Nitrogen-containing heterocyclic compound and use thereof

Abstract

Disclosed in the present invention are a nitrogen-containing heterocyclic compound and the use thereof. Specifically, disclosed in the present invention is a compound as represented by formula (I), or a stereoisomer, tautomer, deuterated substance, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. The compound of the present invention is a PARP1 inhibitor which can be used for treating and / or preventing PARP1-related diseases.

Description

Nitrogen-containing heterocyclic compounds and uses thereof TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a class of nitrogen-containing heterocyclic compounds and uses thereof. BACKGROUND

[0002] When the survival of a cell is highly dependent on the normal function of a second gene due to the mutation or inactivation of the first gene, the two genes are said to have a "synthetic lethal" relationship. This concept was first proposed based on studies of fruit flies and other organisms, but has been greatly expanded in cancer treatment in the past two decades. Drugs based on the synthetic lethal concept have achieved many important results, greatly expanding the range of targetable drug targets.

[0003] Poly-ADP-ribose-polymerase 1 / 2 (PARP1 / 2) proteins are a class of proteins that play an important role in DNA damage repair. They can bind to single or double strand breaks in DNA and recruit related proteins for DNA repair through auto-PARylation. Some tumor cells with homologous recombination deficiency (HRD) such as BRCA protein mutations rely heavily on PARP-mediated DNA repair to manage the large amount of DNA damage generated during rapid division and proliferation. When the activity of PARP1 / 2 in such HRD tumor cells is inhibited, the accumulated DNA damage during rapid replication cannot be effectively repaired, and a large amount of accumulated DNA damage will lead to inhibition of tumor cell proliferation and eventually death. Based on this synthetic lethal concept, the PARP inhibitor olaparib was approved for marketing in 2014 for the treatment of ovarian cancer, which is the first successful application of the synthetic lethal concept in clinical practice and an important milestone in the development of synthetic lethal drugs. Since then, several PARP inhibitors have been approved for marketing, and their indications have been expanded to other solid tumors such as breast cancer and prostate cancer.

[0004] On the other hand, the currently marketed PARP inhibitors have also shown significant adverse side effects in clinical use, such as anemia, thrombocytopenia, and other hematologic toxicities, which have greatly limited their application. Further studies have shown that the synthetic lethal effect of PARP inhibitors mainly comes from the inhibition of PARP1, while the inhibition of PARP2 may be related to side effects such as hematologic toxicity. Therefore, developing highly selective PARP1 inhibitors to reduce the off-target toxicity of PARP2 has very important clinical significance. SUMMARY

[0005] To solve the above problems, the present application provides a nitrogen-containing heterocyclic compound acting on PARP1 protein.

[0006] The application also provides a preparation method of the nitrogen-containing heterocyclic compound.

[0007] The application also provides a use of the nitrogen-containing heterocyclic compound as a selective inhibitor of PARP1.

[0008] The application also provides a kit comprising the nitrogen-containing heterocyclic compound or the pharmaceutical composition.

[0009] The application also provides a use of the nitrogen-containing heterocyclic compound in the preparation of a drug for a PARP1-related disease.

[0010] The application also provides a method for preventing or treating a PARP1-related disease.

[0011] To solve the above technical problems, the application provides the following technical solutions.

[0012] In a first aspect of the application, a compound as shown in formula (I), a stereoisomer, a tautomer, a deuterated compound, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof is provided,

[0013] X is CR a or N; Q is CR b ; W is CR c ;

[0014] R a and R c one of which is selected from the group consisting of H, D, halogen, cyano, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, SF5, OR 7 , -COOR 8 , -P(O)(R 8 )2, NR 10 R 11 , -CONR 12 R 13 , -N(R 30 )CONR 12 R 13 , -S(O)2R 8 , -S(O)2NR 12 R 13 , -N(R 30)S(O)2NR 12 R 13 C 3-10 Carbocyclic group, 4-12 membered heterocyclic group, C 6-12 Aryl, 5-12-membered heteroaryl, wherein each of the above-mentioned groups may optionally be further replaced by one or more groups selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, oxo groups (=O), -S(O)2C 1-6 Alkyl, -COC 1-6 Alkyl groups are substituted;

[0015] R a and R c Another R b The atoms bonded to it together form C 4-10 Carbon rings, 4-12 membered heterocycles, C 6-12 Aromatic rings, 5-12 member heteroaryl rings, or 8-12 member fused bicyclic rings;

[0016] Or R a R b R c The atoms bonded to it together form 8-16 member fused bicyclic rings;

[0017] The carbon rings, heterocycles, aromatic rings, heteroaromatic rings, or fused bicyclic rings formed by the above cyclization may optionally be further bonded by 1-5 R groups. d replace;

[0018] Each R d Each is independently selected from the following groups: halogen, cyano, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 Alkyne group, SF5, OR 7 -COOR 8 -COR 8 -P(O)(R 8 2. SR 9 NR 31 R 32 -CONR 33 R 34 -S(O)2R 8 -S(O)2NR 33 R 34 -N(R) 30 )S(O)2NR 33 R 34 Oxide group (=O), C 3-10 Carbocyclic group, 4-12 membered heterocyclic group, C 6-12Aryl, 5-12-membered heteroaryl, wherein each of the above-mentioned groups may optionally be further replaced by one or more groups selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, oxo groups (=O), -S(O)2C 1-6 Alkyl, -COC 1-6 Alkyl groups are substituted;

[0019] Alternatively, two R atoms connected to two adjacent carbon atoms d The two carbon atoms bonded to it together form a carbon-carbon double bond;

[0020] Z is CR e Or N;

[0021] R e Selected from the following groups: H, D, halogen, cyano, hydroxyl, NR 14 R 15 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups;

[0022] Ring A is selected from the following group: C 6-14 Aryl, 5-12 membered heteroaryl rings, and ring A can be connected to Z by any possible ring atom;

[0023] Each R 1 Independently selected from the following groups: H, halogen, cyano, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 Alkyne group, SF5, OR 7 -COOR 8 -P(O)(R 8 2. SR 9 NR 16 R 17 -CONR 18 R 19 -N(R) 30 CONR 18 R 19 -N(R) 30 COOR 8 -S(O)2R 8 -S(O)2NR 18 R 19 -N(R) 30 )S(O)2NR 18 R 19 , O group (=O), -C 0-4Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4-8-membered heterocyclic groups, wherein each of the above-mentioned groups may optionally be further surrounded by 1, 2, 3 or 4 R groups. i replace;

[0024] Each R i Independently selected from the following groups: halogen, cyano, hydroxyl, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O)2C 1-6 Alkyl, -COC 1-6 alkyl;

[0025] B is Furthermore, B is connected to a nitrogen atom through ring C and Y is connected to a carbon atom, or Y is connected to a nitrogen atom and ring C is connected to a carbon atom.

[0026] The carbon ring (C) is selected from the following group: 4-10 membered carbon rings and 4-10 membered heterocycles;

[0027] Y is selected from the following group: -C(R) 4a )2-、-NR 4b -, -O-, -S-, -S(O)-, -S(O)2-;

[0028] Each R 4 Each element is independently selected from the following groups: H, D, halogen, hydroxyl, C. 1-6 Alkyl, C 1-6 Alkoxy, -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkyl-4-8-membered heterocyclic group, oxo group (=O), the above groups may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O)2C 1-6 alkyl;

[0029] Alternatively, two R atoms connected to two adjacent carbon atoms 4 The two carbon atoms bonded to it together form a carbon-carbon double bond;

[0030] Each R 4a Each is independently selected from the following groups: H, D, halogens, C 1-6 Alkyl, -C 1-4 Hydroxyalkyl, -C 1-4 Alkylene-C1-6 Alkoxy, -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4-8-membered heterocyclic group, wherein the above-described groups may optionally be further substituted with one or more halogens;

[0031] Or, two Rs 4a Together with the carbon atoms attached to it, they form C=O;

[0032] Or, two Rs 4a Together with the carbon atom attached thereto, they form a 3-8 membered carbon ring or a 4-8 membered heterocycle, which may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, =O, -COC 1-6 Alkyl group, -S(O)2C 1-6 alkyl;

[0033] R 4b Selected from the following groups: H, C 1-6 Alkyl, -C 2-4 Hydroxyalkyl, -C 2-4 Alkylene-C 1-6 Alkoxy, -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4-8-membered heterocyclic group, wherein the above-described groups may optionally be further substituted with one or more halogens;

[0034] Each R 5 and each R 6 Each is independently selected from the following groups: H, D, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkyl-4-8-membered heterocyclic group, wherein the above-described groups may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O)2C 1-6 alkyl;

[0035] Or, R e With an R 5 And the two carbon atoms they are attached to together form a carbon-carbon double bond;

[0036] Alternatively, two R atoms attached to the same carbon atom 5 Together form = O;

[0037] Or, two Rs 5 All atoms bonded to it further form a 3-8 membered carbon ring or a 4-8 membered heterocycle, which may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, =O, -COC 1-6 Alkyl group, -S(O)2C 1-6 alkyl;

[0038] Or, two Rs 6 All atoms bonded to it further form a 3-8 membered carbon ring or a 4-8 membered heterocycle, which may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, =O, -COC 1-6 Alkyl group, -S(O)2C 1-6 alkyl;

[0039] Or, any R 5 Any R 6 The atoms bonded to it together form a 3-8 membered carbon ring or a 4-8 membered heterocycle, which may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, =O, -COC 1-6 Alkyl group, -S(O)2C 1-6 alkyl;

[0040] Each R 7 Independently selected from the following groups: H, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkyl-4-8-membered heterocyclic group, -C 0-4 Alkylene-OC 3-10 cycloalkyl, -C 0-4 alkylene-O-4-10-membered heterocyclic group, C 6-12Aryl, 5-12 membered heteroaryl, and each of the above groups may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O)2(C 1-6 alkyl), -CO(C) 1-6 Alkyl group), =O;

[0041] Each R 8 Independently selected from the following groups: H, C 1-6 Alkyl, -C 2-4 Hydroxyalkyl, -C 2-4 Alkylene-C 1-6 Alkoxy, -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkyl-4-8-membered heterocyclic group, -C 0-4 Alkylphenylene, wherein each of the above-described groups may optionally be further substituted with one or more halogens;

[0042] Each R 9 Select independently from the following group: C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-12 Aryl, 5-12 heteroaryl;

[0043] Each R 10 R 11 R 14 R 15 R 16 R 17 R 31 and R 32 Each is independently selected from the following groups: H, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-10 cycloalkyl, -C 0-4 Alkyl-4-10 heterocyclic group, -C 0-4 Alkylene-OC 3-10 cycloalkyl, -C 0-4 Alkylene-O-4-10-membered heterocyclic group, -S(O)2(C 1-6 alkyl), -CO(C) 1-6 Alkyl groups, wherein each of the above-described groups may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups;

