Lactam ring compound and application thereof

Abstract

The invention discloses a lactam ring compound and application thereof, and belongs to the technical field of chemical medicines. The lactam ring compound as shown in the formula I provided by the invention can be used as a PARP1 inhibitor, has the advantages of high activity and high selectivity, and also has excellent pharmacokinetic properties and safety. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of chemical medicine and relates to a class of iso-lactam ring compounds and uses thereof. Background Art

[0002] During the growth of cells, their DNA will be constantly damaged by various internal and surrounding adverse factors. Among DNA damage, the most serious types of damage are single-strand breaks and double-strand breaks, among which single-strand breaks are more common. If these breaks are not repaired promptly and accurately, they will lead to genomic instability, causing cancer and even directly causing cell death. For single-strand breaks of DNA, its repair mainly depends on the PARP enzyme. For double-strand breaks, there are two ways to repair double-stranded DNA: non-homologous end joining repair and homologous recombination repair. Homologous recombination repair is a high-fidelity, error-free repair method, and it is also the main way to repair double-stranded DNA. There are many proteins involved in homologous recombination repair, among which the most well-known is the BRCA protein. Two studies in 2005 (Farmer H, McCabe N, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy [J]. Nature, 2005, 434 (7035): 917-921. Bryant, H., Schultz, N., Thomas, H. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly (ADP-ribose) polymerase. Nature 434, 913–917 (2005)) showed that tumor cells lacking BRCA1 or BRCA2 would be selectively inhibited by PARP inhibitors. Based on this research result, scholars proposed the concept of synthetic lethality: the loss of either BRCA or PARP gene is not lethal in itself, but the simultaneous inactivation of both will lead to cell death. Based on the theory of synthetic lethality, PARP inhibitors (PARPi) have been developed to selectively target cancer cells with BRCA1 / 2 mutations.

[0003] PARP inhibitors have shown excellent clinical efficacy in patients with homologous recombination-deficient cancers. However, whether used as a single agent or in combination therapy, hematological toxicity (anemia, neutropenia, and thrombocytopenia) and other toxicities limit the application of this type of drug. Related studies have shown (Harris PA, Boloor A, Cheung M, et al. Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfon amide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor. [J]. Journal of Medicinal Chemistry, 2008, 51(15): 4632.) that these adverse reactions may be due to the inhibition of PARP2 by the PARP inhibitors on the market, which is not necessary for efficacy. Highly selective PARP1 inhibitors can reduce blood toxicity, increase the therapeutic safety window, and increase the potential for combination with other chemotherapy or targeted drugs.

[0004] Therefore, there is an unmet clinical need for effective and safe PARP inhibitors, especially PARP inhibitors that are selective for PARP 1. The novel PARP 1 inhibitors described in the present invention are unexpectedly more selective for PARP 1 than other PARP family members (such as PARP2, PARP3, PARP5a and PARP6) and can be used to treat diseases related to PARP function. Summary of the invention

[0005] The purpose of the present invention is to provide a class of heterocyclic compounds and uses thereof, so as to achieve highly selective and efficient prevention or treatment of diseases related to PARP function.

[0006] In a first aspect, the present invention provides a compound represented by formula I or a pharmaceutically acceptable form thereof, wherein the structure of formula I is as follows:

[0007]

[0008] in:

[0009] Structural unit Select from the following structures:

[0010]

[0011] R x1 , Ry1 independently selected from hydrogen, deuterium, halogen, cyano, amino or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl; R x1 and R y1 In the above, the substituent is selected from the group consisting of: deuterium, halogen, oxo, -OH, -NH 2 、-CN、C 1-4 Alkyl, C 1-4 Fluorinated alkyl, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-OC 1-4 Alkyl or 3-6 membered cycloalkyl; R x1 and R y1 wherein the 4- to 6-membered heterocycloalkyl group and the 5- to 6-membered heteroaryl group contain 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0012] R x2 is selected from hydrogen, deuterium or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl; R x2 In the above, the substituent is selected from the group consisting of: deuterium, halogen, -OH, -NH 2 、-CN、oxo、C 1-4 Alkyl, C 1-4 Fluorinated alkyl, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-OC 1-4 Alkyl or 3-6 membered cycloalkyl; R x2 wherein the 4- to 6-membered heterocycloalkyl group and the 5- to 6-membered heteroaryl group contain 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0013] R 7 Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Fluoroalkoxy, -OC 1-4 Alkyl, -OC 1-4 Fluorinated alkyl, -OC 1-4 Deuterated alkyl, -NH-C 1-4 Alkyl or -N(C 1-4 alkyl) 2 At least one of; n4 is selected from 1, 2, 3, 4, 5, 6;

[0014] R 8 Selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Deuterated alkyl or 3-6 membered cycloalkyl;

[0015] Z 1 Selected from bond, O, NR a1 , CR a2 R a3 Or C=Z 4 ;

[0016] Z 2 Selected from O, NR b1 or CR b2 R b3 ;

[0017] Z 3 Select from O or CR c1 R c2 ;

[0018] R a1 , R b1 is independently selected from hydrogen, deuterium or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl; R a1 and R b1 In the above, the substituent is selected from the group consisting of: deuterium, halogen, -OH, -NH 2 , -CN or 3-6 membered cycloalkyl; R a1 and R b1 wherein the 4- to 6-membered heterocycloalkyl group and the 5- to 6-membered heteroaryl group contain 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0019] R a2 , R a3 , R b2 , R b3, R c1 , R c2 are independently selected from hydrogen, deuterium, fluorine, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl or C 1-4 Hydroxyl substituted alkyl;

[0020] R 1 Selected from hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl or C 1-4 Hydroxyl substituted alkyl;

[0021] R 2 , R 3 are independently selected from hydrogen, deuterium, fluorine, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl or C 1-4 Hydroxyl substituted alkyl, or R 2 and R 3 Together with the atoms to which they are attached, they form a 3-6 membered alkyl ring;

[0022] Ring A is selected from 4- to 8-membered heterocycloalkyl groups; in Ring A, the 4- to 8-membered heterocycloalkyl group contains 1 to 3 N heteroatoms, and one of the N atoms is connected;

[0023] R 4 Selected from hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy or C 1-4 At least one of the fluoroalkoxy groups; or any two of R 4 Together with the atoms to which they are attached, they form a 3-6 membered alkyl ring or a 5-7 membered alkyl heterocyclic ring; any two R 4 When forming a ring with the atoms to which they are attached, the 5-7 membered alkyl heterocyclic ring contains 1 to 3 heteroatoms selected from at least one of N and O;

[0024] L is selected from a bond, O, NR L1 or CR L2 R L3 ;

[0025] R L1 Selected from hydrogen, deuterium, C 1-4Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl or C 1-4 Hydroxyl substituted alkyl;

[0026] R L2 and R L3 are independently selected from hydrogen, deuterium, fluorine, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl or C 1-4 Hydroxyl substituted alkyl;

[0027] Ring B is selected from a 5-10 membered aryl group or a 5-10 membered heteroaryl group; in ring B, the 5-10 membered heteroaryl group contains 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0028] R 5 Selected from hydrogen, deuterium, halogen, cyano, -(CR 5a R 5b ) n3 OR 5c 、-(CR 5a R 5b ) n3 N(R 5c R 5d ), -COOR 5c 、-CONH 2 ,-CONHR 5c 、-CON(R 5c R 5d ),-NHCOR 5c 、-SO 2 R 5c 、-SO 2 NHR 5c 、-SO 2 NR 5c R 5d , By one or more R 6 Substituted with the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl; or two adjacent R 5 Together with the atoms to which they are attached, they form a 5-6 membered alkyl ring, a 5-6 membered alkyl heterocyclic ring, a benzene ring or a 5-6 membered heteroaromatic ring; R 5 The 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S, and O; two adjacent R 5When forming a ring with the atoms to which they are attached, the 5-6 membered alkyl heterocyclic ring or 5-6 membered heteroaromatic ring contains 1 to 3 heteroatoms selected from at least one of N, S and O;

[0029] or R 5 With R 4 Together with the atoms to which they are attached, they form a 5-7 membered alkyl heterocyclic ring; R 5 With R 4 When forming a ring with the atoms to which they are connected, the 5-7 membered alkyl heterocyclic ring contains 1 to 3 heteroatoms selected from at least one of N and O;

[0030] R 5a and R 5b are independently selected from hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy or C 1-4 At least one of fluoroalkoxy; or R 5a and R 5b Together with the atoms to which they are attached, they form a 3- to 6-membered alkyl ring or a 4- to 6-membered alkyl heterocyclic ring substituted with 0-6 substituents; R 5a and R 5b When forming a ring with the atoms to which they are attached, the substituents are selected from hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy or C 1-4 At least one of the fluoroalkoxy groups; R 5a and R 5b When forming a ring with the atoms to which they are attached, the 5-6 membered alkyl heterocyclic ring contains 1 to 3 heteroatoms selected from at least one of N, S and O;

[0031] R 5c and R 5d independently selected from hydrogen, deuterium or the following groups substituted by 0-6 substituents: C 1-4 Alkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, 3-8 membered cycloalkyl, 6-10 membered spirocycloalkyl, 6-10 membered heterospirocycloalkyl, 6-10 membered bridged cycloalkyl or 6-10 membered heterobridged cycloalkyl; R 5c and R 5d In the above, the substituent is selected from: deuterium, halogen, -OH, -CN, C1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 alkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, 3- to 6-membered cycloalkylmethylene, 4- to 6-membered heterocycloalkylmethylene, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl) 2 、-OC 1-6 Alkyl, -CONH 2 or-CONH-C 1-6 alkyl;

[0032] R 5c and R 5d wherein the 5- to 10-membered heteroaryl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered heterospirocycloalkyl, and 6- to 10-membered heterobridged cycloalkyl contain 1 to 3 heteroatoms selected from at least one of N, S, and O; R 5c and R 5d In the substituent, the 4- to 6-membered heterocycloalkyl and 4- to 6-membered heterocycloalkylmethylene groups contain 1 to 3 heteroatoms selected from at least one of N, S and O;

[0033] Or, R 5a With R 5c , R 5a With R 5d , R 5b With R 5c , R 5b With R 5d or R 5c With R 5d Together with the atoms to which they are attached, they form a 4-6 membered alkane heterocyclic ring substituted with 0-6 substituents selected from hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy or C 1-4 at least one of the fluoroalkoxy groups, wherein the 4-6 membered alkyl heterocyclic ring contains 1 to 3 heteroatoms selected from at least one of N, S or O;

[0034] R 6 Selected from H, deuterium, fluorine, C 1-4 Alkyl, C 1-4 Deuterated alkyl or C 1-4 Fluorinated alkyl;

[0035] n1 is selected from 1, 2, 3, 4, 5, 6, 7, 8;

[0036] n2 is selected from 1, 2, 3, 4, 5;

[0037] n3 is selected from 0, 1, 2, 3, 4, 5;

[0038] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotopically labeled substances, metabolites or prodrugs.

[0039] In some embodiments of the present invention, R 1 Selected from hydrogen, deuterium, fluorine, hydroxyl, amino or C 1-4 alkyl.

[0040] In some preferred embodiments of the present invention, R 1 is selected from hydrogen, deuterium, fluorine or methyl.

[0041] In some embodiments of the present invention, R 2 , R 3 independently selected from hydrogen, deuterium, fluorine, C 1-4 Alkyl or C 1-4 The hydroxyl group replaces the alkyl group.

