and dissolved in DMF (30 ml). DIPEA (21 ml, 121.6 mmol) and HATU (5.6 g, 14.73 mmol) were then added and stirred at room temperature for 20 min. Finally, compound 3A (1.4 g, 9.24 mmol) (synthesized according to patent WO2020249664A1) was added and reacted at room temperature for 1 hour. After completion of the reaction, the mixture was purified by silica gel column chromatography (PE:EA (v:v) = 2:1) to obtain compound 3B (1.1 g, 28.20% yield).

[0133] LC-MS (ESI): m / z = 423.7 [M+H] + .

[0134] Step 2: Compound 3B (1.1 g, 2.60 mmol) was added to a reaction flask and dissolved in DCM (30 ml). Trifluoroacetic acid (10 ml) was then added and allowed to react at room temperature for 1 hour. After completion of the reaction, as monitored 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 dried to afford the crude trifluoroacetic acid salt of compound 3C (800 mg), which was then directly processed into the next step.

[0135] LC-MS (ESI): m / z = 323.3 [M+H] + .

[0136] Step 3: The trifluoroacetic acid salt 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 a reaction flask, dissolved in ACN (20 ml), and reacted at 70°C for 2 hours. After completion of the reaction, as monitored by TLC, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH (v:v) = 10:1) to provide compound 3 (142 mg, 20.88% yield).

[0137] 1 H NMR(400MHz,DMSO-d6)δ9.91(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).

[0138] LC-MS (ESI): m / z = 549.1 [M+H] + .

[0139] Example 4

[0140] Step 1: The trifluoroacetic acid salt 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 completion of the reaction, monitored by TLC, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH (v:v) = 10:1) to provide compound 4 (57 mg, 8.73% yield).

[0141] 1 H NMR(400MHz,DMSO-d6)δ9.91(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).

[0142] LC-MS (ESI): m / z = 527.2 [M+H] + .

[0143] Example 5

[0144] Step 1: To a 100 mL eggplant-shaped flask, add methyl 1-methyl-1H-pyrazole-4-carboxylate (5.2 g, 30 mmol) and AgF2 (17.5 g, 120 mmol), followed by acetonitrile (40 mL). The mixture was allowed to react overnight at room temperature under N2 protection. Filter through a pad of Celite, wash the filter residue with ethyl acetate, and concentrate the filtrate. The resulting residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 10:1) to obtain the title compound 5A (3.9 g, 82.3%).

[0145] LC-MS (ESI): m / z = 159.2 [M+H] + .

[0146] Step 2: Compound 5A (1 g, 6.3 mmol) was weighed and dissolved in tetrahydrofuran (20 mL). 2M lithium hydroxide solution (4 mL) was added with stirring and allowed to react at room temperature overnight. After complete conversion of the starting material as determined by LCMS, the pH was adjusted to 5-6 with 1M hydrochloric acid. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate, and concentrated. The resulting residue was recrystallized (petroleum ether:ethyl acetate (v:v) = 4:1) to yield the target compound 5B (624 mg, 68.1%).

[0147] LC-MS (ESI): m / z = 143.2 [MH] - .

[0148] Step 3: Compound 5B (144 mg, 1 mmol) was weighed into a 25 mL eggplant-shaped flask, and dichlorothionyl (5 mL) was added. The mixture was refluxed at 60°C for 2 h. After concentration, the target compound 5C (142 mg, crude product) was obtained and used directly in the next step without further purification.

[0149] Step 4: Compound 5D (4 g, 21 mmol) was dissolved in dichloromethane (50 mL), and pyridine (2.5 mL, 32 mmol) and acetyl chloride (1.7 mL, 23 mmol) were added at room temperature. After TLC detection of the disappearance of the starting material, the system was concentrated and slurried with ethyl acetate / petroleum ether (v:v) = 1 / 15 (160 mL) to give compound 5E (4 g, 90%).

