Lactam compounds and uses thereof

Abstract

The application discloses a kind of lactam compounds and purposes thereof, and belongs to the technical field of chemical medicine.The lactam compound provided in the application can be used as a PARP1 inhibitor, has the advantages of high activity and high selectivity, and also has excellent pharmacokinetic properties, excellent safety and potential for brain penetration.

Description

Technical Field

[0001] This invention belongs to the field of chemical medicine and relates to a class of lactam compounds and their uses. Background Technology

[0002] During cell growth, its DNA is constantly damaged by various internal and external adverse factors. Among DNA damage types, the most serious are single-strand breaks and double-strand breaks, with single-strand breaks being more common. If these breaks are not repaired promptly and accurately, they can lead to genomic instability, resulting in carcinogenesis or even cell death. For single-strand DNA breaks, repair primarily relies on PARP enzymes. For double-strand breaks, there are two main repair mechanisms: non-homologous end linkage repair and homologous recombination repair. Homologous recombination repair is a high-fidelity, error-free repair method and the main pathway for double-strand DNA repair. Many proteins are involved in homologous recombination repair, the most well-known being BRCA proteins. 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 tumors with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005)) showed that tumor cells lacking BRCA1 or BRCA2 were selectively inhibited by PARP inhibitors. Based on these findings, researchers proposed the concept of synthetic lethality: the deletion of either BRCA or PARP genes is not fatal in itself, but the simultaneous inactivation of both leads 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 demonstrated excellent clinical efficacy in patients with homologous recombination-deficient cancers. However, hematological toxicities (anemia, neutropenia, and thrombocytopenia) and other toxicities limit their application, whether used as monotherapy or in combination therapy. Related research (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-benzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor.[J]. Journal of Medicinal Chemistry, 2008, 51(15):4632.) suggests that these adverse reactions may stem from the inhibition of PARP2 by existing PARP inhibitors, which is not essential for therapeutic efficacy. Highly selective PARP1 inhibitors can reduce hematological toxicity, improve the therapeutic safety window, and increase the potential for combination therapy with other chemotherapy or targeted drugs.

[0004] Therefore, there is an unmet clinical need for effective and safe PARP inhibitors, particularly PARP inhibitors selective for PARP1. The novel PARP1 inhibitor described in this invention exhibits unexpectedly high selectivity for PARP1 compared to 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 this invention is to provide a class of PARP1-targeting compounds and their uses to achieve highly selective and efficient prevention or treatment of diseases related to PARP function; in particular, the PARP1-targeting compounds of this invention are surprisingly able to penetrate the blood-brain barrier (BBB); therefore, the PARP1-targeting compounds of this invention can be used to treat diseases and conditions occurring in central nervous system tissues (e.g., the brain and spinal cord).

[0006] In a first aspect, the present invention provides a compound of Formula I or a pharmaceutically acceptable form thereof, the structure of Formula I being as follows:

[0007]

[0008] in:

[0009] R1 is selected from hydrogen, deuterium, halogen, substituted or unsubstituted groups of the following: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl or 3- to 4-membered cycloalkyl; in R1, the substituents of the substituted groups are selected from deuterium or halogens;

[0010] X is selected from N or CR4; Y is selected from N or CR5;

[0011] R4 and R5 are independently selected from hydrogen, deuterium, amino, cyano, halogen, and C. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, 3-6 membered cycloalkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy groups;

[0012] Alternatively, R5 may be bonded to R1 or R4 to R5, and the atoms to which they are attached, to form substituted or unsubstituted rings of the following: 5-6 membered alkyl rings, 5-6 membered alkenyl rings, 5-6 membered alkyl heterocycles, benzene rings, or 5-6 membered heteroaryl rings; when R5 is bonded to R1 or R4 to R5, and the atoms to which they are attached form rings, the substituents of the substituted rings are selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, C 1-4 Hydroxy-substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 At least one of fluoroalkoxy or 3-4 membered cycloalkyl; when R5 is connected to R1 or R4 to R5 and the atoms to which they are attached to form a ring, the 5-6 membered alkyl heterocycle or 5-6 membered heteroaryl ring contains 1 to 3 heteroatoms selected from at least one of N, S or O;

[0013] L1 is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or (In these structures, the left-hand bonds are connected in the direction of the lactam ring in Formula I, and the right-hand bonds are connected in the direction of ring A in Formula I).

[0014] R 2a R 2b Independently selected from hydrogen, deuterium, fluorine, substituted or unsubstituted C 1-4 Alkyl; R 2a R 2b In, the replaced C 1-4 The alkyl substituent is selected from hydrogen, deuterium, fluorine, hydroxyl, amino, or cyano; or, R 2a and R 2b They bond with the atoms they are attached to to form 3- to 4-membered alkyl rings;

[0015] Ring A is selected from: , , , , , , , , , , , , or (In these structures, the connection direction of the left-hand bonds is L1 in Equation I, and the connection direction of the right-hand bonds is L2 in Equation I).

[0016] R 6a Selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, fluoromethyl or deuterated methyl;

[0017] R 6b Selected from hydrogen, deuterium, fluorine, chlorine, or bromine;

[0018] L2 is selected from bonds, alkynyl groups, O, NH or N(CH3);

[0019] Ring B is selected from benzene ring, 5-10 membered heteroaryl ring or 5-10 membered partially unsaturated heteroaryl ring; in ring B, the 5-10 membered heteroaryl ring or 5-10 membered partially unsaturated heteroaryl ring contains 1 to 3 heteroatoms selected from at least one of N, S or O;

[0020] R3 is selected from hydrogen, deuterium, halogen, cyano, and -(CR). 3a R 3b ) n3 OR 3c 、-(CR 3a R 3b ) n3 N(R 3c R 3d -COOR 3c -COR 3c -CONHR 3c -CONHOR 3c -CON(R) 3c R 3d ), -NHCOR 3c -SO2R 3c -SO2NHR 3c -SO2N(R) 3c R 3d ), or, the following groups substituted with 0 to 6 substituents: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The substituent is selected from alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl; or, two adjacent R3s are bonded to the atoms they are attached to, forming a 5-6 membered alkyl ring, a 5-6 membered alkyl heterocycle, a benzene ring, or a 5-6 membered heteroaryl ring; in R3, the substituent is selected from deuterium, fluorine, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, C 1-4 Hydroxy-substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy or C 1-4 At least one of fluoroalkoxy groups; in R3, the 4-6 membered heterocyclic alkyl or 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S, and O; when two adjacent R3s are connected to the atoms to which they are attached to form a ring, the 5-6 membered alkyl heterocycle or 5-6 membered heteroaryl ring contains 1 to 3 heteroatoms selected from at least one of N, S, and O.

[0021] R 3a R 3b Independently selected from hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4Deuterated alkyl, C 1-4 Fluoroalkyl, C 1-4 Hydroxy-substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy or C 1-4 At least one of the fluoroalkoxy groups; or, R 3a and R 3b They are attached to the atoms to form 3-6 membered alkyl rings or 4-6 membered alkyl heterocycles substituted with 0-6 substituents; R 3a and R 3b When the substituents are linked to the atoms they are attached to to form a ring, the substituents are selected from hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, C 1-4 Hydroxy-substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy or C 1-4 At least one of the fluoroalkoxy groups; R 3a and R 3b When the 5-6 membered alkyl heterocycles are linked to the atoms they are connected to to form a ring, the alkyl heterocycles contain 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0022] R 3c R 3d Independently selected from hydrogen, deuterium, or the following groups substituted with 0-6 substituents: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne, 6-10 aryl, 5-10 heteroaryl, 4-8 heterocycloalkyl, 3-8 cycloalkyl, 6-10 spirocycloalkyl, 6-10 heterospirocycloalkyl, 6-10 bridged cycloalkyl or 6-10 heterobridged cycloalkyl; R 3c R 3d In this context, the substituents are selected from deuterium, halogens, hydroxyl groups, amino groups, cyano groups, and C6 groups. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, C 1-4 Hydroxy-substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Fluoroalkoxy, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 3-6 membered cycloalkylmethylene, 4-6 membered heterocycloalkylmethylene, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -OC 1-6 Alkyl, -CONH2 or -CONH-C 1-6 Alkyl; R6c R 6d In this context, the 5-10-membered heteroaryl, 4-8-membered heterocycloalkyl, 6-10-membered heterospirocycloalkyl, and 6-10-membered heterobridged cycloalkyl groups contain 1-3 heteroatoms selected from at least one of N, S, or O; R 3c R 3d In the substituents, the 4-6 membered heterocyclic alkyl group and the 4-6 membered heterocyclic alkyl methylene group contain 1-3 heteroatoms selected from at least one of N, S or O;

[0023] Or, R 3a With R 3c R 3a With R 3d R 3b With R 3c R 3b With R 3d or R 3c With R 3d They are bonded to the atoms to form 4-6 membered alkane heterocycles substituted with 0-6 substituents, wherein the substituents are selected from hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, C 1-4 Hydroxy-substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy or C 1-4 At least one of fluoroalkoxy groups, wherein the 4-6 membered alkyl heterocycle contains 1 to 3 heteroatoms selected from at least one of N, S or O;

[0024] Alternatively, when L2 is the bond, R3 and R 6a They are bonded to atoms to form substituted or unsubstituted 6-7 membered alkyl rings or 6-8 membered alkyl heterocycles; R3 and R 6a When the substituents are linked to the atoms they are attached to to form a ring, the substituents are selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, C 1-4 Hydroxy-substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 At least one of fluoroalkoxy or 3-4 membered cycloalkyl; R3 and R 6a When the 6-8 membered alkyl heterocycles are linked to the atoms they are connected to to form a ring, the 6-8 membered alkyl heterocycles contain 1 to 3 heteroatoms selected from at least one of N, S or O;

[0025] n1 is selected from 0 or 1;

[0026] n2 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0027] n3 is selected from 0, 1, 2, or 3;

[0028] And the compound is not:

[0029] or ;

[0030] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotope-labeled substances, metabolites, or prodrugs.

[0031] In some embodiments of the present invention, R1 is selected from hydrogen, deuterium, halogen, substituted or unsubstituted groups of the following: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl or 3- to 4-membered cycloalkyl; in R1, the substituents of the substituted groups are selected from deuterium or halogens;

[0032] R4 and R5 are independently selected from hydrogen, deuterium, amino, cyano, halogen, and C. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, 3-6 membered cycloalkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy groups;

[0033] Alternatively, R5 may be bonded to R1 or R4 to R5, and to the atoms to which they are attached, to form substituted or unsubstituted rings of the following: 5-6 membered alkyl rings, 5-6 membered alkyl heterocycles, benzene rings, or 5-6 membered heteroaryl rings; when R5 is bonded to R1 or R4 to R5, and to the atoms to which they are attached, the substituents of the substituted rings are selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, C 1-4 Hydroxy-substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 At least one of fluoroalkoxy or 3-4 membered cycloalkyl; when R5 is connected to R1 or R4 to R5 and the atoms to which they are attached to form a ring, the 5-6 membered alkyl heterocycle or 5-6 membered heteroaryl ring contains 1 to 3 heteroatoms selected from at least one of N, S or O;

[0034] L1 is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ;

[0035] Ring A is selected from: , , , , , , , , , , , or .

[0036] In some embodiments of the present invention, R1 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, fluoromethyl, fluoroethyl, deuterated methyl, deuterated ethyl, vinyl, ethynyl, methoxy, fluoromethoxy, methylthio, fluoromethylthio, or cyclopropyl.

[0037] In some preferred embodiments of the present invention, structural units Selected from the following groups:

[0038] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or X is selected from N, CH, or CCH3; Y is selected from N, CH, or CCH3; R1 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, ethyl, fluoromethyl, fluoroethyl, deuterated methyl, deuterated ethyl, vinyl, ethynyl, methoxy, fluoromethoxy, methylthio, fluoromethylthio, or cyclopropyl; R 1a It is selected from one, two, or three of the following groups: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, ethyl, fluoromethyl, fluoroethyl, deuterated methyl, deuterated ethyl, vinyl, ethynyl, methoxy, fluoromethoxy, methylthio, fluoromethylthio, or cyclopropyl.

[0039] In some preferred embodiments of the present invention, structural units Selected from the following groups:

[0040] , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , or .

[0041] In some embodiments of the present invention, structural units Selected from: , , , , , , , , , , , , or .

[0042] In some embodiments of the present invention, R 2a R 2b Independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, fluoromethyl, or deuterated methyl; or, R 2a and R 2b They bond with the atoms they are attached to to form cyclopropane.

[0043] In some preferred embodiments of the present invention, structural units Selected from:

[0044] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or (In these structures, the left-hand bonds are connected in the direction of the lactam ring in Formula I, and the right-hand bonds are connected in the direction of the ring A in Formula I).

[0045] In some embodiments of the present invention, structural units Selected from: , , , , , , , or .

[0046] In some embodiments of the present invention, ring A is selected from the following groups:

[0047] , , , , , , , , , , , , , , , , , , , , , , , , , , , , or (In these structures, the connection direction of the left-hand bonds is L1 in Equation I, and the connection direction of the right-hand bonds is L2 in Equation I).

[0048] In some preferred embodiments of the present invention, ring A is selected from: or .

[0049] In some preferred embodiments of the present invention Selected from the following groups:

[0050] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or (In these structures, the left-end key is connected in the direction of L1 in Formula I, and the right-end key is connected in the direction of ring B in Formula I; in the structure with three wavy lines, the left-end key is connected in the direction of L1 in Formula I, and the two right-end keys are connected to ring B in Formula I).

[0051] In some embodiments of the present invention, ring B is selected from benzene ring, pyridine ring, pyridothiazole ring, pyrazole[1,5-a]pyrimidine ring, benzopyrazole ring, benzimidazolium ring, thiazole ring, [1,2,4]triazolo[1,5-a]pyridine ring, thiophene ring, furan ring, imidazole ring, pyrazole ring, pyridazinopyrrole ring, pyridopyridine ring, pyridopyrazole ring, pyridoxazole ring, pyrimidine ring, pyridazine ring, pyrazine ring, etc. or ( In the formula, the connection direction of the left-hand key is L2 in formula I, and the connection direction of the right-hand key is R3 in formula I.

[0052] In some preferred embodiments of the present invention, ring B is selected from... , , , , , , or .

[0053] In some embodiments of the present invention, R3 is selected from hydrogen, deuterium, halogen, cyano, -(CR) 3a R 3b ) n4 OR 3c 、-(CR 3a R 3b ) n4 N(R 3c R 3d -COOR 3c -COR 3c -CONHR 3c -CONHOR 3c -CON(R) 3c R 3d ), -NHCOR 3c -SO2R 3c -SO2NHR 3c -SO2N(R) 3c R 3d ), or, substituted or unsubstituted of the following groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4The 5-6 membered alkyl ring, 3-6 membered cycloalkyl ring, or phenyl ring may be formed by two adjacent R3s bonded to the atoms they are attached to, forming a 5-6 membered alkyl ring, a 5-6 membered alkyl heterocycle, a benzene ring, or a 5-6 membered heteroaromatic ring. In R3, the substituent of the following groups is selected from at least one of: deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, deuterated methyl, fluoromethyl, hydroxy-substituted methyl, methoxy, deuterated methoxy, or fluoromethoxy. When two adjacent R3s are bonded to the atoms they are attached to form a ring, the 5-6 membered alkyl heterocycle or 5-6 membered heteroaromatic ring contains 1-2 heteroatoms selected from at least one of N, S, and O.

[0054] R 3a R 3b Independently selected from at least one of hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, methyl, deuterated methyl, fluoromethyl, hydroxy-substituted methyl, methoxy, deuterated methoxy, or fluoromethoxy; or, R 3a and R 3b They bond with the atoms to form substituted or unsubstituted 3-6 membered alkyl rings or 4-6 membered alkyl heterocycles; R 3a and R 3b When the substituents are linked to the atoms to form a ring, the substituents are selected from at least one of hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, deuterated methyl, fluoromethyl, hydroxy-substituted methyl, methoxy, deuterated methoxy, or fluoromethoxy; R 3a and R 3b When the 5-6 membered alkyl heterocycles are linked to the atoms they are connected to to form a ring, the alkyl heterocycles contain 1 to 2 heteroatoms selected from at least one of N, S, and O;

[0055] R 3c R 3d The group independently selected from hydrogen, deuterium, or substituted or unsubstituted groups of the following: methyl, ethyl, vinyl, ethynyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. , , or ;R 3c R 3d In this context, the substituents of the following groups are selected from: deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, deuterated methyl, fluoromethyl, hydroxy-substituted methyl, methoxy, deuterated methoxy, fluoromethoxy, or cyclopropyl.

[0056] Or, R 3a With R 3c R 3a With R 3d R 3b With R 3c R 3b With R 3dor R 3c With R 3d They are connected to the atoms to form substituted or unsubstituted 4-6 membered alkane heterocycles, wherein the substituents are selected from at least one of hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, methyl, deuterated methyl, fluoromethyl, hydroxy-substituted methyl, methoxy, deuterated methoxy, or fluoromethoxy, and the 4-6 membered alkyl heterocycles contain 1-2 heteroatoms selected from at least one of N, S, or O;

[0057] Alternatively, when L2 is the bond, R3 and R 6a They are bonded to atoms to form substituted or unsubstituted 6-7 membered alkyl rings or 6-8 membered alkyl heterocycles; R3 and R 6a When the substituents are linked to the atoms to form a ring, the substituents are selected from at least one of hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, deuterated methyl, fluoromethyl, hydroxy-substituted methyl, methoxy, deuterated methoxy, fluoromethoxy, or cyclopropyl; R3 and R 6a When the 6-8 membered alkyl heterocycles are linked to the atoms they are connected to to form a ring, the alkyl heterocycles contain 1 to 2 heteroatoms selected from at least one of N, S or O.

[0058] In some preferred embodiments of the present invention, R3 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, deuterated methyl, fluoromethyl, vinyl, ethynyl, methoxy, deuterated methoxy, fluoromethoxy, methylamino, deuterated methylamino, fluoromethylamino, acetyl, deuterated acetyl, fluoroacetyl, propionyl, deuterated propionyl, fluoropropionyl, aminoacyl, methylaminoacyl, deuterated methylaminoacyl, fluoromethylaminoacyl, ethylaminoacyl, deuterated ethylaminoacyl, fluoroethylaminoacyl, cyclopropylaminoacyl, fluorocyclopropylaminoacyl, cyclobutylaminoacyl, fluorocyclobutylaminoacyl. , , , , , , , , , , ;

[0059] Alternatively, when L2 is the bond, R3 and R 6a They connect with the atoms to form the following rings: , or (In these structures, the two bonds on the left end are connected to ring A, and the two bonds on the right end are connected to ring B).

[0060] In some embodiments of the present invention, structural units Selected from the following groups:

[0061] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0062] This invention also provides some specific compounds selected from:

[0063] .

[0064] Secondly, the present invention provides a pharmaceutical composition in which the active ingredient comprises the aforementioned compound of the present invention or a pharmaceutically acceptable form thereof, supplemented by a pharmaceutically acceptable carrier.