[0042] In some preferred embodiments of the present invention, R 2 and R 3 are independently selected from hydrogen, deuterium, fluorine, methyl or hydroxymethyl.

[0043] In some embodiments of the present invention, L is selected from a bond, O, NR L1 or CR L2 R L3 ; R L1 is selected from hydrogen, deuterium, methyl, deuterated methyl, fluoromethyl or hydroxymethyl; R L2 and R L3 are independently selected from hydrogen, deuterium, fluorine, hydroxy, amino, methyl, deuterated methyl, fluoromethyl or hydroxymethyl.

[0044] In some preferred embodiments of the present invention, L is selected from a bond, O or NH.

[0045] In some embodiments of the present invention, R 4 At least one selected from hydrogen, deuterium, fluorine, hydroxyl, amino, methyl, deuterated methyl, fluoromethyl, ethyl, methoxy, deuterated methoxy, fluoromethoxy or hydroxymethyl; or two R connected to adjacent C atoms 4 Together with the atoms to which they are attached, they form a 3-5-membered alkyl ring or a 5-6-membered alkyl heterocyclic ring; two R atoms connected to adjacent C atoms 4When forming a ring with the atoms to which they are connected, the 5-6 membered alkyl heterocycle contains 1 to 2 heteroatoms selected from at least one of N and O; n1 is selected from 1, 2, 3, and 4.

[0046] In some preferred embodiments of the present invention, R 4 At least one selected from hydrogen, deuterium, fluorine, hydroxyl, amino, methyl, ethyl, hydroxymethyl, methoxy; or two R connected to adjacent carbon atoms 4 Together with the atoms to which they are attached, they form a 3-5-membered alkyl ring or a 5-6-membered alkyl heterocyclic ring; two R atoms connected to adjacent C atoms 4 When forming a ring with the atoms to which they are attached, the 5-6 membered alkyl heterocyclic ring contains 1 O heteroatom; n1 is selected from 1, 2.

[0047] In some embodiments of the present invention, the structural unit Selected from: or (The left ends of these structures are related to the structural unit connected to the left and right, and the right end is connected to L).

[0048] In some preferred embodiments of the present invention, the structural unit Selected from: or (The left ends of these structures are related to the structural unit connected to the right end and L).

[0049] In some more preferred embodiments of the present invention, the structural unit Select from (left end and connected to, the right end connected to L) is selected from or (The left ends of these structures are related to the structural unit connected to the right end and L).

[0050] In some embodiments of the present invention, ring B is selected from phenyl, pyridyl, imidazolyl, imidazo[1,2-a]pyrazinyl, 1,7-naphthypyridyl, pyridazinyl, pyrazinyl, pyridothiazolyl, pyrazolo[1,5-a]pyrimidinyl, benzopyrazolyl, benzimidazolyl, thiazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, thienyl, furanyl, pyrazolyl, pyridazinopyrrolyl, pyridopyrazolyl, pyridooxazolyl or pyrimidinyl.

[0051] In some preferred embodiments of the present invention, ring B is selected from or (The wavy bond in these structures is connected to L).

[0052] In some embodiments of the present invention, R 5 Selected from hydrogen, fluorine, chlorine, bromine, cyano, amino, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Fluorinated alkoxy, 3-6 membered cycloalkyl, C 1-4 Alkyl aminoacyl, C 1-4 Deuterated alkylaminoyl, C 1-4 Fluoroalkylaminoacyl, C 1-4 Alkoxy substituted C 1-4 at least one of alkylaminoacyl, 3-6-membered cycloalkylaminoacyl, 3-6-membered fluorocycloalkylaminoacyl, 4-6-membered heterocycloalkylaminoacyl, 6-membered arylaminoacyl or 5-6-membered heteroarylaminoacyl, or two adjacent R 5 Together with the atoms to which they are attached, they form a 5-6 membered alkyl ring or a 5-6 membered alkyl heterocyclic ring; R 5 wherein the 4-6 membered heterocycloalkylaminoacyl group and the 5-6 membered heteroarylaminoacyl group contain 1 to 2 heteroatoms selected from at least one of N, S and O; and the two adjacent R 5 When forming a ring with the atoms to which they are connected, the 5-6 membered alkyl heterocycle contains 1 to 2 heteroatoms selected from at least one of N, S, and O; n2 is selected from 1, 2, and 3.

[0053] In some preferred embodiments of the present invention, R 5 is selected from hydrogen, fluorine, chlorine, cyano, amino, methyl, deuterated methyl, fluoromethyl, ethyl, deuterated ethyl, fluoroethyl, cyclopropyl, cyclobutyl, methylamino, deuterated methylamino, fluoromethylamino, methylaminoacyl, deuterated methylaminoacyl, fluoromethylaminoacyl, ethylaminoacyl, deuterated ethylaminoacyl, fluoroethylaminoacyl, methoxyethylaminoacyl, cyclopropylaminoacyl, fluorocyclopropylaminoacyl, cyclobutylaminoacyl, fluorocyclobutylaminoacyl or At least one of; n2 is selected from 1, 2.

[0054] In some embodiments of the present invention, the structural unit Selected from:

[0055] or

[0056] In some embodiments of the present invention, Z 3 Selected from O, CH2 , CHF or CF 2 .

[0057] In some preferred embodiments of the present invention, Z 3 Select from O or CH 2 .

[0058] In some embodiments of the present invention, Z 2 Selected from O, NR b1 or CR b2 R b3 ; R b1 is selected from hydrogen, deuterium or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl; R b1 In the above, the substituent is selected from: deuterium, fluorine, -OH, -NH 2 , -CN or 3-4 membered cycloalkyl; R b1 wherein the 4- to 6-membered heterocycloalkyl group contains 1 to 2 heteroatoms selected from N or O; R b2 and R b3 are independently selected from hydrogen, deuterium, fluorine or C 1-4 alkyl.

[0059] In some preferred embodiments of the present invention, Z 2 Selected from O, NR b1 or CR b2 R b3 ; R b1 is selected from hydrogen, deuterium or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl or 3-4 membered cycloalkyl; R b1 In the above, the substituent is selected from: deuterium, fluorine, -OH, -NH 2 , -CN or 3-4 membered cycloalkyl; R b2 and R b3 are independently selected from hydrogen, deuterium, fluorine or methyl.

[0060] In some more preferred embodiments of the present invention, Z 2 Selected from O, CH 2 NH, NCH 3 、NCD 3 Or N-cyclopropyl.

[0061] In some embodiments of the present invention, when Z 1 Selected from bond, O, NR a1 or CR a2 R a3 When R a1 is selected from hydrogen, deuterium or the following groups optionally substituted by 0-3 substituents: C 1-4Alkyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl; R a1 In the above, the substituent is selected from: deuterium, fluorine, -OH, -NH 2 , -CN or 3-4 membered cycloalkyl; R a1 wherein the 4- to 6-membered heterocycloalkyl group contains 1 to 2 heteroatoms selected from N or O; R a2 and R a3 are independently selected from hydrogen, deuterium, fluorine or C 1-4 alkyl.

[0062] In some preferred embodiments of the present invention, when Z 1 Selected from bond, O, NR a1 or CR a2 R a3 When R a1 is selected from hydrogen, deuterium or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl or 3-4 membered cycloalkyl; R a1 In the above, the substituent is selected from: deuterium, fluorine, -OH, -NH 2 , -CN or 3-4 membered cycloalkyl; R a2 and R a3 are independently selected from hydrogen, deuterium, fluorine or methyl.

[0063] In some more preferred embodiments of the present invention, when Z 1 Selected from bond, O, NR a1 or CR a2 R a3 When Z 1 Selected from O, CH 2 NH, NCH 3 、NCD 3 Or N-cyclopropyl.

[0064] In some preferred embodiments of the present invention, R x1 , R y1 are independently selected from hydrogen, deuterium, halogen, cyano, amino, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl) 2 、-OC 1-4 Alkyl, -SC 1-4 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered fluorinated cycloalkyl or phenyl;

[0065] R x2 Selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4Fluorinated alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered fluorinated cycloalkyl or phenyl;

[0066] R 7 Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Fluoroalkoxy, -NH-C 1-4 Alkyl or -N(C 1-4 alkyl) 2 At least one of; n4 is selected from 1, 2, 3, 4;

[0067] R 8 Selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Deuterated alkyl or 3-4 membered cycloalkyl.

[0068] In some more preferred embodiments of the present invention, R x1 , R y1 are independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, cyclopropyl or fluorocyclopropyl;

[0069] R x2 is selected from hydrogen, deuterium, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, cyclopropyl or fluorocyclopropyl;

[0070] R 7 is selected from hydrogen, deuterium, fluorine, chlorine, amino, methylamino, deuterated methylamino, fluoromethylamino, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, cyclopropyl, fluorocyclopropyl, methoxy, deuterated methoxy or fluoromethoxy; n4 is selected from 1 and 2;

[0071] R 8 is selected from hydrogen, methyl, deuterated methyl or fluoromethyl.

[0072] In some most preferred embodiments of the present invention, the structural unit Selected from: or The present invention also provides some specific compounds of formula I, which are selected from:

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079] The present invention also provides some specific compounds, which are selected from:

[0080]

[0081] Based on the above-mentioned compound of formula I, the present invention also provides a class of compounds, wherein the structural unit Replace with:

[0082] The present invention also provides some specific compounds, which are selected from:

[0083]

[0084] In a second aspect, the present invention provides a pharmaceutical composition, which comprises the aforementioned compound (Formula I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope-labeled substance, metabolite or prodrug thereof as an active ingredient, supplemented with a pharmaceutically acceptable carrier.

[0085] A further object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, which comprises combining any compound of Formula I or a pharmaceutically acceptable form thereof, or a mixture thereof, with one or more pharmaceutically acceptable carriers.

[0086] The pharmaceutically acceptable carrier that can be used in the pharmaceutical composition of the present invention is a pharmaceutically acceptable carrier, and examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).

[0087] The pharmaceutical composition can be administered in any form as long as it prevents, alleviates, prevents or cures the symptoms of a human or animal patient. For example, it can be prepared into various suitable dosage forms according to the administration route.

[0088] In other embodiments, the administration of the compounds or pharmaceutical compositions of the present invention may be combined with another therapeutic method. The other therapeutic method may be selected from, but not limited to: radiotherapy, chemotherapy, immunotherapy, or a combination thereof.

[0089] The present invention also relates to a pharmaceutical preparation comprising any compound of formula I or a pharmaceutically acceptable form thereof, or a mixture thereof as an active ingredient, or a pharmaceutical composition of the present invention. In some embodiments, the preparation is in the form of a solid preparation, a semisolid preparation, a liquid preparation or a gaseous preparation.

[0090] A further object of the present invention is to provide an article of manufacture, for example, in the form of a kit. Articles of manufacture as used herein are intended to include, but are not limited to, kits and packages. The article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition located in the first container, wherein the composition comprises: a first therapeutic agent, the first therapeutic agent comprising: any compound of Formula I or a pharmaceutically acceptable form thereof, or a mixture thereof; (c) an optional package insert indicating that the pharmaceutical composition can be used to treat a neoplastic condition (as defined below); and (d) a second container.

[0091] The first container is a container for holding a pharmaceutical composition. This container can be used for preparation, storage, transportation and / or individual / batch sales. The first container is intended to cover bottles, jars, vials, flasks, syringes, tubes (e.g., for cream products), or any other container for preparing, holding, storing or dispensing pharmaceutical products.