[0044] Each R 12 R 13 R 18 R 19 R 33 and R 34 Each is independently selected from the following groups: H, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-10 cycloalkyl, -C 0-4 Alkyl-4-10 heterocyclic group, -C 0-4 Alkylene-OC 3-10 cycloalkyl, -C 0-4 Alkylene-O-4-10-membered heterocyclic group, wherein each of the above-described groups may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O)2C 1-6 alkyl;

[0045] Or, R attached to the same nitrogen atom 10 and R 11 R 12 and R 13 R 14 and R 15 R 16 and R 17 Or R 18 and R 19 The nitrogen atom attached to it forms a 4-10 membered heterocycle, which may optionally be further substituted by one or more substituents selected from the group consisting of halogens, hydroxyl groups, C, and so on. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O)2C 1-6 Alkyl, -CO(C) 1-6 Alkyl group), =O;

[0046] Each R 30 Each is independently selected from the following groups: H, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-10 cycloalkyl, -C 0-4 Alkyl-4-10 heterocyclic group, -C 0-4 Alkylene-OC 3-10 cycloalkyl, -C 0-4Alkylene-O-4-10-membered heterocyclic group, wherein each of the above-described groups may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups;

[0047] s and t are each independently 0, 1, 2, 3, 4, 5 or 6;

[0048] Unless otherwise specified, the heteroaryl or heterocyclic group is an aromatic cyclic group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S on a cyclic skeleton; the heterocyclic group or heterocycle is a saturated or partially unsaturated cyclic group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S that is not aromatic, and it is a monocyclic, fused, bridged or spirocyclic group.

[0049] In another preferred embodiment, X is CR a Or N; Q is CR b W is CR c ;

[0050] R a and R c One of them is selected from the following group: H, D, halogen, cyano, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, SF5, OR 7 -COOR 8 -P(O)(R 8 2. NR 10 R 11 -CONR 12 R 13 -N(R) 30 CONR 12 R 13 -S(O)2R 8 -S(O)2NR 12 R 13 -N(R) 30 )S(O)2NR 12 R 13 C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 4-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, and each of the above groups may optionally be further surrounded by one or more elements selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, oxo groups (=O), -S(O)2C1-6 Alkyl, -COC 1-6 Alkyl groups are substituted;

[0051] R a and R c Another R b The atoms bonded to it together form C 4-8 Carbon rings, 4-10 membered heterocycles, C 6-10 Aromatic rings, 5-10 member heteroaryl rings, or 8-12 member densely packed bicyclic rings;

[0052] Or R a R b R c The atoms bonded to it together form 8-14 member fused bicyclic rings;

[0053] The carbon rings, heterocycles, aromatic rings, heteroaromatic rings, or fused bicyclic rings formed by the above cyclization may optionally be further bonded by 1-5 R groups. d replace;

[0054] Each R d Each is independently selected from the following groups: halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, SF5, OR 7 -COOR 8 -COR 8 -P(O)(R 8 2. SR 9 NR 31 R 32 -CONR 33 R 34 -S(O)2R 8 -S(O)2NR 33 R 34 -N(R) 30 )S(O)2NR 33 R 34 Oxide group (=O), C 3-8 Carbocyclic group, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-10 heteroaryl, and each of the above groups may optionally be further surrounded by one or more elements selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, oxo groups (=O), -S(O)2C 1-6 Alkyl, -COC 1-6 Alkyl groups are substituted;

[0055] Alternatively, two R atoms connected to two adjacent carbon atomsd The two carbon atoms bonded to it together form a carbon-carbon double bond;

[0056] R 7 R 8 R 10 R 11 R 12 R 13 R 30 R 31 R 32 R 33 R 34 The definition is as described above.

[0057] Preferably, X is CR a Or N; Q is CR b W is CR c ;

[0058] R a and R c One of them is selected from the following group: H, D, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, SF5, OR 7 -COOR 8 -P(O)(R 8 2. NR 10 R 11 -CONR 12 R 13 -N(R) 30 CONR 12 R 13 -S(O)2R 8 -S(O)2NR 12 R 13 -N(R) 30 )S(O)2NR 12 R 13 C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 4-6 membered heterocyclic, phenyl, 5-8 membered heteroaryl, wherein each of the above groups may optionally be further selected by one or more groups selected from halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, oxo groups (=O), -S(O)2C 1-6 Alkyl, -COC 1-6 Alkyl groups are substituted;

[0059] R a and R c Another Rb The atoms bonded to it together form C 4-6 Carbon rings, 4-8 membered heterocycles, benzene rings, naphthalene rings, 5-10 membered heteroaromatic rings, or 8-10 membered fused bicyclic rings;

[0060] Or R a R b R c The atoms bonded to it together form 8-12 member fused bicyclic rings;

[0061] The carbon rings, heterocycles, aromatic rings, heteroaromatic rings, or fused bicyclic rings formed by the above cyclization may optionally be further bonded by 1-5 R groups. d replace;

[0062] Each R d Each is independently selected from the following groups: halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, SF5, OR 7 -COOR 8 -COR 8 -P(O)(R 8 2. SR 9 NR 31 R 32 -CONR 33 R 34 -S(O)2R 8 -S(O)2NR 33 R 34 -N(R) 30 )S(O)2NR 33 R 34 Oxide group (=O), C 3-6 Carbocyclic, 4-10 membered heterocyclic, phenyl, 5-10 membered heteroaryl, each of the above groups may optionally be further surrounded by one or more groups selected from halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, oxo groups (=O), -S(O)2C 1-6 Alkyl, -COC 1-6 Alkyl groups are substituted;

[0063] Alternatively, two R atoms connected to two adjacent carbon atoms d The two carbon atoms bonded to it together form a carbon-carbon double bond;

[0064] More preferably, X is CR a Or N; Q is CR b W is CR c ;

[0065] R a Selected from the following groups: H, D, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, SF5, OR 7 -COOR 8 -P(O)(R 8 2. NR 10 R 11 -CONR 12 R 13 -N(R) 30 CONR 12 R 13 -S(O)2R 8 -S(O)2NR 12 R 13 -N(R) 30 )S(O)2NR 12 R 13 C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 4-6 membered heterocyclic, phenyl, 5-8 membered heteroaryl, wherein each of the above groups may optionally be further selected by one or more groups selected from halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, oxo groups (=O), -S(O)2C 1-6 Alkyl, -COC 1-6 Alkyl groups are substituted;

[0066] R b R c The atoms bonded to it together form C 4-6 Carbon rings, 4-8 membered heterocycles, benzene rings, naphthalene rings, 5-10 membered heteroaromatic rings, 5-6 membered heteroaromatic rings with 5-6 membered partial saturation, 5-6 membered heteroaromatic rings with 5-6 membered partial saturation carbon rings, benzo[5-6] membered partial saturation heterocycles, benzo[5-6] membered partial saturation carbon rings, wherein each of the above groups may optionally be further surrounded by 1-5 R[…]. d replace;

[0067] More preferably, X is CR a Or N; Q is CR b W is CR c ;

[0068] R a Selected from the following groups: H, D, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, SF5, C1-4 Alkoxy, -C 1-4 alkylene hydroxyl, -C 1-4 Alkylene-C 1-4 Alkoxy, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic alkyl group, carboxyl group, -COO-C 1-4 Alkyl, NR 10 R 11 -CONR 12 R 13 -N(R) 30 CONR 12 R 13 -S(O)2(C 1-4 Alkyl group), -S(O)2NR 12 R 13 -N(R) 30 )S(O)2NR 12 R 13 C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, wherein each of the above groups may optionally be further selected by one or more groups selected from halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, oxo groups (=O), -S(O)2C 1-4 Alkyl, -COC 1-4 Alkyl groups are substituted;

[0069] R b R c The atoms bonded to it together form C 4-6 Carbocyclic rings, 4-8 membered heterocycles, benzene rings, 5-10 membered heteroaromatic rings, benzo5-6 membered partially saturated heterocycles, and each of the above groups may optionally be further surrounded by 1-5 R groups. d replace;

[0070] Each R d Each is independently selected from the following groups: halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne, SF5, hydroxyl, C 1-4 Alkoxy, -C 1-4 alkylene hydroxyl, -C 1-4 Alkylene-C 1-4 Alkoxy, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic alkyl group, carboxyl group, -COO-C 1-4 Alkyl, -CO-C 1-4 Alkyl, -P(O)(C 1-4Alkyl)2, -SCF3, NR 31 R 32 -CONR 33 R 34 -S(O)2(C 1-4 Alkyl group), -S(O)2NR 33 R 34 -N(R) 30 )S(O)2NR 33 R 34 Oxide group (=O), C 3-6 Carbocyclic, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, each of the above groups may optionally be further surrounded by one or more groups selected from halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, oxo groups (=O), -S(O)2C 1-4 Alkyl, -COC 1-4 Alkyl groups are substituted;

[0071] Alternatively, two R atoms connected to two adjacent carbon atoms d The two carbon atoms bonded to it together form a carbon-carbon double bond;

[0072] R 10 R 11 R 31 and R 32 Each is independently selected from the following groups: H, C 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-2 Alkyl-4-6-membered heterocyclic group, -C 0-2 Alkylene-OC 3-6 cycloalkyl, -C 0-2 alkylene-O-4-6-membered heterocyclic groups, -S(O)2(C 1-4 alkyl), -CO(C) 1-4 Alkyl groups, wherein each of the above-described groups may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups;

[0073] R 12 R 13 R 33 and R 34 Each is independently selected from the following groups: H, C 1-4 Alkyl, -C 0-2Alkylene-C 3-6 cycloalkyl, -C 0-2 Alkyl-4-6-membered heterocyclic group, -C 0-2 Alkylene-OC 3-6 cycloalkyl, -C 0-2 Alkylene-O-4-6-membered heterocyclic group, wherein each of the above-described groups may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, C 1-6 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, -S(O)2C 1-4 alkyl;

[0074] Each R 30 Each is independently selected from the following groups: H, C 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-2 Alkyl-4-6-membered heterocyclic group, -C 0-2 Alkylene-OC 3-6 cycloalkyl, -C 0-2 Alkylene-O-4-6-membered heterocyclic group, wherein each of the above-described groups may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups.