[0150] LC-MS (ESI): m / z = 233.1 [M+H] +

[0151] Step 5: 5E (4 g, 17 mmol), N-Boc-piperazine (3.8 g, 21 mmol), Pd 2( dba)3 (1.6 g, 1.7 mmol), RuPhos (1.4 g, 3.2 mmol) and t-BuOK (4.8 g, 43 mmol) were placed in a round-bottom flask, and 100 mL of 1,4-dioxane was added. After replacing the nitrogen atmosphere, the temperature was raised to reflux and stirred overnight. After cooling to room temperature, silica gel was added, concentrated, and separated by column chromatography (PE:EA (v:v) = 5:1 to 1:3) to obtain compound 5F (1.1 g, 19%).

[0152] LC-MS (ESI): m / z = 338.1 [M+H] +

[0153] 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 to obtain a crude trifluoroacetate salt of compound 5G (744 mg), which was directly used for the next step.

[0154] LC-MS (ESI): m / z = 238.2 [M+H] +

[0155] Step 7: Dissolve the crude compound 5G (744 mg) and 2D (675 mg, 2.2 mmol) in 30 mL of acetonitrile, add 6 mL of DIPEA, and heat to 60°C for 2 h. After cooling to room temperature, most of the acetonitrile was concentrated to dryness, and the product was separated by reverse phase column chromatography (water / acetonitrile (v:v) = 1:1) to give compound 5H (320 mg, 27%, 2 steps).

[0156] LC-MS (ESI): m / z = 464.1 [M+H] +

[0157] Step 8: Dissolve compound 5H (320 mg, 0.76 mmol) in 12 mL of a 2:1 mixed solvent of concentrated hydrochloric acid and ethanol, heat to 70°C, and react for 1 h. After cooling to room temperature, the mixture was concentrated to dryness to obtain crude compound 5I hydrochloride (410 mg), which was directly used in the next step.

[0158] LC-MS (ESI): m / z = 422.2 [M+H] +

[0159] Step 9: Disperse crude 5I (410 mg) in dichloromethane (10 mL), add pyridine (2 mL), and add a dichloromethane solution (5 mL) of 5C (142 mg, crude) dropwise with stirring. The mixture is allowed to react at room temperature for 2 h. After concentration, the resulting residue is separated by silica gel column chromatography (dichloromethane:methanol (v:v) = 20:1) to afford compound 5 (147 mg, 35.3%, 2 steps).

[0160] 1 H NMR(400MHz,DMSO-d6)δ12.99(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).

[0161] LC-MS (ESI): m / z = 549.2 [M+H] + .

[0162] Example 6

[0163] Step 1: Compound 6A (10 g, 61 mmol) was dissolved in THF (200 mL). 5 g of sodium hydride (60%) was added at 0°C and stirred for 30 min. Iodomethane (6 mL, 96 mmol) was added, and the mixture was slowly warmed to room temperature for 2 h. The reaction was then quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate, and the organic phase was concentrated and separated by column chromatography (PE:EA = 20:1 to 5:1) to afford compound 6B (6.01 g, 56%).

[0164] 1 H NMR (400MHz, CDCl3) δ7.23-7.21(m,1H),3.77-3.75(m,3H).

[0165] Step 2: Compound 6B (3.42 g, 19 mmol) was dissolved in THF (50 mL) and cooled to -78°C. n-Butyl lithium (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 reaction was maintained at -78°C for 1 h. The mixture was quenched with ethyl acetate and water, followed by extraction with ethyl acetate. The organic phase was collected, concentrated, and separated by column chromatography (PE:EA = 15:1 to 2:1) to afford compound 6C (840 mg, 35%).

[0166] LC-MS (ESI): m / z = 129.1 [M+H] + .

[0167] Step 3: Dissolve compound 6C (400 mg, 2.8 mmol) in 0.375 M KMnO₄ solution, heat to 75°C, and react for 1 h. Cool to room temperature, then add 10% aqueous KOH to alkaline the system, causing the appearance of solids. Filter the filtrate, adjust the pH to 2 with hydrochloric acid, and extract three times with ethyl acetate / methanol (10 / 1) (200 mL). Concentrate the resulting organic phase to yield crude compound 6D (300 mg).

[0168] LC-MS (ESI): m / z = 145.1 [M+H] + .

[0169] Step 4: Add 20 mL of dichloromethane and 10 mL of thionyl chloride to the crude compound 6D. Heat the system to 50°C under a nitrogen atmosphere and react for 1 h. Cool to room temperature and concentrate until no solvent remains to obtain the target compound 6E, which is used directly in the next reaction.