[0092] The second container is a container for accommodating the first container and optional package instructions. Examples of the second container include, but are not limited to, boxes (e.g., paper or plastic boxes), boxes, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The package instructions may be physically adhered to the outside of the first container via a cable tie, glue, staples, or other adhesion means, or they may be placed inside the second container without any physical tool for adhesion to the first container. Alternatively, the package instructions are located outside the second container. When located outside the second container, it is preferred that the package instructions are physically adhered via a cable tie, glue, staples, or other adhesion means. Alternatively, it may abut or contact the outside of the second container without physical adhesion.

[0093] The package insert is a trademark, label, label, or the like, which lists information related to the pharmaceutical composition located in the first container. The listed information is usually determined by the regulatory agency (e.g., the U.S. Food and Drug Administration) that governs the area where the product is to be sold. Preferably, the package insert specifically lists the indications for which the pharmaceutical composition is approved. The package insert can be made of any material from which the information contained therein or thereon can be read. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper or plastic, etc.) on which the desired information can be formed (e.g., printed or applied).

[0094] In a third aspect, the present invention provides the use of the aforementioned compound of formula I, and related specific compounds or pharmaceutically acceptable forms thereof, or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating PARP1 enzyme-related diseases.

[0095] The present invention provides a method for preventing or treating PARP1 enzyme-related diseases, comprising administering a compound of formula I or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention to an individual in need thereof.

[0096] The present invention provides a compound of formula I or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention for use in preventing or treating PARP1 enzyme-related diseases.

[0097] The present invention provides a method for preventing or treating PARP1 enzyme-related diseases in combination with a compound of formula I or a pharmaceutically acceptable form thereof or a pharmaceutical composition of the present invention, wherein the additional treatment method includes but is not limited to: radiotherapy, chemotherapy, immunotherapy, or a combination thereof.

[0098] In some embodiments, the PARP1 enzyme-related disease is a disease that is sensitive or responsive to PARP1 enzyme inhibition.

[0099] In some embodiments, the PARP1 enzyme-related disease is a tumor disorder.

[0100] In some preferred embodiments, the oncological disorder lacks a HR-dependent DNA DSB repair pathway.

[0101] In some preferred embodiments, the neoplastic disorder comprises one or more cancer cells having a reduced or absent ability to repair DNA DSBs by HR relative to normal cells.

[0102] In some preferred embodiments, the cancer cells have a BRCA1 or BRCA2 deficient phenotype.

[0103] In some embodiments, the PARP1 enzyme-related disease is a tumor-related disorder, including but not limited to solid and hematological malignancies. In further embodiments, the tumor-related disorders include but are not limited to breast cancer, colorectal cancer, colon cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchioloalveolar carcinoma) and prostate cancer, as well as bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer and vulvar cancer, as well as leukemia (including chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL) and chronic myeloid leukemia (CML)), multiple myeloma or lymphoma.

[0104] In some preferred embodiments, the PARP1 enzyme-related disease is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer or lung cancer.

[0105] In a further preferred embodiment, the compounds of the present invention can be used in combination with chemoradiotherapy or immunotherapy to prevent or treat cancer.

[0106] In a fourth aspect, the present invention provides the use of the aforementioned compound of formula I, and related specific compounds or pharmaceutically acceptable forms thereof, or the pharmaceutical composition of the present invention in the preparation of PARP1 inhibitors.

[0107] Beneficial effects of the present invention:

[0108] The present invention provides a novel class of highly active and highly selective PARP1 inhibitors, which can achieve at least one of the following technical effects: (1) high inhibitory activity against PARP1 enzyme; (2) selective inhibition of PARP1 enzyme, with high selectivity for other PARP family enzymes such as PARP2, PARP5a, and PARP5b; (3) strong inhibitory activity against homologous recombination-deficient tumor cells, and weak inhibitory effect on non-homologous recombination-deficient cells; (4) excellent pharmacokinetic properties (e.g., good bioavailability, suitable half-life and duration of action); (5) excellent safety (lower toxicity and / or fewer side effects, wider therapeutic window), etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0109] Figure 1 This is a graph showing the in vivo pharmacodynamic results of compound 25 in the MDA-MB-436 model. DETAILED DESCRIPTION

[0110] The scheme of the present invention will be explained below in conjunction with embodiments. It will be appreciated by those skilled in the art that the following embodiments are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. Where specific techniques or conditions are not indicated in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are followed.

[0111] The reagents and raw materials used in the examples of the present invention are commercially available.

[0112] Table 1 Abbreviations and their meanings in the present invention

[0113]

[0114]

[0115] The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR is determined using a Bruker AVANCE-400 nuclear magnetic spectrometer, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) was internally standardized with tetramethylsilane (TMS) and the chemical shift was based on 10 -6 The unit is (ppm). MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, signal: 6110).

[0116] HPLC determination was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfirc C18, 150×4.6 mm, 5 μm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18, 150×4.5 mm, 5 μm column).

[0117] The thin layer chromatography silica gel plate used was Qingdao Ocean GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) had a specification of 0.15mm-0.2mm, and the thin layer chromatography separation and purification product used a 0.4mm-0.5mm silica gel plate.

[0118] Column chromatography generally uses Qingdao Ocean 100-200, 200-300 mesh silica gel as the carrier.

[0119] Unless otherwise specified in the following examples, the reactions were carried out under an argon atmosphere or a nitrogen atmosphere. Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L. Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1 L. The hydrogenation reaction is usually evacuated, filled with hydrogen, and the operation is repeated 3 times.

[0120] Intermediate INT1: N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0121]

[0122] Step 1: Add compounds INT1a (1 g, 4.6 mmol), INT1b (1.7 g, 5.5 mmol), Pd(dppf)Cl 2 (0.3g, 0.46mmol) and potassium carbonate (1.6g, 11.5mmol), then replace nitrogen three times, and react at 90°C under nitrogen protection for 2h. After TLC detection is complete, the reaction is cooled to room temperature, 30ml of dichloromethane and 20ml of water are added, and the layers are separated in a separatory funnel. The aqueous phase is extracted twice with dichloromethane, and the organic phases are combined and then washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product is purified by column chromatography to obtain compound INT1c (1g, white solid).

[0123] Step 2: Add INT1c (1 g, 3 mmol), methylamine aqueous solution (5 g, 161.3 mmol) and anhydrous methanol (20 ml) into a 100 ml reaction bottle and stir overnight at room temperature. After the reaction is complete as monitored by TLC, the reaction solution is concentrated under reduced pressure to dryness to obtain compound INT1d (0.8 g, white solid).

[0124] Step 3: Add compound INT1d (0.5 g, 1.5 mmol) to 10 ml of anhydrous methanol, then add 10 ml of 4 mol / L hydrochloric acid dioxane solution, stir at room temperature for 0.5-1 h, and after TLC monitoring, concentrate the reaction solution under reduced pressure to dryness to obtain compound INT1 (0.5 g, white solid). MS / ESI[M+H] + =218.1.

[0125] The preparation of intermediates INT2 and INT3 refers to intermediate INT1.

[0126] Table 2 Intermediates INT2~INT3

[0127]

[0128]

[0129] Intermediate INT4: N-cyclopropyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0130]

[0131] Step 1: Weigh INT1c (1.4 g, 4.5 mmol), add 20 mL MeOH to dissolve, add 5 mL water, add lithium hydroxide (570 mg, 13.5 mmol), react at room temperature for 12 h, monitor the reaction by TLC, add 2 M HCl after the reaction is complete to adjust the pH to 6, add (3 x 25 mL) EA to extract, combine the organic phases, dry over anhydrous sodium sulfate, and vacuum dry to obtain the product INT4a (460 mg, light yellow solid).

[0132] Step 2: Weigh INT4a (180 mg, 0.6 mmol), EDCI (144 mg, 0.75 mmol), HOBT (100 mg, 0.75 mmol) 2 mL DMF, N-methylmorpholine (290 mg, 3.2 mmol), and cyclopropylamine (34 mg, 0.6 mmol), react at warm for 12 h, monitor by TLC, and after the raw materials are completely consumed, dilute with water, extract with EA, wash the organic phase with water 5 times, dry over anhydrous sodium sulfate, and spin dry to obtain the crude product INT4b (180 mg, yellow oily liquid).

[0133] Step 3: Add methanol (5 mL) to dissolve the crude product of INT4b (171 mg, 0.5 mmol), then add 4M HCl1,4-dioxane (0.9 mL) solution, react at room temperature for 12 h, monitor the reaction by TLC, add potassium carbonate after the reaction is complete, stir for 30 minutes, filter and remove potassium carbonate to obtain the crude product of compound INT4 (180 mg, yellow-brown solid). MS / ESI[M+H] + =244.1.

[0134] The preparation of intermediates INT5-INT8 refers to intermediate INT4.

[0135] Table 3 Intermediates INT5-INT8

[0136]

[0137]

[0138] Intermediate INT9: N-methyl-5-(piperazine-1-yl)pyridineamide

[0139]

[0140] Step 1: Compound INT1a (5.66 g, 26.21 mmol, 1.05 eq), compound INT9a (4.65 g, 25.0 mmol, 1.00 eq), Cs 2 CO 3(16.27 g, 50.0 mmol, 2.00 eq) and RuPhos-Pd-G3 (1.04 g, 1.25 mmol, 0.05 eq) were added to 1,4-dioxane (50 mL) and stirred at 120 ° C overnight under a nitrogen atmosphere. After the reaction was completed by LCMS, the mixture was allowed to cool to room temperature. The reaction solution was diluted with water (100 mL) and then extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with brine (2 x 50 mL) and washed with anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel column chromatography to obtain compound INT9b (white solid, 4.5 g). MS / ESI[M+H] + =322.1.

[0141] Step 2: Compound INT9b (1.92 g, 6.0 mmol, 1.0 eq) was added to a solution of methylamine (8 mL, 25-30 wt% aqueous solution) in methanol (7 mL) and stirred at room temperature for 3 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with saturated aqueous ammonium chloride solution (30 mL) at room temperature. The resulting mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layer was washed with brine (2 x 50 mL) and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to obtain compound INT9c (1.65 g) as a light yellow oil. MS / ESI [M+H] + =321.3.

[0142] Step 3: Compound INT9c (482 mg, 1.50 mmol, 1.00 eq) and 1,4-dioxane solution of HCl (3.7 mL, 15.0 mmol, 10.0 eq, 4.0 M) were stirred at room temperature for 2 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure by LCMS monitoring to obtain compound INT9 (392 mg, crude product) as a yellow solid. The crude product was used directly in the next step without further purification. MS / ESI[M+H] + =221.3.

[0143] The preparation of intermediates INT10 and INT11 referred to intermediate INT9.

[0144] Table 4 Intermediates INT10 and INT11

[0145]

[0146]

[0147] Intermediate INT12: N-cyclopropyl-5-(piperazine-1-yl)pyridineamide

[0148]

[0149] Step 1: Weigh INT9b (1.4 g, 4.5 mmol), add 20 mL MeOH to dissolve, add 5 mL water, add lithium hydroxide (570 mg, 13.5 mmol), react at room temperature for 12 h, monitor the reaction by TLC, add 2 M HCl after the reaction is complete to adjust the pH to 6, add (3 x 25 mL) EA to extract, combine the organic phases, dry over anhydrous sodium sulfate, and vacuum dry to obtain the product INT12a (845 mg).