[0075] In another preferred embodiment, X is CR a Or N; Q is CR b W is CR c ;

[0076] R a Selected from the following groups: H, D, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, -C 1-4 alkylene hydroxyl, -C 1-4 Alkylene-C 1-4 Alkoxy, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic alkyl group, carboxyl group, -COO-C 1-4 Alkyl, NR 10 R 11 -CONR 12 R 13 C 3-6 cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl;

[0077] R b R c The atoms bonded to it together form C 4-6 Carbon rings, 4-8 membered heterocycles, benzene rings, 5-6 membered mono-heteroaromatic rings, 9-10 membered di-heteroaromatic rings, benzo5-6 membered partially saturated heterocycles, and each of the above groups may optionally be further surrounded by 1-5 R groups. d replace;

[0078] Each R d Each is independently selected from the following groups: halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, hydroxyl, C 1-4 Alkoxy, -C 1-4 alkylene hydroxyl, -C 1-4 Alkylene-C 1-4 Alkoxy, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic alkyl group, carboxyl group, -CO-C 1-4 Alkyl, -COO-C 1-4 Alkyl, -P(O)(C 1-4 Alkyl)2, -SCF3, NR 31 R 32 -CONR 33 R 34 -S(O)2(C 1-4 Alkyl), oxo (=O), C 3-6 Carbocyclic, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl;

[0079] R 31 and R 32 Each is independently selected from the following groups: H, C 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-2 Alkyl-4-6-membered heterocyclic group, -C 0-2 Alkylene-OC 3-6 cycloalkyl, -C 0-2 Alkylene-O-4-6-membered heterocyclic group.

[0080] In another preferred embodiment, X is CR a Q is CR b W is CR c ;R a R b R cThe atoms bonded to it together form a fused heterocyclic ring selected from the group consisting of: a 5-7 membered heteroaromatic ring with a 5-7 membered partially saturated heterocycle, a 5-7 membered heteroaromatic ring with a 5-7 membered partially saturated carbon ring, a benzo[5-7] partially saturated heterocycle, and a benzo[5-7] partially saturated carbon ring, wherein the above groups may optionally be further bonded by 1-5 R[…]. d Replace, R d The definition is the same as before.

[0081] In another preferred embodiment, R c Selected from the following groups: H, D, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, SF5, C 1-4 Alkoxy, -C 1-4 alkylene hydroxyl, -C 1-4 Alkylene-C 1-4 Alkoxy, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic alkyl group, carboxyl group, -COO-C 1-4 Alkyl, NR 10 R 11 -CONR 12 R 13 -N(R) 30 CONR 12 R 13 -S(O)2(C 1-4 Alkyl group), -S(O)2NR 12 R 13 -N(R) 30 )S(O)2NR 12 R 13 C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, wherein each of the above groups may optionally be further selected by one or more groups selected from halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, oxo groups (=O), -S(O)2C 1-4 Alkyl, -COC 1-4 Alkyl groups are substituted;

[0082] R b R a The atoms bonded to it together form C 4-6 Carbocyclic rings, 4-8 membered heterocyclic rings, benzene rings, 5-6 membered heteroaromatic rings, and optionally each of the above groups may be further surrounded by 1-5 R groups. d replace;

[0083] Each Rd Each is independently selected from the following groups: halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne, SF5, hydroxyl, C 1-4 Alkoxy, -C 1-4 alkylene hydroxyl, -C 1-4 Alkylene-C 1-4 Alkoxy, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic alkyl group, carboxyl group, -COO-C 1-4 Alkyl, -P(O)(C 1-4 Alkyl)2, -SCF3, NR 31 R 32 -CONR 33 R 34 -S(O)2(C 1-4 Alkyl group), -S(O)2NR 33 R 34 -N(R) 30 )S(O)2NR 33 R 34 Oxide group (=O), C 3-6 Carbocyclic, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, each of the above groups may optionally be further surrounded by one or more groups selected from halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, oxo groups (=O), -S(O)2C 1-4 Alkyl, -COC 1-4 Alkyl groups are substituted;

[0084] Alternatively, two R atoms connected to two adjacent carbon atoms d The two carbon atoms connected to it together form a carbon-carbon double bond.

[0085] In another preferred embodiment, each R 1 Independently selected from the following groups: H, halogen, cyano, C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, SF5, OR 7 -COOR 8 -P(O)(R 8 2. SR 9 NR 16 R 17 -CONR 18 R 19 -N(R) 30 CONR 18 R19 -N(R) 30 COOR 8 -S(O)2R 8 -S(O)2NR 18 R 19 -N(R) 30 )S(O)2NR 18 R 19 , O group (=O), -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 Alkylene-4-6-membered heterocyclic groups, wherein each of the above-mentioned groups may optionally be further surrounded by 1, 2, 3 or 4 R groups. i replace;

[0086] R 7 R 8 R 9 R 16 R 17 R 18 R 19 R 30 R i The definition is as described above.

[0087] Preferably, each R 1 Each is independently selected from the following groups: H, halogen, cyano, C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, SF5, OR 7 -COOR 8 -P(O)(R 8 2. SR 9 NR 16 R 17 -CONR 18 R 19 -N(R) 30 CONR 18 R 19 -N(R) 30 COOR 8 -S(O)2R 8 -S(O)2NR 18 R 19 -N(R) 30 )S(O)2NR 18 R 19 , O group (=O), -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-2 Alkylene-4-6-membered heterocyclic groups, wherein each of the above-mentioned groups may optionally be further surrounded by 1, 2, 3 or 4 R groups. ireplace.

[0088] More preferably, each R 1 Each is independently selected from the following groups: H, halogen, cyano, C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne, SF5, hydroxyl, C 1-4 Alkoxy, -C 1-4 alkylene hydroxyl, -C 1-4 Alkylene-C 1-4 Alkoxy, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic alkyl group, carboxyl group, -COO-C 1-4 Alkyl, -P(O)(C 1-4 Alkyl)2, -SCF3, NR 16 R 17 -CONR 18 R 19 -N(R) 30 CONR 18 R 19 -N(R) 30 )C(O)-C 1-4 Alkoxy, -S(O)2(C 1-4 Alkyl group), -S(O)2NR 18 R 19 -N(R) 30 )S(O)2NR 18 R 19 , O group (=O), -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-2 Alkylene-4-6-membered heterocyclic groups, wherein each of the above-mentioned groups may optionally be further substituted with 1, 2, 3 or 4 halogens;

[0089] R 16 and R 17 Each is independently selected from the following groups: H, C 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-2 Alkyl-4-6-membered heterocyclic group, -C 0-2 Alkylene-OC 3-6 cycloalkyl, -C 0-2 alkylene-O-4-6-membered heterocyclic groups, -S(O)2(C 1-4 alkyl), -CO(C) 1-4 Alkyl groups, wherein each of the above-described groups may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups;

[0090] R 18 and R 19 Each is independently selected from the following groups: H, C 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-2 Alkyl-4-6-membered heterocyclic group, -C 0-2 Alkylene-OC 3-6 cycloalkyl, -C 0-2 Alkylene-O-4-6-membered heterocyclic group, wherein each of the above-described groups may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, C 1-6 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, -S(O)2C 1-4 alkyl;

[0091] Each R 30 Each is independently selected from the following groups: H, C 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-2 Alkyl-4-6-membered heterocyclic group, -C 0-2 Alkylene-OC 3-6 cycloalkyl, -C 0-2 Alkylene-O-4-6-membered heterocyclic group, wherein each of the above-described groups may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups.

[0092] More preferably, each R 1 Each is independently selected from the following groups: H, halogen, cyano, C. 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 alkenyl, C 2-8 Alkyne, hydroxyl, SF5, -COOR 8 -P(O)(R 8 2. SR 9 NR 16 R 17 -CONR 18 R 19 -N(R) 30 CONR 18 R19 -N(R) 30 COOR 8 -S(O)2R 8 -S(O)2NR 18 R 19 -N(R) 30 )S(O)2NR 18 R 19 , O group (=O), -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4-8-membered heterocyclic groups, wherein each of the above-mentioned groups may optionally be further surrounded by 1, 2, 3 or 4 R groups. i replace;

[0093] Each R i Independently selected from the following groups: halogen, cyano, hydroxyl, oxo (=O), C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, -S(O)2C 1-4 Alkyl, -COC 1-4 alkyl;

[0094] Each R 8 Independently selected from the following groups: H, C 1-4 alkyl;

[0095] Each R 9 Select independently from the following group: C 1-6 Alkyl, C 1-4 Halogenated alkyl groups;

[0096] Each R 16 Each R 17 Each is independently selected from the following groups: H, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-10 cycloalkyl, -C 0-4 Alkyl-4-10 heterocyclic group, -C 0-4 Alkylene-OC 3-10 cycloalkyl, -C 0-4 alkylene-O-4-10-membered heterocyclic group;

[0097] Each R 18 Each R 19 Each is independently selected from the following groups: H, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-10 cycloalkyl, -C 0-4 Alkyl-4-10 heterocyclic group, -C 0-4Alkylene-OC 3-10 cycloalkyl, -C 0-4 Alkylene-O-4-10-membered heterocyclic group, wherein each of the above-described groups may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O)2C 1-6 alkyl;

[0098] Each R 30 Each is independently selected from the following groups: H, C 1-4 alkyl.

[0099] In another preferred embodiment, ring A is selected from the following group: C 6-10 Aryl, containing 1-4 5-10 membered heteroaryl rings selected from N, O or S heteroatoms;

[0100] Preferably, ring A is selected from the group consisting of: benzene rings, 5-6 membered heteroaromatic rings containing 1-4 heteroatoms optionally selected from N, O or S;

[0101] More preferably, ring A is selected from the group consisting of: benzene ring, furan, pyrrole, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazolium, pyridine, pyrimidine, pyridazine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetraazine;

[0102] More preferably, ring A is selected from the group consisting of: benzene ring, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazolium, pyridine, pyrimidine, pyridazine, and pyrazine.

[0103] More preferably, ring A is selected from the group consisting of: benzene ring, imidazole, pyrazole, pyridine, pyrimidine, pyridazine, and pyrazine.

[0104] In another preferred embodiment, Z is CR e Or N;

[0105] R e Selected from the following groups: H, D, halogen, cyano, hydroxyl, NR 14 R 15 C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups;

[0106] Each R 5 and each R 6Each is independently selected from the following groups: H, D, halogens, C 1-4 Alkyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-2 Alkyl-4-6-membered heterocyclic group, wherein the above-described groups may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, -S(O)2C 1-4 alkyl;

[0107] Or, R e With an R 5 And the two carbon atoms they are attached to together form a carbon-carbon double bond;

[0108] Or, two Rs 5 All atoms bonded to it further form a 3-6 membered carbon ring or a 4-6 membered heterocycle, which may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, =O, -COC 1-4 Alkyl group, -S(O)2C 1-4 alkyl;

[0109] Or, two Rs 6 All atoms bonded to it further form a 3-6 membered carbon ring or a 4-6 membered heterocycle, which may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, =O, -COC 1-4 Alkyl group, -S(O)2C 1-4 alkyl;

[0110] Or, any R 5 Any R 6 The atoms bonded to it together form a 3-6 membered carbon ring or a 4-6 membered heterocycle, which may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4Halogenated alkoxy groups, =O, -COC 1-4 Alkyl group, -S(O)2C 1-4 alkyl;

[0111] Preferably, Z is N.