[0065] A further object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, the method comprising combining any compound of formula I or a pharmaceutically acceptable form thereof, or a mixture thereof, with one or more pharmaceutically acceptable carriers.

[0066] The pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention are pharmaceutically acceptable carriers, and examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).

[0067] Pharmaceutical compositions can be administered in any form, as long as they achieve the purpose of preventing, alleviating, preventing, or curing symptoms in human or animal patients. For example, they can be formulated into various suitable dosage forms depending on the route of administration.

[0068] In other embodiments, the administration of the compounds or pharmaceutical compositions of the present invention may be combined with other treatment methods. These other treatment methods may be selected from, but are not limited to, radiotherapy, chemotherapy, immunotherapy, or combinations thereof.

[0069] This invention also relates to a pharmaceutical formulation comprising any compound of formula I or a pharmaceutically acceptable form thereof, or a mixture thereof, as an active ingredient, or the pharmaceutical composition of this invention. In some embodiments, the formulation is in the form of a solid dosage form, a semi-solid dosage form, a liquid dosage form, or a gaseous dosage form.

[0070] A further object of the present invention is to provide an article of manufacture, for example, in the form of a kit. The article of manufacture as used herein is intended to include, but is not limited to, medicine boxes and packaging. The article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition contained in the first container, wherein the composition comprises: a first therapeutic agent comprising: any compound of formula I or a pharmaceutically acceptable form thereof, or a mixture thereof; (c) optionally present packaging instructions stating that the pharmaceutical composition may be used to treat a cancerous condition (as defined below); and (d) a second container.

[0071] The first container is a container for containing a pharmaceutical composition. This container may be used for the preparation, storage, transportation, and / or individual / bulk sales. The first container is intended to encompass bottles, jars, vials, flasks, syringes, tubes (e.g. for cream products), or any other container for the preparation, containment, storage, or dispensing of pharmaceutical products.

[0072] The second container is a container for holding the first container and optional instruction manuals. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic boxes), cartons, cartons, bags (e.g., paper or plastic bags), sachets, and cloth bags. The instruction manuals may be physically attached to the outside of the first container by cable ties, glue, U-staples, or other adhesive methods, or they may be placed inside the second container without any physical means of attachment to the first container. Alternatively, the instruction manuals may be located outside the second container. When located outside the second container, it is preferable that the instruction manuals be physically attached by cable ties, glue, U-staples, or other adhesive methods. Alternatively, they may be adjacent to or in contact with the outside of the second container without physical attachment.

[0073] The packaging instructions, such as trademarks, labels, or markings, list information relating to the pharmaceutical composition contained within the first container. The listed information is typically determined by the regulatory authority governing the region where the product is to be sold (e.g., the U.S. Food and Drug Administration). Preferably, the packaging instructions specifically list the approved indications for which the pharmaceutical composition is used. The packaging instructions can be made of any material from which information contained therein or on the material can be read. Preferably, the packaging instructions are made of a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper, or plastic) on which the desired information can be formed (e.g., printed or coated).

[0074] Thirdly, the present invention provides the use of the aforementioned compounds, compounds of formula I, and related specific compounds or pharmaceutically acceptable forms thereof, or the pharmaceutical compositions of the present invention, in the preparation of PARP1 inhibitors or medicaments for the prevention or treatment of PARP1 enzyme-related diseases.

[0075] The present invention provides a method for preventing or treating PARP1 enzyme-related diseases, the method comprising administering to an individual in need a compound of formula I or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention.

[0076] The present invention provides compounds of formula I or their pharmaceutically acceptable forms, or pharmaceutical compositions thereof, for the prevention or treatment of PARP1 enzyme-related diseases.

[0077] The present invention provides a method for preventing or treating PARP1 enzyme-related diseases by combining a compound of Formula I or a pharmaceutically acceptable form thereof, or a pharmaceutical composition thereof, with other treatment methods including but not limited to: radiotherapy, chemotherapy, immunotherapy, or combinations thereof.

[0078] In some implementations, the PARP1 enzyme-related disease is a disease that is sensitive to or responsive to PARP1 enzyme inhibition.

[0079] In some implementations, the PARP1 enzyme-related disease is a tumor-related condition.

[0080] In some preferred embodiments, the tumor-related diseases lack the HR-dependent DNA DSB repair pathway.

[0081] In some preferred embodiments, the tumor-like condition comprises one or more cancer cells that have a reduced or absent ability to repair DNA DSB via HR compared to normal cells.

[0082] In some preferred embodiments, the cancer cells have a BRCA1 or BRCA2 defective phenotype.

[0083] In some implementations, the PARP1 enzyme-related diseases are oncological conditions, including but not limited to solid and hematologic malignancies. In further implementations, the oncological conditions include, but are not limited to, breast cancer, colorectal cancer, colon cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer, or bronchioloalveolar carcinoma), prostate cancer, bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer, vulvar cancer, hematologic malignancies (including chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or chronic myeloid leukemia (CML)), multiple myeloma, lymphoma, meningioma, pituitary adenoma, craniopharyngioma, schwannoma, glioma, ependymoma, primitive neuroectodermal tumors, central nervous system lymphoma, germ cell tumors, metastatic tumors, primary peritoneal cancer, brain cancer, or central nervous system cancer.

[0084] In some preferred embodiments, the PARP1 enzyme-related diseases are breast cancer, ovarian cancer, primary peritoneal cancer, pancreatic cancer, prostate cancer, hematologic malignancies, gastrointestinal cancer, glioblastoma, or lung cancer.

[0085] The compounds of this invention can penetrate the blood-brain barrier (BBB), therefore, in some preferred embodiments, the tumor is a brain metastasis or glioma.

[0086] In a further preferred embodiment, the compounds of the present invention can be used in combination with radiotherapy, chemotherapy, or immunotherapy to prevent or treat cancer.

[0087] The present invention also provides the use of the aforementioned compounds, compounds of formula I, and related specific compounds or their pharmaceutically acceptable forms, or the use of the pharmaceutical compositions of the present invention in the preparation of PARP1 inhibitors.

[0088] The beneficial effects of this invention are:

[0089] This invention provides a novel class of highly active and selective PARP1 inhibitors that can achieve at least one of the following technical effects: (1) high inhibitory activity against PARP1 enzymes; (2) selective inhibition of PARP1 enzymes, with high selectivity for other PARP family enzymes such as PARP2, PARP5a, and PARP5b; (3) strong inhibitory activity against homologous recombination-deficient tumor cells, with weak inhibitory effect against non-homologous recombination-deficient cells; (4) excellent pharmacokinetic properties (e.g., good bioavailability, suitable half-life, and duration of action); (5) excellent safety (low toxicity and / or fewer side effects, and a wide therapeutic window); and (6) the PARP1-targeting compounds of this invention are surprisingly able to penetrate the blood-brain barrier (BBB) ​​and can be used to treat diseases and conditions occurring in central nervous system tissues (e.g., the brain and spinal cord).

[0090] Terminology definition:

[0091] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by those skilled in the art. The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps. Those skilled in the art will understand that the foregoing term “comprising” encompasses the meaning of “consisting of.”

[0092] In this invention, the terms "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted as indicating that the composition comprises "one or more" pharmaceutically acceptable excipients.

[0093] When the lower and upper limits of a numerical range are disclosed, any numerical value falling within that range and any included range are specifically disclosed. In particular, each range of values ​​disclosed herein (in the form of “about a to b”, or equivalently, “approximately a to b”, or equivalently, “about ab”) should be understood to represent each numerical value and range encompassed within a wider range.

[0094] For example, the expression "C" 1-8 "This should be understood as encompassing any subrange and each point value, such as C." 2-5 C 3-4 C 1-2 And so on, as well as C1, C3, C6, etc. For example, the expression "C 2-8 "It should also be understood in a similar way, for example, it can encompass any subrange and point value contained within it, such as C." 6-8 C 6-7 And C3, C5, C8, etc. For example, the expression "3-6 yuan" should be understood as covering any subrange and each point value, such as 3-4 yuan, 3-6 yuan, 4-6 yuan, etc., as well as 3, 5 yuan, etc.

[0095] In this invention, unless otherwise stated, halogen refers to fluorine, chlorine, bromine or iodine.

[0096] In this invention, unless otherwise stated, "alkyl" includes straight-chain or branched monovalent saturated hydrocarbon groups. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, C1-4 in "C1-4 alkyl" refers to a group containing 1, 2, 3, or 4 carbon atoms arranged in a straight-chain or branched form.

[0097] In this invention, unless otherwise stated, "cycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group. Common cycloalkyl groups include (but are not limited to) monocyclic cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclobutene, cyclopentene, cyclohexene, etc.; or bicyclic cycloalkyl groups, including fused rings, bridged rings, or spirocyclic groups, such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, bicyclic [5.2.0]nonyl, decahydronaphthyl, etc. For example, "C3-12 cycloalkyl" refers to a cycloalkyl group having 3-12 ring carbon atoms (such as 3, 6, 7, 10, or 12).

[0098] "Cycloalkenyl" refers to a non-aromatic hydrocarbon group containing at least one unsaturated double bond, either monocyclic or polycyclic (such as fused-cyclic, bridged-cyclic, or spirocyclic bicyclic groups). When the cycloalkenyl or cycloidenyl group is a polycyclic system, it can be a ring system composed of an aryl group and a non-aromatic carbocyclic ring, such as... It is not aromatic as a whole. The cycloalkenyl groups in this invention are optionally substituted with one or more substituents described in this invention.

[0099] In this invention, unless otherwise stated, "halogenated alkyl" refers to the alkyl group described above, wherein one or more hydrogen atoms are replaced by a halogen. For example, the term "C" 1-6 "Halogenated alkyl" refers to a C-aryl group optionally substituted with one or more (e.g., 1-3) halogens. 1-6 Alkyl groups. Those skilled in the art will understand that when there is more than one halogen substituent, the halogens can be the same or different, and can be located on the same or different C atoms. Examples of alkyl halogens include, for example, -CH2F, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2Cl, or -CH2CH2CF3.

[0100] In this invention, unless otherwise stated, "fluoroalkyl" refers to the alkyl group described above, wherein one or more hydrogen atoms are replaced by fluorine atoms. For example, the term "C 1-4 "Fluoroalkyl" refers to a C-aryl group that is optionally substituted with one or more (e.g., 1-3) fluorine atoms. 1-4 Alkyl groups. Those skilled in the art will understand that when there is more than one fluorine atom substituent, the fluorine atoms can be the same or different, and can be located on the same or different C atoms. Examples of haloalkyl groups include, for example, -CH2F, -CHF2, -CF3, -C2F5, -CH2CF3, -CH2CH2CF3, etc.

[0101] In this invention, unless otherwise stated, "alkenyl" refers to a straight-chain or branched aliphatic hydrocarbon group having at least one C=C double bond. For example, "C..." 2-4 "Alkenyl" refers to an alkenyl group having 2 to 4 carbon atoms. Common alkenyl groups include (but are not limited to) vinyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, n-octenyl, n-decenyl, etc.

[0102] In this invention, unless otherwise stated, "substituted" means that one or more hydrogen atoms in a group are replaced by the same or different substituents.

[0103] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but a different atomic mass or mass number than the dominant atomic mass or mass number found in nature. Examples of isotopes suitable for inclusion in the compounds of this invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium). 2 H), tritium ( 3 H); carbon isotopes (e.g., H); 13 C and 14 C); isotopes of chlorine (e.g.) 37 Cl); isotopes of iodine (e.g., Cl); 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes ... 32 P); and isotopes of sulfur (e.g., ... 34 S).

[0104] In this invention, "polymorph" refers to different solid crystalline phases resulting from the presence of two or more different molecular arrangements in the solid state of certain compounds of this invention. Some compounds of this invention may exist in more than one crystal form, and this invention aims to include various crystal forms and mixtures thereof. Typically, crystallization produces solvates of the compounds of this invention. The term "solvate" as used in this invention refers to an aggregate comprising one or more molecules of the compound of this invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Therefore, the compounds of this invention can exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., and corresponding solvated forms. The compounds of this invention can form true solvates, but in some cases, they may also remain only as indeterminate water or a mixture of water and a portion of indeterminate solvent. The compounds of this invention can react in a solvent or precipitate or crystallize from a solvent. The solvates of the compounds of this invention are also included within the scope of this invention. This invention also covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0105] In this invention, "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of this invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, and imine-enamine tautomers. It is to be understood that the scope of this invention covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0106] In this invention, pharmaceutically acceptable salts include their acid addition salts and base addition salts. Suitable acid addition salts are formed by acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed by bases that form pharmaceutically acceptable salts. A review of suitable salts can be found, for example, in “Remington’s Pharmaceutical Sciences,” Mack Publishing Company, Easton, Pa., (2005); and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use,” Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of this invention are known to those skilled in the art. “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic or organic acid that retains the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobroms, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecanoate, glycolate, gluconate, lactate, sebate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylic acid, and naphthalenedisulfonate. These salts can be prepared by methods known in this patent. "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Preferred inorganic salts are ammonium salts, sodium salts, calcium salts, and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in this patent.

[0107] In this invention, unless otherwise stated, "ester" refers to an ester derived from the compounds described herein, including physiologically hydrolyzable esters (compounds of this invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of this invention may themselves be esters.

[0108] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0109] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form nitrogen oxides because nitrogen requires available lone pairs of electrons to be oxidized. Those skilled in the art will identify nitrogen-containing heterocycles capable of forming nitrogen oxides. They will also recognize that tertiary amines can form nitrogen oxides. Synthetic methods for preparing nitrogen oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, alkyl peroxides such as tert-butyl peroxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for preparing nitrogen oxides have been extensively described and reviewed in the literature, see, for example: T.L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp. 748-750 (AR. Katritzky and A.J. Boulton, Eds., Academic Press); and G.W. H. Heeseman and E.S. G. Wierstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp. 390-392 (AR. Katritzky and A.J. Boulton, Eds., Academic Press).

[0110] In this invention, "metabolite" refers to a substance formed in the body upon administration of a compound of the present invention. Metabolites of the compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of the present invention, including compounds obtained by methods that expose the compounds of the present invention to mammals for a time sufficient to produce their metabolites.

[0111] In this invention, a "prodrug" refers to certain derivatives of the compounds of the invention that, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of the invention having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that readily convert in vivo into the desired therapeutically active compounds. Further information regarding the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs of the invention can be prepared, for example, by replacing suitable functional groups present in the compounds of the invention with portions known to those skilled in the art as "pro-moiety" (e.g., as described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)).

[0112] In this application, "pharmaceutical composition" refers to a formulation of the compounds of the present invention with a medium generally accepted in the art for delivering bioactive compounds to mammals (e.g., humans). This medium includes pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate administration to the organism, promote the absorption of the active ingredient, and thereby exert its bioactivity.

[0113] In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that is permitted by the relevant government regulatory authority or is acceptable for human or livestock use.

[0114] As used herein, the terms “drug combination,” “drug co-administration,” “combination therapy,” “administration of other treatments,” and “administration of other therapeutic agents” refer to pharmaceutical treatments achieved by mixing or combining more than one active ingredient, including fixed and non-fixed combinations of active ingredients. The term “fixed combination” refers to the simultaneous administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity or dosage form. The term “non-fixed combination” refers to the simultaneous, combined, or sequential administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity at variable intervals. These also apply to cocktail therapies, such as the administration of three or more active ingredients.

[0115] In this invention, unless otherwise stated, "tumor" includes, but is not limited to, diseases such as leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, squamous cell carcinoma of the lung, adenocarcinoma of the lung, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, intestinal cancer, nasal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, and oral cancer.

[0116] In this invention, unless otherwise stated, "treatment" means reversing, alleviating, or inhibiting the progression of a disease or condition or one or more symptoms of such a disease or condition, or preventing such a disease or condition or one or more symptoms of such a disease or condition.

[0117] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention. Detailed Implementation

[0118] The present invention will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they shall be performed in accordance with the techniques or conditions described in the literature in the art or in accordance with the product manual.

[0119] The reagents and raw materials used in the embodiments of this invention are all commercially available.

[0120] Table 1. Abbreviations and their meanings in this invention.

[0121]

[0122] The structure of the compound described in this invention was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS). Chemical shifts were expressed as 10⁻⁶. -6 (ppm) is given as the unit.

[0123] MS measurements were performed using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, signal: 6110).

[0124] HPLC determinations were performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfirc C18, 150X 4.6mm, 5µm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18, 150X 4.5mm, 5µm column).

[0125] The silica gel plates used for thin-layer chromatography are Qingdao Ocean GF254 silica gel plates. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15mm-0.2mm, while the silica gel plates used for thin-layer chromatography separation and purification of products have a diameter of 0.4mm-0.5mm.

[0126] Column chromatography typically uses Qingdao Marine 100-200 or 200-300 mesh silica gel as a carrier.

[0127] Unless otherwise specified in the following examples, all reactions are carried out under an argon or nitrogen atmosphere. An argon or nitrogen atmosphere refers to a reaction flask connected to an approximately 1L argon or nitrogen balloon. A hydrogen atmosphere refers to a reaction flask connected to an approximately 1L hydrogen balloon. Hydrogenation reactions are typically performed under vacuum, followed by hydrogen filling, and repeated three times.

[0128] Intermediate int-1: N-methyl-5-(piperazin-1-yl)pyridine amide

[0129]

[0130] Step 1: Compound int-1a (5.66 g, 26.21 mmol, 1.05 eq), compound int-2a (4.65 g, 25.0 mmol, 1.00 eq), Cs₂CO₃ (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 overnight at 120 °C under nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature by LC-MS. The reaction mixture was diluted with water (100 mL) and then extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound int-1b (white solid, 4.5 g). MS / ESI[M+H] + =322.1.

[0131] Step 2: Compound int-1b (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 LC-MS. The reaction was quenched at room temperature with a saturated aqueous solution of ammonium chloride (30 mL). The resulting mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give compound int-1c (1.65 g) as a pale yellow oil. MS / ESI [M+H] + =321.3.

[0132] Step 3: Compound int-1c (482 mg, 1.50 mmol, 1.00 eq) and a 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 monitored by LCMS, the resulting mixture was concentrated under reduced pressure to give compound int-1 (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.

[0133] The preparation of intermediates int-2 to int-4 is based on intermediate int-1.

[0134] Table 2 Intermediates int-2 to int-4

[0135]

[0136] Intermediate int-5: 6-fluoro-N-methyl-5-(4-oxomylidenecyclohex-1-enyl)pyridine-2-carboxamide

[0137]

[0138] Step 1: Preparation of methyl 6-fluoro-5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine-2-carboxylate

[0139] Methyl 5-bromo-6-fluoropyridine-2-carboxylate (2 g, 8.546 mmol), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaboranecyclopentane (2.27 g, 8.546 mmol), Pd(dppf)Cl2 (0.62 g, 0.855 mmol), and potassium carbonate (3.54 g, 25.639 mmol) were added to dioxane (30 mL) and water (3 mL). The mixture was heated to 90 °C for 12 h under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the concentrate was subjected to column chromatography (petroleum ether: ethyl acetate = 10%). The product was collected to give 2.7 g of crude methyl 6-fluoro-5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine-2-carboxylate. MS / ESI [M+H] + =294.2.