[0150] Step 2: Weigh INT12a (180 mg, 0.6 mmol), EDCI (144 mg, 0.75 mmol), HOBT (100 mg, 0.75 mmol) 2 mL DMF, N-methylmorpholine (290 mg, 3.2 mmol), cyclopropylamine (34 mg, 0.6 mmol), react at room temperature for 12 h, monitor by TLC, dilute with water after the raw materials are completely consumed, extract with EA, wash the organic phase with water 5 times, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to remove the solvent to obtain the crude product INT12b (165 mg). MS / ESI[M+H] + =347.2.

[0151] Step 3: Dissolve the crude product of INT12b (150 mg, 0.4 mmol) in 5 mL MeOH, then add 0.9 mL 4M HCl in dioxane solution, react at room temperature for 12 h, monitor the reaction by TLC, add potassium carbonate after the reaction is complete, stir for 30 minutes, filter and remove potassium carbonate to obtain the crude product of compound INT12 (120 mg, yellow-brown solid). MS / ESI[M+H] + =247.1.

[0152] The preparation method of intermediates INT13-INT16 refers to intermediate INT12.

[0153] Table 5 Intermediates INT13-INT16

[0154]

[0155]

[0156] Intermediate INT17: 5-Fluoro-1',2',3',6'-tetrahydro-2,4'-bipyridine

[0157]

[0158] Step 1: Add compound INT17a (0.5 g, 2.8 mmol), INT1b (0.92 g, 3.4 mmol), Pd(dppf)Cl to a mixed solvent of 7 ml of dioxane, 3 ml of anhydrous ethanol and 4 ml of water. 2 (0.21g, 0.52mmol) and potassium carbonate (0.99g, 13mmol), then replace nitrogen three times, and react at 90°C for 2h under nitrogen protection. After TLC detection is complete, the reaction is cooled to room temperature, 30ml of dichloromethane and 20ml of water are added, and the layers are separated in a separatory funnel. The aqueous phase is extracted twice with dichloromethane, and the organic phases are combined and then washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product is purified by column chromatography to obtain compound INT17b (0.7g, white solid).

[0159] Step 2: Add compound INT17b (0.5 g, 1.8 mmol) to 10 ml of anhydrous methanol, then add 10 ml of 4 mol / L hydrochloric acid dioxane solution, stir at room temperature for 0.5-1 h, and after TLC monitoring, concentrate the reaction solution under reduced pressure to dryness to obtain compound INT17 (0.3 g, white solid). MS / ESI[M+H] + =179.1.

[0160] The preparation method of intermediates INT18 and INT19 refers to intermediate INT17.

[0161] Table 6 Intermediates INT18 and INT19

[0162]

[0163] Intermediate INT20: 1-(5-fluoropyridin-2-yl)piperazine

[0164]

[0165] Step 1: Compound INT17a (1 g, 5.00 mmol) and compound INT9a (838 mg, 4.5 mmol) were dissolved in toluene (15 mL), palladium acetate (112 mg, 0.5 mmol) and BINAP (311 mg, 0.5 mmol) were added, the reaction flask was replaced with nitrogen and placed in an oil bath at 120 ° C for reaction, and water (20 mL) was added after reaction for 16 h to quench, and ethyl acetate (3 x 30 mL) was added for extraction, the organic phases were combined and concentrated under reduced pressure, and the crude product was purified by column chromatography (PE: EA = 5: 1) to obtain compound INT20a (yellow solid, 1.4 g), MS / ESI [M+H] + =282.1.

[0166] Step 2: Add compound INT20a (0.5 g, 1.8 mmol) to anhydrous methanol (10 ml), then add 4 mol / L hydrochloric acid dioxane solution (10 ml), stir at room temperature for 1 h, and after TLC monitoring, concentrate the reaction solution under reduced pressure to obtain compound INT20 (0.4 g, white solid). MS / ESI[M+H] + =182.1.

[0167] The preparation methods of intermediates INT21 and INT22 refer to intermediate INT20.

[0168] Table 7 Intermediates INT21 and INT22

[0169]

[0170] Intermediate INT23: (R)-N-methyl-5-(2-methylpiperazine-1-yl)picolinamide

[0171]

[0172] Step 1: Compound INT1a (5.66 g, 26.21 mmol, 1.05 eq), compound INT23a (5.00 g, 24.96 mmol, 1.00 eq), Cs 2 CO 3 (16.27 g, 49.93 mmol, 2.00 eq) and RuPhos-Pd-G3 (1.04 g, 1.25 mmol, 0.05 eq) were added to 1,4-dioxane (50 mL) and stirred at 120 ° C overnight under a nitrogen atmosphere. After the reaction was completed by LCMS, the mixture was allowed to cool to room temperature. The reaction solution was diluted with water (100 mL) and then extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with brine (2 x 50 mL) and washed with anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound INT23b (white solid, 5.00 g, 59.71%). MS / ESI [M+H] + =336.1.

[0173] Step 2: Compound INT23b (2.00 g, 5.96 mmol, 1.00 eq) was added to a solution of methylamine (8 mL, 25-30 wt% aqueous solution) in methanol (7 mL) and stirred at room temperature for 3 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with saturated aqueous ammonium chloride (30 mL) at room temperature. The resulting mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layer was washed with brine (2 x 50 mL) and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to obtain compound INT23c (1.70 g, 85.25%) as a light yellow oil. MS / ESI [M+H] + =335.3.

[0174] Step 3: Compound INT23c (500 mg, 1.50 mmol, 1.00 eq) and 1,4-dioxane solution of HCl (3.7 mL, 14.95 mmol, 10.0 eq, 4.0 M) were stirred at room temperature for 2 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure by LCMS monitoring to obtain compound INT23 (400 mg, crude product) as a yellow solid. The crude product was used directly in the next step without further purification. MS / ESI[M+H] + =235.3.

[0175] Intermediate INT24: 3-(Bromomethyl)-7-fluoro-1,3,4,5-tetrahydro-6H-pyrano[4,3-c]isoquinolin-6-one

[0176]

[0177] The first step: a solution of (benzyloxy)acetaldehyde INT24a (100.0 g, 666 mmol) and 3-butene-1-ol INT24b (48.0 g, 666 mmol) in dichloromethane (550 mL) was added dropwise to a solution of trifluoroacetic acid (228 g, 2.0 mol) in dichloromethane (500 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure to remove the solvent. The residue was dissolved in methanol (450 ml), potassium carbonate (276 g, 2.0 mol) was added, the reaction mixture was stirred at 20 ° C for 5 hours, and the mixture was filtered. The filtrate was diluted with water and extracted with ethyl acetate, the organic layers were combined, dried and filtered using anhydrous sodium sulfate, and the product was collected by column chromatography (PE: EA = 4: 1) to obtain compound INT24c (81.2 g), MS / ESI [M + H] + =223.1.

[0178] Step 2: Add 550 mL of dichloromethane to a mixture of compound INT24c (81.2 g, 365.6 mmol) and pyridinium chromate chloride (94.4 g, 448.7 mmol) and stir at room temperature for 18 h. Filter the mixture and then concentrate under reduced pressure to remove the solvent. The residue is purified by chromatography on a silica gel column (eluent: 20% ethyl acetate-petroleum ether) to obtain a colorless oily product INT24d (55 g). MS / ESI[M+H] + =221.3.

[0179] Step 3: Compound INT24d (5 g, 22.7 mmol), methyl 2-bromo-6-fluorobenzoate INT24e (5.3 g, 22.7 mmol), Pd 2 (dba) 3 (0.83g, 0.9mmol), XantPhos (1.05g, 1.8mmol) and cesium carbonate (9.6g, 29.5mmol) were added to 1,4-dioxane (80ml), nitrogen was protected, and the temperature was raised to 110℃ for 12h. After the reaction was completed, the filtrate was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=10:1~3:1) to obtain compound INT24f (2.8g), MS / ESI[M+H] + =341.1.

[0180] Step 4: Compound INT24f (2.8 g, 8.2 mmol) was added to ammonia methanol solution (20 ml), and the temperature was raised to 110 °C under nitrogen protection for 4 h. After the reaction, the mixture was concentrated under reduced pressure to obtain compound INT24g (2.6 g). MS / ESI [M+H] + =340.3.

[0181] Step 5: Compound INT24g (2.6 g, 7.7 mmol) was added to dichloromethane, and boron tribromide (10 ml) was added at room temperature to react for 0.5 h. After the reaction was complete, methanol was added to quench the reaction, and the reaction was concentrated under reduced pressure. The residue was purified by column chromatography (DCM: MeOH = 20: 1) to obtain compound INT24h (1.4 g), MS / ESI [M+H] + =251.2.

[0182] Step 6: Compound INT24h (1.4 g, 5.6 mmol) was added to DMF, triphenylphosphine (2.9 g, 11.2 mmol) was added, and the mixture was reacted at room temperature for 30 min. Carbon tetrabromide (3.7 g, 11.2 mmol) was added, and the mixture was reacted at room temperature for 12 h. After the reaction, the reaction solution was added to water (40 mL), and ethyl acetate (60 mL) was added for extraction. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM: MeOH = 20: 1) to obtain compound INT24 (1.6 g). MS / ESI [M+H] + =313.1.

[0183] The preparation method of intermediates INT25-INT39 refers to intermediate INT24.

[0184] Table 8 Intermediates INT25-INT39

[0185]

[0186]

[0187] Intermediate INT40: 3-(bromomethyl)-7-fluoro-1,3,4,5-tetrahydrophenanthridine-6(2H)-one

[0188]

[0189] Step 1: To a solution of trimethylsilyl trifluoromethanesulfonate (0.034 mL) in dry dichloromethane (5 mL) was added 1,2-bis(trimethylsilyloxy)ethane INT40b (4.55 mL) and then methyl 3-oxocyclohexanecarboxylate INT40a (2.9 g). The reaction mixture was stirred at -78 °C for 3 hours. Pyridine (0.5 mL) was added to quench and saturated NaHCO was poured into 3 The solution was added to the solution and extracted with ether. 2 CO 3 / Na 2 SO 4 The organic layer was dried. The organic phase was concentrated under reduced pressure to remove the solvent, and purified by column chromatography to obtain compound INT40c (2.2 g). MS / ESI [M+H] + =201.2.

[0190] Step 2: In a 100 ml round-bottom flask, lithium aluminum hydride (1 g) was added to ether (20 ml) to obtain a suspension. Compound INT40c (1 g) dissolved in ether (5 ml) was slowly added via a syringe. The mixture was stirred overnight at room temperature. After cooling to 0 ° C, the reaction was quenched with water. The product was extracted with ether (2 x 10 ml). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to remove the solvent and purified by column chromatography to obtain compound INT40d (0.5 g), MS / ESI [M+H] + =173.2.

[0191] Step 3: Add compound INT40d (1.7 g, 10 mmol) to DMF (20 mL), cool to 0°C, slowly add NaH (60 wt%, 0.44 g, 11 mmol), and continue stirring at 0°C for 30 minutes after the addition. Add benzyl bromide (1.88 g, 11 mmol) to the reaction solution, return the reaction solution to room temperature and stir for 2 hours. After TLC detection, cool to 0°C, add saturated aqueous ammonium chloride solution to quench, and extract with ethyl acetate. The organic phases are combined and washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to remove the solvent. The residue is purified by column chromatography to obtain compound INT40e (2.2 g). MS / ESI[M+H] + =263.3.