[0170] Step 5: Dissolve the crude compound 5G (1.6 g) and 1F (1.2 g, 4.2 mmol) in 50 mL of acetonitrile, add 6 mL of DIPEA, and heat to 60°C for 2 h. Concentrate to remove the solvent, add water (20 mL), shake thoroughly, and filter. After drying the filter cake, the target compound 6F (768 mg) was obtained.

[0171] LC-MS (ESI): m / z = 443.2 [M+H] + .

[0172] Step 6: Compound 6F (768 mg, 1.73 mmol) was dissolved in 12 mL of a 2:1 mixed solvent of concentrated hydrochloric acid and ethanol. The mixture was heated to 70°C for 1 h. Saturated sodium bicarbonate solution was slowly added dropwise until no bubbles were generated. The mixture was filtered, and the filter cake was washed with water and dried to obtain the target compound 6G (577 mg, 83.8%).

[0173] LC-MS (ESI): m / z = 401.2 [M+H] + .

[0174] Step 7: Disperse 6G (577 mg, 1.44 mmol) in dichloromethane (20 mL), add pyridine (4 mL), and add a dichloromethane solution (5 mL) of 6E (142 mg, crude) dropwise with stirring. The mixture was allowed to react at room temperature for 2 h. The resulting residue was concentrated and separated by silica gel column chromatography (dichloromethane:methanol (v:v) = 20:1) to afford compound 6 (174 mg, 22.9%).

[0175] LC-MS (ESI): m / z = 527.2 [M+H] + .

[0176] 1 H NMR (400MHz, DMSO-d6) δ11.59-10.27(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).

[0177] Example 7

[0178] Step 1: Dissolve compound 7A (1 g, 5.46 mmol) in a mixed solvent of dichloromethane (20 mL) and trifluoroacetic acid (5 mL), stir at room temperature for 4 h, and concentrate the reaction system to obtain the crude trifluoroacetic acid salt of compound 7B (800 mg).

[0179] LC-MS (ESI): m / z = 84.3 [M+H] +

[0180] Step 2: The crude trifluoroacetic acid salt of compound 7B (700 mg, 5.46 mmol) and compound 1B (1.8 g, 1 mmol) were dissolved in DMF (30 mL), and HATU (2.28 g, 6 mmol) was added. The mixture was reacted at room temperature for 16 h. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain compound 7C (1.5 g, 65.7%).

[0181] LC-MS (ESI): m / z = 391.4 [M+H] +

[0182] Step 3: Dissolve compound 7C (300 mg, 0.77 mmol) in a mixed solvent of dichloromethane (6 mL) and trifluoroacetic acid (1.5 mL), stir at room temperature for 4 h, and concentrate the reaction system to obtain a crude trifluoroacetic acid salt of compound 7D (250 mg).

[0183] LC-MS (ESI): m / z = 291.1 [M+H] +

[0184] Step 4: The crude trifluoroacetic acid salt of 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 for 16 h. The reaction system was concentrated and separated by column chromatography (dichloromethane:methanol (v:v) = 20:1) to obtain compound 7 (30 mg, 8.4%).

[0185] LC-MS (ESI): m / z = 517.2 [M+H] +

[0186] 1 HNMR(400MHz,DMSO-d6)δ13.00(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)

[0187] Example 8

[0188] Step 1: 8A (0.5 g, 1.53 mmol, synthesized according to WO2023056039A1), 7B (0.25 g, 3.06 mmol), 2-(7-aza-1H-benzotriazole-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 completion of the reaction, the product was spin-dried and purified by normal phase (petroleum ether: ethyl acetate (v:v) = 4:1) to obtain product 8B (0.3 g, 50%).

[0189] LC-MS(ESI):m / z=336.2[M-56+H] + .

[0190] Step 2: Dissolve 8B (0.25 g, 0.64 mmol) in dichloromethane (4 mL), add trifluoroacetic acid (1.53 g, 13.42 mmol), and react at room temperature for 2 hours. After the reaction is complete, the crude product 8C (0.18 g, crude product) is obtained by direct spin drying.

[0191] LC-MS (ESI): m / z = 292.2 [M+H] + .