[0140] Step 2: Preparation of 6-fluoro-N-methyl-5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine-2-carboxamide

[0141] Methyl 6-fluoro-5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine-2-carboxylate (2.70 g, 9.206 mmol) was added to methanol (20 mL), followed by methylamine (6 mL), and the reaction was carried out at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain 2.6 g of crude 6-fluoro-N-methyl-5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine-2-carboxamide, which was analyzed by MS / ESI [M+H]. + =293.2.

[0142] Step 3: Preparation of 6-fluoro-N-methyl-5-(4-oxomylidenecyclohex-1-enyl)pyridine-2-carboxamide

[0143] 2.6 g (8.895 mmol) of 6-fluoro-N-methyl-5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine-2-carboxamide was added to dichloromethane (20 mL), followed by trifluoroacetic acid (6 mL). The reaction mixture was allowed to react overnight at room temperature. The reaction solution was concentrated under reduced pressure to give 2 g of crude 6-fluoro-N-methyl-5-(4-oxoylidenecyclohex-1-enyl)pyridine-2-carboxamide, yield: 90.63%, MS / ESI [M+H]. + =294.2.

[0144] Example 1: 6-Fluoro-N-methyl-5-(4-(3-(1-oxo-1,2-dihydroisoquinoline-3-yl)prop-2-yn-1-yl)piperazin-1-yl)pyridinecarboxamide (Compound 1)

[0145]

[0146] Step 1: Preparation of 3-bromo-1-methoxyisoquinoline: 1,3-Dibromoisoquinoline (4 g, 13.940 mmol) was added to methanol (40 mL), followed by sodium methoxide (2.26 g, 41.819 mmol). The mixture was heated to 70 °C and reacted for 3 h. After the reaction was complete, water was added to quench the reaction, and the mixture was concentrated under reduced pressure. The concentrate was extracted with dichloromethane, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated to obtain 3-bromo-1-methoxyisoquinoline, yield: 93.41%. LC-MS: ESI [M+H] + =238.1.

[0147] Step 2: Preparation of 3-bromoquinoline-1(2H)-one: 3-bromo-1-methoxyisoquinoline (4 g, 13.874 mmol) was added to dichloromethane (30 mL), the temperature was lowered to 0℃, and boron tribromide (6.52 g, 26.042 mmol) was added. The reaction was carried out at room temperature for 3 h. After the reaction was completed, saturated sodium bicarbonate water was added to quench the reaction. The mixture was separated, and the concentrate was subjected to column chromatography (DCM: MeOH = 5%) to obtain 3-bromoquinoline-1(2H)-one, yield: 27.42%, LC-MS: ESI [M+H] + =224.1.

[0148] Step 3: Preparation of 3-(3-hydroxyprop-1-yn-1-yl)isoquinoline-1(2H)-one: 3-bromoquinoline-1(2H)-one (0.4 g, 1.785 mmol), prop-2-yn-1-ol (0.2 g, 3.570 mmol), triethylamine (0.542 g, 5.356 mmol), Pd(dppf)Cl2 (0.130 g, 0.179 mmol), and cuprous iodide (0.113 g, 0.357 mmol) were added to DMF (10 In a nitrogen atmosphere, the mixture was heated to 90 °C for 12 h. After the reaction was complete, water was added to quench the reaction, and the mixture was concentrated under reduced pressure. The concentrate was then subjected to column chromatography (DCM: MeOH = 6%) to give 3-(3-hydroxyprop-1-yn-1-yl)isoquinoline-1(2H)-one, yield: 64.67%. LC-MS: ESI [M+H] + =200.2.

[0149] Step 4: Preparation of 3-(3-bromoprop-1-yn-1-yl)isoquinoline-1(2H)-one: 0.2 g (1.004 mmol) of 3-(3-hydroxyprop-1-yn-1-yl)isoquinoline-1(2H)-one was added to dichloromethane (4 mL), followed by carbon tetrabromide (0.5 g, 1.506 mmol) and triphenylphosphine (0.395 g, 1.506 mmol). The reaction was carried out at room temperature for 12 h. After the reaction was completed, water was added to quench the reaction, and the mixture was concentrated under reduced pressure. The concentrate was then subjected to column chromatography (DCM: MeOH = 5%) to give 3-(3-bromoprop-1-yn-1-yl)isoquinoline-1(2H)-one. Crude product yield: 100%. LC-MS: ESI [M+H] + =264.1.

[0150] Step 5: Preparation of 6-fluoro-N-methyl-5-(4-(3-(1-oxo-1,2-dihydroisoquinoline-3-yl)prop-2-yn-1-yl)piperazin-1-yl)pyridinecarboxamide: 3-(3-bromoprop-1-yn-1-yl)isoquinoline-1(2H)-one (50 mg, 0.191 mmol) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide hydrochloride (45 mg, 0.191 mmol) were added to acetonitrile (2 mL), followed by the addition of cesium carbonate (247 mg, 0.763 mmol). After the addition was complete, the mixture was heated to 75 °C and reacted for 3 minutes. After the reaction was completed, the mixture was concentrated under reduced pressure, and the concentrate was subjected to column chromatography (DCM: MeOH = 5%). The concentrate was then sent to the preparation section to give 6-fluoro-N-methyl-5-(4-(3-(1-oxo-1,2-dihydroisoquinoline-3-yl)prop-2-yn-1-yl)piperazin-1-yl)pyridinecarboxamide (40 mg, yield 49.99%), LC-MS: ESI [M+H). +=420.2; 1 H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 8.43-8.39 (m, 1H), 8.17-8.17 (m, 1H), 7.86 (dd, J = 8.0, 1.4 Hz, 1H), 7.74-7.71 (m, 1H), 7.67 – 7.63(m, 1H), 7.62-7.59 (m, 1H), 7.53-7.49 (m, 1H), 6.85 (s, 1H), 3.66 (s, 2H),3.22 (dd, J = 6.3, 3.5 Hz, 4H), 2.77-2.74 (m, 7H).

[0151] Example 2: 6-Fluoro-N-methyl-5-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)prop-2-yn-1-yl)piperazin-1-yl)pyridinecarboxamide (Compound 2)

[0152]

[0153] Step 1: Preparation of 2-bromoquinazoline-4(3H)-one: 2,4-Dibromoquinazoline (5 g, 17.365 mmol) was added to tetrahydrofuran and water (30 mL each), along with sodium hydroxide (3.47 g, 86.824 mmol). The reaction was carried out at room temperature for 1 h. After the reaction was completed, 1N hydrochloric acid was added to adjust the pH to 2-3. The mixture was filtered, and the filtrate was collected and dried under reduced pressure to obtain 2-bromoquinazoline-4(3H)-one. Yield: 76.77%. LC-MS: ESI [M+H] + =225.1.

[0154] The second, third, and fourth steps of the synthesis were performed according to Example 1, yielding 6-fluoro-N-methyl-5-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)prop-2-yn-1-yl)piperazin-1-yl)pyridinecarboxamide (3 mg, yield 1.15%), LC-MS: ESI [M+H + =421.2; 1H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 8.41 (t, J = 4.8 Hz, 1H), 8.10 (dd, J = 8.0, 1.5 Hz, 1H), 7.88 – 7.80 (m, 2H), 7.67 – 7.58 (m, 2H), 7.56-7.52 (m, 1H), 3.71 (s, 2H), 3.22 (t, J = 5.0 Hz, 4H), 2.77-2.75 (m, 7H).

[0155] Example 3: 6-Chloro-N-methyl-5-(4-(3-(1-oxo-1,2-dihydroisoquinoline-3-yl)prop-2-yn-1-yl)piperazin-1-yl)pyridinecarboxamide (Compound 3)

[0156]

[0157] The preparation of 6-chloro-N-methyl-5-(4-(3-(1-oxo-1,2-dihydroisoquinolin-3-yl)prop-2-yn-1-yl)piperazin-1-yl)pyridinecarboxamide was performed according to Example 1, yielding compound 3 (18 mg, yield 21.65%), LC-MS: ESI [M+H]. + =436.2; 1 H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 8.46-8.42 (m, 1H), 8.17-8.15(m, 1H), 7.86 (dd, J = 8.0, 1.4 Hz, 1H), 7.31-7.65 (m, 3H), 7.53-7.49 (m,1H), 6.85 (s, 1H), 3.66 (s, 2H), 3.22 (dd, J = 6.3, 3.5 Hz, 4H), 2.80-2.75(m,7H).

[0158] Example 4: 6-Fluoro-N-methyl-5-(4-(4-(1-oxo-1,2-dihydroisoquinoline-3-yl)but-3-yn-2-yl)piperazin-1-yl)pyridinecarboxamide (Compound 4)

[0159]

[0160] The preparation of 6-fluoro-N-methyl-5-(4-(4-(1-oxo-1,2-dihydroisoquinoline-3-yl)but-3-yn-2-yl)piperazin-1-yl)pyridinecarboxamide was performed according to Example 1, yielding compound 4 (7.5 mg, yield 9.55%), LC-MS: ESI [M+H]. + =434.2; 1 H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.41 (q, J = 4.6 Hz, 1H), 8.21 – 8.11 (m, 1H), 7.86 (dd, J = 8.1, 1.4 Hz, 1H), 7.74 – 7.55 (m, 3H),7.52-7.48(m, 1H), 6.83 (d, J = 1.7 Hz, 1H), 3.88 (t, J = 7.1 Hz, 1H), 3.27 –3.11 (m, 4H), 2.91 – 2.80 (m, 2H), 2.76 (d, J = 4.8 Hz, 3H), 2.70 (d, J = 6.3Hz, 2H), 1.39 (d, J = 6.9 Hz, 3H).

[0161] Example 5: 6-Chloro-N-methyl-5-(4-(4-(1-oxo-1,2-dihydroisoquinoline-3-yl)but-3-yn-2-yl)piperazin-1-yl)pyridinecarboxamide (Compound 5)

[0162]

[0163] The preparation method of 6-chloro-N-methyl-5-(4-(4-(1-oxo-1,2-dihydroisoquinoline-3-yl)but-3-yn-2-yl)piperazin-1-yl)pyridinecarboxamide was as described in Example 1, yielding compound 5 (3 mg, yield 1.84%), LC-MS: ESI [M+H]. + =450.2; 1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 8.44 (d, J = 5.0 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.76 – 7.62 (m, 2.71 (d, J = 6.1 Hz, 2H), 1.40 (d,J = 7.1 Hz, 3H).

[0164] Example 6: 6-Fluoro-N-methyl-5-(4-{[1-(4-oxoylide-3H-quinazolin-2-yl)bicyclo[1.1.1]pent-3-yl]methyl}piperazin-1-yl)pyridine-2-carboxamide (Compound 6)

[0165]

[0166] Step 1: Preparation of methyl 1-{[(2-formamidophenyl)amino]carbonyl}bicyclo[1.1.1]pentane-3-carboxylate: 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (5 g, 29.384 mmol) was added to DCM (50 mL), the temperature was lowered to 0 °C, and oxaloyl chloride (4.48 g, 35.261 mmol) was added. The reaction was carried out at room temperature for 3 h. The reaction solution was concentrated under reduced pressure. 2-aminophenyl-1-carboxamide (4 g, 29.384 mmol) and pyridine (5.81 g, 73.460 mmol) were added to DCM (50 mL). The above concentrate was added to a solution (mL), and the reaction was carried out at room temperature for 3 h. After the reaction was completed, water was added to quench the reaction, and the solution was concentrated under reduced pressure. The concentrate was extracted with ethyl acetate, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated to dryness, and the concentrate was subjected to column chromatography (DCM: MeOH = 5%) to give methyl 1-{[(2-formamidophenyl)amino]carbonyl}bicyclo[1.1.1]pentane-3-carboxylate, yield: 60.2%, LC-MS: ESI [M+H]. + =289.3.

[0167] Step 2: Preparation of 1-(4-oxoylide-3H-quinazolin-2-yl)bicyclo[1.1.1]pentane-3-carboxylic acid: Methyl 1-{[(2-formamidophenyl)amino]carbonyl}bicyclo[1.1.1]pentane-3-carboxylic acid (4 g, 13.874 mmol) was added to methanol (40 mL), followed by sodium hydroxide (2.22 g, 55.498 mmol). The mixture was heated to 70 °C and reacted for 3 h. After the reaction was complete, the mixture was concentrated under reduced pressure. The concentrate was adjusted to pH 2-3 with 1N hydrochloric acid, filtered, and the filtrate was collected and dried under reduced pressure to obtain 1-(4-oxoylide-3H-quinazolin-2-yl)bicyclo[1.1.1]pentane-3-carboxylic acid, yield: 56.3%, LC-MS: ESI [M+H]. + =257.2.

[0168] Step 3: Preparation of 2-[3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl]-3,4-dihydroquinazoline-4-one: 1-(4-oxoylide-3H-quinazoline-2-yl)bicyclo[1.1.1]pentane-3-carboxylic acid (2 g, 7.805 mmol) was added to tetrahydrofuran (20 mL), followed by lithium aluminum hydride (0.59 g, 15.609 mmol). The reaction was carried out at room temperature for 1 h. After the reaction was complete, water was added to quench the reaction, and the mixture was concentrated under reduced pressure. The solid was washed with dichloromethane and methanol in a 5:1 ratio, and the filtrate was concentrated to dryness to obtain 2-[3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl]-3,4-dihydroquinazoline-4-one, yield: 79.3%. LC-MS: ESI [M+H] + =243.3.

[0169] Step 4: Preparation of 2-[3-(bromomethyl)bicyclo[1.1.1]pent-1-yl]-3,4-dihydroquinazolin-4-one: 2-[3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl]-3,4-dihydroquinazolin-4-one (0.9 g, 3.715 mmol) was added to dichloromethane (20 mL), followed by carbon tetrabromide (1.847 g, 5.572 mmol) and triphenylphosphine (1.948 g, 7.429 mmol). The reaction was carried out at room temperature for 12 h. After the reaction was complete, water was added to quench the reaction, and the mixture was concentrated under reduced pressure. The concentrate was then subjected to column chromatography (DCM: MeOH = 5%) to give 2-[3-(bromomethyl)bicyclo[1.1.1]pent-1-yl]-3,4-dihydroquinazolin-4-one, yield: 30.87%, LC-MS: ESI [M+H]. + =306.1.

[0170] The preparation method of 6-fluoro-N-methyl-5-(4-{[1-(4-oxoylide-3H-quinazolin-2-yl)bicyclo[1.1.1]pent-3-yl]methyl}piperazin-1-yl)pyridine-2-carboxamide was as described in Example 1, yielding compound 6 (6 mg, yield 7.9%), LC-MS: ESI [M+H] + =463.5; 1 H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 8.43 (s, 1H), 8.10-8.07 (m, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.83 – 7.73 (m, 1H), 7.62 (d, J= 8.1 Hz, 2H), 7.53 – 7.43 (m, 1H), 3.62-3.44 (m, 4H), 3.20-3.10 (m, 4H), 2.77 (d, J = 4.7 Hz, 3H), 2.70-2.55 (m, 2H), 2.40-2.06 (s, 6H).

[0171] Example 7: 6-Chloro-N-methyl-5-(4-{[1-(4-oxoylide-3H-quinazolin-2-yl)bicyclo[1.1.1]pent-3-yl]methyl}piperazin-1-yl)pyridine-2-carboxamide (Compound 7)

[0172]

[0173] The preparation method of 6-chloro-N-methyl-5-(4-{[1-(4-oxoylide-3H-quinazolin-2-yl)bicyclo[1.1.1]pent-3-yl]methyl}piperazin-1-yl)pyridine-2-carboxamide was as described in Example 1, yielding compound 7 (18 mg, yield 12.74%), LC-MS: ESI [M+H]. + =479.2; 1H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 8.44 (d, J =5.0 Hz, 1H), 8.09 (dd, J = 8.0, 1.5 Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.80-7.76 (m, 1H), 7.65 (dd, J = 23.0, 8.2 Hz, 2H), 7.52 – 7.43 (m, 1H), 3.12 (s,4H), 2.79 (d, J = 4.7 Hz, 3H), 2.63 (s, 4H), 2.54 (s, 2H), 2.15 (s, 6H).

[0174] Example 8: 6-Fluoro-5-(4-(1-(5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)azacyclobutane-3-yl)piperazin-1-yl)-N-methylpyridinecarboxamide (Compound 8)

[0175]

[0176] Step 1: Preparation of tert-butyl 3-(4-{2-fluoro-6-[(methylamino)carbonyl]pyridin-3-yl}piperazin-1-yl)azacyclobutane-1-carboxylate: 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridin-2-carboxamide hydrochloride (1.0 g, 3.214 mmol) was added to dichloromethane (10 mL), followed by triethylamine (0.65 g, 6.427 mmol) and tert-butyl 3-oxomylidene-azacyclobutane-1-carboxylate (0.55 g, 3.214 mmol). After the addition was complete, the mixture was reacted at room temperature for 0.5 h. Then, sodium triacetoxyborohydride (1.02 g, 4.820 mmol) was added. After the reaction was complete, water was added to quench the reaction, followed by extraction with dichloromethane. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated to dryness, and the concentrate was subjected to column chromatography (DCM: MeOH = 5%) to give tert-butyl 3-(4-{2-fluoro-6-[(methylamino)carbonyl]pyridin-3-yl}piperazin-1-yl)azacyclobutane-1-carboxylate, yield: 94.9%, LC-MS: ESI [M+H]. + =394.2.

[0177] Step 2: Preparation of 5-[4-(azacyclobut-3-yl)piperazin-1-yl]-6-fluoro-N-methylpyridine-2-carboxamide hydrochloride: 1.2 g (3.05 mmol) of tert-butyl 3-(4-{2-fluoro-6-[(methylamino)carbonyl]pyridine-3-yl}piperazin-1-yl)azacyclobutane-1-carboxylate was added to dichloromethane (10 mL), followed by dioxane hydrochloride (10 mL). The reaction was carried out at room temperature for 12 h. After the reaction was completed, the solution was concentrated under reduced pressure to obtain 5-[4-(azacyclobut-3-yl)piperazin-1-yl]-6-fluoro-N-methylpyridine-2-carboxamide hydrochloride, yield: 81.4%. LC-MS: ESI [M+H] + =294.2.