[0192] Step 4: At room temperature, add a solution of compound INT40e (524 mg, 2.0 mmol) in acetone (4 mL) to a 1N HCl aqueous solution (3.0 mL). Heat the reaction solution to reflux for 2 hours, cool to room temperature, and add a saturated sodium bicarbonate aqueous solution to the mixture. Extract with dichloromethane, combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to remove the solvent. The residue is purified by column chromatography to obtain compound INT40f (0.3 g), MS / ESI [M+H] + =219.3.

[0193] Step 5: Compound INT40f (4.95 g, 22.7 mmol), methyl 2-bromo-6-fluorobenzoate INT24e (5.3 g, 22.7 mmol), Pd 2 (dba) 3 (0.83g, 0.9mmol), XantPhos (1.05g, 1.8mmol) and cesium carbonate (9.6g, 29.5mmol) were added to 1,4-dioxane (80ml), nitrogen was protected, and the temperature was raised to 110℃ for 12h. After the reaction was completed, the filtrate was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=10:1~3:1) to obtain compound INT40g (3.2g), MS / ESI[M+H] +=339.1.

[0194] Step 4: Add compound INT40g (2.8 g, 8.2 mmol) to ammonia methanol solution (20 ml), and heat to 110 °C under nitrogen protection for 4 h. After the reaction, concentrate under reduced pressure to obtain compound INT40h (2.5 g). MS / ESI [M+H] + =338.3.

[0195] Step 5: Compound INT40h (2.36 g, 7.0 mmol) was added to dichloromethane, and boron tribromide (10 ml) was added at room temperature to react for 0.5 h. After the reaction was complete, methanol was added to quench the reaction, and the reaction was concentrated under reduced pressure. The residue was purified by column chromatography (DCM: MeOH = 20: 1) to obtain compound INT24i (1.4 g), MS / ESI [M+H] + =249.2.

[0196] Step 6: Add compound INT40i (1.4 g, 5.6 mmol) to DMF, add triphenylphosphine (2.9 g, 11.2 mmol), react at room temperature for 30 min, add carbon tetrabromide (3.7 g, 11.2 mmol), and react at room temperature for 12 h. After the reaction, add the reaction solution to water (40 mL), add ethyl acetate (60 mL) for extraction, concentrate the organic phase under reduced pressure, and purify the residue by column chromatography (DCM: MeOH = 20: 1) to obtain compound INT40 (1.5 g), MS / ESI [M+H] + =311.1.

[0197] The preparation method of intermediates INT41-INT71 refers to intermediate INT40.

[0198] Table 9 Intermediates INT41-INT71

[0199]

[0200]

[0201]

[0202]

[0203] Intermediate INT72: 3-(Bromomethyl)-7-fluoro-2-methyl-1,3,4,5-tetrahydrobenzo[c][1,6]naphthyridin-6(2H)-one

[0204]

[0205] The preparation method of 3-(bromomethyl)-7-fluoro-2-methyl-1,3,4,5-tetrahydrobenzo[c][1,6]naphthyridin-6(2H)-one is based on the intermediate INT40, MS / ESI[M+H] + =325.2.

[0206] The preparation method of intermediates INT73-INT87 refers to intermediate INT40.

[0207] Table 10 Intermediates INT73-INT87

[0208]

[0209]

[0210] Intermediate INT88: 3-(Bromomethyl)-7-fluoro-1,3,4,5-tetrahydrobenzo[c][1,6]naphthyridin-6(2H)-one

[0211]

[0212] Step 1: To a solution of trimethylsilyl trifluoromethanesulfonate (0.034 mL) in dry dichloromethane (5 mL) was added 1,2-bis(trimethylsilyloxy)ethane INT40b (4.55 mL), followed by compound INT88a (4.1 g). The reaction mixture was stirred at -78 °C for 3 hours. Pyridine (0.5 mL) was added to quench, and saturated NaHCO 3 The solution was added to the solution and extracted with ether. 2 CO 3 / Na 2 SO 4 The organic layer was dried. The organic phase was concentrated under reduced pressure to remove the solvent, and purified by column chromatography to obtain compound INT88b (3.2 g). MS / ESI [M+H] + =301.2.

[0213] Step 2: In a 100 ml round-bottom flask, lithium aluminum hydride (1 g) was added to ether (20 ml) to obtain a suspension. Compound INT88b (1 g) dissolved in ether (5 ml) was slowly added via a syringe. The mixture was stirred overnight at room temperature. After cooling to 0 ° C, the reaction was quenched with water. The product was extracted with ether (2 x 10 ml). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to remove the solvent and purified by column chromatography to obtain compound INT88c (0.5 g), MS / ESI [M+H] + =274.2.

[0214] Step 3: Add compound INT88c (2.7 g, 10 mmol) to DMF (20 mL), cool to 0°C, slowly add NaH (60 wt%, 0.44 g, 11 mmol), and continue stirring at 0°C for 30 minutes after the addition. Add benzyl bromide (1.88 g, 11 mmol) to the reaction solution, return the reaction solution to room temperature and stir for 2 hours. After TLC detection, cool to 0°C, add saturated aqueous ammonium chloride solution to quench, and extract with ethyl acetate. The organic phases are combined and washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to remove the solvent. The residue is purified by column chromatography to obtain compound INT88d (3.1 g). MS / ESI[M+H] + =364.3.

[0215] Step 4: At room temperature, add a solution of compound INT88d (726 mg, 2.0 mmol) in acetone (4 mL) to a 1N HCl aqueous solution (3.0 mL). Heat the reaction solution to reflux for 2 hours, cool to room temperature, and add a saturated sodium bicarbonate aqueous solution to the mixture. Extract with dichloromethane, combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to remove the solvent. The residue was purified by column chromatography to obtain compound INT88e (0.5 g), MS / ESI [M+H] + =220.3.

[0216] Step 5: Triethylamine (19.2 g, 190 mmol) was added to a stirred solution of compound INT88e (28.7 g, 131 mmol) in methanol (300 mL) and stirred for 5 min. Boc 2 O (34 g, 168 mmol), and then DMAP (0.4 g, 3 mmol) was added. The solution was stirred at room temperature for 20 hours. The ethanol was removed by concentration under reduced pressure, and the crude product was dissolved in dichloromethane (100 mL). The organic phase was treated with HCl (2 M, 2×70 mL), saturated Na 2 CO 3 (70 mL) and saturated NaCl (50 mL), and washed with Na 2 SO 4 Dry, filter, and concentrate the filtrate under reduced pressure to remove the solvent to obtain compound INT88f. MS / ESI[M+H] + =320.3.

[0217] Step 6: Compound INT88f (7.24 g, 22.7 mmol), methyl 2-bromo-6-fluorobenzoate INT24e (5.3 g, 22.7 mmol), Pd 2 (dba) 3(0.83g, 0.9mmol), XantPhos (1.05g, 1.8mmol) and cesium carbonate (9.6g, 29.5mmol) were added to 1,4-dioxane (80ml), nitrogen was protected, and the temperature was raised to 110℃ for 12h. After the reaction was completed, the filtrate was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=10:1~3:1) to obtain compound INT88g (5.1g), MS / ESI[M+H] + =440.1.

[0218] Step 7: Compound INT88g (4.4 g, 10 mmol) was added to ammonia methanol solution (20 ml), and the temperature was raised to 110 °C under nitrogen protection for 4 h. After the reaction, the mixture was concentrated under reduced pressure to obtain compound INT88h (4.1 g). MS / ESI [M+H] + =439.3.

[0219] Step 8: Compound INT88h (3.1 g, 7.0 mmol) was added to dichloromethane, and boron tribromide (10 ml) was added at room temperature to react for 0.5 h. After the reaction was complete, methanol was added to quench the reaction, and the reaction was concentrated under reduced pressure. The residue was purified by column chromatography (DCM: MeOH = 20: 1) to obtain compound INT88i (1.4 g), MS / ESI [M+H] + =249.2.

[0220] Step 9: Compound INT88i (1.4 g, 5.6 mmol) was added to DMF, triphenylphosphine (2.9 g, 11.2 mmol) was added, and the mixture was reacted at room temperature for 30 min. Carbon tetrabromide (3.7 g, 11.2 mmol) was added, and the mixture was reacted at room temperature for 12 h. After the reaction, the reaction solution was added to water (40 mL), and ethyl acetate (60 mL) was added for extraction. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM: MeOH = 20: 1) to obtain compound INT88 (1.1 g). MS / ESI [M+H] + =311.1.

[0221] The preparation method of intermediates INT89-INT103 refers to intermediate INT88.

[0222] Table 11 Intermediates INT89-INT103

[0223]

[0224]

[0225] Intermediate INT104: N-methyl-5-(((2R,3S)-2-methylazetidin-3-yl)oxy)picolinamide

[0226]

[0227] Step 1: Add 5-hydroxypicolinic acid methyl ester INT104a (2.0 g, 13.1 mmol) and (2R, 3R)-3-hydroxy-2-methylazetidine-1-carboxylic acid tert-butyl ester INT104b (3.651 g, 19.5 mol) to tetrahydrofuran (200 mL), cool the reaction solution to 0°C, add triphenylphosphine (20.54 g, 78.3 mmol), replace with nitrogen 3 times, stir for 1 hour, add DEAD (11.36 g, 65.3 mol), add, stir at room temperature for 12 hours, after the reaction is completed, concentrate the reaction solution under reduced pressure, and collect the product by column chromatography (PE:EA=10:1~1:1) to obtain a crude compound INT104c, MS / ESI[M+H] + =323.2.

[0228] Step 2: Compound INT104c (4.5 g, 13.9 mol) was added to methanol (20 mL), and methylamine alcohol solution (20 mL) was added. After the addition was complete, the mixture was reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude compound INT104d. MS / ESI [M+H] + =322.2.

[0229] Step 3: Add the compound INT104d (4.5 g, 13.9 mol) obtained in the previous step into dichloromethane (20 mL), add dioxane hydrochloride solution (20 mL), and react at room temperature for 1 h. After the reaction is completed, the reaction solution is concentrated under reduced pressure, ethyl acetate is added to the concentrate for pulping, filtered, and the filter cake is collected to obtain compound INT104. MS / ESI[M+H] + =222.2.

[0230] The preparation method of intermediates INT105-INT107 refers to intermediate INT104.

[0231] Table 12 Intermediates INT105-INT107

[0232]

[0233] Intermediate INT108: N-(cyclopropylmethoxy)-5-(piperazine-1-yl)pyridineamide

[0234]

[0235] Preparation of N-(cyclopropylmethoxy)-5-(piperazin-1-yl)picolinamide reference intermediate INT12. LC-MS:ESI[M+H] + =277.2.

[0236] Intermediate INT109: 6-Fluoro-N-methyl-5-(piperidin-4-yl)picolinamide

[0237]

[0238] Compound INT2 (0.2 g, 0.84 mmol) was dissolved in DCM (20 mL), Pd / C (10%, 0.1 g) was added, and the mixture was replaced with hydrogen three times, and stirred at 25°C for 12 h under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain compound INT109 (0.2 g, crude). LC-MS: ESI [M+H] + =238.2.

[0239] Intermediate INT110: 2-Chloro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0240]

[0241] The preparation method of 2-chloro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide refers to intermediate INT1. MS / ESI[M+H] + =252.1.