[0192] 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, the product was concentrated to dryness and directly spin-dried for HPLC preparation. Method: Instrument: Waters 2767 Preparative HPLC; 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, yielding compound 8 (50 mg, 19%).

[0193] LC-MS (ESI): m / z = 496.2 [M+H] + .

[0194] 1 H NMR(400MHz,DMSO-d6)δ8.80(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).

[0195] Example 9

[0196] 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, then dissolved in acetonitrile (5 ml) and reacted at 50°C for 2 hours. After completion of the reaction, monitored by TLC, the mixture was cooled to room temperature and filtered. The filter cake was washed once with acetonitrile (5 ml) and once with ethyl acetate (10 ml). The filter cake was collected and dried to obtain compound 9 (140 mg, 39.44% yield).

[0197] LC-MS (ESI): m / z = 481.3 [M+H] + .

[0198] 1 H NMR (400MHz, DMSO) δ12.42(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).

[0199] Example 10

[0200] Step 1: The crude trifluoroacetic acid salt of compound 7D (300 mg) and compound 1F (250 mg, 0.88 mmol) were dissolved in acetonitrile (10 mL). DIPEA (1 mL) was added and the reaction system was heated to 50°C for 2 h. The reaction system was concentrated and separated by column chromatography (DCM:MeOH (v:v) = 15:1) to obtain compound 10 (105 mg, 24.14%).

[0201] LC-MS (ESI): m / z = 495.4 [M+H] +

[0202] 1 H NMR(400MHz,DMSO-d6)δ12.43(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).

[0203] Example 11

[0204] 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-dimethylformamide (8 mL) and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water, extracted with ethyl acetate three times, and the combined organic phases were spin-dried and purified by normal phase purification (petroleum ether: ethyl acetate = 4:1) to obtain product 11B (0.18 g, 91.6%).

[0205] LC-MS(ESI):m / z=372.0[M-56+H] + .

[0206] 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 is complete, the crude product 11C (0.027 g, crude product) is obtained by direct spin drying.

[0207] LC-MS (ESI): m / z = 328.2 [M+H] + .

[0208] Step 3: Dissolve 11C (0.027 g, 0.082 mmol), 1F (0.028 g, 0.098 mmol), and diisopropylethylamine (0.042 g, 0.33 mmol) in acetonitrile (5 mL) and react at 50°C for 3 hours. After completion, concentrate to dryness and purify using preparative HPLC. Method: Instrument: Waters 2767 preparative HPLC; 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, yielding compound 11 (11 mg, 25%).

[0209] LC-MS (ESI): m / z = 532.7 [M+H] + .

[0210] 1H NMR(400MHz,DMSO-d6)δ8.96(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).

[0211] Example 12

[0212] Step 1: Compound 1B (950 mg, 2.86 mmol) was dissolved in DMF (10 mL). HATU (1.53 g, 4.03 mmol), diisopropylethylamine (2 mL), and compound 11A (400 mg, 3.36 mmol) were then added sequentially. The mixture was allowed to react at room temperature for 16 h. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was slurried with a mixture of ethyl acetate and petroleum ether (EA:petroleum ether = 1:2), filtered, and dried to obtain the target compound 12A (826 mg, 56.98%).

[0213] LC-MS (ESI): m / z = 427.2 [M+H] + .

[0214] Step 2: Compound 12A (213 mg, 0.5 mmol) was weighed into dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. After the addition was complete, the mixture was stirred at room temperature for 2 h. The dichloromethane and excess trifluoroacetic acid were concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 12B (160 mg). The crude product was used directly in the next reaction.

[0215] LC-MS (ESI): m / z = 327.1 [M+H] + .

[0216] Step 3: Weigh the trifluoroacetate salt of compound 12B (160 mg) and dissolve it in acetonitrile (20 mL). Then add diisopropylethylamine (2 mL) and compound 9A (140 mg, 0.5 mmol). After the addition is complete, heat to 65°C and react for 3 h. After the reaction is complete, directly filter it hot. Wash the filter cake with acetonitrile and dry it to obtain the target compound 12 (160 mg, 62.01%).

[0217] LC-MS (ESI): m / z = 517.2 [M+H] + .