[0178] Step 3: Preparation of 6-fluoro-5-(4-(1-(5-fluoro-4-oxo-3,4-dihydroquinazoline-2-yl)azacyclobutane-3-yl)piperazin-1-yl)-N-methylpyridinecarboxamide: 2-chloro-5-fluoroquinazoline-4-phenol (100 mg, 0.504 mmol) was added to DMF (2 mL), followed by DIEA (325 mg, 2.518 mmol) and 5-[4-(azacyclobutane-3-yl)piperazin-1-yl]-6-fluoro-N-methylpyridine-2-carboxamide hydrochloride (148 mg, 0.448 mmol). After the addition was complete, the temperature was raised to 110℃ and the reaction proceeded for 3 minutes. After the reaction was completed, the mixture was concentrated under reduced pressure, and the concentrate was subjected to column chromatography (DCM: MeOH = 5%). The concentrate was then sent to the preparation section to give 6-fluoro-5-(4-(1-(5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)azacyclobutane-3-yl)piperazin-1-yl)-N-methylpyridinecarboxamide (40 mg, yield 17.4%), LC-MS: ESI [M+H). + =456.2; 1 H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.41 (q, J = 4.8 Hz, 1H), 7.85 (dd, J = 8.0, 1.4 Hz, 1H), 7.62 – 7.48 (m, 2H), 7.05 (d, J = 8.3 Hz, 1H), 6.87 – 6.78 (m, 1H), 4.15 (dd, J = 9.1, 7.1 Hz, 2H), 3.95 (dd, J = 9.2, 5.1 Hz, 2H), 3.30 (s, 1H), 3.23 – 3.14 (m, 4H), 2.76(d, J = 4.8 Hz, 3H), 2.54 (d, J = 2.5 Hz, 4H).

[0179] Example 9: (S)-6-fluoro-5-(4-(1-(5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-3-yl)piperazin-1-yl)-N-methylpyridinecarboxamide (Compound 9)

[0180]

[0181] Step 1: Preparation of tert-butyl (3S)-3-(4-{2-fluoro-6-[(methylamino)carbonyl]pyridin-3-yl}piperazin-1-yl)tetrahydropyrrole-1-carboxylate: 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridin-2-carboxamide hydrochloride (0.5 g, 1.607 mmol) was added to DMF (10 mL), followed by DIEA (1.036 g, 8.034 mmol) and (3S)-3-bromotetrahydropyrrole-1-carboxylate-2-methylpropyl-2-yl ester (0.402 g, 1.607 mmol). After the addition was complete, the temperature was raised to 110°C and the reaction proceeded for 4 days. After the reaction was complete, water was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated to dryness, and the concentrate was subjected to column chromatography (DCM: MeOH = 5%) to give (3S)-3-(4-{2-fluoro-6-[(methylamino)carbonyl]pyridin-3-yl}piperazin-1-yl)tetrahydropyrrole-1-carboxylic acid tert-butyl ester, yield: 30.55%, LC-MS: ESI [M+H]. + =408.2.

[0182] Step 2: Preparation of 6-fluoro-5-{4-[(3S)-tetrahydro-1H-pyrrolo-3-yl]piperazin-1-yl}-N-methylpyridine-2-carboxamide hydrochloride: 0.2 g (0.491 mmol) of (3S)-3-(4-{2-fluoro-6-[(methylamino)carbonyl]pyridine-3-yl}piperazin-1-yl)tetrahydropyrrolo-1-carboxylic acid tert-butyl ester was added to dichloromethane (2 mL), followed by dioxane hydrochloride (2 mL). The reaction was carried out at room temperature for 12 h. After the reaction was completed, the solution was concentrated under reduced pressure to obtain 6-fluoro-5-{4-[(3S)-tetrahydro-1H-pyrrolo-3-yl]piperazin-1-yl}-N-methylpyridine-2-carboxamide hydrochloride, yield: 81.42%, LC-MS: ESI [M+H]. + =308.2.

[0183] Step 3: The preparation method of (S)-6-fluoro-5-(4-(1-(5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-3-yl)piperazin-1-yl)-N-methylpyridinecarboxamide was as described in Example 8, yielding compound 9 (10 mg, yield 5.29%), LC-MS: ESI [M+H] +=470.5; 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.41 (q, J =4.8 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.61-7.48 (m, 2H), 7.03 (d, J = 8.3Hz, 1H), 6.81 – 6.72 (m, 1H), 3.85 (t, J = 8.8 Hz, 1H), 3.73 (t, J = 9.6 Hz, 1H), 3.45 (d, J = 8.2 Hz, 1H), 3.30 (s, 1H), 3.20 (d, J = 5.0 Hz, 4H), 2.97(s, 1H), 2.77 (d, J = 4.7 Hz, 3H), 2.69-2.50 (m, 4H), 2.59 (s, 1H), 2.19 (s,1H), 1.87 – 1.77 (m, 1H).

[0184] Example 10: 6-fluoro-5-(4-(3-(5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pent-1-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide (Compound 10)

[0185]

[0186] The preparation method of 6-fluoro-5-(4-(3-(5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pent-1-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide was described in Example 6, yielding compound 10. LC-MS: ESI [M+H] + =481.5. 1H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.41 (d, J = 4.7 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.78-7.73 (m, 1H), 7.63 – 7.53 (m, 1H), 7.43 (d, J= 8.2 Hz, 1H), 7.28 – 7.19 (m, 1H), 3.73 (d, J = 10.5 Hz, 1H), 3.30 – 3.10(m, 5H), 2.78 (d, J = 4.9 Hz, 3H), 2.60 (d, J = 5.8 Hz, 3H), 2.28 (s, 2H),2.14 (s, 5H).

[0187] Example 11: 5-(4-((3-(5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pent-1-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridineamide (compound 11)

[0188]

[0189] The preparation method of 5-(4-((3-(5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pent-1-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridine amide was described in Example 6, yielding compound 11. LC-MS: ESI [M+H] + =477.2. 1 H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.43 (d, J = 5.2 Hz, 1H), 7.86 – 7.71 (m, 2H), 7.50 (d, J = 8.2 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H),7.24-7.20 (m, 1H), 3.65-3.59 (m, 1H), 3.18-3.09(m, 1H), 2.96 (s, 3H), 2.81(d, J = 4.8 Hz, 3H), 2.71-2.52 (m, 7H), 2.34 (s, 1H), 2.27-2.06 (s, 5H), 2.03 (s, 1H).

[0190] Example 12: 6-chloro-5-(4-(3-(5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pent-1-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide (Compound 12)

[0191]

[0192] The preparation method of 6-chloro-5-(4-(3-(5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pent-1-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide was described in Example 6, yielding compound 12. LC-MS: ESI [M+H] + =497.2. 1 H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 8.44 (d, J = 5.0 Hz, 1H), 8.09 (dd, J = 8.0, 1.5 Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.80-7.76 (m, 1H),7.65 (dd, J = 23.0, 8.2 Hz, 2H), 7.52 – 7.43 (m, 1H), 3.12 (s, 4H), 2.79 (d,J = 4.7 Hz, 3H), 2.63 (s, 4H), 2.54 (s, 2H), 2.15 (s, 6H).

[0193] Example 13: 5-(4-((3-(5,8-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pent-1-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridinecarboxamide (Compound 13)

[0194]

[0195] The preparation method of 5-(4-((3-(5,8-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pent-1-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridinecarboxamide was described in Example 6, yielding compound 13. LC-MS: ESI [M+H] + =499.2.

[0196] Example 14: 5-(4-((3-(5,8-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pent-1-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridineamide (compound 14)

[0197]

[0198] The preparation method of 5-(4-((3-(5,8-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pent-1-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridine amide was described in Example 6, yielding compound 14. LC-MS: ESI [M+H] + =495.2.

[0199] Example 15: 6-chloro-5-(4-(3-(5,8-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pent-1-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide (Compound 15)

[0200]

[0201] The preparation method of 6-chloro-5-(4-(3-(5,8-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pent-1-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide was described in Example 6, yielding compound 15. LC-MS: ESI [M+H] + =515.2.

[0202] Example 16: 5-(4-((3-(5,7-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pent-1-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridinecarboxamide (Compound 16)

[0203]

[0204] The preparation method of 5-(4-((3-(5,7-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pent-1-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridinecarboxamide was described in Example 6, yielding compound 16. LC-MS: ESI [M+H] + =499.2.

[0205] Example 17: 5-(4-((3-(5,7-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pent-1-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridineamide (compound 17)

[0206]

[0207] The preparation method of 5-(4-((3-(5,7-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pent-1-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridine amide was described in Example 6, yielding compound 17. LC-MS: ESI [M+H] + =495.2.

[0208] Example 18: 6-chloro-5-(4-(3-(5,7-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pent-1-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide (Compound 18)

[0209]

[0210] The preparation method of 6-chloro-5-(4-(3-(5,7-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pent-1-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide was described in Example 6, yielding compound 18. LC-MS: ESI [M+H] + =515.2.

[0211] Example 19: 6-Fluoro-5-(4-(3-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pent-1-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide (Compound 19)

[0212]

[0213] The preparation method of 6-fluoro-5-(4-(3-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pent-1-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide was described in Example 6, yielding compound 19. LC-MS: ESI [M+H] + =481.5.

[0214] Example 20: 5-(4-((3-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pent-1-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridineamide (compound 20)

[0215]

[0216] The preparation method of 5-(4-((3-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pent-1-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridine amide was described in Example 6, yielding compound 20. LC-MS: ESI [M+H] + =477.2.

[0217] Example 21: 6-chloro-5-(4-(3-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pent-1-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide (Compound 21)

[0218]

[0219] The preparation method of 6-chloro-5-(4-(3-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pent-1-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide was described in Example 6, yielding compound 21. LC-MS: ESI [M+H] + =497.2.

[0220] Example 22: 6-Fluoro-N-methyl-5-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[2.1.1]hexane-1-yl)methyl)piperazin-1-yl)pyridinecarboxamide (Compound 22)

[0221]

[0222] The preparation method of 6-fluoro-N-methyl-5-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[2.1.1]hexane-1-yl)methyl)piperazin-1-yl)pyridinecarboxamide was described in Example 6, yielding compound 22. LC-MS: ESI [M+H] + =477.5.

[0223] Example 23: N,6-Dimethyl-5-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[2.1.1]hexane-1-yl)methyl)piperazin-1-yl)pyridinecarboxamide (Compound 23)

[0224]

[0225] The preparation method of N,6-dimethyl-5-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[2.1.1]hexane-1-yl)methyl)piperazin-1-yl)pyridinecarboxamide was described in Example 6, yielding compound 23. LC-MS: ESI [M+H] + =473.2.

[0226] Example 24: 6-Chloro-N-methyl-5-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[2.1.1]hexane-1-yl)methyl)piperazin-1-yl)pyridinecarboxamide (Compound 24)

[0227]

[0228] The preparation method of 6-chloro-N-methyl-5-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[2.1.1]hexane-1-yl)methyl)piperazin-1-yl)pyridinecarboxamide was described in Example 6, yielding compound 24. LC-MS: ESI [M+H] + =493.2.

[0229] Example 25: 6-fluoro-5-(4-(4-(5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[2.1.1]hexane-1-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide (Compound 25)

[0230]

[0231] The preparation method of 6-fluoro-5-(4-(4-(5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[2.1.1]hexane-1-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide was described in Example 6, yielding compound 25. LC-MS: ESI [M+H] + =495.5. 1 H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 8.41 (q, J = 4.8 Hz, 1H), 7.85 (dd, J = 8.0, 1.4 Hz, 1H), 7.78-7.21 (m, 1H), 7.57 9-7.55(m, 1H), 7.41(d, J = 8.2 Hz, 1H), 7.23-7.18 (m, 1H), 3.18 (t, J = 4.7 Hz, 4H), 2.77 (d, J= 4.8 Hz, 3H), 2.60-2.55 (m, 6H), 2.08 – 2.01 (m, 2H), 1.89-1.84 (m, 2H),1.79 – 1.69 (m, 2H), 1.65-1.63 (m, 2H).

[0232] Example 26: 5-(4-((4-(5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[2.1.1]hex-1-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridineamide (compound 26)

[0233]

[0234] The preparation method of 5-(4-((4-(5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[2.1.1]hex-1-yl)methyl)piperazin-1-yl)-N,6-dimethylpyridine amide was described in Example 6, yielding compound 26. LC-MS: ESI [M+H] + =491.2.

[0235] Example 27: 6-chloro-5-(4-(4-(5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[2.1.1]hexane-1-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide (Compound 27)

[0236]

[0237] The preparation method of 6-chloro-5-(4-(4-(5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[2.1.1]hexane-1-yl)methyl)piperazin-1-yl)-N-methylpyridinecarboxamide was described in Example 6, yielding compound 27. LC-MS: ESI [M+H] + =511.2.

[0238] Example 28: 6-Fluoro-5-(4-(3-(5-Fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)prop-2-yn-1-yl)piperazin-1-yl)-N-methylpyridineamide (Compound 28)

[0239]

[0240] Step 1: Synthesis of 2-bromo-5-fluoroquinazoline-4-phenol

[0241] 5-Fluoro-1,2,3,4-Tetrahydroquinazoline-2,4-dione (5.0 g, 27.756 mmol), phosphorus tribromide (39.79 g, 138.781 mmol), and DIEA (7.17 g, 55.512 mmol) were added to a reaction flask, and the mixture was heated to 120°C and reacted for 5 h. After the reaction was completed, the reaction solution was added to dichloromethane (200 mL), and the reaction was quenched with water (50 mL). The mixture was separated, the organic phase was washed with water, and the organic phase was concentrated under reduced pressure. The crude product was subjected to column chromatography (dichloromethane; methanol = 7%), and the product was collected to give 1 g of 2-bromo-5-fluoroquinazoline-4-phenol, yield: 14.82%. LC-MS: ESI [M+H] + =243.2.

[0242] Step 2: Synthesis of 5-fluoro-2-(3-hydroxypropyl-1-ynyl)quinazolin-4-phenol

[0243] 2-Bromo-5-fluoroquinazoline-4-phenol (1.0 g, 4.115 mmol), 2,2-dimethyl-3-oxa-2-silazhex-5-yne (1.06 g, 8.229 mmol), Pd(dppf)Cl2 (0.30 g, 0.411 mmol), cuprous iodide (0.26 g, 0.823 mmol), and triethylamine (1.716 mL, 12.344 mmol) were added to DMF (20 mL) and reacted at 60 °C for 12 h under nitrogen protection. The reaction solution was quenched with water (50 mL), extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude product was subjected to column chromatography (dichloromethane; methanol = 6%), and the product was collected to give 100 mg of 5-fluoro-2-(3-hydroxypropyl-1-ynyl)quinazoline-4-phenol, yield: 11.14%.

[0244] Step 3: Synthesis of 2-(3-bromoprop-1-ynyl)-5-fluoroquinazoline-4-phenol

[0245] 5-Fluoro-2-(3-hydroxyprop-1-ynyl)quinazoline-4-phenol (100 mg, 0.458 mmol) was added to dichloromethane (3 mL), followed by carbon tetrabromide (227.99 mg, 0.687 mmol) and triphenylphosphine (180.81 mg, 0.687 mmol). The reaction was carried out at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and the crude product was subjected to column chromatography (dichloromethane; methanol = 6%). The product was collected to give 190 mg of crude 2-(3-bromoprop-1-ynyl)-5-fluoroquinazoline-4-phenol, yield not considered.

[0246] Step 4: Synthesis of 6-fluoro-5-{4-[3-(5-fluoro-4-hydroxyquinazolin-2-yl)prop-2-ynyl]piperazin-1-yl}-N-methylpyridin-2-carboxamide

[0247] 2-(3-bromoprop-1-ynyl)-5-fluoroquinazoline-4-phenol (90 mg, 0.320 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide hydrochloride (70.37 mg, 0.256 mmol), DIEA (41.39 mg, 0.320 mmol), and acetonitrile (3 mL) were reacted at 80 °C for 3 h. The reaction solution was concentrated under reduced pressure, and the crude product was subjected to column chromatography (dichloromethane; methanol = 6%). The product was collected to give 5 mg of 6-fluoro-5-{4-[3-(5-fluoro-4-hydroxyquinazoline-2-yl)prop-2-ynyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide; yield: 3.56%.

[0248] LC-MS:ESI[M+H] + =439.2.

[0249] 1 H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.44-8.40 (m, 1H), 7.86 (dd, J = 8.0, 1.4 Hz, 1H), 7.82-7.76 (m, 1H), 7.60 (dd, J = 10.7, 8.1 Hz,1H), 7.46 (d, J = 8.1 Hz, 1H), 7.30-7.25 (m, 1H), 3.71 (s, 2H), 3.22 (t, J =5.0 Hz, 4H), 2.85-2.67 (m, 7H).

[0250] Example 29: 6-Fluoro-N-methyl-5-(4-{[3-(1-oxoylide-2H-isoquinoline-3-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)pyridine-2-carboxamide (Compound 29)

[0251]

[0252] Step 1: Preparation of N,N-diethyl-2-methylbenzamide

[0253] 2-Methylbenzoic acid (2 g, 12.975 mmol) and diethylamine (1.337 mL, 12.975 mmol) were added to dichloromethane (10 mL), followed by DIEA (8.39 g, 64.876 mmol) and HATU (7.40 g, 19.463 mmol). The reaction was carried out at room temperature for 1 h, quenched with water (3 mL), extracted with dichloromethane (10 mL), concentrated, and the concentrate was subjected to column chromatography (DCM; MeOH = 5%) to give 1.5 g of N,N-diethyl-2-methylbenzamide, yield: 55.24%. LC-MS: ESI [M+H] + =192.2.

[0254] Step 2: Preparation of 3-[1-(3,3,4,4-tetramethyl-2-oxa-3-silazopent-1-yl)bicyclo[1.1.1]pent-3-yl]-1,2-dihydroisoquinoline-1-one

[0255] N,N-diethyl-2-methylbenzamide (180 mg, 0.860 mmol) was added to tetrahydrofuran (5 mL), the temperature was lowered to -78°C, LDA was added, the mixture was stirred for 1 h, 1-(3,3,4,4-tetramethyl-2-oxa-3-silazopent-1-yl)bicyclo[1.1.1]pentane-3-carboxynitrile (496 mg, 2.091 mmol) was added, and the mixture was reacted overnight at room temperature. Quenching with water (3 mL), extraction with dichloromethane (10 mL), concentration, and column chromatography of the concentrate (petroleum ether: ethyl acetate = 15%) yielded 400 mg of 3-[1-(3,3,4,4-tetramethyl-2-oxa-3-silaxopent-1-yl)bicyclo[1.1.1]pentan-3-yl]-1,2-dihydroisoquinolin-1-one, yield: 53.80%, LC-MS: ESI [M+H]. + =356.2.

[0256] Step 3: Preparation of 3-[3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl]-1,2-dihydroisoquinoline-1-one

[0257] 3-[1-(3,3,4,4-tetramethyl-2-oxa-3-silazopent-1-yl)bicyclo[1.1.1]pent-3-yl]-1,2-dihydroisoquinoline-1-one (400 mg, 1.125 mmol) was added to tetrahydrofuran (4 mL), followed by tetrabutylammonium fluoride (882 mg, 3.375 mmol). The reaction was allowed to proceed overnight at room temperature. The reaction was quenched with water (3 mL), extracted with ethyl acetate (10 mL), concentrated, and the concentrate was subjected to column chromatography (DCM; MeOH = 5%). The product was collected to give 230 mg of 3-[3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl]-1,2-dihydroisoquinoline-1-one, yield: 84.73%. LC-MS: ESI [M+H] + =242.2.