[0112] In another preferred embodiment, Z is CR e ;

[0113] R e Selected from the following groups: H, D, halogen, cyano, hydroxyl, NR 14 R 15 C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups.

[0114] In another preferred embodiment, Z is CR e And R e With an R 5 And the two carbon atoms they are on together form a carbon-carbon double bond.

[0115] In another preferred embodiment, B is Furthermore, B is connected to a nitrogen atom through ring C and Y is connected to a carbon atom, or Y is connected to a nitrogen atom and ring C is connected to a carbon atom.

[0116] The C ring is selected from the following group: 4-6 member monocyclic carbon ring, 5-8 member bicyclic carbon ring, 4-6 member monocyclic heterocyclic ring, and 5-8 member bicyclic heterocyclic ring;

[0117] Y is selected from the following group: -C(R) 4a )2-、-NR 4b -, -O-, -S-, -S(O)-, -S(O)2-;

[0118] Each R 4 Each element is independently selected from the following groups: H, D, halogen, hydroxyl, C. 1-4 Alkyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-4 Alkyl-4-6-membered heterocyclic group, oxo group (=O), the above groups may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, -S(O)2C 1-4 alkyl;

[0119] Alternatively, two R atoms connected to two adjacent carbon atoms 4 The two carbon atoms bonded to it together form a carbon-carbon double bond;

[0120] Each R 4a Each is independently selected from the following groups: H, D, halogens, C 1-6 Alkyl, -C 1-4 Hydroxyalkyl, -C 1-4 Alkylene-C 1-4 Alkoxy, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 Alkylene-4-6-membered heterocyclic groups, wherein the groups described above may optionally be further substituted with one or more halogens;

[0121] Or, two Rs 4a Together with the carbon atoms attached to it, they form C=O;

[0122] Or, two Rs 4a Together with the carbon atom attached thereto, they form a 3-6 membered carbon ring or a 4-6 membered heterocycle, which may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, =O, -COC 1-4 Alkyl group, -S(O)2C 1-4 alkyl;

[0123] R 4b Selected from the following groups: H, C 1-4 Alkyl, -C 2-4 Hydroxyalkyl, -C 2-4 Alkylene-C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-2 Alkylene-4-6-membered heterocyclic groups, wherein the groups described above may optionally be further substituted with one or more halogens;

[0124] The definition of s is as described above.

[0125] Preferably, the ring C is selected from the group consisting of: cyclobutane, cyclopentane, cyclohexane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[4.1.0]heptane, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, spiro[3.3]heptane, bicyclo[2.2.2]octane, spiro[4.3]octane, and heterocyclic systems obtained by substituting an atom at any possible position of the ring system in each of the above-mentioned ring systems with O or N; Y is selected from the group consisting of: -C(R 4a )2-、-NR 4b -, -O-, -S-, -S(O)-, -S(O)2-;

[0126] Each R 4 Each element is independently selected from the following groups: H, D, halogen, hydroxyl, C. 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 alkylene hydroxyl, -C 1-4 alkylene cyano, -C 1-4 Alkane-C 1-4 Alkoxy, oxo (=O), and the above-mentioned groups may optionally be further substituted by one or more halogens;

[0127] Alternatively, two R atoms connected to two adjacent carbon atoms 4 The two carbon atoms bonded to it together form a carbon-carbon double bond;

[0128] Each R 4a Each is independently selected from the following groups: H, D, halogens, C 1-4 Alkyl, -C 1-4 Hydroxyalkyl, -C 1-4 Alkylene-C 1-4 Alkoxy groups, the above-described groups may optionally be further substituted with one or more halogens;

[0129] Or, two Rs 4a Together with the carbon atoms attached to it, they form C=O;

[0130] Or, two Rs 4a Together with the carbon atom attached thereto, they form a 3-4 membered carbon ring or a 4-6 membered heterocycle, which may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, =O, -COC 1-2 Alkyl group, -S(O)2C 1-2 alkyl;

[0131] R 4bSelected from the following groups: H, C 1-4 Alkyl, -C 2-4 Hydroxyalkyl, -C 2-4 Alkylene-C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-2 Alkylene-4-6-membered heterocyclic groups, wherein the groups described above may optionally be further substituted with one or more halogens;

[0132] s is selected from 0, 1, 2, 3 or 4.

[0133] In another preferred embodiment, the compound has the structure shown in formula (II) or formula (III).

[0134] Where m and n are each independently 0, 1, 2, 3, 4 or 5;

[0135] Each R 2 Each is independently selected from the following groups: H, halogen, cyano, C. 1-8 Alkyl, C 2-8 alkenyl, C 2-8 Alkyne group, SF5, OR 7 -COOR 8 -P(O)(R 8 2. SR 9 NR 16 R 17 -S(O)2R 8 -S(O)2NR 18 R 19 -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4-8-membered heterocyclic groups, wherein each of the above-mentioned groups may optionally be further surrounded by 1, 2, 3 or 4 R groups. i replace;

[0136] Ring D is selected from the following group: C 4-8 Carbon rings, 4-8 membered heterocycles, C 6-10 Aromatic rings, 5-10 member heteroaryl rings, or 8-12 member densely packed bicyclic rings;

[0137] A, B, Z, R 5 R 6 R 18 R 19 R a R d and R i The definition is as described above.

[0138] In another preferred embodiment, the compound has the following structure:

[0139] In the formula, ring C is a 4-5 membered carbon ring or a 4-6 membered heterocycle, and the heterocycle has 1-2 heteroatoms selected from the group consisting of N and O;

[0140] Y is -C(R) 4a )2-、-NR 4b -, -O-, or -S-, where each R 4a Each is independently selected from the following groups: H, D, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl; or, two Rs 4a Together with the carbon atoms attached to it, they form a 3-5 membered carbon ring; R 4b For H or C 1-6 Alkyl groups; other substituents are defined as above.

[0141] In another preferred embodiment, the compound has the structure shown in formula (IV) or formula (V).

[0142] Where m1 is 0, 1, or 2; n1 is 0, 1, 2, 3, 4, or 5;

[0143] Each R 2a R 3a Each is independently selected from the following groups: H, halogen, cyano, C. 1-8 Alkyl, C 2-8 alkenyl, C 2-8 Alkyne group, SF5, OR 7 -COOR 8 -P(O)(R 8 2. SR 9 NR 16 R 17 -S(O)2R 8 -S(O)2NR 18 R 19 -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4-8-membered heterocyclic groups, wherein each of the above-mentioned groups may optionally be further surrounded by 1, 2, 3 or 4 R groups. i replace;

[0144] Ring D is selected from the following group: C 4-8 Carbon rings, 4-8 membered heterocycles, C 6-10 Aromatic rings, 5-10 member heteroaryl rings, or 8-12 member densely packed bicyclic rings;

[0145] B, Z, R 5 R 6 R18 R 19 R a R d and R i The definition is as described above.

[0146] In another preferred embodiment, the compound has the following structure:

[0147] In the formula, ring C is a 4-5 membered carbon ring or a 4-6 membered heterocycle, and the heterocycle has 1-2 heteroatoms selected from the group consisting of N and O;

[0148] Y is -C(R) 4a )2-、-NR 4b -, -O-, or -S-, where each R 4a Each is independently selected from the following groups: H, D, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl; or, two Rs 4a Together with the carbon atoms attached to it, they form a 3-5 membered carbon ring; R 4b For H or C 1-6 alkyl;

[0149] Other substituents are defined as before.

[0150] In another preferred embodiment, Selected from: s is 0, 1, 2 or 3, and R is... 4 Independently selected from: halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 alkoxy- or hydroxy-substituted C 1-4 Alkyl, C 1-4 alkoxy-substituted C 1-4 Alkyl group, =O.

[0151] In another preferred embodiment, where possible, the groups attached to ring C can be either cis or trans in arrangement.

[0152] In another preferred embodiment, when ring C is attached to a nitrogen atom, the Y atom attached to ring C and the nitrogen atom are in cis or trans configuration.

[0153] In another preferred embodiment, the compound is selected from the group consisting of:

[0154] A second aspect of the present invention provides a pharmaceutical composition comprising:

[0155] (i) the compounds, stereoisomers, tautomers, deuterated derivatives, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as described in the first aspect of the invention; and

[0156] (ii) Pharmaceutically acceptable carriers, excipients or excipients.

[0157] A third aspect of the present invention provides the use of a compound, stereoisomer, tautomer, deuterated form, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug as described in the first aspect of the present invention, or a pharmaceutical composition as described in the second aspect of the present invention, characterized in that it is used to prepare a treatment for and / or prevention of diseases related to PARP1.

[0158] Preferably, the PARP1-related disease is cancer;

[0159] More preferably, the PARP1-related diseases are selected from the group consisting of: breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer, lung cancer, kidney cancer, liver cancer, cervical cancer, endometrial cancer, myeloma, leukemia, lymphoma, acoustic neuroma, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, bronchial cancer, sarcoma, chordoma, choriocarcinoma, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, hemangioendothelioma, ependymoma, epithelial carcinoma, esophageal cancer, and primary hemangioblastoma. Thrombocytosis, Ewing's tumor, testicular cancer, glioma, heavy chain disease, angioblastoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, neuroblastoma, NUT midline carcinoma, glioma, bone cancer, nasopharyngeal carcinoma, oral cancer, thyroid cancer, pineal tumor, polycythemia vera, retinoblastoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, synovial malformation, sweat gland carcinoma, Waldenström macroglobulinemia, Wilms' tumor;

[0160] More preferably, the cancer is selected from the group consisting of: breast cancer, ovarian cancer, endometrial cancer, prostate cancer, gastric cancer, colorectal cancer, and lung cancer.

[0161] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0162] Through long-term and in-depth research and extensive screening, the inventors have for the first time developed a compound of formula (I), its stereoisomers, tautomers, deuterated derivatives, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs. The compound of this invention is a selective PARP1 inhibitor and can be used to treat and / or prevent PARP1-related diseases. Based on this, the inventors completed this invention.

[0163] the term

[0164] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed-ended. In other words, the terms also include “consistently made of” or “made of”.

[0165] As used herein, the term "alkyl" refers to a monovalent, straight-chain or branched saturated hydrocarbon group consisting of carbon and hydrogen atoms, for example, "C 1-6 "Alkyl" means an alkyl group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl. In this application, alkyl is also intended to include deuterated alkyl groups, examples of which include, but are not limited to, CD3, CD2CD3, and CD2CD2CD3.