[0218] 1 H NMR (400MHz, DMSO-d6) δ12.43(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).

[0219] Example 13

[0220] Step 1: The crude trifluoroacetic acid salt of compound 12B (250 mg) and compound 1F (142 mg, 0.5 mmol) were dissolved in acetonitrile (10 mL). DIPEA (322 mg, 2.5 mmol) was added and the reaction system was heated to 65°C for 2 h. The reaction system was concentrated and separated by column chromatography (dichloromethane:methanol (v:v) = 20:1) to obtain compound 13 (140 mg, 52.8%).

[0221] LC-MS (ESI): m / z = 531.3 [M+H] +

[0222] 1 H NMR(400MHz,DMSO-d6)δ12.43(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)

[0223] Example 15

[0224] Step 1: Compound 1B (170 mg, 0.51 mmol), 3-(difluoromethylene)cyclobutylamine trifluoroacetate (180 mg, 0.76 mmol, synthesized according to patent WO2023025324A1) and DIPEA (0.9 ml, 5.10 mmol) were added to the reaction flask, dissolved with DMF (10 ml), and then HATU (230 mg, 0.61 mmol) was added and reacted at room temperature for 2 hours. After TLC monitoring, the reaction was diluted with water (50 ml). It was then extracted twice with ethyl acetate (40 ml × 2), the organic phases were combined and dried, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EA = 1: 1) to give compound 15A (180 mg, yield: 84.51%).

[0225] LC-MS (ESI): m / z = 419.1 [M+H] + .

[0226] Step 2: Compound 15A (180 mg, 0.43 mmol) was added to a reaction flask and dissolved in DCM (10 ml). Trifluoroacetic acid (1 ml) was then added and allowed to react at room temperature for 3 hours. After completion of the reaction, as monitored by TLC, the mixture was concentrated under reduced pressure to afford compound 15B (200 mg, trifluoroacetate salt, used directly in the next step).

[0227] LC-MS (ESI): m / z = 319.1 [M+H] + .

[0228] Step 3: Compound 15B (200 mg, 0.46 mmol) and compound 2D (140 mg, 0.46 mmol) were added to a reaction flask and dissolved in acetonitrile (10 ml). DIPEA (0.4 ml, 2.30 mmol) was then added and the mixture was reacted at 80°C for 3 hours. After completion of the reaction, as monitored by TLC, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified on a C18 column (A / B = 0.1% AcONH4 in H2O / ACN, B: 10% to 60%) to afford compound 15 (52 mg, 20.80% yield).

[0229] 1H NMR(400MHz,DMSO-d6)δ8.65-8.55(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).

[0230] LC-MS (ESI): m / z = 545.4 [M+H] + .

[0231] Example 16

[0232] Step 1: Dissolve 8C (0.15 g, 0.51 mmol), 2D (0.17 g, 0.56 mmol), and N,N-diisopropylethylamine (0.2 g, 1.53 mmol) in acetonitrile (8 mL). The mixture was reacted at 55°C for 3 hours. After completion, the mixture was directly dried and then purified by HPLC. Method: Instrument: Waters 2767 Preparative HPLC; 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, yielding compound 16 (70 mg, 26%).

[0233] LC-MS (ESI): m / z = 518.3 [M+H] + .

[0234] 1 H NMR(400MHz,Chloroform-d)δ10.00(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).

[0235] Example 17

[0236] The first step: Compound 8A (150 mg, 0.46 mmol), 3-(difluoromethylene)cyclobutylamine trifluoroacetate (160 mg, 0.69 mmol, synthesized according to patent WO2023025324A1) and DIPEA (0.8 ml, 4.60 mmol) were added to the reaction flask, dissolved with DMF (10 ml), and then HATU (210 mg, 0.55 mmol) was added and reacted at room temperature for 2 hours. After the reaction was completed by TLC monitoring, water (50 ml) was added for dilution. It was then extracted twice with ethyl acetate (40 ml × 2), the organic phases were combined and dried, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EA = 1: 1) to give compound 17A (80 mg).

[0237] LC-MS(ESI):m / z=364.1[M-56+H] + .