[0258] Step 4: Preparation of [3-(1-oxoylidene-2H-isoquinolin-3-yl)bicyclo[1.1.1]pent-1-yl]methane aldehyde

[0259] 3-[3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl]-1,2-dihydroisoquinolin-1-one (80 mg, 0.332 mmol) was added to dichloromethane (2 mL), followed by DESS-MARTIN (281 mg, 0.663 mmol), and the reaction was carried out at room temperature for 1 h. The reaction was quenched with water (3 mL), extracted with dichloromethane (10 mL), concentrated, and the concentrate was subjected to column chromatography (DCM; MeOH = 5%). The product was collected to give 70 mg of [3-(1-oxoylide-2H-isoquinolin-3-yl)bicyclo[1.1.1]pent-1-yl]methane aldehyde, yield: 88.24%, LC-MS: ESI [M+H]. + =240.1.

[0260] Step 5: Preparation of 6-fluoro-N-methyl-5-(4-{[3-(1-oxoylide-2H-isoquinolin-3-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)pyridine-2-carboxamide

[0261] [3-(1-oxoylide-2H-isoquinoline-3-yl)bicyclo[1.1.1]pent-1-yl]methane aldehyde (70 mg, 0.293 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide dihydrochloric acid (91.04 mg, 0.293 mmol) were added to dichloromethane (2 mL), followed by DIEA (75.63 mg, 0.585 mmol). The mixture was stirred at room temperature for 10 min, then 1 drop of glacial acetic acid was added, and the mixture was reacted at room temperature for 10 min. Finally, sodium triacetoxyborohydride (124.01 mg, 0.585 mmol) was added, and the mixture was reacted at room temperature for 1 h. Quenching with water (3 mL), extraction with dichloromethane (10 mL), and concentration were performed. The crude product was subjected to Pre-HPLC to obtain 60 mg of 6-fluoro-N-methyl-5-(4-{[3-(1-oxoylide-2H-isoquinolin-3-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)pyridine-2-carboxamide; yield: 44.44%, LC-MS: ESI [M+H] + =462.20; 1 H NMR (400 MHz, DMSO-d6) δ 11.25 –11.20 (m, 1H), 8.41 (q, J = 4.7 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.86 (dd,J = 8.1, 1.4 Hz, 1H), 7.71 – 7.62 (m, 1H), 7.62 – 7.53 (m, 2H), 7.47 – 7.39(m, 1H), 6.28 (d, J = 1.7 Hz, 1H), 3.19 (dd, J = 6.1, 3.7 Hz, 4H), 2.78 (d, J= 4.7 Hz, 3H), 2.61 (t, J = 4.9 Hz, 4H), 2.54-2.52 (m, 2H), 2.10-2.05 (m, 6H).

[0262] Example 30: 5-(4-{[3-(8-fluoro-4-hydroxyquinazoline-2-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)-6,N-dimethylpyridine-2-carboxamide (Compound 30)

[0263]

[0264] The preparation method of 5-(4-{[3-(8-fluoro-4-hydroxyquinazoline-2-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)-6,N-dimethylpyridine-2-carboxamide was described in Example 6, yielding compound 30. LC-MS: ESI [M+H] + =477.2; 1 H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 8.45-8.41 (m, 1H), 7.91 (dd,J = 8.0, 1.4 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.69-7.64 (m, 1H), 7.53 –7.42 (m, 2H), 3.18 (d, J = 5.2 Hz, 2H), 2.96 (t, J = 4.7 Hz, 4H), 2.81 (d, J= 4.8 Hz, 3H), 2.64 (d, J = 5.2 Hz, 4H), 2.55 (s, 3H), 2.17 (s, 6H).

[0265] Example 31: 6-fluoro-5-(4-{[3-(8-fluoro-4-oxoylide-3H-quinazolin-2-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)-N-methylpyridin-2-carboxamide (Compound 31)

[0266]

[0267] The preparation method of 6-fluoro-5-(4-{[3-(8-fluoro-4-oxoylide-3H-quinazolin-2-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)-N-methylpyridin-2-carboxamide was described in Example 6, yielding compound 31. LC-MS: ESI [M+H] + =481.2; 1 H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 8.41 (d, J = 5.1 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.69-7.65 (m, 1H), 7.61 –7.56 (m, 1H), 7.50 – 7.44 (m, 1H), 3.21-3.16 (m, 4H), 2.78 (d, J = 4.7 Hz,5H), 2.65-2.54 (m, 4H), 2.17 (s, 6H).

[0268] Example 32: 6-Fluoro-N-methyl-5-(4-{[3-(8-methyl-4-oxoylide-3H-quinazolin-2-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)pyridine-2-carboxamide (Compound 32)

[0269]

[0270] The preparation method of 6-fluoro-N-methyl-5-(4-{[3-(8-methyl-4-oxoylide-3H-quinazolin-2-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)pyridine-2-carboxamide was described in Example 6, yielding compound 32. LC-MS: ESI [M+H] + =477.2; 1 H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.41-8.38 (m, 1H), 7.94 –7.88 (m, 1H), 7.86 – 7.81 (m, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.58-7.54 (m,1H), 7.34 (t, J = 7.6 Hz, 1H), 3.17 (t, J = 4.8 Hz, 4H), 2.76 (d, J = 4.7 Hz,3H), 2.60 (t, J = 4.9 Hz, 4H), 2.51 (s, 7H), 2.13 (s, 4H).

[0271] Example 33: 5-(4-{[3-(7-fluoro-1-oxoylide-2H-isoquinoline-3-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)-6,N-dimethylpyridine-2-carboxamide (Compound 33)

[0272]

[0273] Step 1: Synthesis of 1-(3,3,4,4-tetramethyl-2-oxa-3-silazopent-1-yl)bicyclo[1.1.1]pentane-3-carboxynitrile

[0274] 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylonitrile (1 g, 8.120 mmol) was added to dichloromethane (10 mL), the reaction system was cooled to 0 °C, and imidazole (0.83 g, 12.179 mmol) and tert-butyldimethylchlorosilane (1.47 g, 9.743 mmol) were added. After the addition was complete, the reaction was carried out at room temperature for 1 h. After the reaction was completed, the reaction solution was added to dichloromethane (20 mL), and water (5 mL) was added to quench the reaction. The mixture was separated, the organic phase was washed with water, and the organic phase was concentrated under reduced pressure. The crude product was subjected to column chromatography (petroleum ether; ethyl acetate = 5%), and the product was collected to give 1.7 g of 1-(3,3,4,4-tetramethyl-2-oxa-3-silaxopent-1-yl)bicyclo[1.1.1]pentane-3-carboxylonitrile, yield: 88.19%.

[0275] Step 2: Synthesis of N,N-diethyl-5-fluoro-2-methylbenzamide

[0276] 5-Fluoro-2-methylbenzoic acid (1 g, 6.488 mmol) and diethylamine (0.671 mL, 6.488 mmol) were added to dichloromethane (10 mL), followed by DIEA (4.19 g, 32.438 mmol) and HATU (3.70 g, 9.731 mmol). The reaction mixture was reacted at room temperature for 1 h. The reaction solution was then added to dichloromethane (20 mL), and the reaction was quenched with water (5 mL). The mixture was separated, the organic phase was washed with water, and the organic phase was concentrated under reduced pressure. The crude product was subjected to column chromatography (petroleum ether; ethyl acetate = 30%), and the product was collected to give 1.2 g of N,N-diethyl-5-fluoro-2-methylbenzamide, yield: 88.39%.

[0277] Step 3: Synthesis of 7-fluoro-3-[1-(3,3,4,4-tetramethyl-2-oxa-3-silazopent-1-yl)bicyclo[1.1.1]pent-3-yl]-1,2-dihydroisoquinolin-1-one

[0278] N,N-diethyl-5-fluoro-2-methylbenzamide (320 mg, 1.529 mmol) was added to tetrahydrofuran (5 mL), the mixture was cooled to -78 °C, 2M diisopropylaminolithium (1.2 mL, 2.447 mmol) was added, the mixture was stirred for 1 h, 1-(3,3,4,4-tetramethyl-2-oxa-3-silazopent-1-yl)bicyclo[1.1.1]pentane-3-carboxynitrile (363.06 mg, 1.529 mmol) was added, and the mixture was reacted at room temperature for 12 h. The reaction was quenched with water (5 mL), extracted with ethyl acetate (20 mL), separated, and the organic phase was concentrated under reduced pressure. The crude product was subjected to column chromatography (petroleum ether; ethyl acetate = 30%), and the product was collected to give 180 mg of 7-fluoro-3-[1-(3,3,4,4-tetramethyl-2-oxa-3-silaxapran-1-yl)bicyclo[1.1.1]pentan-3-yl]-1,2-dihydroisoquinoline-1-one, yield: 31.51%.

[0279] Step 4: Synthesis of 7-fluoro-3-[3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl]-1,2-dihydroisoquinolin-1-one

[0280] 7-Fluoro-3-[1-(3,3,4,4-tetramethyl-2-oxa-3-silazopent-1-yl)bicyclo[1.1.1]pent-3-yl]-1,2-dihydroisoquinoline-1-one (180 mg, 0.482 mmol) was added to tetrahydrofuran (4 mL), followed by tetrabutylammonium fluoride (377.99 mg, 1.446 mmol). The reaction was allowed to proceed at room temperature for 12 h. The reaction was quenched with water (5 mL), and the mixture was extracted with ethyl acetate (20 mL). The liquid was separated, and the organic phase was concentrated under reduced pressure. The crude product was subjected to column chromatography (dichloromethane; methanol = 8%), and the product was collected to give 80 mg of 7-fluoro-3-[3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl]-1,2-dihydroisoquinoline-1-one, yield: 64.03%.

[0281] Step 5: Synthesis of [3-(7-fluoro-1-oxoyne-2H-isoquinolin-3-yl)bicyclo[1.1.1]pent-1-yl]methane

[0282] 7-fluoro-3-[3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl]-1,2-dihydroisoquinoline-1-one (50 mg, 0.193 mmol) was added to dichloromethane (2 mL), cooled to 0 °C, and DESS-MARTIN (122.69 mg, 0.289 mmol) was added. The reaction was maintained at this temperature for 1 h, and the reaction was quenched with water (5 mL). The mixture was extracted with dichloromethane (20 mL), separated, and the organic phase was concentrated under reduced pressure. The crude product was subjected to column chromatography (dichloromethane; methanol = 8%), and the product was collected to give 50 mg of [3-(7-fluoro-1-oxoylide-2H-isoquinoline-3-yl)bicyclo[1.1.1]pent-1-yl]methane aldehyde, yield: 100%.

[0283] Step 6: Synthesis of 5-(4-{[3-(7-fluoro-1-oxoylide-2H-isoquinoline-3-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)-6,N-dimethylpyridin-2-carboxamide

[0284] [3-(7-fluoro-1-oxoylide-2H-isoquinoline-3-yl)bicyclo[1.1.1]pent-1-yl]methane aldehyde (50 mg, 0.194 mmol) and 6,N-dimethyl-5-(piperazin-1-yl)pyridine-2-carboxamide (45.54 mg, 0.194 mmol) were added to dichloromethane (3 mL), followed by sodium triacetoxyborohydride (61.79 mg, 0.292 mmol), and the mixture was reacted at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and the crude product was subjected to column chromatography (dichloromethane; methanol = 6%). The product was collected to give 22 mg of 5-(4-{[3-(7-fluoro-1-oxoylide-2H-isoquinolin-3-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)-6,N-dimethylpyridin-2-carboxamide; yield: 23.80%, LC-MS: ESI [M+H] + =476.2; 1H NMR (400 MHz, DMSO-d6) δ11.38 (s, 1H), 8.45-8.41 (m, 1H), 7.82-7.79 (m, 2H), 7.71 (dd, J = 8.8, 5.3Hz, 1H), 7.60-7.55 (m, 1H), 7.49 (d, J = 8.3 Hz, 1H), 6.34 (d, J = 1.7 Hz,1H), 3.18 (d, J = 5.2 Hz, 2H), 2.96 (t, J = 4.7 Hz, 4H), 2.81 (d, J = 4.8 Hz,3H), 2.63 (s, 3H), 2.54 (s, 4H), 2.08 (s, 6H).

[0285] Example 34: 6-fluoro-5-(4-{[3-(7-fluoro-1-oxoylide-2H-isoquinolin-3-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)-N-methylpyridin-2-carboxamide (Compound 34)

[0286]

[0287] The preparation method of 6-fluoro-5-(4-{[3-(7-fluoro-1-oxoylide-2H-isoquinolin-3-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)-N-methylpyridin-2-carboxamide was described in Example 33, yielding compound 34. LC-MS: ESI [M+H] + =480.2; 1 H NMR (400 MHz, DMSO-d6) δ 11.41 – 11.36 (m, 1H), 8.41 (q, J = 4.7Hz, 1H), 7.86 (dd, J = 8.1, 1.4 Hz, 1H), 7.80 (dd, J = 9.5, 2.8 Hz, 1H), 7.71(dd, J = 8.8, 5.3 Hz, 1H), 7.60-7.55 (m, 2H), 6.33 (d, J = 1.7 Hz, 1H), 3.20-3.17 (m, 6H), 2.78 (d, J = 4.8 Hz, 3H), 2.64-2.57 (m, 4H), 2.08 (s, 6H).

[0288] Example 35: 6,N-Dimethyl-5-(4-{[3-(8-methyl-4-oxoylide-3H-quinazolin-2-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)pyridine-2-carboxamide (Compound 35)

[0289]

[0290] The preparation method of 6,N-dimethyl-5-(4-{[3-(8-methyl-4-oxoylide-3H-quinazolin-2-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)pyridine-2-carboxamide was as described in Example 6, yielding compound 35. LC-MS: ESI [M+H] + =473.2; 1 H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 8.43 (d, J = 5.1 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 7.2 Hz, 1H),7.50 (d, J = 8.3 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 2.97 (s, 4H), 2.81 (d, J= 4.8 Hz, 3H), 2.64 (s, 4H), 2.55 (s, 10H), 2.16 (s, 4H).

[0291] Example 36: 6-Fluoro-N-methyl-5-(4-{[3-(5-oxoylidene-6H-pyrido[4,3-b]pyridin-7-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)pyridine-2-carboxamide (Compound 36)

[0292]

[0293] The preparation method for 6-fluoro-N-methyl-5-(4-{[3-(5-oxoylidene-6H-pyrido[4,3-b]pyridin-7-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)pyridine-2-carboxamide was described in Example 33, yielding compound 36. LC-MS: ESI [M+H] + =463.2; 1H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 8.87 (dd, J =4.6, 1.8 Hz, 1H), 8.49 – 8.38 (m, 2H), 7.86 (dd, J = 8.0, 1.4 Hz, 1H), 7.58(dd, J = 10.6, 8.1 Hz, 1H), 7.44 (dd, J = 8.0, 4.6 Hz, 1H), 6.34 (d, J = 1.7Hz, 1H), 3.19 (t, J = 4.7 Hz, 4H), 2.78 (d, J = 4.7 Hz, 3H), 2.62 (t, J = 4.8Hz, 4H), 2.58-2.52(m, 2H), 2.11(s, 6H).

[0294] Example 37: 6-fluoro-5-(4-{[3-(3-fluoro-5-oxoyne-6H-pyrido[4,3-b]pyridin-7-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)-N-methylpyridin-2-carboxamide (Compound 37)

[0295]

[0296] The preparation method of 6-fluoro-5-(4-{[3-(3-fluoro-5-oxoylide-6H-pyrido[4,3-b]pyridin-7-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)-N-methylpyridin-2-carboxamide was described in Example 33, yielding compound 37. LC-MS: ESI [M+H] + =481.2; 1 H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.94 (d, J = 3.0Hz, 1H), 8.41 (d, J = 5.0 Hz, 1H), 8.22 (dd, J = 8.7, 3.0 Hz, 1H), 7.88 –7.85 (m, 1H), 7.58 (dd, J = 10.6, 8.0 Hz, 1H), 6.39 (d, J = 1.6 Hz, 1H), 3.20-3.17(m, 4H), 2.78-2.74 (m, 5H), 2.65-2.59 (m, 4H), 2.11 (s, 6H).

[0297] Example 38: 6-fluoro-5-(4-{[3-(8-fluoro-1-oxoylide-2H-isoquinolin-3-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)-N-methylpyridin-2-carboxamide (Compound 38)

[0298]

[0299] Step 1: Preparation of methyl 3-(3,3,4,4-tetramethyl-2-oxa-3-silazopent-1-yl)bicyclo[1.1.1]pentane-1-carboxylate

[0300] Methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (9 g, 57.626 mmol) was added to dichloromethane (100 mL), cooled to 0 °C, and then imidazole (7.85 g, 115.252 mmol) and TBSCI (13.03 g, 86.439 mmol) were added. The reaction was maintained at this temperature for 12 h. The mixture was quenched with water (3 mL), separated, concentrated, and the concentrate was subjected to column chromatography (petroleum ether: ethyl acetate = 15%) to give 15 g of methyl 3-(3,3,4,4-tetramethyl-2-oxa-3-silaxapran-1-yl)bicyclo[1.1.1]pentane-1-carboxylate, yield: 96.25%.

[0301] Step 2: Preparation of [1-(3,3,4,4-tetramethyl-2-oxa-3-silazopent-1-yl)bicyclo[1.1.1]pentan-3-yl]methanol

[0302] 15 g (55.465 mmol) of methyl 3-(3,3,4,4-tetramethyl-2-oxa-3-silaxapran-1-yl)bicyclo[1.1.1]pentane-1-carboxylate was added to methanol (100 mL), followed by sodium borohydride (4.20 g, 110.930 mmol). The reaction was carried out at room temperature for 1 h. The reaction solution was quenched with saturated ammonium chloride (10 mL), concentrated, and extracted with ethyl acetate (100 mL). The concentrate was subjected to column chromatography (petroleum ether: ethyl acetate = 25%), and the product was collected to give 8 g of [1-(3,3,4,4-tetramethyl-2-oxa-3-silaxapran-1-yl)bicyclo[1.1.1]pentan-3-yl]methanol, yield: 59.50%.

[0303] Step 3: Preparation of [1-(3,3,4,4-tetramethyl-2-oxa-3-silazopent-1-yl)bicyclo[1.1.1]pentan-3-yl]methane aldehyde

[0304] [1-(3,3,4,4-tetramethyl-2-oxa-3-silaxapran-1-yl)bicyclo[1.1.1]pentan-3-yl]methanol (8 g, 32.999 mmol) was added to dichloromethane (80 mL), cooled to 0 °C, and DESS-MARTIN (16.80 g, 39.599 mmol) was added. The reaction was maintained at 0 °C for 2 h, quenched with water (30 mL), extracted with dichloromethane (100 mL), concentrated, and the concentrate was subjected to column chromatography (petroleum ether: ethyl acetate = 20%). The product was collected to give 6 g of [1-(3,3,4,4-tetramethyl-2-oxa-3-silaxapran-1-yl)bicyclo[1.1.1]pentan-3-yl]methane aldehyde, yield: 75.63%.