[0242] Intermediate INT111: 6-Chloro-N-methyl-5-(piperazin-1-yl)picolinamide

[0243]

[0244] The preparation method of 6-chloro-N-methyl-5-(piperazine-1-yl)picolinamide refers to intermediate INT9. MS / ESI[M+H] + =255.3.

[0245] Intermediate INT112: Preparation of (R)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazolidine-9-carboxamide hydrochloride

[0246]

[0247] Step 1: Add (R)-3-(Hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (5g, 23.118mmol) to DMF (50mL), add p-methoxybenzyl chloride (3.62g, 23.118mmol) and potassium carbonate (9.58g, 69.355mmol), heat to 60°C and react for 24h. After the reaction is completed, add water to quench the reaction, add ethyl acetate to extract, wash the organic phase with water 3 times, and concentrate the organic phase under reduced pressure. The obtained crude product is purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain compound INT112b (6g, yield: 77.14%). LCMS = 337.4; 1 H NMR(400MHz,Chloroform-d)δ7.14(d,J=8.3Hz,2H),6.79(d,J=8.3Hz,2H),3.88(d,J=13.2Hz,1H),3.81-3.76(m,1H),3.72(s,3H), 3.60(m,1H),3.51(m,2H),3.28(d,J=13.1Hz,2H),3.07(s,1H),2.69(d,J=12.3Hz,1H),2.56-2.42(m,1H),2.18(m,1H),1.38(s,9H).

[0248] Step 2: Add compound INT112b (6 g, 17.834 mmol) and 6-bromo-2-(bromomethyl)-3-fluoropyridine (4.80 g, 17.834 mmol) to DMF (100 mL), cool to 0°C, add sodium hydrogen (1.07 g, 26.751 mmol), react at room temperature for 12 h, add water to quench the reaction, add ethyl acetate to extract, wash the organic phase with water 3 times, concentrate the organic phase under reduced pressure, and purify the crude product by column chromatography (petroleum ether: ethyl acetate = 5:1 to 1:1) to obtain compound INT112d (4.2 g). LCMS = 525.4. 1 H NMR(400MHz,Chloroform-d)δ7.37-7.34(m,1H),7.23-7.19(m,1H),7.16-7.10(m,2H),6.79-6.73(m,2H),4.66-4.51(m,2H),3.84(s,1H), 3.72(s,3H),3.59-3.55(m,2H),3.43(d,J=13.1Hz,1H),3.29(d,J=13.3Hz,1H),3.11(s,2H),2.61-2.53(m,2H),2.09(s,1H),1.37(s,9H).

[0249] Step 3: Compound INT112d (4.2 g, 8.009 mmol), PdCl 2 (PPh 3 ) 2 (1.12 g, 1.602 mmol) and DIEA (3.11 g, 24.026 mmol) were added to DMF (30 mL) and ethanol (30 mL), and the temperature was raised to 90°C for reaction for 12 h under the protection of carbon monoxide. The reaction solution was added to water, and ethyl acetate was added for extraction. The organic phase was washed with water for 3 times, and the organic phase was concentrated under reduced pressure. The obtained crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1 to 2:1) to obtain compound INT112e (2 g, yield: 48.25%). LCMS = 518.2.

[0250] Step 4: Add compound INT112e (500 mg, 0.966 mmol) to acetonitrile (10 mL) and water (10 mL), cool to 0°C, add cerium ammonium nitrate (2.647 g, 4.83 mmol), stir at room temperature for 12 hours, after the reaction is completed, add the reaction solution to saturated sodium bicarbonate aqueous solution to adjust pH=8-9, add ethyl acetate for extraction, wash the organic phase with water 3 times, concentrate the organic phase under reduced pressure, and purify the obtained crude product by column chromatography (dichloromethane: methanol=8:1) to obtain crude compound INT112f (100 mg, yield: 26.05%). LCMS=398.2.

[0251] Step 5: Compound INT112f (85 mg, 0.214 mmol) and DIEA (82.93 mg, 0.642 mmol) were added to NMP (3 mL), heated to 180°C and stirred for 6 hours. After the reaction was completed, the reaction solution was added to water, extracted with ethyl acetate, the organic phase was washed with water 3 times, and the organic phase was concentrated under reduced pressure to obtain compound INT112g (80 mg, yield: 99.11%). LCMS=378.2.

[0252] Step 6: Add compound INT112g (80 mg, 0.212 mmol) and methylamine alcohol solution (2 mL) into methanol (2 mL), stir at room temperature for 1 h, and after the reaction, concentrate the reaction solution under reduced pressure to obtain crude compound INT112h (80 mg, yield: 100%). LCMS=363.4.

[0253] Step 7: Add compound INT112h (80 mg, 0.221 mmol) to dioxane (2 mL), add dioxane hydrochloride (1 mL), stir at room temperature for 1 hour, after the reaction is completed, concentrate the reaction solution under reduced pressure to obtain compound INT112 (hydrochloride 80 mg), LCMS=263.2.

[0254] Example 1

[0255] Preparation of N-methyl-5-(4-((6-oxo-3,4,5,6-tetrahydro-1H-pyrano[4,3-c]isoquinolin-3-yl)methyl)piperazin-1-yl)picolinamide

[0256]

[0257] Compound INT25 (230 mg, 0.7849 mmol), compound INT9 (229 mg, 0.7849 mmol), potassium carbonate (541 mg, 3.9245 mmol) and potassium iodide (13 mg, 0.078 mmol) were added to DMF (6 mL), and the temperature was raised to 70°C for reaction for 48 h. After the reaction was completed, the reaction solution was added to water (15 mL), and ethyl acetate (60 mL) was added for extraction. The organic phase was washed with water (60 mL), and the organic phase was concentrated under reduced pressure. The concentrate was subjected to column chromatography (dichloromethane: methanol = 20: 1 to 10: 1), the product was collected, and concentrated under reduced pressure to obtain the target compound 1 (7 mg, 5.0% yield), MS / ESI [M+H] + =434.1, HNMR(400M-d-DMSO):11.30(s,1H),8.47-8.45(m,1H),8.34(s,1H),8.27-8.25(m,1H),7.90(d,J=8.8Hz,1H),7.78-7.74(s,1H),7. 54-7.43(m,3H),4.98(d,J=14.4Hz,1H),4.75-4.71(m,1H),4.08-3.99(m,1H),3.43-3.01(m,3H),2.84(d,J=4.8Hz,3H),2.75-2.60(m,9H).

[0258] The preparation methods of compounds 2 to 308 of Example 2 to Example 308 refer to Example 1.

[0259] Table 13 Compounds 2 to 308

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320] Biological activity test:

[0321] 1. PARP enzyme assay

[0322] Experimental materials: PARP1 protein (BPS, Cat. No. 80501), PARP2 protein (BPS, Cat. No. 80502), PARP5A protein (BPS, Cat. No. 80504), Biotin-NAD+ (R&D, Cat. No. 6573), Strep-HRP (ThermoPierce, Cat. No. 21127), NAD+ (TCI, Cat. No. D0919-5G), quantitative enhanced chemiluminescence HRP substrate kit (Thermo Pierce, Cat. No. 15159), histone (Active Motif, Cat. No. 81167), activated DNA (Genscript, Cat. No. L05182-01&02&03), anti-rabbit IgG, HRP-linked Antibody (CST, Cat. No. 7074P2), anti-Poly / Mono-ADP Ribose (E6F6A) Rabbit mAb (CST, Cat. No. 83732S), SuperSignal ELISA Femto Substrate (THERMO PIERCE, Cat. No. 37074).

[0323] 1.1 PARP1 enzyme assay

[0324] 1.1.1 Preparation of buffer: PBST: 1X PBS, 0.05% Tween-20, blocking solution: 1X PBS, 0.05% Tween-20, 5% BSA, reaction buffer: 50mM Tris-HCl (pH7.5), 0.005% Tween-20, 0.01% BSA.

[0325] 1.1.2 Coating: Prepare 50 ng / mL Histone coating solution with 1xPBS, transfer 25uL of coating solution to a 384-well reaction plate, and coat overnight at 4°C.

[0326] 1.1.3 Washing: After coating, discard the coating solution and wash with PBST solution. The method is to transfer 50uL PBST to a 384-well reaction plate, let it stand for 5 minutes, discard the washing solution, refill it, repeat the washing 3 times, and finally pat the reaction plate dry and wait for the next step of blocking.

[0327] 1.1.4 Blocking: Transfer 50uL of blocking solution to a 384-well reaction plate and let stand for 1 hour.

[0328] Washing: After blocking, discard the blocking solution and wash three times with PBST solution according to step 2, and finally pat the reaction plate dry.

[0329] 1.1.5 Prepare 1000 times the compound, transfer 1uL of the compound to 199uL of reaction buffer in a 96-well plate, mix well, and transfer 5uL of the mixed compound to a 384-well reaction plate.

[0330] 1.1.6 Prepare 25 / 10 times PARP1-DNA solution with reaction buffer, transfer 10uL PARP1-DNA solution to the 384-well reaction plate. For the negative control well, transfer 10uL DNA solution. The final concentration of PARP1 is 0.02nM and the final concentration of DNA is 0.8nM.

[0331] 1.1.7 Prepare 25 / 10 times NAD+ solution with reaction buffer, transfer 10uL NAD+ solution to a 384-well reaction plate, the final NAD+ concentration is 3.5uM, and incubate at room temperature for 60 minutes.

[0332] 1.1.8 Prepare 25 / 10 times NAD+ solution with reaction buffer, transfer 10uL NAD+ solution to a 384-well reaction plate, the final NAD+ concentration is 3.5uM, and incubate at room temperature for 60 minutes.

[0333] 1.1.9 Washing: After the reaction is completed, discard the reaction solution and wash three times with PBST solution according to step 2, and finally pat the reaction plate dry.

[0334] 1.1.10 Dilute the primary antibody (anti-Poly / Mono-ADP Ribose Rabbit mAb) 2000 times with blocking solution, add 20uL of primary antibody, and incubate at room temperature for 1.5 hours.

[0335] 1.1.11 Washing: Discard the primary antibody and wash three times with PBST solution according to step 2, and finally pat the reaction plate dry.

[0336] 1.1.12 Dilute the secondary antibody (anti-rabbit IgG, HRP-linked Antibody) 2000 times with blocking solution, add 20uL of secondary antibody, and incubate at room temperature for 1 hour.

[0337] 1.1.13 Washing: Discard the secondary antibody and wash three times with PBST solution according to step 2, and finally pat the reaction plate dry.

[0338] 1.1.14 Color development: Mix Femto-ECL Substrate A and Femto-ECL Substrate B in a 1:1 ratio and transfer 25uL to a 384-well reaction plate.

[0339] 1.1.15 Reading: Use Envision to read the chemiluminescence value RLU.

[0340] The test results are shown in Table 14 below:

[0341] Table 14 PARP-1 enzyme test results

[0342]

[0343]

[0344] +++ indicates IC 50 Less than or equal to 50nM

[0345] ++ indicates IC 50 Between 50nM and 500nM;

[0346] + indicates IC 50 Greater than 500nM

[0347] Conclusion: The compounds of the present invention have good inhibitory activity on PARP1 enzyme.