[0166] As used herein, the term "alkylene" refers to the group obtained by removing a hydrogen atom from an alkyl group as described above, such as methylene (-CH2-), ethylene (-CH2CH2-), etc.

[0167] As used herein, the term "alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon group consisting of carbon and hydrogen atoms and having at least one double bond, such as "C 2-6 "Alkenyl" refers to an alkenyl group having 2 to 6 (e.g., 2, 3, 4, 5, or 6) carbon atoms. Examples of alkenyl groups include, but are not limited to: vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl.

[0168] As used herein, the term "alkynyl" refers to a straight-chain or branched unsaturated hydrocarbon group consisting of carbon and hydrogen atoms and having at least one triple bond. For example, "C 2-6 "Alynyl" refers to an alkynyl group having 2 to 6 (e.g., 2, 3, 4, 5, or 6) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl.

[0169] As used herein, the term "carbocyclic" refers to a saturated or partially saturated carbocyclic system composed of carbon and hydrogen atoms, such as a monocyclic, bicyclic, or tricyclic system, wherein the ring structure as a whole is not aromatic but may contain one or more unsaturated structures. The ring may be further substituted by one or more substituents. When two or more rings are present in the carbocyclic group, fused rings, bridged rings, spirocyclic rings, or any combination thereof may be formed between the rings. A "carbocyclic group" is a group formed by the loss of a hydrogen atom from a ring in the corresponding "carbocyclic" system.

[0170] As used herein, the term "cycloalkyl" refers to a monovalent saturated carbocyclic group consisting of carbon and hydrogen atoms, such as "C". 3-8 "Cycloalkyl" refers to a cycloalkyl group containing 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8) carbon atoms, preferably C4. 3-6 Cycloalkyl groups. Cycloalkyl groups can be monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or similar groups, or bicyclic, such as fused rings, bridged rings or spirocyclic rings.

[0171] As used herein, the term "cycloalkenyl" refers to an unsaturated cyclic hydrocarbon group having at least one double bond, such as "C". 3-8 "Cycloalkenyl refers to a cycloalkenyl group having 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8) carbon atoms, preferably C." 3-6 Cycloalkenyl groups. Examples of cycloalkenyl groups include, but are not limited to: cyclopentenyl, cyclohexenyl, cyclohexadienyl, etc.

[0172] As used herein, the term "alkoxy" refers to the formula -OR z Group, wherein R z R is an alkyl group as defined in this paper. z ' is an alkylene group. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, isopropoxy, tert-butoxy, etc.

[0173] As used herein, the term "hydroxyalkyl" refers to an alkyl group containing one or more hydroxyl groups, and the definition of an alkyl group is as described above. Examples of hydroxyalkyl groups include, but are not limited to: -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH(OH)CH2OH, -CH2CH(OH)CH3, etc.

[0174] As used herein, "halogen" refers to halogens and their isotopes, including but not limited to F, 18 F, 32 Cl, Br, I.

[0175] As used in this article, the term "nitro" refers to -NO2.

[0176] As used in this article, the term "cyano" refers to -CN.

[0177] As used in this article, the term "amino" refers to -NH2.

[0178] As used in this article, the term "carboxyl group" refers to -COOH.

[0179] As used in this article, the term "oxo" refers to the =O portion.

[0180] As used herein, the term "ester group" refers to -COOR y , where R y It can be independently selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclic groups. Examples of ester groups include, but are not limited to: -COOCH3, -COOCH2CH3, -COOCH2CH2CH3, -COOCH2CH(CH3)2, etc.

[0181] As used herein, the term "amide group" refers to -CONR x R x ', where R x and R x It can be independently selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclic. R x and R x They can be the same or different. Examples of amide groups include, but are not limited to: -CONH2, -CONHCH3, -CON(CH3)2, etc.

[0182] As used herein, the term "haloalkyl" refers to a group obtained by substituting one or more hydrogen atoms in an alkyl group as described above with the same or different halogens. Specifically, "haloC" refers to a group obtained by substituting one or more hydrogen atoms in an alkyl group with the same or different halogens. 1-6 "alkyl" is preferably a halogenated C 1-4 Alkyl groups, examples of which include, but are not limited to: -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl groups (e.g., -CF3-, -CF2CF3), etc.

[0183] As used herein, the term "heterocyclic" refers to a fully or partially saturated monocyclic, bicyclic, or polycyclic cyclic system containing one or more heteroatoms selected from N, S, or O. For example, "4-7 membered heterocycle" refers to a cyclic system having 4-7 (e.g., 4, 5, 6, or 7) ring atoms. Nitrogen or sulfur atoms may be oxidized or quaternized. A "heterocyclic group" is a group formed by the loss of a hydrogen atom from a ring in a corresponding "heterocyclic" system. Heterocyclic groups can be attached to any heteroatom or carbon residue in a ring or cyclic molecule. Monocyclic heterocyclic groups include, but are not limited to: azacyclic butyl, pyrrolyl, oxacyclic butyl, pyrazolinyl, imidazolinyl, imidazoalkyl, oxazolinyl, isoxazolinyl, thiazoalkyl, isothiazolinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylyl, hexahydroachenginyl, 4-piperidinoneyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxane, and tetrahydro-1,1-dioxothiophene, etc. Polycyclic heterocyclic groups include, but are not limited to, spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0184] As used herein, the term "aromatic ring" refers to aromatic cyclic hydrocarbon systems (including monocyclic, bicyclic, or polycyclic systems), such as "C 6-12 An "aromatic ring" refers to an aromatic cyclic hydrocarbon system having 6 to 12 (6, 7, 8, 9, 10, 11, or 12) ring carbon atoms. The term "aryl" is a group formed by losing a hydrogen atom from the corresponding "aromatic ring" system. Examples of aryl groups (especially monocyclic and bicyclic groups) include, but are not limited to, phenyl, naphthyl, and anthracene.

[0185] As used herein, the term "heteroaromatic ring" refers to an aromatic cyclic system (including monocyclic, bicyclic, or polycyclic systems) whose ring skeleton contains one or more heteroatoms selected from N, S, or O. For example, "5-12 membered heteroaromatic ring" refers to an aromatic monocyclic, bicyclic, or tricyclic system having 5 to 12 (5, 6, 7, 8, 9, 10, 11, or 12) ring atoms. The term "heteroaryl" is a group formed by losing a hydrogen atom from a corresponding "heteroaromatic ring" system. Examples of heteroaryl groups include, but are not limited to: imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thiophene, furanyl, pyranyl, pyridinyl, pyrroleyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophene, benzothiaranyl, benzimidazole, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzopyranyl, indoleyl, isoindoleyl, triazolyl, triazinyl, quinoxolinyl, purine, quinazolinyl, quinazinyl, naphthidyl, pteridinyl, carbazoleyl, and azazolyl. basalt, diazoxide acridine group, etc.

[0186] As used in this article, the term "multi-substitution" refers to a substance that includes two or more substitutions.

[0187] As used herein, the term "fluorinated" refers to the substitution of one or more hydrogen atoms in a group with fluorine, for example, 1, 2, 3, 4, 5, or 6 hydrogen atoms being substituted with fluorine.

[0188] As used herein, “deuterated” means that one or more hydrogen atoms in a compound or group are replaced by deuterium. Deuteration can be monosubstituted, disubstituted, polysubstituted, or total substituted. The terms “one or more deuterated” and “one or more deuterated” are used interchangeably.

[0189] As used herein, the term "deuterated compound" refers to a compound in which one or more hydrogen atoms (H) are replaced by a deuterium atom (D).

[0190] As used herein, the term "fused bicyclic" refers to a bicyclic system formed by the fusion of two rings, with the ring skeleton containing 1, 2, 3, 4, or 5 heteroatoms selected from N, S, or O; preferably, one ring is a benzene ring or a 5-7 membered heteroaromatic ring, and the other ring is a partially saturated 5-8 membered carbon ring or a partially saturated 5-8 membered heterocycle, but the fused bicyclic system as a whole is not aromatic. The term "fused bicyclic group" is a group formed by the loss of a hydrogen atom from a corresponding "fused bicyclic" system. Fused bicyclic systems can be linked to other groups at any possible position. Examples of fused bicyclic systems include, but are not limited to, for example: wait.

[0191] When a group loses one hydrogen atom, it becomes a subunit of the corresponding group, and it is a divalent group. For example, an alkyl group loses one hydrogen atom to become an alkylene group (e.g., methylene, ethylene, propylene, isopropylene). ), butylide (such as) ), pentylene (e.g.) ), hexyl (such as) ), subheptagen (such as ) etc.; cycloalkyl corresponds to cyclohexane (e.g.: (etc.); heterocyclic groups correspond to subheterocyclic groups (e.g.: Alkoxy groups correspond to alkoxy groups (e.g., -CH2O-, -CH2CH2O-, -OCH2CH2CH2-), and heteroalkyl groups correspond to heteroalkyl groups (e.g., -CH2-O-CH2CH2-, -CH2-O-(CH2)2CH2-, -CH2CH2-O-CH2CH2-, -CH2-O-CH2CH2CH2-, -CH2-S-CH2CH2-, -CH2-S-(CH2)2CH2-, -CH2CH2-S-CH2CH2-, -CH2-S-CH2CH2CH2-, -CH2-NH-CH2CH2-, -CH2-NH-(CH2)2CH2-, -CH2CH2-NH-CH2CH2-, -CH2-NH-CH2CH2CH2-, etc.).

[0192] In this invention, the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, unless otherwise specified, include substituted alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups. The substituents include, but are not limited to, halogen, hydroxyl, cyano, acyl, sulfonyl, ester, sulfinyl, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, acyl, and ester groups.

[0193] As used herein, the term "substitution" refers to the replacement of one or more hydrogen atoms on a particular group by a particular substituent. The particular substituent is either the substituent described accordingly above or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a particular group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible.

[0194] Unless otherwise specified, the groups described in this invention may be substituted with substituents selected from the group consisting of: D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-12 membered heterocyclic groups, C3-C6 alkyl, ... 12 cycloalkyl, 5-10 heteroaryl and C6-C 10 Aryl, -S(O)2(C 1-6 Alkyl group), -CONH2, -CONH(C 1-6 Alkyl), -CON(C) 1-6 Alkyl)2.

[0195] In this document, “optionally” means that the event or condition described below may, but is not required to, occur, and the description includes both the possibility that the event or condition occurs and the possibility that the event or condition does not occur.

[0196] In this article, the term "multiple" refers to 2, 3, 4, 5, 6, or a positive integer greater than 6.

[0197] Active ingredients

[0198] As used herein, “compound of the present invention” means a compound of formula (I), and also includes its stereoisomers, its optical isomers, its conformational isomers, its tautomers, its pharmaceutically acceptable salts, its crystal forms, its isotopic derivatives, its prodrugs, its metabolites, its solvates or hydrates thereof.