[0305] Step 4: Preparation of 1-(1-ethynylbicyclo[1.1.1]pent-3-yl)-3,3,4,4-tetramethyl-2-oxa-3-silazopentane

[0306] [1-(3,3,4,4-tetramethyl-2-oxa-3-silazopent-1-yl)bicyclo[1.1.1]pentan-3-yl]methane aldehyde (1 g, 4.159 mmol) was added to methanol (10 mL), followed by potassium carbonate (1.44 g, 10.398 mmol). The mixture was stirred for 30 min, and then dimethyl phosphonate (1-diazo-2-oxopropyl)phosphonate (0.88 g, 4.575 mmol) was added. The reaction was carried out at room temperature for 12 h, quenched with water (30 mL), extracted with dichloromethane (100 mL), concentrated, and the concentrate was subjected to column chromatography (petroleum ether: ethyl acetate = 10%). The product was collected to give 760 mg of 1-(1-ethynylbicyclo[1.1.1]pentan-3-yl)-3,3,4,4-tetramethyl-2-oxa-3-silazopentane, yield: 77.28%.

[0307] Step 5: Preparation of methyl 2-fluoro-6-{[3-(3,3,4,4-tetramethyl-2-oxa-3-silazopent-1-yl)bicyclo[1.1.1]pent-1-yl]ethynyl}benzoate

[0308] Methyl 6-bromo-2-fluorobenzoate (700 mg, 3.004 mmol), 1-(1-ethynylbicyclo[1.1.1]pent-3-yl)-3,3,4,4-tetramethyl-2-oxa-3-silazopentane (710.24 mg, 3.004 mmol), tetraphenylphosphine palladium (347.11 mg, 0.300 mmol), and cuprous iodide (76.26 mg, 0.240 mmol) were added to triethylamine (4 mL) and tetrahydrofuran (8 mL). The mixture was then heated to 60 °C for 12 h under nitrogen protection. The reaction solution was concentrated under reduced pressure, the concentrate was washed with water, extracted with EA, washed with water, and subjected to column chromatography with PE (EA = 5%). The product was collected to give 1 g of methyl 2-fluoro-6-{[3-(3,3,4,4-tetramethyl-2-oxa-3-silaxopent-1-yl)bicyclo[1.1.1]pent-1-yl]ethynyl}benzoate, yield: 85.68%, LC-MS: ESI [M+H] + =389.2.

[0309] Step 6: Preparation of 8-fluoro-3-[1-(3,3,4,4-tetramethyl-2-oxa-3-silaxapran-1-yl)bicyclo[1.1.1]pentan-3-yl]-1,2-dihydroisoquinoline-1-one

[0310] Methyl 2-fluoro-6-{[3-(3,3,4,4-tetramethyl-2-oxa-3-silaxapran-1-yl)bicyclo[1.1.1]pentan-1-yl]ethynyl}benzoate (1 g, 2.574 mmol) was added to ammonia-methanol (2 mL), and the mixture was heated to 90°C and reacted for 2 h. The reaction solution was concentrated under reduced pressure to obtain 1.1 g of crude 8-fluoro-3-[1-(3,3,4,4-tetramethyl-2-oxa-3-silaxapran-1-yl)bicyclo[1.1.1]pentan-3-yl]-1,2-dihydroisoquinolin-1-one. LC-MS: ESI [M+H] + =374.2.

[0311] Steps 7, 8, and 9: Preparation of 6-fluoro-5-(4-{[3-(8-fluoro-1-oxoylide-2H-isoquinoline-3-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)-N-methylpyridine-2-carboxamide

[0312] The preparation methods for the seventh, eighth, and ninth steps are the same as in Example 33, yielding compound 38. LC-MS: ESI [M+H] + =480.2; 1HNMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.43-8.39 (m, 1H), 7.87-7.84(m, 1H),7.71 (d, J = 7.7 Hz, 1H), 7.67-7.62(m, 1H), 7.60-7.52(m, 1H), 7.29-7.24 (m,1H), 5.89 (s, 1H), 3.21-3.17 (m, 4H), 2.78 (d, J = 4.7 Hz, 3H), 2.64-2.58 (m,4H), 2.47 (s, 2H), 2.08 (s, 6H).

[0313] Example 39: 5-(4-{[2,2-difluoro-3-(5-fluoro-4-oxoylide-3H-quinazolin-2-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)-6-fluoro-N-methylpyridin-2-carboxamide (Compound 39)

[0314]

[0315] Step 1: Synthesis of methyl 3-{[(2-formamido-3-fluorophenyl)amino]carbonyl}-2,2-difluorobicyclo[1.1.1]pentane-1-carboxylate

[0316] 2,2-Difluoro-1-(methoxycarbonyl)bicyclo[1.1.1]pentane-3-carboxylic acid (500 mg, 2.426 mmol) was added to DCM (50 mL), the mixture was cooled to 0 °C, and oxaloyl chloride (369 mg, 2.911 mmol) was added. The reaction mixture was reacted at room temperature for 3 h, and the reaction solution was concentrated under reduced pressure. 2-Amino-6-fluorobenzene-1-carboxamide (374 mg, 2.462 mmol) and pyridine (480 mg, 6.064 mmol) were added to DCM (50 mL). The above concentrate was added to a solution (mL), and the reaction was carried out at room temperature for 3 h. After the reaction was completed, water was added to quench the reaction, and the solution was concentrated under reduced pressure. The concentrate was extracted with ethyl acetate, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated to dryness, and the concentrate was subjected to column chromatography (DCM; MeOH = 5%) to give 600 mg of methyl 3-{[(2-formamido-3-fluorophenyl)amino]carbonyl}-2,2-difluorobicyclo[1.1.1]pentane-1-carboxylate, yield: 72.27%, LC-MS: ESI [M+H]. + =343.2.

[0317] Step 2: Synthesis of 2,2-difluoro-3-(5-fluoro-4-oxoylide-3H-quinazolin-2-yl)bicyclo[1.1.1]pentane-1-carboxylic acid

[0318] Methyl 3-{[(2-formamido-3-fluorophenyl)amino]carbonyl}-2,2-difluorobicyclo[1.1.1]pentane-1-carboxylic acid (500 mg, 1.461 mmol) was added to methanol (40 mL), followed by sodium hydroxide (234 mg, 5.843 mmol). The mixture was heated to 70 °C and reacted for 3 h. After the reaction was complete, the mixture was concentrated under reduced pressure. The concentrate was adjusted to pH 2-3 with 1 N hydrochloric acid, filtered, and the filtrate was collected and dried under reduced pressure to obtain crude 2,2-difluoro-3-(5-fluoro-4-oxoylide-3H-quinazolin-2-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (500 mg). LC-MS: ESI [M+H] + =311.2.

[0319] Step 3: Synthesis of 2-[2,2-difluoro-3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl]-5-fluoro-3,4-dihydroquinazolin-4-one

[0320] 2,2-Difluoro-3-(5-fluoro-4-oxoylide-3H-quinazolin-2-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (500 mg, 1.612 mmol) was added to tetrahydrofuran (6 mL), followed by lithium aluminum hydride (98 mg, 2.579 mmol). The reaction was carried out at room temperature for 1 h. After the reaction was completed, water was added to quench the reaction, and the mixture was concentrated under reduced pressure. The filter cake was washed with a dichloromethane:methanol solution (5:1), and the filtrate was concentrated to dryness to give 100 mg of 2-[2,2-difluoro-3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl]-5-fluoro-3,4-dihydroquinazolin-4-one, yield: 20.94%. LC-MS: ESI [M+H] + =297.3.

[0321] Step 4: Synthesis of [2,2-difluoro-3-(5-fluoro-4-oxoylide-3H-quinazolin-2-yl)bicyclo[1.1.1]pent-1-yl]methane aldehyde

[0322] 2-[2,2-difluoro-3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl]-5-fluoro-3,4-dihydroquinazolin-4-one (50 mg, 0.169 mmol) was added to dichloromethane (20 mL), cooled to 0 °C, and DESS-MARTIN (85.90 mg, 0.203 mmol) was added. The reaction was maintained at this temperature for 1 h. After the reaction was complete, water was added to quench the reaction, and the mixture was concentrated under reduced pressure. The concentrate was then subjected to column chromatography (DCM: MeOH = 5%) to give 40 mg of [2,2-difluoro-3-(5-fluoro-4-oxoylide-3H-quinazolin-2-yl)bicyclo[1.1.1]pent-1-yl]methane aldehyde, yield: 80.55%, LC-MS: ESI [M+H].+ = 295.2.

[0323] Step 5: Synthesis of 5-(4-{[2,2-difluoro-3-(5-fluoro-4-oxoylide-3H-quinazolin-2-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)-6-fluoro-N-methylpyridin-2-carboxamide

[0324] [2,2-difluoro-3-(5-fluoro-4-oxoylide-3H-quinazolin-2-yl)bicyclo[1.1.1]pent-1-yl]methane aldehyde (50 mg, 0.170 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide hydrochloride (53 mg, 0.170 mmol) were added to dichloromethane (3 mL), followed by sodium triacetoxyborohydride (72 mg, 0.340 mmol). The mixture was reacted at room temperature for 1 h. The reaction solution was concentrated under reduced pressure. The crude product was subjected to Pre-HPLC to obtain 5-(4-{[2,2-difluoro-3-(5-fluoro-4-oxoylide-3H-quinazolin-2-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)-6,N-dimethylpyridine-2-carboxamide 11 mg; Yield: 12.35%, LC-MS: ESI [M+H] + =517.2; 1 H NMR (400 MHz, DMSO-d6) δ 12.41 (s,1H), 8.44-8.40 (m, 1H), 7.86 (dd, J = 8.1, 1.4 Hz, 1H), 7.83-7.77 (m, 1H),7.62-7.56 (m, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.32 – 7.23 (m, 1H), 3.20-3.18(m, 4H), 2.78 (d, J = 4.7 Hz, 3H), 2.73 (d, J = 2.5 Hz, 2H), 2.65-2.62 (m,4H), 2.40-2.29 (m, 2H), 2.20-2.15 (m, 2H).

[0325] Example 40: 5-(4-{[2,2-difluoro-3-(5-fluoro-4-oxoylide-3H-quinazolin-2-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)-6,N-dimethylpyridine-2-carboxamide (Compound 40)

[0326]

[0327] The preparation method of 5-(4-{[2,2-difluoro-3-(5-fluoro-4-oxoylide-3H-quinazolin-2-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)-6,N-dimethylpyridine-2-carboxamide was described in Example 39, yielding compound 40. LC-MS: ESI [M+H] + =513.2; 1 H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 8.43 (q, J = 4.9Hz, 1H), 7.79 (dd, J = 12.2, 7.9 Hz, 2H), 7.49 (t, J = 7.5 Hz, 2H), 7.28 (dd,J = 11.0, 8.1 Hz, 1H), 2.97 (t, J = 4.6 Hz, 4H), 2.81 (d, J = 4.9 Hz, 3H), 2.74 (s, 2H), 2.65 (m, 4H), 2.52 (s, 3H), 2.38 -2.70(m, 2H), 2.18 (t, J = 10.6Hz, 2H).

[0328] Example 41: 6-Fluoro-N-methyl-5-(4-{[3-(4-oxoylide-3,5,6,7-tetrahydrocyclopentano[1,2-d]pyrimidin-2-yl)bicyclo[1.1.1]pentan-1-yl]methyl}piperazin-1-yl)pyridine-2-carboxamide (Compound 41)

[0329]

[0330] Step 1: Preparation of methyl 3-{[(2-cyanocyclopentan-1-enyl)amino]carbonyl}bicyclo[1.1.1]pentane-1-carboxylate

[0331] 1-(methoxycarbonyl)bicyclo[1.1.1]pentane-3-carboxylic acid (3 g, 17.630 mmol) was added to dichloromethane (50 mL), the reaction mixture was cooled to 0 °C, and oxaloyl chloride (1.790 mL, 21.157 mmol) was added. The reaction mixture was then reacted at room temperature for 3 h. The reaction solution was concentrated under reduced pressure, and the crude product was added to dichloromethane (50 mL) and pyridine (3.565 mL, 44.076 mmol), and 2-aminocyclopent-1-ene-1-carboxynitrile (1.91 g, 17.630 mmol). The reaction mixture was then reacted at room temperature for 3 h. Quenching with water (3 mL), extraction with dichloromethane (10 mL), concentration, and column chromatography (DCM; MeOH = 5%) yielded 3 g of methyl 3-{[(2-cyanocyclopentan-1-enyl)amino]carbonyl}bicyclo[1.1.1]pentane-1-carboxylate, yield: 65.37%, LC-MS: ESI [M+H]. + =261.2.

[0332] Step 2: Preparation of methyl 3-(4-oxoylide-6,7-dihydro-5H-cyclopentano[1,2-d][1,3]oxazacyclohexamyl-2-yl)bicyclo[1.1.1]pentane-1-carboxylate

[0333] Methyl 3-{[(2-cyanocyclopentan-1-enyl)amino]carbonyl}bicyclo[1.1.1]pentane-1-carboxylate (500 mg, 1.921 mmol), sodium hydroxide (153.67 mg, 3.842 mmol), hydrogen peroxide (85%) (3 mL), and ethanol (10 mL) were added to a reaction flask, and the mixture was heated to 80°C for 5 h. The reaction was quenched with water (3 mL), extracted with ethyl acetate (10 mL), concentrated, and the concentrate was subjected to column chromatography (DCM; MeOH = 5%) to give 90 mg of methyl 3-(4-oxoylidene-6,7-dihydro-5H-cyclopentano[1,2-d][1,3]oxazacyclohexamyl-2-yl)bicyclo[1.1.1]pentane-1-carboxylate, yield: 17.93%, LC-MS: ESI [M+H]. + =262.2.

[0334] Step 3: Preparation of 2-[3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl]-4,5,6,7-tetrahydrocyclopenta[1,2-d][1,3]oxazacyclohexane-4-one

[0335] 3-(4-oxoylide-6,7-dihydro-5H-cyclopenta[1,2-d][1,3]oxazacyclohexamyl-2-yl)bicyclo[1.1.1]pentane-1-carboxylate (90 mg, 0.344 mmol) was added to tetrahydrofuran (2 mL), the temperature was lowered to 0 °C, lithium aluminum hydride (19.61 mg, 0.517 mmol) was added, and the reaction was maintained at this temperature for 1 h. Quenching with water (3 mL), extraction with ethyl acetate (10 mL), concentration, and column chromatography (DCM; MeOH = 5%) yielded 50 mg of 2-[3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl]-4,5,6,7-tetrahydrocyclopenta[1,2-d][1,3]oxazacyclohexane-4-one, yield: 62.23%. LC-MS: ESI [M+H] + =234.2.

[0336] Step 4: Preparation of 2-[3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl]-4,5,6,7-tetrahydro-3H-cyclopenta[1,2-d]pyrimidin-4-one

[0337] 110 mg (0.472 mmol) of 2-[3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl]-4,5,6,7-tetrahydrocyclopenta[1,2-d][1,3]oxazacyclohexane-4-one was added to ammonia water (3 mL), and the mixture was heated to 100 °C for 2 h. The reaction solution was concentrated under reduced pressure to give 50 mg of 2-[3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl]-4,5,6,7-tetrahydro-3H-cyclopenta[1,2-d]pyrimidin-4-one, yield: 45.65%, LC-MS: ESI [M+H]. + =233.2.

[0338] Step 5: Preparation of [3-(4-oxoylidene-3,5,6,7-tetrahydrocyclopentano[1,2-d]pyrimidin-2-yl)bicyclo[1.1.1]pentan-1-yl]methane aldehyde

[0339] 2-[3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl]-4,5,6,7-tetrahydro-3H-cyclopenta[1,2-d]pyrimidin-4-one (30 mg, 0.129 mmol) was added to dichloromethane (3 mL), cooled to 0 °C, and DESS-MARTIN (65.74 mg, 0.155 mmol) was added. The reaction was maintained at this temperature for 1 h, quenched with water (3 mL), extracted with dichloromethane (10 mL), concentrated, and the concentrate was subjected to column chromatography (DCM: MeOH = 5%). The product was collected to give 10 mg of [3-(4-oxoylidene-3,5,6,7-tetrahydrocyclopenta[1,2-d]pyrimidin-2-yl)bicyclo[1.1.1]pent-1-yl]methane aldehyde, yield: 33.62%, LC-MS: ESI [M+H] + =231.1.

[0340] Step 6: Preparation of 6-fluoro-N-methyl-5-(4-{[3-(4-oxoylidene-3,5,6,7-tetrahydrocyclopenta[1,2-d]pyrimidin-2-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)pyridine-2-carboxamide

[0341] [3-(4-oxoylide-3,5,6,7-tetrahydrocyclopentano[1,2-d]pyrimidin-2-yl)bicyclo[1.1.1]pent-1-yl]methane aldehyde (10 mg, 0.043 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide dihydrochloride (13.51 mg, 0.043 mmol) were added to dichloromethane (3 mL), followed by sodium triacetoxyborohydride (54.02 mg, 0.255 mmol), and the reaction was carried out at room temperature for 1 h. Quenching with water (3 mL), extraction with dichloromethane (10 mL), and concentration were performed. The crude product was subjected to Pre-HPLC to yield 6 mg of 6-fluoro-N-methyl-5-(4-{[3-(4-oxoylide-3,5,6,7-tetrahydrocyclopentano[1,2-d]pyrimidin-2-yl)bicyclo[1.1.1]pentan-1-yl]methyl}piperazin-1-yl)pyridine-2-carboxamide; yield: 30.53%, LC-MS: ESI [M+H] + =453.2; 1H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.48-8.44 (m, 1H), 7.90 (dd,J = 8.1, 1.4 Hz, 1H), 7.62 (dd,J = 10.6, 8.1 Hz, 1H), 3.27 – 3.18 (m, 4H), 2.83 (d, J = 4.8 Hz, 3H), 2.80 – 2.75 (m, 2H), 2.71-2.60 (m, 8H), 2.12 (s, 6H), 2.04-1.96 (m, 2H).

[0342] Example 42: 6-Fluoro-5-{4-[4-(5-fluoro-4-oxoylide-3H-quinazolin-2-yl)-2-azabicyclo[2.1.1]hex-2-yl]cyclohex-1-enyl}-N-methylpyridine-2-carboxamide (Compound 42)

[0343]

[0344] Step 1: Preparation of 4-{[(2-formamido-3-fluorophenyl)amino]carbonyl}-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

[0345] 2-Amino-6-fluorobenzyl-1-carboxamide (400 mg, 2.595 mmol) and 3-{[(2-methylprop-2-yl)oxy]carbonyl}-3-azabicyclo[2.1.1]hexane-1-carboxylic acid (589 mg, 2.595 mmol) were added to pyridine (8 mL), followed by EDCI (596.96 mg, 3.114 mmol). The reaction was carried out at room temperature for 3 h. The reaction was quenched with water (3 mL), extracted with ethyl acetate (10 mL), concentrated, and the concentrate was subjected to column chromatography (DCM: MeOH = 5%) to give 700 mg of 4-{[(2-carboxamido-3-fluorophenyl)amino]carbonyl}-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester, yield: 74.23%, LC-MS: ESI [M+H]. + =364.2.