[0238] Step 2: Compound 17A (80 mg, 0.19 mmol) was added to a reaction flask and dissolved in DCM (5 ml). Trifluoroacetic acid (0.5 ml) was then added and allowed to react at room temperature for 3 hours. After completion of the reaction, as monitored by TLC, the mixture was concentrated under reduced pressure to afford compound 15B (100 mg, trifluoroacetate salt, used directly in the next step).

[0239] LC-MS (ESI): m / z = 320.3 [M+H] + .

[0240] Step 3: Compound 17B (100 mg, 0.23 mmol) and compound 1F (65 mg, 0.23 mmol) were added to a reaction flask and dissolved in acetonitrile (10 ml). DIPEA (0.2 ml, 1.15 mmol) was then added and the mixture was reacted at 80°C for 3 hours. After completion of the reaction, as monitored by TLC, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified on a C18 column (A / B = 0.1% AcONH4 in H2O / ACN, B: 10% to 60%) to afford compound 17 (5 mg, 4.17% yield).

[0241] 1H NMR(400MHz,DMSO-d6)δ12.40(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,1 H),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).

[0242] LC-MS (ESI): m / z = 524.3 [M+H] + .

[0243] Example 18

[0244] 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 completion of the reaction, the product was concentrated to dryness and directly spin-dried for HPLC preparation. Method: Instrument: Waters 2767 Preparative HPLC; 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, yielding compound 18 (0.12 g, yield: 48.40%).

[0245] LC-MS (ESI): m / z = 482.4 [M+H] + .

[0246] 1 H NMR(400MHz,DMSO-d6)δ8.80(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).

[0247] Biological testing

[0248] 1. PARP1 enzyme activity test

[0249] Compounds were tested for PARP1 / 2 enzymatic activity inhibition using the FP method. The substrate tracer fluorescent probe (from Aisiyipu Biotechnology) 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 fluorescent probe in the reaction mixture were 5 / 10 nM and 2.5 nM, respectively. The positive reference, olaparib, was used starting at 1 μM and diluted three-fold across 10 concentrations. 0.1 μL of compound in 100% DMSO was transferred to a 384-well plate (Corning, 4514) using an acoustic liquid delivery device (Echo 655) and centrifuged at 1000 rpm for 1 minute. 5 μL of PARP enzyme solution was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute, followed by incubation at 25°C for 10 minutes. 5 μL of substrate solution was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute, followed by incubation at 25°C for 60 minutes. Finally, the mP signal was measured using the fluorescence polarization module of a BMG PHERAstar FSX (ex / em: 485 nm / 520 nm). Nonlinear regression curves were then fitted with four parameters to calculate IC50 values ​​using GraphPad Prism 8 software. The inhibition rate was calculated according to formula 1, where RLUsample is the compound well reading, RLUmax is the solvent control well reading, and RLUmin is the PARP1 / 2 enzyme-free control well reading. GraphPad Prism software was used to perform curve fitting using four parameters (log (inhibitor) vs. response--Variable slope) and calculate the IC 50 value.

[0250] Inhibition% = (1-(RLUsample-RLUmin) / (RLUmax-RLUmin))×100% (Formula 1)

[0251] Table 1 PARP-1 enzyme activity

[0252] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a significant inhibitory effect on PARP-1 enzyme activity in vitro.

[0253] 2. DLD-1 cell activity test experiment

[0254] DLD-1 (150 cells / well / 100 μL) (ATCC, CCL-221) and DLD-1 BRCA2 KO (1500 cells / well / 100 μL) (from Aisi Yipu Bio) were seeded into 96-well plates (Greiner, 655090) at an appropriate cell density and cultured overnight in a 37°C cell culture incubator. The test compound was diluted with the corresponding cell culture medium and added to the well plate for 7 days. On the fourth day, fresh culture medium was replaced with the same concentration of compound. After the CellTiter-Glo reagent (CTG, Vazyme, DD1101-03) and culture plate were removed from the well plate and returned to room temperature, 60 μL of CTG reagent was added to the cells and shaken for 2 minutes to fully lyse the cells. After standing at room temperature for 30 minutes, the fluorescence signal value was read using a microplate reader (PHERAstar FSX). The medium wells were set as negative controls, and the DMSO wells as positive controls. The inhibitory activity percentage of the compound was normalized by the readings of the negative and positive controls. The inhibition rate calculation formula is:

[0255] 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% (Formula 2)

[0256] Table 2 DLD-1 cell activity

[0257] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity.