[0348] 2. Cell anti-proliferation activity test:

[0349] BRCA mutant cells MDA-MB-436 cells were cultured in DMEM medium containing 10% fetal bovine serum, 100U / mL penicillin, and 100μg / mL streptomycin, and cultured in a 5% saturated CO2 incubator at 37°C. When the cells grew to 80% confluence, the cells were collected, centrifuged at 300g for 10min, and plated on a 96-well plate at 1200 cells / well. After 24h, different final concentrations of PARPi (0, 0.01, 0.1, 1, 10, 100, 1000nM) were added and cultured for 72h. The cells were treated with a change of medium (PARPi was re-added with the same final concentration) and cultured for 96h. The 96-well plate was taken out, and the OD value at a wavelength of 450nM was detected by CCK8 method, and the cell inhibition rate was calculated:

[0350] Inhibition rate % = 1-(average OD value of the drug administration group-average OD value of the Blank group) / (average OD value of the Control group-average OD value of the Blank group)*100%.

[0351] BRCA wild-type cells DLD-1 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum, 100U / mL penicillin, and 100μg / mL streptomycin, and cultured in a 5% saturated CO2 incubator at 37°C. When the cells grew to 80% confluence, the cells were collected, centrifuged at 300g for 10min, and plated at 1000 cells / well in a 96-well plate. After 24h, different final concentrations of PARPi (0, 1, 10μM) were added and cultured for another 72h. The cells were treated with a change of medium (PARPi was re-added at the same final concentration) and cultured for another 96h. The 96-well plate was taken out, and the OD value at a wavelength of 450nM was detected by CCK8 method, and the cell inhibition rate was calculated:

[0352] Inhibition rate % = 1-(average OD value of the drug administration group-average OD value of the Blank group) / (average OD value of the Control group-average OD value of the Blank group)*100%.

[0353] The test results are shown in Table 15 below:

[0354] Table 15 Cell antiproliferative activity test results

[0355]

[0356] Conclusion: The compounds of the present invention have a significant inhibitory effect on BRCA mutant MDA-MB-436 cells, but have no significant inhibitory effect on BRCA wild-type DLD-1 cells, indicating that the compounds of the present invention specifically inhibit tumor cells with homologous recombination defects.

[0357] 3. Pharmacokinetic evaluation of the compound in Balb / c mice

[0358] Experimental purpose: To understand the pharmacokinetics of the compound.

[0359] Experimental basis: Technical guidelines for non-clinical pharmacokinetic studies of chemical drugs, 2014.

[0360] Experimental plan: The pharmacokinetics of the compound were investigated by intravenous administration (1 mg·kg-1) and oral administration (1 mg·kg-1) to Balb / c mice.

[0361] Sample preparation: weigh about 0.2 mg of the compound, add 10 μL DMSO to dissolve, and then add sodium chloride solution for injection to make a 0.1 mg·mL-1 compound solution for administration.

[0362] Sample collection: 6 Balb / c mice (Chengdu Dashuo Experimental Animal Co., Ltd., license number: SCXK (Chuan) 2020-030), male, 3 mice were intravenously administered (IV) at 1 mg·kg-1, and 3 mice were gavaged (PO) at 1 mg·kg-1. About 0.05 mL of blood was collected at 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, 24h and 48h after administration. The collected blood was centrifuged at 3500rpm for 15min, and the supernatant plasma was collected and frozen at -40℃ for testing. The blood drug concentration was quantitatively analyzed by LC-MS / MS analysis method, and pharmacokinetic parameters such as peak time (Cmax), area under the drug-time curve (AUC(0-t)), half-life (T 1 / 2 ), clearance rate (CL), tissue distribution (Vdss), bioavailability (F), etc.

[0363] Table 16 Pharmacokinetic test results of compounds in Balb / c mice

[0364]

[0365] Conclusion: The compounds of the present invention have good pharmacokinetic properties in Balb / c mice.

[0366] 4. In vivo pharmacodynamic study of compound 25 on MDA-MB-436 nude mouse subcutaneous transplant tumor model

[0367] Experimental process: 30 female NOD / SCID mice were randomly divided into blank control group, compound 25 (0.3, 1, 3 mg / kg) dose group, and reference compound Olaparib 100 mg / kg group, a total of 5 groups, 6 mice in each group, all were orally administered once a day. At the same time, the body weight was weighed every 2 days and the length and width of the tumor were measured with a vernier caliper. After 30 days of administration, the tumor-bearing mice were anesthetized and killed, the tumor tissue was peeled off, weighed and photographed, and the tumor inhibition rate was calculated. The reference compound Olaparib was purchased from Shanghai MedChemExpress.

[0368] Conclusion: The experimental results are as follows Figure 1As shown. After cell inoculation, each drug-treated group was continuously administered for 30 days. Compared with the blank control group, each drug-treated group (Olaparib 100mg / kg, compound 25 0.3, 1, 3mg / kg) had a significant inhibitory effect on the growth of human breast cancer cell MDA-MB-436 cell line NOD / SCID mouse subcutaneous tumor model. The tumor inhibition rates of each drug-treated group were 65.81%, 66.19%, 82.84%, and 92.44%, respectively; the relative tumor proliferation rate T / C% values ​​were 29.23%, 29.05%, 16.49%, and 6.46%, respectively. Among the drug-treated groups, the tumor inhibition effect of the compound 25 3mg / kg group was the best; the tumor inhibition effect of the compound 25 3mg / kg group was better than that of the reference drug Olaparib 100mg / kg group.

Claims

1. A compound of formula I or a pharmaceutically acceptable form thereof, characterized in that: The structure of Formula I is as follows: in: Structural unit Select from the following structures: R x1 , R y1 independently selected from hydrogen, deuterium, halogen, cyano, amino or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl; R x1 and R y1 In the above, the substituent is selected from the group consisting of: deuterium, halogen, oxo, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, -NH-C 1-4 Alkyl, -N(C 1-4 Alkane)2, -OC 1-4 Alkyl or 3-6 membered cycloalkyl; R x1 and R y1 wherein the 4- to 6-membered heterocycloalkyl group and the 5- to 6-membered heteroaryl group contain 1 to 3 heteroatoms selected from at least one of N, S, and O; R x2 is selected from hydrogen, deuterium or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl; R x2 In the above, the substituent is selected from the group consisting of: deuterium, halogen, -OH, -NH2, -CN, oxo, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -OC 1-4 Alkyl or 3-6 membered cycloalkyl; R x2 wherein the 4- to 6-membered heterocycloalkyl group and the 5- to 6-membered heteroaryl group contain 1 to 3 heteroatoms selected from at least one of N, S, and O; R7 is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Fluoroalkoxy, -OC 1-4 Alkyl, -OC 1-4 Fluorinated alkyl, -OC 1-4 Deuterated alkyl, -NH-C 1-4 Alkyl or -N(C 1-4 alkyl)2; n4 is selected from 1, 2, 3, 4, 5, 6; R8 is selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Deuterated alkyl or 3-6 membered cycloalkyl; Z1 is selected from a bond, O, NR a1 , CR a2 R a3 Or C = Z4; Z2 is selected from O, NR b1 or CR b2 R b3 ; Z3 is selected from O or CR c1 R c2 ; R a1 , R b1 is independently selected from hydrogen, deuterium or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl; R a1 and R b1 wherein the substituent is selected from: deuterium, halogen, -OH, -NH2, -CN or a 3- to 6-membered cycloalkyl group; R a1 and R b1 wherein the 4- to 6-membered heterocycloalkyl group and the 5- to 6-membered heteroaryl group contain 1 to 3 heteroatoms selected from at least one of N, S, and O; R a2 , R a3 , R b2 , R b3 , R c1 , R c2 are independently selected from hydrogen, deuterium, fluorine, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl or C 1-4 Hydroxyl substituted alkyl; R1 is selected from hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl or C 1-4 Hydroxyl substituted alkyl; R2 and R3 are independently selected from hydrogen, deuterium, fluorine, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl or C 1-4 Hydroxyl replaces alkyl, or R2 and R3 and the atoms to which they are attached form a 3-6 membered alkyl ring; Ring A is selected from 4- to 8-membered heterocycloalkyl groups; in Ring A, the 4- to 8-membered heterocycloalkyl group contains 1 to 3 N heteroatoms, and one of the N atoms is connected; R4 is selected from hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy or C 1-4 At least one of the fluoroalkoxy groups; or any two R4 together with the atoms to which they are attached form a 3-6-membered alkyl ring or a 5-7-membered alkyl heterocycle; when any two R4 together with the atoms to which they are attached form a ring, the 5-7-membered alkyl heterocycle contains 1 to 3 heteroatoms selected from at least one of N and O; L is selected from a bond, O, NR L1 or CR L2 R L3 ; R L1 Selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl or C 1-4 Hydroxyl substituted alkyl; R L2 and R L3 are independently selected from hydrogen, deuterium, fluorine, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl or C 1-4 Hydroxyl substituted alkyl; Ring B is selected from a 5-10 membered aryl group or a 5-10 membered heteroaryl group; in ring B, the 5-10 membered heteroaryl group contains 1 to 3 heteroatoms selected from at least one of N, S, and O; R5 is selected from hydrogen, deuterium, halogen, cyano, -(CR 5a R 5b ) n3 OR 5c 、-(CR 5a R 5b ) n3 N(R 5c R 5d ), -COOR 5c , -CONH2, -CONHR 5c 、-CON(R 5c R 5d ),-NHCOR 5c 、-SO2R 5c 、-SO2NHR 5c 、-SO2NR 5c R 5d , The following groups substituted by one or more R6: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; or two adjacent R5s and the atoms to which they are connected form a 5-6 membered alkyl ring, a 5-6 membered alkyl heterocycle, a benzene ring or a 5-6 membered heteroaryl ring; in R5, the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl contains 1-3 heteroatoms selected from at least one of N, S and O; when two adjacent R5s and the atoms to which they are connected form a ring, the 5-6 membered alkyl heterocycle or 5-6 membered heteroaryl contains 1-3 heteroatoms selected from at least one of N, S and O; Or R5 and R4 form a 5-7 membered alkyl heterocycle with the atoms to which they are connected; when R5 and R4 form a ring with the atoms to which they are connected, the 5-7 membered alkyl heterocycle contains 1 to 3 heteroatoms selected from at least one of N and O; R 5a and R 5b are independently selected from hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy or C 1-4 At least one of fluoroalkoxy; or R 5a and R 5b Together with the atoms to which they are attached, they form a 3- to 6-membered alkyl ring or a 4- to 6-membered alkyl heterocyclic ring substituted with 0-6 substituents; R 5a and R 5b When forming a ring with the atoms to which they are attached, the substituents are selected from hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy or C 1-4 At least one of the fluoroalkoxy groups; R 5a and R 5b When forming a ring with the atoms to which they are attached, the 5-6 membered alkyl heterocyclic ring contains 1 to 3 heteroatoms selected from at least one of N, S and O; R 5c and R 5d independently selected from hydrogen, deuterium or the following groups substituted by 0-6 substituents: C 1-4 Alkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, 3-8 membered cycloalkyl, 6-10 membered spirocycloalkyl, 6-10 membered heterospirocycloalkyl, 6-10 membered bridged cycloalkyl or 6-10 membered heterobridged cycloalkyl; R 5c and R 5d In the above, the substituent is selected from: deuterium, halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 alkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, 3- to 6-membered cycloalkylmethylene, 4- to 6-membered heterocycloalkylmethylene, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -OC 1-6 Alkyl, -CONH2 or -CONH-C 1-6 alkyl; R 5c and R 5d wherein the 5- to 10-membered heteroaryl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered heterospirocycloalkyl, and 6- to 10-membered heterobridged cycloalkyl contain 1 to 3 heteroatoms selected from at least one of N, S, and O; R 5c and R 5d In the substituent, the 4- to 6-membered heterocycloalkyl and 4- to 6-membered heterocycloalkylmethylene groups contain 1 to 3 heteroatoms selected from at least one of N, S and O; Or, R 5a With R 5c , R 5a With R 5d , R 5b With R 5c , R 5b With R 5d or R 5c With R 5d Together with the atoms to which they are attached, they form a 4-6 membered alkane heterocyclic ring substituted with 0-6 substituents selected from hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy or C 1-4 at least one of the fluoroalkoxy groups, wherein the 4-6 membered alkyl heterocyclic ring contains 1 to 3 heteroatoms selected from at least one of N, S or O; R6 is selected from H, deuterium, fluorine, C 1-4 Alkyl, C 1-4 Deuterated alkyl or C 1-4 Fluorinated alkyl; n1 is selected from 1, 2, 3, 4, 5, 6, 7, 8; n2 is selected from 1, 2, 3, 4, 5; n3 is selected from 0, 1, 2, 3, 4, 5; The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotopically labeled substances, metabolites or prodrugs.