[0346] Step 2: Preparation of tert-butyl 4-(5-fluoro-4-oxoylide-3H-quinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

[0347] 4-{[(2-formamido-3-fluorophenyl)amino]carbonyl}-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (500 mg, 1.376 mmol) was added to DME (10 mL), followed by potassium hydroxide (154.41 mg, 2.752 mmol). The reaction mixture was heated to 60 °C for 2 h. The reaction solution was concentrated under reduced pressure, and the concentrate was subjected to column chromatography (DCM: MeOH = 5%) to give 400 mg of 4-(5-fluoro-4-oxoylide-3H-quinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester, yield: 84.17%, LC-MS: ESI [M+H]. + =346.2.

[0348] Step 3: Preparation of 5-fluoro-2-(3-azabicyclo[2.1.1]hex-1-yl)-3,4-dihydroquinazolin-4-one hydrochloride

[0349] 500 mg (1.448 mmol) of tert-butyl 4-(5-fluoro-4-oxoylide-3H-quinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate was added to dichloromethane (5 mL), followed by dioxane hydrochloride solution (5 mL). The mixture was reacted at room temperature for 1 h. The reaction solution was concentrated to dryness under reduced pressure to obtain 400 mg (98.08%) of 5-fluoro-2-(3-azabicyclo[2.1.1]hex-1-yl)-3,4-dihydroquinazolin-4-one hydrochloride. LC-MS: ESI [M+H] + =246.2.

[0350] Step 4: Preparation of 6-fluoro-5-{4-[4-(5-fluoro-4-oxoylide-3H-quinazolin-2-yl)-2-azabicyclo[2.1.1]hex-2-yl]cyclohex-1-enyl}-N-methylpyridine-2-carboxamide

[0351] 5-fluoro-2-(3-azabicyclo[2.1.1]hex-1-yl)-3,4-dihydroquinazolin-4-one hydrochloride (80 mg, 0.284 mmol) and 6-fluoro-N-methyl-5-(4-oxomylidenecyclohex-1-enyl)pyridine-2-carboxamide (70 mg, 0.284 mmol) were added to dichloromethane (3 mL), stirred at room temperature for 10 min, and then sodium triacetoxyborohydride (90.28 mg, 0.426 mmol) was added. The reaction was carried out at room temperature for 1 h. Quenching with water (3 mL), extraction with dichloromethane (10 mL), and concentration were performed. The crude product was subjected to Pre-HPLC to obtain 10 mg of 6-fluoro-5-{4-[4-(5-fluoro-4-oxoylide-3H-quinazolin-2-yl)-2-azabicyclo[2.1.1]hex-2-yl]cyclohex-1-enyl}-N-methylpyridin-2-carboxamide; yield: 7.37%, LC-MS: ESI [M+H] + =478.2; 1 H NMR (400MHz, DMSO-d6) δ 12.18 (s, 1H), 8.64 (d, J = 6.5 Hz, 1H), 8.25 – 8.03 (m, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.88 – 7.69 (m, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.25(d, J = 10.0 Hz, 1H), 6.33 – 6.09 (m, 1H), 3.71 (s, 1H),3.60-3.43 (s,2 H),3.23-2.94 (m, 2H), 2.93-2.66 (m, 5H), 2.42-2.28 (m, 1H), 2.25-2.04 (m, 3H), 2.01-1.78 (m, 2H), 1.54 (s, 1H).

[0352] Example 43: 6-fluoro-5-(4-{[3-(5-fluoro-4-oxoylide-3H-pyrrolo[2,1-f][1,2,4]triazacyclohexamyl-2-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)-N-methylpyridin-2-carboxamide (Compound 43)

[0353]

[0354] Step 1: Synthesis of ethyl 1-amino-3-fluoropyrrole-2-carboxylate

[0355] Ethyl 3-fluoro-1H-pyrrole-2-carboxylate (5 g, 31.819 mmol) was added to DMF (50 mL), cooled to 0°C, and sodium hydride (1.65 g, 41.364 mmol) was added in portions. The reaction mixture was kept at this temperature for 30 min, and then 2,4-dinitrophenylhydroxylamine (9.50 g, 47.728 mmol) was added. The reaction mixture was reacted overnight at room temperature. The reaction solution was quenched with water (3 mL), extracted with ethyl acetate (10 mL), concentrated, and the concentrate was subjected to column chromatography (petroleum ether:ethyl acetate = 10:1). The product was collected to give 5 g of ethyl 1-amino-3-fluoropyrrole-2-carboxylate, yield: 91.28%. LC-MS: ESI [M+H] + =173.2.

[0356] Step 2: Preparation of ethyl pyrrole-2-carboxylate of 3-fluoro-1-({[3-(3,3,4,4-tetramethyl-2-oxa-3-silazopent-1-yl)bicyclo[1.1.1]pent-1-yl]carbonyl}amino)pyrrole-2-carboxylate

[0357] Ethyl 1-amino-3-fluoropyrrole-2-carboxylate (200 mg, 1.162 mmol), 1-(3,3,4,4-tetramethyl-2-oxa-3-silaxapran-1-yl)bicyclo[1.1.1]pentane-3-carboxylic acid (297 mg, 1.162 mmol) were added to DMF (3 mL), the mixture was cooled to 0 °C, and then DIEA (450.45 mg, 3.485 mmol) and HATU (662.59 mg, 1.743 mmol) were added. The reaction was carried out at room temperature for 1 h, and the reaction was quenched with water (3 mL). Ethyl ethyl acetate (10 mL) was added to the solution. Extracted (mL), concentrated, and the concentrate was subjected to column chromatography (DCM: MeOH = 5%) to give 3 g of ethyl pyrrole-2-carboxylate, yield: 33.55%, LC-MS: ESI [M+H]. + =411.2.

[0358] Step 3: Preparation of 3-fluoro-1-({[1-(3,3,4,4-tetramethyl-2-oxa-3-silazopent-1-yl)bicyclo[1.1.1]pentan-3-yl]carbonyl}amino)pyrrole-2-carboxamide

[0359] Ethyl 3-fluoro-1-({[3-(3,3,4,4-tetramethyl-2-oxa-3-silaxapran-1-yl)bicyclo[1.1.1]pentan-1-yl]carbonyl}amino)pyrrole-2-carboxylate (1.2 g, 2.923 mmol) was added to ammonia-methanol (30 mL), and the mixture was heated to 60°C and reacted for 3 h. The reaction solution was concentrated to dryness under reduced pressure to obtain crude 3-fluoro-1-({[1-(3,3,4,4-tetramethyl-2-oxa-3-silaxapran-1-yl)bicyclo[1.1.1]pentan-3-yl]carbonyl}amino)pyrrole-2-carboxamide 1.2 g, LC-MS: ESI [M+H] + =382.2.

[0360] Step 4: Preparation of 5-fluoro-2-[1-(3,3,4,4-tetramethyl-2-oxa-3-silazopent-1-yl)bicyclo[1.1.1]pent-3-yl]-3,4-dihydropyrrolo[2,1-f][1,2,4]triazacyclohexane-4-one

[0361] 3-fluoro-1-({[1-(3,3,4,4-tetramethyl-2-oxa-3-silaxopent-1-yl)bicyclo[1.1.1]pentan-3-yl]carbonyl}amino)pyrrole-2-carboxamide (100 mg, 0.262 mmol) and potassium hydroxide (29.41 mg, 0.524 mmol) were added to DME (2 mL). The mixture was heated to 70 °C and reacted for 2 h. The reaction solution was quenched with water (3 mL), filtered, and the filtrate was collected to give 90 mg of 5-fluoro-2-[1-(3,3,4,4-tetramethyl-2-oxa-3-silazopent-1-yl)bicyclo[1.1.1]pent-3-yl]-3,4-dihydropyrrolo[2,1-f][1,2,4]triazacyclohexane-4-one, yield: 94.46%, LC-MS: ESI [M+H] + =364.2.

[0362] Step 5: Preparation of 5-fluoro-2-[3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl]-3,4-dihydropyrrolo[2,1-f][1,2,4]triazacyclohexane-4-one

[0363] 5-Fluoro-2-[1-(3,3,4,4-tetramethyl-2-oxa-3-silazopent-1-yl)bicyclo[1.1.1]pent-3-yl]-3,4-dihydropyrrolo[2,1-f][1,2,4]triazacyclohexane-4-one (90.00 mg, mmol) was added to tetrahydrofuran (2 mL), followed by tetrabutylammonium fluoride (3 mL). The reaction was carried out at room temperature for 1 h, quenched with water (3 mL), and then precipitated with ethyl acetate (10 mL). Extracted (mL), concentrated, and the concentrate was subjected to column chromatography (DCM: MeOH = 5%) to give 20 mg of 5-fluoro-2-[3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl]-3,4-dihydropyrrolo[2,1-f][1,2,4]triazacyclohexane-4-one, yield: 32.38%, LC-MS: ESI [M+H]. + =250.2.

[0364] Step 6: Preparation of [3-(5-fluoro-4-oxoylide-3H-pyrrolo[2,1-f][1,2,4]triazacyclohexyl-2-yl)bicyclo[1.1.1]pent-1-yl]methane aldehyde

[0365] 5-Fluoro-2-[3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl]-3,4-dihydropyrrolo[2,1-f][1,2,4]triazacyclohexane-4-one (20 mg, 0.080 mmol) was added to dichloromethane (2 mL), cooled to 0 °C, and DESS-MARTIN (68 mg, 0.160 mmol) was added. The reaction was carried out at room temperature for 2 h, quenched with water (3 mL), and then dichloromethane (10 mL) was added. Extracted (mL), concentrated, and the concentrate was subjected to column chromatography (DCM: MeOH = 5%). The product was collected to yield 10 mg of [3-(5-fluoro-4-oxoylide-3H-pyrrolo[2,1-f][1,2,4]triazacyclohexamyl-2-yl)bicyclo[1.1.1]pent-1-yl]methane aldehyde, yield: 75.61%, LC-MS: ESI [M+H]. + =248.2.

[0366] Step 7: Preparation of 6-fluoro-5-(4-{[3-(5-fluoro-4-oxoylide-3H-pyrrolo[2,1-f][1,2,4]triazacyclohexyl-2-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)-N-methylpyridine-2-carboxamide)

[0367] 6-Fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide dihydrochloric acid (25 mg, 0.081 mmol) was added to dichloromethane (2 mL), followed by [3-(5-fluoro-4-oxoylide-3H-pyrrolo[2,1-f][1,2,4]triazacyclohexyl-2-yl)bicyclo[1.1.1]pent-1-yl]methane aldehyde (20 mg, 0.081 mmol). The mixture was reacted at room temperature for 10 min, and then sodium triacetoxyborohydride (34.29 mg, 0.162 mmol) was added. The mixture was reacted at room temperature for 2 h. Quenching with water (3 mL), extraction with dichloromethane (10 mL), and concentration were performed. The crude product was subjected to Pre-HPLC to obtain 16 mg of 6-fluoro-5-(4-{[3-(5-fluoro-4-oxoylide-3H-pyrrolo[2,1-f][1,2,4]triazacyclohexamyl-2-yl)bicyclo[1.1.1]pent-1-yl]methyl}piperazin-1-yl)-N-methylpyridin-2-carboxamide; yield: 42.13%, LC-MS: ESI [M+H] + =470.20; 1 H NMR (400 MHz, DMSO-d6) δ 11.61 (s,1H), 8.41 (q, J = 4.7 Hz, 1H), 7.85 (dd, J = 8.0, 1.4 Hz, 1H), 7.57 (dd, J =10.6, 8.1 Hz, 1H), 7.47 (dd, J = 4.6, 3.1 Hz, 1H), 6.42 (d, J = 3.2 Hz, 1H), 3.34 (s, 2H), 3.21-3.14 (m, 4H), 2.77 (d, J = 4.8 Hz, 3H), 2.63-2.55 (m, 4H), 2.10 (s, 6H).

[0368] Bioactivity test

[0369] 1. PARP enzyme assay

[0370] 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 (Thermo Pierce, 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-ADPRibose (E6F6A) Rabbit mAb (CST, Cat. No. 83732S), SuperSignal ELISA FemtoSubstrate (THERMO PIERCE, Cat. No. 37074).

[0371] 1.1 PARP enzyme assay

[0372] 1.1.1 Preparation of buffer solutions: PBST: 1X PBS, 0.05% Tween-20; Blocking buffer: 1X PBS, 0.05% Tween-20, 5% BSA; Reaction buffer: 50mM Tris-HCl (pH 7.5), 0.005% Tween-20, 0.01% BSA.

[0373] 1.1.2 Coating: Prepare 50 ng / mL Histone coating solution with 1xPBS, transfer 25 μL of the coating solution to a 384-well reaction plate, and coat overnight at 4ºC.

[0374] 1.1.3 Washing: After coating, discard the coating solution and wash with PBST solution. The method is to transfer 50 μL of PBST to a 384-well reaction plate, let it stand for 5 minutes, discard the washing solution, refill the plate, repeat the washing 3 times, and finally pat the reaction plate dry and wait for the next step of blocking.

[0375] 1.1.4. Blocking: Transfer 50 μL of blocking solution to a 384-well reaction plate and let stand for 1 hour.

[0376] Washing: After the blocking is completed, discard the blocking solution, wash the plate three times with PBST solution according to the method in step 1.1.3, and finally pat the reaction plate dry.

[0377] 1.1.5. Prepare a 1000-fold dilution of the compound, transfer 1 μL of the compound to a 96-well plate containing 199 μL of reaction buffer, mix well, and then transfer 5 μL of the mixed compound to a 384-well reaction plate.

[0378] 1.1.6 Prepare a 25 / 10-fold PARP1 / 2-DNA solution using reaction buffer. Transfer 10 μL of PARP1 / 2-DNA solution to a 384-well reaction plate. For the negative control wells, transfer 10 μL of DNA solution. The final concentration of PARP1 / 2 is 0.02 nM, and the final concentration of DNA is 0.8 nM.

[0379] 1.1.7 Prepare a 25 / 10 NAD+ solution using reaction buffer, transfer 10 μL of NAD+ solution to a 384-well reaction plate, with a final NAD+ concentration of 3.5 μM, and incubate at room temperature for 60 minutes.

[0380] 1.1.8 Washing: After the reaction is complete, discard the reaction solution, wash the plate three times with PBST solution as described in step 1.1.3, and finally pat the reaction plate dry.

[0381] 1.1.9 Dilute the primary antibody (anti-Poly / Mono-ADP Ribose Rabbit mAb) 2000 times with blocking buffer, add 20 μL of primary antibody, and incubate at room temperature for 1.5 hours.

[0382] 1.1.10 Washing: Discard the primary antibody, wash three times with PBST solution as described in step 1.1.3, and finally pat the reaction plate dry.

[0383] 1.1.11 Dilute the secondary antibody (anti-rabbit IgG, HRP-linked Antibody) 2000 times with blocking buffer, add 20uL of secondary antibody, and incubate at room temperature for 1 hour.

[0384] 1.1.12 Washing: Discard the secondary antibody, wash three times with PBST solution according to step 1.1.3, and finally pat the reaction plate dry.

[0385] 1.1.13. Color development: Mix Femto-ECL Substrate A and Femto-ECL Substrate B in a 1:1 ratio and transfer 25 μL to a 384 reaction plate.

[0386] 1.1.14. Reading: Use Envision to read the chemiluminescence value RLU.

[0387] Inhibition rate = (maximum value - sample value) / (maximum value - minimum value) * 100. The test results are shown in Table 3 below.

[0388] Table 3. Results of PARP-1 / 2 enzyme assay

[0389]

[0390] A: 75% ≤ inhibition rate; B: 50% ≤ inhibition rate < 75%; C: inhibition rate < 50%.

[0391] Conclusion: The compounds of this invention have a significant inhibitory effect on PARP1 and exhibit significant selectivity for PARP1 within the PARP family.

[0392] 2. Cell anti-proliferation activity test

[0393] BRCA mutant MDA-MB-436 cells were cultured in DMEM medium containing 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin, and incubated at 37°C in a 5% CO2 saturated incubator. When cells reached 80% confluence, they were harvested, centrifuged at 300g for 10 min, and seeded at 1200 cells / well in 96-well plates. After 24 h, different final concentrations of PARPi (0, 0.01, 0.1, 1, 10, 100, 1000 nM) were added, and the cells were cultured for another 72 h. The medium was then changed (with the same final concentration of PARPi added), and the cells were cultured for another 96 h. The OD values ​​at 450 nM were measured using the CCK8 assay, and the cell inhibition rate was calculated as follows: Inhibition rate % = 1 - (mean OD value of the drug group - mean OD value of the Blank group) / (mean OD value of the control group - mean OD value of the Blank group) * 100%.

[0394] BRCA wild-type DLD-1 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin, and incubated at 37°C in a 5% CO2 saturated incubator. When cells reached 80% confluence, they were collected, centrifuged at 300g for 10 min, and seeded at 1000 cells / well in 96-well plates. After 24 h, different final concentrations of PARPi (0, 1, 10 μM) were added, and the cells were cultured for another 72 h. The medium was then changed (with the same final concentration of PARPi added), and the cells were cultured for another 96 h. The 96-well plates were then examined, and the OD value at 450 nM was measured using the CCK8 assay. The cell inhibition rate was calculated as follows: Inhibition rate % = 1 - (mean OD value of the drug group - mean OD value of the Blank group) / (mean OD value of the control group - mean OD value of the Blank group) * 100%. The reference compound AZD9574 was purchased from MedChemExpress Shanghai.

[0395] The test results are shown in Table 4 below.

[0396] Table 4 Results of Cell Antiproliferation Activity Test

[0397]

[0398] ++++: IC 50 <10 nM, +++: 10 nM≤IC 50 <100 nM, ++: 100 nM ≤ IC 50 <1000 nM, +: 1000 nM ≤ IC 50 .

[0399] Conclusion: The compound of the present invention has a significant inhibitory effect on BRCA mutant MDA-MB-436 cells, but no significant inhibitory effect on BRCA wild-type DLD-1 cells, indicating that the compound of the present invention specifically inhibits homologous recombination defective tumor cells.

[0400] 3. Inhibition experiment of the compound on hERG potassium ion channel

[0401] Cell Culture and Processing: Stable hERG-expressing CHO cells were cultured in cell culture flasks at 37°C in a 5% CO2 incubator. When the cell density reached 60-80%, the culture medium was aspirated, the cells were washed once with PBS, and then digested with Detachin. After complete digestion, the cells were neutralized with culture medium, centrifuged, the supernatant was aspirated, and the cells were resuspended in culture medium to adjust the cell density to 2-5 × 10⁶ cells / year. 6 / mL for later use.