[0199] Unless otherwise specified, the structural formulas described in this invention are intended to include all stereoisomers (such as cis-trans isomers, enantiomers, diastereomers, and conformational isomers): R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, cis-trans isomers of cycloalkanes, etc. Therefore, any single stereochemical isomer of the compounds of this invention, or a mixture of its enantiomers, diastereomers, or conformational isomers, is within the scope of this invention.

[0200] The compounds of this invention may contain cis-trans isomers, one or more chiral carbon atoms, and thus can produce cis-trans isomers, enantiomers, diastereomers, and other combinations of stereoisomers. Cis-trans isomerism refers to the diastereomeric phenomenon in which different functional groups in a compound molecule are arranged differently in space due to a restrictive factor that limits free rotation. This restrictive factor is generally caused by non-rotating functional groups in the structure of organic compounds, such as C=C double bonds, C=N double bonds, C=S double bonds, N=N double bonds, heterocycles, or cycloalkanes. Organic molecules containing such isomers, such as alkenes, azo compounds, and cycloalkanes, are considered cis-trans isomers. Cis refers to the same ligands being in adjacent positions, generally denoted by "cis" or "cis-"; trans refers to the same ligands being in diagonal positions, generally denoted by "trans" or "trans-". Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. This invention aims to include all possible isomers, their racemic and optically pure forms. The compounds of this invention can be prepared using racemic, cis-trans, diastereomers, or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0201] To design the synthesis of specific enantiomers of the compounds of this invention, it can be prepared asymmetrically or derivatized with a chiral cofactor. The resulting stereomixture is then separated, and the chiral cofactor is removed to obtain the pure enantiomer. If the molecule contains a cis-trans isomer center, it can be purified by column chromatography (normal-phase silica gel column or reverse-phase high-performance liquid chromatography) to obtain the pure cis or trans product. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed with a suitable optically active acid or base to form a diastereomer salt, which is then separated by conventional methods such as separation crystallization or chromatography to obtain the pure enantiomer.

[0202] This invention also includes isotopically labeled compounds (i.e., isotopic derivatives), equivalent to the original compounds disclosed herein. However, it is common practice to see one or more atoms replaced by atoms with different atomic weights or mass numbers. Examples of isotopes in the isotopic derivatives of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, respectively as follows: 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S,18 F and 36 Cl. Isotope derivatives of the compounds of this invention are all within the scope of protection of this invention. In this document, 3 H-labeled compounds and 14 C-labeled compounds are useful in tissue distribution experiments of drugs and substrates. Tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) Labeled compounds are relatively easy to prepare and detect, making them the preferred choice among isotopes. Furthermore, heavier isotope substitutions, such as deuterium, are also possible. 2 H, due to its excellent metabolic stability, offers advantages in certain therapies, such as increasing half-life or reducing dosage in vivo, and therefore may be preferred in some cases. Isotopically labeled compounds can be prepared using general methods, by replacing the non-isotopic reagent with an readily available isotopically labeled reagent, according to the scheme disclosed in the examples.

[0203] As used herein, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0204] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain 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, propionates, hexanoates, octanoates, decanoates, undecenoates, glycolates, gluconates, lactates, sebates, adipates, glutarate, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartate, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbic acid salts, salicylates, 4-aminosalicylic acid salts, and naphthalene disulfonates. These salts can be prepared using methods known in this field.

[0205] "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, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, 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, polyamine resins, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

[0206] Metabolites of the compound represented by formula (I) and its pharmaceutically acceptable salts, as well as prodrugs that can be converted in vivo into the compound represented by formula (I) and its pharmaceutically acceptable salts, are also included within the scope of protection of this invention.

[0207] As used herein, the term "solvent" refers to a complex of a compound of formula (I) coordinated with a solvent molecule in a specific ratio.

[0208] As used herein, the term "hydrate" refers to a complex of the compound represented by formula (I) coordinated with water molecules in a specific ratio.

[0209] As described herein, the compounds of the present invention can be substituted with any number of substituents or functional groups to broaden their scope. Generally, the term "substitution" refers to replacing a hydrogen radical with a substituent of a specified structure. When multiple positions in a particular structure are substituted by multiple specific substituents, each position of the substituent can be the same or different. The term "substitution" as used herein includes all permissible organic group substitutions. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic groups. As described herein, heteroatomic nitrogen may be supplemented with a hydrogen substituent or any permissible organic group described above to complete its valence state. Furthermore, the present invention is not intended to limit permissible substituted organic groups in any way. The present invention considers the combination of substituents and variable groups to be beneficial in the treatment of diseases in the form of stable compounds. The term "stable" here means having a stable compound that, when tested over a sufficiently long period, maintains sufficient integrity of the compound structure, preferably remaining effective for a sufficiently long period, and is used herein for the purposes described above.

[0210] Pharmaceutical Compositions and Administration

[0211] Because the compounds of this invention can inhibit poly-ADP ribotransferase 1 (PARP1) and are used to treat cancers such as breast cancer and ovarian cancer, the compounds of this invention, their stereoisomers, their optical isomers, their pharmaceutically acceptable salts, their crystal forms, their isotopic derivatives, their prodrugs, their metabolites, their solvates or hydrates thereof, and pharmaceutical compositions containing the compounds of this invention as the main active ingredient can be used to prevent and / or treat (stabilize, alleviate or cure) PARP1-related diseases (such as breast cancer, ovarian cancer, etc.).

[0212] The pharmaceutical compositions of the present invention comprise the compound of the present invention within a safe and effective range and a pharmaceutically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0213] "Pharmaceutically acceptable carriers" refer to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0214] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include, but are not limited to, oral administration and parenteral administration (intravenous, intramuscular, or subcutaneous).

[0215] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0216] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0217] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0218] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0219] In addition to the active ingredient, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0220] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0221] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as needed.

[0222] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0223] When administered in combination, the pharmaceutical composition further comprises one or more (two, three, four, or more) other pharmaceutically acceptable compounds. One or more (two, three, four, or more) of these other pharmaceutically acceptable compounds may be used simultaneously, separately, or sequentially with the compounds of the present invention for the prevention and / or treatment of PARP1-related diseases.

[0224] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to the mammal (such as a human) requiring treatment. The dosage at the time of administration is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1-2000 mg, preferably 20-500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0225] The main advantages of this invention are:

[0226] The compounds of this invention exhibit very strong DNA-trapping activity against PAPR1, but weaker DNA-trapping activity against PAPR2. Their selectivity is superior to existing clinical competitors, making them a highly specific PAPR1 selective inhibitor. They can more effectively avoid the potential toxic side effects caused by off-target inhibition of PAPR2 and have good development potential.

[0227] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, were generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0228] In the following embodiments, the characterization methods used are as described below.

[0229] 1H NMR spectrum 1 H NMR):

[0230] Nuclear magnetic resonance spectra of reaction products and intermediates ( 1 The 1H NMR spectrum was obtained using a Bruker AVANCE III HD 400 / 500 NMR spectrometer. Sample preparation involved completely dissolving an appropriate amount of sample in approximately 0.5 mL of deuterated solvent in a clean, dry glass NMR tube. Most compounds exhibit good solubility in DMSO-d6, making it the preferred deuterated solvent. However, it tends to solidify at lower room temperatures, requiring thawing with a blower before sample loading. Other suitable deuterated reagents, such as CDCl3 and CD3OD, can be selected depending on the testing requirements. Tetramethylsilane (TMS) was used as an internal standard at room temperature, with a chemical shift of 0 ppm.

[0231] Preparation of intermediates

[0232] Preparation of Intermediate 1: 6-Fluoro-N-methyl-5-(piperazin-1-yl)methylpyridine amide

[0233] Step 1: Tert-butylpiperazine-1-carboxylic acid ester (1.02 g, 5.38 mmol), methyl 5-bromo-6-fluoromethylpyridinium ester (1.07 g, 4.49 mmol), cesium carbonate (3.73 g, 11.22 mmol), and methanesulfonate (2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (229.75 mg, 269.21 μmol) were added to a reaction flask. The system was purged with nitrogen three times, and then 1,4-dioxane (20 mL) was added. The mixture was heated to 80 °C and stirred for 16 hours. After cooling to room temperature, the reaction solution was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, filtered, and the crude product was purified by normal phase column chromatography after concentration to obtain tert-butyl 4-(2-fluoro-6-(methyl ester <methoxycarbonyl>)pyridin-3-yl)piperazine-1-carboxylate (1.24 g, yield: 81.44%).

[0234] Step 2: 1.23 g (3.62 mmol) of tert-butyl 4-(2-fluoro-6-(methyl ester <methoxycarbonyl>)pyridin-3-yl)piperazine-1-carboxylic acid ester was dissolved in 10 mL (27%) of methylamine in ethanol and stirred at room temperature for 5.5 hours. The reaction solution was concentrated and purified by normal-phase column chromatography to obtain 1.1 g (yield: 89.69%) of tert-butyl 4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylic acid ester.

[0235] Step 3: Add a 1,4-dioxane solution (4M, 1 mL) of hydrochloric acid to a 2 mL solution of tert-butyl-4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylic acid ester (200 mg, 591.05 μmol). After stirring the reaction solution at room temperature for 0.5 hours, concentrate to obtain 6-fluoro-N-methyl-5-(piperazine-1-yl)methylpyridineamide hydrochloride (210 mg).

[0236] Intermediate 1a can be prepared by selecting appropriate raw materials by referring to the synthesis method of intermediate 1, and its structure is shown in Table 1.

[0237] Table 1. Structural formula and chemical name of intermediate 1a

[0238] Preparation of intermediate 2: tert-butyl-3-formyl-3-methylacetidine-1-carboxylic acid ester

[0239] Step 1: Dissolve 1-(tert-butoxycarbonyl)-3-methylacetidine-3-carboxylic acid (2.3 g, 10.69 mmol) in tetrahydrofuran (30 mL), add triethylamine (1.3 g, 11.77 mmol) and isobutyl chloride (1.11 g, 11.77 mmol) at 0 °C, and stir the reaction mixture at this temperature for 0.5 h. After the reaction is complete, filter the reaction solution. Dissolve sodium borohydride (791 mg, 21.28 mmol) in 7 mL of water, and slowly add it dropwise to the filtrate at 0 °C. Continue stirring the reaction mixture for 0.5 h after the addition is complete. After the reaction is complete, quench the reaction with saturated ammonium chloride solution (200 mL), and extract with ethyl acetate. Wash the organic phase with saturated brine and dry it with anhydrous sodium sulfate. After filtration and concentration of the filtrate, the crude product was purified by normal-phase column chromatography to obtain tert-butyl-3-(hydroxymethyl)-3-methylacetidine-1-carboxylic acid ester (800 mg, yield: 37.2%).