[0258] 3. PARP selectivity experiment

[0259] A549 WT, A549 PARP1 KO, and A549 PARP2 KO cell lines were seeded into 384-well plates at 2500 μL / well and incubated overnight at 37°C, 5% CO2. The next day, 40 nL of serially diluted compounds were added, and the cells were incubated at 37°C, 5% CO2 for 1 hour. Stimulation was performed by adding 5 μL of H2O2 per well, with a final concentration of 200 μM for 5 minutes for A549 WT and A549 PARP2 KO, and 20 mM for 45 minutes for A549 PARP1 KO. After stimulation, the supernatant was discarded, 40 μL of pre-chilled methanol was added, and the cells were fixed at 4°C for 20 minutes. The cells were washed twice with PBS, and 20 μL of blocking buffer was added for 1 hour. The primary antibody cocktail (pADPr Antibody (10H): sc-56198 antibody diluted 1:500 in blocking buffer) was added, and the cells were incubated overnight at 4°C. Wash three times with PBST, add secondary antibody mixture (Goat anti-Mouse IgG (H + L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor TM Antibody 488 was added in blocking buffer (1:500 dilution) and incubated at room temperature for 1 hour. The sections were washed three times with PBST, and 20 μL of DAPI solution (1:5000 dilution) was added. The sections were incubated at room temperature for 10 minutes before scanning.

[0260] Data analysis methods

[0261] Checking the stability of the assay with DMSO and Talazoparib data:

[0262] H=Ave(DMSO); L=Ave(Talazoparib 5μM); SD(H)=STDEV(DMSO); SD(L)=STDEV(Talazoparib 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

[0263] The IC values ​​of the compounds were fitted according to the nonlinear regression equation. 50 : Y = bottom + (top - bottom) / (1 + 10^((LogIC50 - X) * Hil slope))

[0264] X: Compound concentration; Y: Inhibition %. The top and bottom are plateaus expressed in units of the Y axis. The Hill slope describes the steepness of the curve.

[0265] Table 3 A549 PARP selectivity

[0266] Conclusion: The compounds of the present invention, especially the example compounds such as compound 2, have good selectivity for PARP1.

[0267] 4. Pharmacokinetic test in rats

[0268] 4.1 Experimental Animals: Male SD rats, approximately 220 g, 6 to 8 weeks old, 6 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0269] 4.2 Experimental Design: On the day of the experiment, 12 SD rats were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0270] Table 4. Dosing Information

[0271] Before and after drug administration, 0.15 ml of blood was collected intraorbitally under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected at 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours for both the intravenous and oral gavage groups. Brain tissue was obtained 24 hours after drug administration, rinsed with cold saline to remove any residual blood, blotted dry, and homogenized. All samples were stored at −80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0272] Table 5. Pharmacokinetic parameters of test compounds in rat plasma

[0273] Conclusion: The compounds of the present invention, such as Example compounds 2 and 8, have good pharmacokinetic characteristics in rats.

[0274] 5. Pharmacokinetic test in mice

[0275] 5.1 Experimental Animals: Male Balb / c mice, 20-25 g, 12 mice per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0276] 5.2 Experimental Design: On the day of the experiment, Balb / c mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0277] Before and after administration, 0.06 mL of blood was collected intraorbitally under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from both the intravenous and oral gavage groups at 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, and 24 hours. Brain tissue was collected at 30 minutes, 2, and 24 hours after compound administration. Brain tissue was collected 24 hours after compound administration, rinsed with cold saline to remove residual blood, blotted dry, and homogenized. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0278] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in mice.

[0279] 6. Beagle dog pharmacokinetic test

[0280] 6.1 Experimental Animals: Male beagle dogs, weighing approximately 8-11 kg, 6 per compound, purchased from Beijing Mas Biotechnology Co., Ltd.

[0281] 6.2 Experimental Methods: On the day of the experiment, beagle dogs were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours prior to dosing. Food was resumed 4 hours after dosing.