[0402] Compound preparation: The stock solution of the compound was diluted with 100% DMSO, i.e., 10 μL of the stock solution was added to 20 μL of DMSO, and serially diluted 3-fold to obtain 6 concentrations. 4 μL of each of the 6 concentrations was added to 396 μL of extracellular fluid, i.e., a 100-fold dilution to obtain 6 intermediate concentrations. Then, 80 μL of each of the 6 intermediate concentrations was added to 320 μL of extracellular fluid, i.e., a 5-fold dilution to the final concentration to be tested. The highest test concentration was 40 μM, with concentrations of 40, 13.33, 4.44, 1.48, 0.49, and 0.16 μM, for a total of 6 concentrations. The DMSO content in the final test concentration did not exceed 0.2%, as this concentration of DMSO has no effect on the hERG potassium channel. The entire dilution process was performed using a Bravo instrument.

[0403] Electrophysiological recording procedure: The entire process of single-cell high-impedance sealing and whole-cell pattern formation was automated by the Qpatch instrument. After obtaining the whole-cell recording pattern, the cells were clamped at -80 mV. Before applying a 5-second +40 mV depolarization stimulus, a 50-millisecond -50 mV pre-voltage was applied, followed by repolarization to -50 mV for 5 seconds, and then back to -80 mV. This voltage stimulation was applied every 15 seconds. After recording for 2 minutes, extracellular fluid was applied for 5 minutes of recording, and then the drug administration process began. The compound concentration started from the lowest test concentration, and each test concentration was administered for 2.5 minutes. After all concentrations were administered, the positive control compound 3 μM Cisapride was administered. At least 3 cells (n≥3) were tested for each concentration.

[0404] Compound IC 50 The following equation was fitted and calculated:

[0405]

[0406] Where X is the Log value of the detected concentration of the test sample, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0407] Conclusion: The compounds of this invention have a weak inhibitory effect on hERG potassium ion channels.

[0408] 4. Evaluation of the distribution of the compound in cerebrospinal fluid and plasma in vivo

[0409] Experimental procedure: Weigh the compound, add a small amount of DMSO, then add sodium chloride solution for injection to prepare a solution of 5 mg / mL. -1 A solution of the compound, ready for administration. For male rats, administer at 5 mg / kg. -1 The drug was administered intravenously. Cerebrospinal fluid and whole blood were collected at 0.25 h and 2 h post-administration, respectively (n=1). Whole blood was centrifuged at 3500 rpm for 15 min, and the supernatant plasma was collected. 10 µL of plasma and 10 µL of cerebrospinal fluid were placed in centrifuge tubes, and 40 µL of a solution containing 20 ng / mL was added. -1 Acetonitrile precipitate of internal standard SAHA, vortex for 30 s, centrifuge at 13000 rpm for 15 min, and collect the supernatant for analysis in a sample vial. Standard curve range: 1~1000 ng·ml -1 The distribution of the compound in rat cerebrospinal fluid and plasma was calculated, and the results are shown in Table 5.

[0410] Table 5 Results of cerebrospinal fluid and plasma distribution tests in rats after compound administration

[0411]

[0412] Conclusion: The compounds of this invention have good brain penetration potential, especially compounds 4, 7, 10, and 12, which have high concentrations in cerebrospinal fluid.

Claims

1. The compound of formula I or a pharmaceutically acceptable form thereof, characterized in that: The structure of Formula I is as follows: in: R1 is selected from hydrogen, deuterium, halogen, substituted or unsubstituted groups of the following: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl or 3- to 4-membered cycloalkyl; in R1, the substituents of the substituted groups are selected from deuterium or halogens; X is selected from N or CR4; Y is selected from N or CR5; R4 and R5 are independently selected from hydrogen, deuterium, amino, cyano, halogen, and C. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, 3-6 membered cycloalkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy groups; Alternatively, R5 may be bonded to R1 or R4 to R5, and the atoms to which they are attached, to form substituted or unsubstituted rings of the following: 5-6 membered alkyl rings, 5-6 membered alkenyl rings, 5-6 membered alkyl heterocycles, benzene rings, or 5-6 membered heteroaryl rings; when R5 is bonded to R1 or R4 to R5, and the atoms to which they are attached form rings, the substituents of the substituted rings are selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, C 1-4 Hydroxy-substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 At least one of fluoroalkoxy or 3-4 membered cycloalkyl; when R5 is connected to R1 or R4 to R5 and the atoms to which they are attached to form a ring, the 5-6 membered alkyl heterocycle or 5-6 membered heteroaryl ring contains 1 to 3 heteroatoms selected from at least one of N, S or O; L1 is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; R 2a R 2b Independently selected from hydrogen, deuterium, fluorine, substituted or unsubstituted C 1-4 Alkyl; R 2a R 2b In, the replaced C 1-4 The alkyl substituent is selected from hydrogen, deuterium, fluorine, hydroxyl, amino, or cyano; or, R 2a and R 2b They bond with the atoms they are attached to to form 3- to 4-membered alkyl rings; Ring A is selected from: , , , , , , , , , , , , or ; R 6a Selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, fluoromethyl, or deuterated methyl; R 6b Selected from hydrogen, deuterium, fluorine, chlorine, or bromine; L2 is selected from bonds, alkynyl groups, O, NH or N(CH3); Ring B is selected from benzene ring, 5-10 membered heteroaryl ring or 5-10 membered partially unsaturated heteroaryl ring; in ring B, the 5-10 membered heteroaryl ring or 5-10 membered partially unsaturated heteroaryl ring contains 1 to 3 heteroatoms selected from at least one of N, S or O; R3 is selected from hydrogen, deuterium, halogen, cyano, and -(CR). 3a R 3b ) n3 OR 3c 、-(CR 3a R 3b ) n3 N(R 3c R 3d -COOR 3c -COR 3c -CONHR 3c -CONHOR 3c -CON(R) 3c R 3d ), -NHCOR 3c -SO2R 3c -SO2NHR 3c -SO2N(R) 3c R 3d ), or, the following groups substituted with 0 to 6 substituents: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The substituent is selected from alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl; or, two adjacent R3s are bonded to the atoms they are attached to, forming a 5-6 membered alkyl ring, a 5-6 membered alkyl heterocycle, a benzene ring, or a 5-6 membered heteroaryl ring; in R3, the substituent is selected from deuterium, fluorine, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, C 1-4 Hydroxy-substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy or C 1-4 At least one of fluoroalkoxy groups; in R3, the 4-6 membered heterocyclic alkyl or 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S, and O; when two adjacent R3s are connected to the atoms to which they are attached to form a ring, the 5-6 membered alkyl heterocycle or 5-6 membered heteroaryl ring contains 1 to 3 heteroatoms selected from at least one of N, S, and O. R 3a R 3b Independently selected from hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, C 1-4 Hydroxy-substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy or C 1-4 At least one of the fluoroalkoxy groups; or, R 3a and R 3b They are attached to the atoms to form 3-6 membered alkyl rings or 4-6 membered alkyl heterocycles substituted with 0-6 substituents; R 3a and R 3b When the substituents are linked to the atoms they are attached to to form a ring, the substituents are selected from hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, C 1-4 Hydroxy-substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy or C 1-4 At least one of the fluoroalkoxy groups; R 3a and R 3b When the 5-6 membered alkyl heterocycles are linked to the atoms they are connected to to form a ring, the alkyl heterocycles contain 1 to 3 heteroatoms selected from at least one of N, S, and O; R 3c R 3d Independently selected from hydrogen, deuterium, or the following groups substituted with 0-6 substituents: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne, 6-10 aryl, 5-10 heteroaryl, 4-8 heterocycloalkyl, 3-8 cycloalkyl, 6-10 spirocycloalkyl, 6-10 heterospirocycloalkyl, 6-10 bridged cycloalkyl or 6-10 heterobridged cycloalkyl; R 3c R 3d In this context, the substituents are selected from deuterium, halogens, hydroxyl groups, amino groups, cyano groups, and C6 groups. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, C 1-4 Hydroxy-substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Fluoroalkoxy, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 3-6 membered cycloalkylmethylene, 4-6 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 6c R 6d In this context, the 5-10-membered heteroaryl, 4-8-membered heterocycloalkyl, 6-10-membered heterospirocycloalkyl, and 6-10-membered heterobridged cycloalkyl groups contain 1-3 heteroatoms selected from at least one of N, S, or O; R 3c R 3d In the substituents, the 4-6 membered heterocyclic alkyl group and the 4-6 membered heterocyclic alkyl methylene group contain 1-3 heteroatoms selected from at least one of N, S or O; Or, R 3a With R 3c R 3a With R 3d R 3b With R 3c R 3b With R 3d or R 3c With R 3d They are bonded to the atoms to form 4-6 membered alkane heterocycles substituted with 0-6 substituents, wherein the substituents are selected from hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, C 1-4 Hydroxy-substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy or C 1-4 At least one of fluoroalkoxy groups, wherein the 4-6 membered alkyl heterocycle contains 1 to 3 heteroatoms selected from at least one of N, S or O; Alternatively, when L2 is the bond, R3 and R 6a They are bonded to atoms to form substituted or unsubstituted 6-7 membered alkyl rings or 6-8 membered alkyl heterocycles; R3 and R 6a When the substituents are linked to the atoms they are attached to to form a ring, the substituents are selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, C 1-4 Hydroxy-substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 At least one of fluoroalkoxy or 3-4 membered cycloalkyl; R3 and R 6a When the 6-8 membered alkyl heterocycles are linked to the atoms they are connected to to form a ring, the 6-8 membered alkyl heterocycles contain 1 to 3 heteroatoms selected from at least one of N, S or O; n1 is selected from 0 or 1; n2 is selected from 0, 1, 2, 3, 4, 5 or 6; n3 is selected from 0, 1, 2, or 3; And the compound is not: or ; The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotope-labeled substances, metabolites, or prodrugs.

2. The compound according to claim 1, or a pharmaceutically acceptable form thereof, characterized in that: R1 is selected from hydrogen, deuterium, halogen, substituted or unsubstituted groups of the following: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl or 3- to 4-membered cycloalkyl; in R1, the substituents of the substituted groups are selected from deuterium or halogens; R4 and R5 are independently selected from hydrogen, deuterium, amino, cyano, halogen, and C. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, 3-6 membered cycloalkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy groups; Alternatively, R5 may be bonded to R1 or R4 to R5, and to the atoms to which they are attached, to form substituted or unsubstituted rings of the following: 5-6 membered alkyl rings, 5-6 membered alkyl heterocycles, benzene rings, or 5-6 membered heteroaryl rings; when R5 is bonded to R1 or R4 to R5, and to the atoms to which they are attached, the substituents of the substituted rings are selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, C 1-4 Hydroxy-substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 At least one of fluoroalkoxy or 3-4 membered cycloalkyl; when R5 is connected to R1 or R4 to R5 and the atoms to which they are attached to form a ring, the 5-6 membered alkyl heterocycle or 5-6 membered heteroaryl ring contains 1 to 3 heteroatoms selected from at least one of N, S or O; L1 is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; Ring A is selected from: , , , , , , , , , , , or .

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof, characterized in that: R1 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, fluoromethyl, fluoroethyl, deuterated methyl, deuterated ethyl, vinyl, ethynyl, methoxy, fluoromethoxy, methylthio, fluoromethylthio, or cyclopropyl. Preferred structural unit Selected from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or X is selected from N, CH, or CCH3; Y is selected from N, CH, or CCH3; R1 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, ethyl, fluoromethyl, fluoroethyl, deuterated methyl, deuterated ethyl, vinyl, ethynyl, methoxy, fluoromethoxy, methylthio, fluoromethylthio, or cyclopropyl; R 1a It is selected from one, two, or three of the following groups: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, ethyl, fluoromethyl, fluoroethyl, deuterated methyl, deuterated ethyl, vinyl, ethynyl, methoxy, fluoromethoxy, methylthio, fluoromethylthio, or cyclopropyl. More preferably, structural unit Selected from the following groups: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; Preferred structural unit Selected from: , , , , , , , , , , , , or .

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof, characterized in that: R 2a R 2b Independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, fluoromethyl, or deuterated methyl; or, R 2a and R 2b They bond with the atoms they are attached to to form cyclopropane; Preferred structural unit Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; Preferred structural unit Selected from: , , , , , , , or .

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof, characterized in that: Ring A is selected from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; Preferred, Selected from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; Preferably, ring A is selected from: or .

6. The compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof, characterized in that: Ring B is selected from benzene ring, pyridine ring, pyridothiazole ring, pyrazole[1,5-a]pyrimidine ring, benzopyrazole ring, benzimidazole ring, thiazole ring, [1,2,4]triazolo[1,5-a]pyridine ring, thiophene ring, furan ring, imidazole ring, pyrazole ring, pyrazinopyrrole ring, pyridopyridine ring, pyridopyrazole ring, pyridooxazole ring, pyrimidine ring, pyridazine ring, pyrazine ring, etc. or ; Preferably, ring B is selected from , , , , , , or .

7. The compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof, characterized in that: R3 is selected from hydrogen, deuterium, halogen, cyano, and -(CR). 3a R 3b ) n4 OR 3c 、-(CR 3a R 3b ) n4 N(R 3c R 3d -COOR 3c -COR 3c -CONHR 3c -CONHOR 3c -CON(R) 3c R 3d ), -NHCOR 3c -SO2R 3c -SO2NHR 3c -SO2N(R) 3c R 3d ), or, substituted or unsubstituted of the following groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 The 5-6 membered alkyl ring, 3-6 membered cycloalkyl ring, or phenyl ring may be formed by two adjacent R3s bonded to the atoms they are attached to, forming a 5-6 membered alkyl ring, a 5-6 membered alkyl heterocycle, a benzene ring, or a 5-6 membered heteroaromatic ring. In R3, the substituent of the following groups is selected from at least one of: deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, deuterated methyl, fluoromethyl, hydroxy-substituted methyl, methoxy, deuterated methoxy, or fluoromethoxy. When two adjacent R3s are bonded to the atoms they are attached to form a ring, the 5-6 membered alkyl heterocycle or 5-6 membered heteroaromatic ring contains 1-2 heteroatoms selected from at least one of N, S, and O. R 3a R 3b Independently selected from at least one of hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, methyl, deuterated methyl, fluoromethyl, hydroxy-substituted methyl, methoxy, deuterated methoxy, or fluoromethoxy; or, R 3a and R 3b They bond with the atoms to form substituted or unsubstituted 3-6 membered alkyl rings or 4-6 membered alkyl heterocycles; R 3a and R 3b When the substituents are linked to the atoms to form a ring, the substituents are selected from at least one of hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, deuterated methyl, fluoromethyl, hydroxy-substituted methyl, methoxy, deuterated methoxy, or fluoromethoxy; R 3a and R 3b When the 5-6 membered alkyl heterocycles are linked to the atoms they are connected to to form a ring, the alkyl heterocycles contain 1 to 2 heteroatoms selected from at least one of N, S, and O; R 3c R 3d The group independently selected from hydrogen, deuterium, or substituted or unsubstituted groups of the following: methyl, ethyl, vinyl, ethynyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. , , or ;R 3c R 3d In this context, the substituents of the following groups are selected from: deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, deuterated methyl, fluoromethyl, hydroxy-substituted methyl, methoxy, deuterated methoxy, fluoromethoxy, or cyclopropyl. Or, R 3a With R 3c R 3a With R 3d R 3b With R 3c R 3b With R 3d or R 3c With R 3d They are connected to the atoms to form substituted or unsubstituted 4-6 membered alkane heterocycles, wherein the substituents are selected from at least one of hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, methyl, deuterated methyl, fluoromethyl, hydroxy-substituted methyl, methoxy, deuterated methoxy, or fluoromethoxy, and the 4-6 membered alkyl heterocycles contain 1-2 heteroatoms selected from at least one of N, S, or O; Alternatively, when L2 is the bond, R3 and R 6a They are bonded to atoms to form substituted or unsubstituted 6-7 membered alkyl rings or 6-8 membered alkyl heterocycles; R3 and R 6a When the substituents are linked to the atoms to form a ring, the substituents are selected from at least one of hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, methyl, deuterated methyl, fluoromethyl, hydroxy-substituted methyl, methoxy, deuterated methoxy, fluoromethoxy, or cyclopropyl; R3 and R 6a When the 6-8 membered alkyl heterocycles are linked to the atoms they are connected to to form a ring, the 6-8 membered alkyl heterocycles contain 1-2 heteroatoms selected from at least one of N, S or O; Preferably, R3 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, deuterated methyl, fluoromethyl, vinyl, ethynyl, methoxy, deuterated methoxy, fluoromethoxy, methylamino, deuterated methylamino, fluoromethylamino, acetyl, deuterated acetyl, fluoroacetyl, propionyl, deuterated propionyl, fluoropropionyl, aminoacyl, methylaminoacyl, deuterated methylaminoacyl, fluoromethylaminoacyl, ethylaminoacyl, deuterated ethylaminoacyl, fluoroethylaminoacyl, cyclopropylaminoacyl, fluorocyclopropylaminoacyl, cyclobutylaminoacyl, fluorocyclobutylaminoacyl. , , , , , , , , , , ; Alternatively, when L2 is the bond, R3 and R 6a They connect with the atoms to form the following rings: , or .

8. The compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof, characterized in that: Structural unit Selected from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable form thereof, characterized in that: The compound is selected from: 。 10. A pharmaceutical composition, characterized in that: Its active ingredient contains the compound of any one of claims 1 to 9 or a pharmaceutically acceptable form thereof, supplemented by a pharmaceutically acceptable carrier.

11. The compound of any one of claims 1 to 9 or a pharmaceutically acceptable form thereof, or the pharmaceutical composition of claim 10, is used in the preparation of a PARP1 inhibitor or in a medicament for the prevention and / or treatment of PARP1 enzyme-related diseases.

12. The use according to claim 11, characterized in that: The PARP1 enzyme-related disease is a tumor-related disease, preferably the tumor-related disease lacks the HR-dependent DNA DSB repair pathway, more preferably the tumor-related disease includes one or more cancer cells, the cancer cells have a reduced or absent ability to repair DNA DSB via HR compared to normal cells, and more preferably the cancer cells have a BRCA1 or BRCA2 defective phenotype.

13. The use according to claim 12, characterized in that: The tumors mentioned include breast cancer, colorectal cancer, colon cancer, lung cancer, prostate cancer, bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer, vulvar cancer, blood cancer, multiple myeloma, lymphoma, meningioma, pituitary adenoma, craniopharyngioma, schwannoma, glioma, ependymoma, primitive neuroectodermal tumors, central nervous system lymphoma, germ cell tumors, metastatic tumors, primary peritoneal cancer, brain cancer, or central nervous system cancer.

14. The use according to claim 12, characterized in that: The tumors mentioned are brain metastases or gliomas.

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