[0240] Step 2: 800 mg (4.02 mmol) of tert-butyl-3-(hydroxymethyl)-3-methylacetidine-1-carboxylic acid ester was dissolved in 15 mL of dichloromethane. Dess-Martin Periodinane (2.5 g, 6.03 mmol) was added at 0 °C, and the mixture was stirred for 1 hour. After the reaction was complete, 200 mL of saturated sodium bicarbonate aqueous solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to obtain 1.1 g (crude) of tert-butyl-3-formyl-3-methylacetidine-1-carboxylic acid ester.

[0241] Preparation of intermediate 3: tert-butyl 3-(((tert-butyldiphenylsilyl)oxo)methyl)-3-formylacrylidine-1-carboxylic acid ester

[0242] Step 1: 1.0 g (4.608 mmol) of tert-butyl-3,3-di(hydroxymethyl)acetidine-1-carboxylic acid ester was dissolved in N,N-dimethylformamide (20 mL). 1.3 g (4.608 mmol) of tert-butyldiphenylchlorosilane and 376 mg (5.530 mmol) of imidazole were added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the crude product was concentrated and purified by normal-phase column chromatography to give 980 mg (yield: 46.67%) of tert-butyl-3-(((tert-butyldiphenylsilyl)oxo)methyl)-3-(hydroxymethyl)acetidine-1-carboxylic acid ester.

[0243] Step 2: tert-Butyl 3-((((tert-Butyldiphenylsilyl)oxo)methyl)-3-(hydroxymethyl)acetidine-1-carboxylic acid ester (780 mg, 1.714 mmol) was dissolved in dichloromethane (10 mL), and pyridine chlorochromate (737 mg, 3.429 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was filtered through diatomaceous earth, the filtrate was concentrated, and the crude product was purified by normal-phase column chromatography to obtain tert-Butyl 3-((((tert-Butyldiphenylsilyl)oxo)methyl)-3-formylacetidine-1-carboxylic acid ester (610 mg, yield: 78.21%).

[0244] Preparation of Intermediate 4: N,6-Dimethyl-5-(piperazin-1-yl)methylpyridine amide

[0245] Step 1: 5-Bromo-6-methylo-pyridinecarboxylic acid (5.0 g, 23.1 mmol) was dissolved in N,N-dimethylformamide (50 mL), and a tetrahydrofuran solution of methylamine (2 M, 23.1 mL, 46.2 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (13.2 g, 34.7 mmol), and N,N-diisopropylethylamine (11.95 g, 92.6 mmol) were added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain 5-bromo-N,6-dimethylmethylpyridineamide (5.1 g, yield: 96.8%).

[0246] Step 2: Dissolve 5-bromo-N,6-dimethylmethylpyridine amide (5.1 g, 22.4 mmol) in 1,4-dioxane (100 mL), and add tert-butylpiperazine carboxylate (4.99 g, 26.88 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (1.87 g, 2.24 mmol), and cesium carbonate (14.6 g, 44.8 mmol). The system was evacuated and purged three times with nitrogen, then heated to 100 °C and stirred overnight. After the reaction was completed, the mixture was cooled to room temperature, the reaction solution was concentrated, and the crude product was purified by normal phase column chromatography to obtain tert-butyl 4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylic acid ester (7.3 g, yield: 97.6%).

[0247] Step 3: Dissolve tert-butyl-4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylic acid ester (7.3 g, 21.86 mmol) in 50 mL of 1,4-dioxane hydrogen chloride solution and stir at room temperature for 1 hour. After the reaction is complete, concentrate to obtain N,6-dimethyl-5-(piperazine-1-yl)methylpyridine amide (6.4 g), which is used directly in the next step.

[0248] Preparation of Intermediate 5: N-Methyl-5-(piperazin-1-yl)-6-(trifluoromethyl)methylpyridine amide

[0249] Step 1: Methyl 6-bromo-5-fluoromethylpyridinium ester (5 g, 21.368 mmol), ethyl 2,2-difluoro-2-(fluorosulfonyl)acetate (12 g, 64.103 mmol), and cuprous iodide (12 g, 64.103 mmol) were dissolved in N,N-dimethylformamide (50 mL). The system was evacuated and purged with nitrogen three times, then heated to 80 °C and stirred for 16 hours. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain methyl 5-fluoro-6-(trifluoromethyl)methylpyridinium ester (3.3 g, yield: 69.25%).

[0250] Step 2: Methyl 5-fluoro-6-(trifluoromethyl)methylpyridinium ester (5 g, 14.350 mmol), tert-butylpiperazine carboxylate (2.7 g, 14.350 mmol), and N,N-diisopropylethylamine (3.7 g, 28.700 mmol) were dissolved in dimethyl sulfoxide (50 mL), and the mixture was heated to 110 °C and stirred for 16 hours. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to give tert-butyl 4-(6-(methyl ester <methoxycarbonyl>)-2-(trifluoromethyl)pyridin-3-yl)piperazine-1-carboxylate (4.4 g, yield: 78.82%).

[0251] Step 3: Dissolve 4.4 g (11.300 mmol) of tert-butyl 4-(6-(methyl ester <methoxycarbonyl>)-2-(trifluoromethyl)pyridin-3-yl)piperazine-1-carboxylic acid ester in methylamine-ethanol solution (45.0 mL) and stir at room temperature for 1 hour. After the reaction is complete, concentrate to obtain 4.5 g (crude product) of tert-butyl 4-(6-(methylcarbamoyl)-2-(trifluoromethyl)pyridin-3-yl)piperazine-1-carboxylic acid ester.

[0252] Step 4: Dissolve tert-butyl 4-(6-(methylcarbamoyl)-2-(trifluoromethyl)pyridin-3-yl)piperazine-1-carboxylic acid ester (4.5 g, 11.586 mmol) in hydrochloric acid-dioxane solution (45.0 mL, 4 M) and stir at room temperature for 1 hour. After the reaction is complete, the system is directly concentrated to obtain N-methyl-5-(piperazine-1-yl)-6-(trifluoromethyl)methylpyridinamide (4.0 g, crude product).

[0253] Preparation of Intermediate 6: 6-Cyano-N-methyl-5-(piperazin-1-yl)methylpyridine amide

[0254] Step 1: Methyl 6-bromo-5-fluoromethylpyridinium ester (5 g, 21.46 mmol) was dissolved in ultradry dimethyl sulfoxide (60 mL), and cuprous cyanide (2.38 g, 26.61 mmol) was added. The mixture was heated to 120 °C and stirred for 3 hours. After the reaction was complete, the system was cooled to room temperature, the reaction solution was filtered, the filtrate was diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain methyl 5-fluoro-6-cyanomethylpyridinium ester (3.17 g, yield: 82.52%).

[0255] Steps 2 through 4 can be performed by referring to the steps 2 through 4 of the preparation of intermediate 5, selecting appropriate raw materials, and finally obtaining 6-cyano-N-methyl-5-(piperazin-1-yl)methylpyridine amide.

[0256] Preparation of Intermediate 7: 6-(difluoromethyl)-N-methyl-5-(piperazin-1-yl)methylpyridine amide

[0257] Step 1: Methyl 6-bromo-5-fluoromethylpyridinium ester (5.76 g, 24.6 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxoboropentan (4.55 g, 29.54 mmol) were dissolved in 1,4-dioxane (115 mL) and water (11.5 mL). Potassium carbonate (6.8 g, 49.2 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (1.83 g, 2.5 mmol) were added sequentially. The system was evacuated and purged three times with nitrogen, then heated to 100 °C and stirred for 16 hours. After the reaction was complete, the system was cooled to room temperature. The crude product was concentrated and purified by normal-phase column chromatography to obtain methyl 5-fluoro-6-vinylmethylpyridinium ester (1.7 g, yield: 38.20%).

[0258] Step 2: Methyl 5-fluoro-6-vinylmethylpyridinium ester (1.7 g, 9.39 mmol) was dissolved in tetrahydrofuran (34 mL) and water (34 mL), and potassium osmium tetroxide dihydrate (14 mg, 0.04 mmol) and sodium periodate (10 g, 47 mmol) were added. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain methyl 5-fluoro-6-formylmethylpyridinium ester (1.4 g, yield: 82.35%).

[0259] Step 3: Methyl 5-fluoro-6-formylmethylpyridinium ester (1.4 g, 7.65 mmol) was dissolved in dichloromethane (20 mL), cooled to 0 °C, and diethylaminosulfur trifluoride (2.46 g, 15.3 mmol) was added. The mixture was then stirred at room temperature for 2 hours. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain methyl 6-(difluoromethyl)-5-fluoromethylpyridinium ester (750 mg, yield: 47.77%).

[0260] Steps four through six can be performed by selecting appropriate raw materials, referring to steps two through four in the preparation of intermediate 5, and finally obtaining 6-(difluoromethyl)-N-methyl-5-(piperazin-1-yl)methylpyridine amide.

[0261] Intermediate 8: Preparation of tert-butyl-4-(tert-butoxy)-2-chloro-7,8-dihydropyrido[3,2-d]pyrimidine-5(6H)-carboxylic acid ester

[0262] Step 1: 2,4-Dichloropyrido[3,2-d]pyrimidine (1 g, 4.999 mmol) was dissolved in tetrahydrofuran (20 mL), and potassium tert-butoxide (5.0 mL, 4.999 mmol, 1 M) was added. The mixture was stirred at room temperature for 8 hours. After the reaction was completed, the mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain 4-(tert-butoxy)-2-chloropyrido[3,2-d]pyrimidine (800 mg, 67.32%).

[0263] Step 2: 4-(tert-butoxy)-2-chloropyrido[3,2-d]pyrimidine (500 mg, 2.104 mmol), platinum dioxide (250 mg), and trifluoroacetic acid (0.2 mL) were dissolved in ethanol (10 mL). The system was evacuated and purged three times with hydrogen, then stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was filtered, and the crude product was purified by normal-phase column chromatography to obtain 4-(tert-butoxy)-2-chloro-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidine (500 mg, 98.33%).

[0264] Step 3: 4-(tert-butoxy)-2-chloro-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidine (1.3 g, 5.378 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0 °C, and then bis(trimethylsilylamino)lithium (10.7 mL, 10.756 mmol) was added. The mixture was stirred at this temperature for 1 hour, followed by the addition of di-tert-butyl methyl dicarbonate (2.35 g, 10.756 mmol). After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the crude product was concentrated and purified by normal-phase column chromatography to obtain tert-butyl-4-(tert-butoxy)-2-chloro-7,8-dihydropyrido[3,2-d]pyrimidine-5(6H)-carboxylic acid ester (800 mg, 67.32%).