[0282] Before and after dosing, 1 ml of blood was collected from the jugular vein or limb vein into an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. Blood was collected at the following time points for both the intravenous and oral administration groups: 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, 24, and 48 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0283] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in dogs.

[0284] 7. Monkey pharmacokinetic test

[0285] 7.1 Experimental Animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4 per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0286] 7.2 Experimental Method: On the day of the experiment, monkeys were randomly divided into groups according to body weight. They were fasted but not watered for 14-18 hours before administration and fed 4 hours after administration.

[0287] Before and after dosing, 1.0 mL of blood was collected from a venous vein in each limb and placed in an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. For the venous blood collection group, the following time points were used: 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, 24, and 48 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0288] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in monkeys.

Claims

1. A compound of formula I-1 or formula I, or a stereoisomer or a pharmaceutically acceptable salt thereof, in, Ring A is selected from R1 is C 1-4 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 3 groups selected from D, halogen, OH, CN, or NH2; R2 is -CONHR A 、-NHCOR A ; Each R A Independently for C 3-6 Cycloalkyl, 5-6 membered heteroaryl substituted by 1-3 halogens, the heteroaryl containing 1-3 heteroatoms selected from N, S, O, the heteroaryl, cycloalkyl is optionally substituted by 1-3 halogens selected from D, =O, C 1-4 Alkyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -CONHC 1-4 Alkyl, -NHCOC 1-4 Alkyl, OH, CN, NH2 and C 1-4 The cycloalkyl group is substituted by at least one =CH2, =CF2, =CHF, =CH(C 1-6 alkyl), =C(C 1-6 Alkyl)2 substituted; m is 0 or 1; Wherein, the compound is not 2. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt, in, Ring A is selected from R1 is C 1-2 Alkyl, C 3-4 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 3 groups selected from D, F, Cl, OH, CN, and NH2; preferably, R1 is methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl are optionally substituted by 1, 2, or 3 groups selected from D, F, Cl, OH, CN, and NH2; Each R A Independently for C 3-6 Cycloalkyl, 5-6 membered heteroaryl substituted by 1-3 halogens, the heteroaryl containing 1-3 heteroatoms selected from N, S, O, the heteroaryl optionally substituted by 1-3 heteroatoms selected from D, =O, C 1-4 Alkyl, OH, CN, NH2 and C 1-2 The cycloalkyl group is substituted by 1 =CH2, =CF2, =CHF, =CH(C 1-2 alkyl), =C(C 1-2 Alkyl)2 substituted; Preferably, each R A is independently a 5-membered heteroaryl substituted by 1, 2 or 3 F or Cl, The heteroaryl group contains 1, 2 or 3 heteroatoms selected from N, S, and O, and the heteroaryl group is optionally substituted by 1, 2 or 3 groups selected from D, =O, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH3, -CH(CH3)CH2CH3, OH, CN, NH2.

3. The compound according to claim 1 or 2, its stereoisomer or pharmaceutically acceptable salt, in, Ring A is selected from The "*" end is connected to the left, and the "*" end is connected to the right; R1 is selected from -CH3, -CH2CH3, -CHF2; R A Each independently selected from 4. A compound of formula I according to claim 1 or 2, a stereoisomer or a pharmaceutically acceptable salt thereof, Ring A is selected from The "*" end is connected to the left, and the "*" end is connected to the right; R1 is selected from -CH3, -CH2CH3, -CHF2; R A Each independently selected from 5. A compound of formula I-1 according to claim 1 or 2, a stereoisomer or a pharmaceutically acceptable salt thereof, Ring A is selected from The "*" end is connected to the left, and the "*" end is connected to the right; R1 is selected from -CH3, -CH2CH3, -CHF2; m is selected from 1; R A Each independently selected from 6. A compound of formula I-1 or formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from one of the following structures:

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

8. Use of the compound according to any one of claims 1 to 6 or its stereoisomer or pharmaceutically acceptable salt or the composition according to claim 7 in the preparation of a medicament 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 1-1440 mg of a compound according to any one of claims 1-6 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 in a mammal, the method 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, the therapeutically effective amount being preferably 1-1440 mg, and the disease being preferably breast cancer, uterine cancer, cervical cancer, ovarian cancer, or prostate cancer.

Images