2. The compound according to claim 1, characterized in that: R1 is selected from hydrogen, deuterium, fluorine, hydroxyl, amino or C 1-4 Alkyl; preferably, R1 is selected from hydrogen, deuterium, fluorine or methyl.

3. The compound according to claim 1 or 2, characterized in that: R2 and R3 are independently selected from hydrogen, deuterium, fluorine, C 1-4 Alkyl or C 1-4 Hydroxy substituted alkyl; preferably, R2 and R3 are independently selected from hydrogen, deuterium, fluorine, methyl or hydroxymethyl.

4. The compound according to any one of claims 1 to 3, characterized in that: L is selected from a bond, O, NR L1 or CR L2 R L3 ; R L1 is selected from hydrogen, deuterium, methyl, deuterated methyl, fluoromethyl or hydroxymethyl; R L2 and R L3 are independently selected from hydrogen, deuterium, fluorine, hydroxy, amino, methyl, deuterated methyl, fluoromethyl or hydroxymethyl; Preferably, L is selected from a bond, O or NH.

5. The compound according to any one of claims 1 to 4, characterized in that: R4 is selected from at least one of hydrogen, deuterium, fluorine, hydroxyl, amino, methyl, deuterated methyl, fluoromethyl, ethyl, methoxy, deuterated methoxy, fluoromethoxy or hydroxymethyl; or two R4 connected to adjacent C atoms together with the atoms to which they are connected form a 3-5-membered alkyl ring or a 5-6-membered alkyl heterocycle; when two R4 connected to adjacent C atoms form a ring with the atoms to which they are connected, the 5-6-membered alkyl heterocycle contains 1 to 2 heteroatoms selected from at least one of N or O; n1 is selected from 1, 2, 3, 4; Preferably, R4 is selected from at least one of hydrogen, deuterium, fluorine, hydroxyl, amino, methyl, ethyl, hydroxymethyl, and methoxy; or two R4 connected to adjacent carbon atoms together with the atoms to which they are connected form a 3-5-membered alkyl ring or a 5-6-membered alkyl heterocycle; when two R4 connected to adjacent C atoms form a ring with the atoms to which they are connected, the 5-6-membered alkyl heterocycle contains 1 heteroatom selected from O; n1 is selected from 1 and 2.

6. The compound according to any one of claims 1 to 5, characterized in that: Structural unit Selected from: or Preferably, the structural unit Selected from: or More preferably, the structural unit Selected from Selected from or 7. The compound according to any one of claims 1 to 6, characterized in that: Ring B is selected from phenyl, pyridyl, imidazolyl, imidazo[1,2-a]pyrazinyl, 1,7-naphthypyridyl, pyridazinyl, pyrazinyl, pyridothiazolyl, pyrazolo[1,5-a]pyrimidinyl, benzopyrazolyl, benzimidazolyl, thiazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, thienyl, furanyl, pyrazolyl, pyridazinopyrrolyl, pyridopyrazolyl, pyridooxazolyl or pyrimidinyl; Preferably, ring B is selected from or 8. The compound according to any one of claims 1 to 7, characterized in that: R5 is selected from hydrogen, fluorine, chlorine, bromine, cyano, amino, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Fluorinated alkoxy, 3-6 membered cycloalkyl, C 1-4 Alkyl aminoacyl, C 1-4 Deuterated alkylaminoyl, C 1-4 Fluoroalkylaminoacyl, C 1-4 Alkoxy substituted C 1-4 At least one of alkylaminoacyl, 3-6-membered cycloalkylaminoacyl, 3-6-membered fluorocycloalkylaminoacyl, 4-6-membered heterocycloalkylaminoacyl, 6-membered arylaminoacyl or 5-6-membered heteroarylaminoacyl, or two adjacent R5s and the atoms to which they are attached form a 5-6-membered alkyl ring or a 5-6-membered alkyl heterocycle; in R5, the 4-6-membered heterocycloalkylaminoacyl or 5-6-membered heteroarylaminoacyl contains 1-2 heteroatoms selected from at least one of N, S and O; when two adjacent R5s and the atoms to which they are attached form a ring, the 5-6-membered alkyl heterocycle contains 1-2 heteroatoms selected from at least one of N, S and O; n2 is selected from 1, 2, and 3; Preferably, R5 is selected from hydrogen, fluorine, chlorine, cyano, amino, methyl, deuterated methyl, fluoromethyl, ethyl, deuterated ethyl, fluoroethyl, cyclopropyl, cyclobutyl, methylamino, deuterated methylamino, fluoromethylamino, methylaminoacyl, deuterated methylaminoacyl, fluoromethylaminoacyl, ethylaminoacyl, deuterated ethylaminoacyl, fluoroethylaminoacyl, methoxyethylaminoacyl, cyclopropylaminoacyl, fluorocyclopropylaminoacyl, cyclobutylaminoacyl, fluorocyclobutylaminoacyl or At least one of; n2 is selected from 1, 2.

9. The compound according to any one of claims 1 to 8, characterized in that: Structural unit Selected from: or 10. The compound according to any one of claims 1 to 9, characterized in that: Z3 is selected from O, CH2, CHF or CF2; Preferably, Z3 is selected from O or CH2.

11. The compound according to any one of claims 1 to 10, characterized in that: Z2 is selected from O, NR b1 or CR b2 R b3 ; R b1 is selected from hydrogen, deuterium or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl; R b1 wherein the substituent is selected from: deuterium, fluorine, -OH, -NH2, -CN or a 3-4 membered cycloalkyl group; R b1 wherein the 4- to 6-membered heterocycloalkyl group contains 1 to 2 heteroatoms selected from N or O; R b2 and R b3 are independently selected from hydrogen, deuterium, fluorine or C 1-4 alkyl; Preferably, Z2 is selected from O, NR b1 or CR b2 R b3 ; R b1 is selected from hydrogen, deuterium or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl or 3-4 membered cycloalkyl; R b1 wherein the substituent is selected from: deuterium, fluorine, -OH, -NH2, -CN or a 3-4 membered cycloalkyl group; R b2 and R b3 are independently selected from hydrogen, deuterium, fluorine or methyl; More preferably, Z2 is selected from O, CH2, NH, NCH3, NCD3 or N-cyclopropyl.

12. The compound according to any one of claims 1 to 11, characterized in that: When Z1 is selected from a bond, O, NR a1 or CR a2 R a3 When R a1 is selected from hydrogen, deuterium or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl; R a1 wherein the substituent is selected from: deuterium, fluorine, -OH, -NH2, -CN or a 3-4 membered cycloalkyl group; R a1 wherein the 4- to 6-membered heterocycloalkyl group contains 1 to 2 heteroatoms selected from N or O; R a2 and R a3 are independently selected from hydrogen, deuterium, fluorine or C 1-4 alkyl; Preferably, when Z1 is selected from a bond, O, NR a1 or CR a2 R a3 When R a1 is selected from hydrogen, deuterium or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl or 3-4 membered cycloalkyl; R a1 wherein the substituent is selected from: deuterium, fluorine, -OH, -NH2, -CN or a 3-4 membered cycloalkyl group; R a2 and R a3 are independently selected from hydrogen, deuterium, fluorine or methyl; More preferably, when Z1 is selected from a bond, O, NR a1 or CR a2 R a3 When Z1 is selected from O, CH2, NH, NCH3, NCD3 or N-cyclopropyl.

13. The compound according to any one of claims 1 to 12, characterized in that: R x1 , R y1 are independently selected from hydrogen, deuterium, halogen, cyano, amino, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -OC 1-4 Alkyl, -SC 1-4 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered fluorinated cycloalkyl or phenyl; R x2 Selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered fluorinated cycloalkyl or phenyl; R7 is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Fluoroalkoxy, -NH-C 1-4 Alkyl or -N(C 1-4 alkyl)2; n4 is selected from 1, 2, 3, 4; R8 is selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Deuterated alkyl or 3-4 membered cycloalkyl; Preferably, R x1 , R y1 are independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, cyclopropyl or fluorocyclopropyl; R x2 is selected from hydrogen, deuterium, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, cyclopropyl or fluorocyclopropyl; R7 is selected from hydrogen, deuterium, fluorine, chlorine, amino, methylamino, deuterated methylamino, fluoromethylamino, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, cyclopropyl, fluorocyclopropyl, methoxy, deuterated methoxy or fluoromethoxy; n4 is selected from 1, 2; R8 is selected from hydrogen, methyl, deuterated methyl or fluoromethyl; More preferably, the structural unit Selected from: or 14. The compound according to any one of claims 1 to 13, characterized in that: The compound is selected from:

15. The compound according to any one of claims 1 to 13, characterized in that: The compound is selected from:

16. The compound according to any one of claims 1 to 3 or 10 to 13, characterized in that: The structural unit Replace with:

17. The compound according to claim 16, characterized in that: The compound is selected from:

18. A pharmaceutical composition, characterized in that: The active ingredient is a compound according to any one of claims 1 to 14 or claims 15 to 17 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug thereof, supplemented with a pharmaceutically acceptable carrier.

19. Use of the compound according to any one of claims 1 to 14 or claims 15 to 17 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug, and the pharmaceutical composition according to claim 18 in the preparation of a medicament for preventing and / or treating PARP1 enzyme-related diseases.

20. The use according to claim 19, characterized in that: The PARP1 enzyme-related disease is a tumor-related disease.

21. The use according to claim 20, characterized in that: The tumor-like disorders are deficient in the HR-dependent DNA DSB repair pathway.

22. The use according to claim 21, characterized in that: The neoplastic disorder comprises one or more cancer cells having a reduced or absent ability to repair DNA DSBs by HR relative to normal cells.

23. The use according to claim 22, characterized in that: The cancer cells have a BRCA1 or BRCA2 deficient phenotype.

24. The use according to any one of claims 20 to 23, characterized in that: The tumor-like disease is breast cancer, ovarian cancer, primary peritoneal cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, glioblastoma or lung cancer.

25. Use of a compound according to any one of claims 1 to 14 or claims 15 to 17 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope-labeled substance, metabolite or prodrug thereof, and a pharmaceutical composition according to claim 18 in the preparation of a PARP1 inhibitor.

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