[0265] Preparation of Intermediate 9: 4-(tert-butoxy)-2-chloro-7-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine

[0266] Step 1: 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 26.31 mmol) was dissolved in N,N-dimethylformamide (50 mL), followed by the addition of potassium carbonate (5.45 g, 39.46 mmol) and 4-methoxybenzyl chloride (4.94 g, 31.57 mmol). The mixture was heated to 55 °C and stirred for 12 hours. After the reaction was complete, the system was cooled to room temperature, the reaction was quenched with water, and the mixture was extracted three times with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the crude product was concentrated and purified by normal-phase column chromatography to obtain 2,4-dichloro-7-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine (6.50 g, yield: 80.16%).

[0267] Step 2: 2,4-Dichloro-7-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 9.74 mmol) was dissolved in tetrahydrofuran (30 mL), cooled to 0 °C, and potassium tert-butoxide (9.74 mL, 1 M tetrahydrofuran solution) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1 hour. After the reaction was complete, saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the crude product was concentrated and purified by normal-phase column chromatography to obtain 4-(tert-butoxy)-2-chloro-7-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine (2.4 g, yield: 71.25%).

[0268] Preparation of intermediate 10: 4-(tert-butoxy)-2-chloro-6,7-difluoroquinazoline

[0269] Step 1: Dissolve 2-amino-4,5-difluorobenzoic acid (10 g, 57.764 mmol) in a mixed solution of acetic acid (1 mL) and water (10 mL), then add it to a solution of potassium cyanate (9.37 g, 115.528 mmol) in water (6 mL). Stir the mixture at room temperature for 16 hours. After the reaction is complete, add sodium hydroxide (46.21 g, 1155 mmol), filter, adjust the pH of the filtrate to 6-7 with dilute hydrochloric acid (1 N), filter again, and concentrate the filtrate to obtain 6,7-difluoro-2-hydroxyquinazoline-4(3H)-one (7.2 g, yield: 62.91%).

[0270] Step 2: Diisopropylethylamine (9 mL) and phosphorus oxychloride (15 mL) were added to 6,7-difluoro-2-hydroxyquinazoline-4(3H)-one (3 g, 15.142 mmol) at 0 °C, and the mixture was heated to 100 °C and stirred for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, concentrated, diluted with water, stirred thoroughly, filtered, and the filter cake solid was collected and dissolved in ethyl acetate. The solution was washed successively with saturated sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the crude product was concentrated and purified by normal phase to obtain 2,4-dichloro-6,7-difluoroquinazoline (1.5 g, yield: 42.15%).

[0271] Step 3: Dissolve 2,4-dichloro-6,7-difluoroquinazoline (500 mg, 2.128 mmol) in THF (5 mL), cool to 0°C, add 2.5 mL of potassium tert-butoxide in tetrahydrofuran, and stir at room temperature for 1 hour after addition. After the reaction is complete, quench the reaction with saturated ammonium chloride solution, and extract three times with ethyl acetate. Wash the organic phase with saturated brine and dry with anhydrous sodium sulfate. Filter, concentrate the filtrate, and purify the crude product by normal phase to obtain 4-(tert-butoxy)-2-chloro-6,7-difluoroquinazoline (330 mg, yield: 56.88%).

[0272] Intermediate 10a can be prepared by selecting appropriate raw materials by referring to the synthesis method of intermediate 10, and its structure is shown in Table 2.

[0273] Table 2. Structural formula and chemical name of intermediate 10a

[0274] Preparation of Intermediate 11: 4-(tert-butoxy)-2-chloro-5,6,8-trifluoroquinazoline

[0275] Step 1: 2,4,5-Trifluoroaniline (5.20 g, 35.350 mmol) was dissolved in dioxane (180 mL), and an aqueous solution (30 mL) of iodine (4.49 g, 17.675 mmol) and iodic acid (6.22 g, 35.350 mmol) was added. The mixture was heated to 110 °C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, quenched in water, and extracted with dichloromethane. The organic phase was washed successively with saturated sodium sulfite solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain 3,4,6-trifluoro-2-iodoaniline (3.6 g, yield: 37.30%).

[0276] Step 2: 3,4,6-trifluoro-2-iodoaniline (3.60 g, 13.187 mmol) was dissolved in methanol (40 mL). Under nitrogen protection, triethylamine (5.484 mL, 39.561 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.96 g, 1.319 mmol) were added. The mixture was purged with carbon monoxide three times, and the carbon monoxide pressure was maintained at 1.5 MPa. The mixture was heated to 80 °C and stirred for 12 hours. After the reaction was complete, the system was cooled to room temperature, concentrated, and the crude product was purified by normal-phase column chromatography to obtain methyl 2-amino-3,5,6-trifluorobenzoate (2.2 g, yield: 81.33%).

[0277] Step 3: Methyl 2-amino-3,5,6-trifluorobenzoate (2000 mg, 9.750 mmol) was dissolved in tetrahydrofuran (50 mL). 2,2,2-trichloroacetyl isocyanate (2755.07 mg, 14.624 mmol) was added under ice bath conditions. After addition, the mixture was slowly brought to room temperature and stirred for 1 hour. After the reaction was complete, the reaction solution was directly concentrated. The crude product was slurried in methyl tert-butyl ether / petroleum ether (5 / 1, 50 mL), filtered, and the filter cake was dried to obtain methyl 2,3,5-trifluoro-6-(3-(2,2,2-trichloroacetyl)ureoyl)benzoate (3.7 g, yield: 96.44%).

[0278] Step 4: Methyl 2,3,5-trifluoro-6-(3-(2,2,2-trichloroacetyl)ureido)benzoate (4000 mg, 10.165 mmol) was dissolved in methanol (80 mL), and ammonia-ethanol solution (10.165 mL, 71.152 mmol, 7 mmol / L) was added under ice bath conditions. The mixture was then stirred at room temperature for 1 hour. After the reaction was complete, a solid precipitated out, which was filtered and the filter cake was dried to give 5,6,8-trifluoro-2-hydroxyquinazoline-4(3H)-one (2 g, yield: 91.04%).

[0279] Steps 5 and 6 can be performed by selecting appropriate starting materials, referring to steps 2 and 3 in the synthesis of intermediate 10, to obtain 4-(tert-butoxy)-2-chloro-5,6,8-trifluoroquinazoline.

[0280] Preparation of Intermediate 12: 4-(tert-butoxy)-2-chloro-5,6-difluoroquinazoline

[0281] Step 1: 6-Bromo-2,3-difluorobenzoic acid (5.00 g, 21.097 mmol) and potassium carbonate (4.37 g, 31.646 mmol) were dissolved in N,N-dimethylformamide (50 mL), and iodomethane (1.576 mL, 25.316 mmol) was added. The mixture was stirred for 12 hours. After the reaction was complete, the reaction was quenched with ice water, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain methyl 6-bromo-2,3-difluorobenzoate (4.6 g, yield: 86.86%).

[0282] Step 2: Methyl 6-bromo-2,3-difluorobenzoate (3750 mg, 14.939 mmol) and tert-butyl carbamate (3500.06 mg, 29.877 mmol) were dissolved in dioxane (75 mL). Under nitrogen protection, palladium acetate (335.38 mg, 1.494 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (864.40 mg, 1.494 mmol), and cesium carbonate (9734.58 mg, 29.877 mmol) were added. The mixture was heated to 100 °C and stirred for 12 hours. After the reaction was complete, the system was cooled to room temperature, filtered, concentrated, and the crude product was purified by normal-phase column chromatography to obtain methyl 6-((tert-butoxycarbonyl)amino)-2,3-difluorobenzoate (1.8 g, yield: 41.95%).

[0283] Step 3: Methyl 6-((tert-butoxycarbonyl)amino)-2,3-difluorobenzoate (2.20 g, 7.658 mmol) was dissolved in dichloromethane (20 mL), and ethyl acetate hydrochloride (10 mL, 40.000 mmol, 4 mol / L) was added under ice bath conditions. The mixture was slowly heated to room temperature and stirred for 2 hours. After the reaction was complete, the system was directly concentrated to give methyl 6-amino-2,3-difluorobenzoate (1.4 g, yield: 97.68%).

[0284] Steps four through seven can be performed by referring to steps three through six in the synthesis of intermediate 11, selecting appropriate raw materials to prepare 4-(tert-butoxy)-2-chloro-5,6-difluoroquinazoline.

[0285] Preparation of Intermediate 13: 2-Chloro-7-fluoro-4,8-di((4-methoxybenzyl)oxo)quinazoline

[0286] Step 1: 2-Amino-4-fluoro-3-methoxybenzoic acid (7.68 g, 41.48 mmol) was dissolved in acetic acid (20 mL), and urea (34.9 g, 580.7 mmol) was added. The mixture was heated to 110 °C and stirred for 5 hours. After the reaction was completed, the reaction solution was concentrated and diluted with water. The mixture was stirred thoroughly to precipitate a solid. The solid was collected by filtration and dried to obtain 7-fluoro-8-methoxyquinazoline-2,4-diol (6 g, yield: 68.82%).

[0287] Step 2: 7-Fluoro-8-methoxyquinazoline-2,4-diol (5.8 g, 27.62 mmol) was dissolved in phosphorus oxychloride (80 mL), and diisopropylethylamine (9 g, 69.05 mmol) was added at room temperature. The mixture was heated to 90 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was concentrated, and then ice water (80 mL) was added and stirred for 1 hour. The mixture was filtered, and the white solid was collected and dried to give 2,4-dichloro-7-fluoro-8-methoxyquinazoline (5 g, yield: 73.59%).

[0288] Step 3: 2,4-Dichloro-7-fluoro-8-methoxyquinazoline (5 g, 20.239 mmol) was dissolved in tetrahydrofuran (50 mL), and potassium tert-butoxide (24.287 mL, 24.287 mmol, 1 mol / L) was added dropwise under ice bath conditions. The mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain 4-(tert-butoxy)-2-chloro-7-fluoro-8-methoxyquinazoline (4 g, yield: 69.42%).

[0289] Step 4: 4-(tert-butoxy)-2-chloro-7-fluoro-8-methoxyquinazoline (2 g, 7.025 mmol) was dissolved in 1,2-dichloroethane (40 mL), and aluminum trichloride (4.68 g, 35.123 mmol) was added. The mixture was heated to 80 °C and stirred for 2 hours. After the reaction was complete, the mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain 2-chloro-7-fluoroquinazoline-4,8-diol (1.4 g, yield: 92.88%).

[0290] Step 5: Dissolve 2-chloro-7-fluoroquinazoline-4,8-diol (1.25 g, 5.825 mmol) in N,N-dimethylformamide (30 mL), add cesium carbonate (6.64 g, 20.389 mmol), and add 4-methoxybenzyl chloride (2.74 g, 17.476 mmol) dropwise under ice bath conditions. After the addition is complete, slowly raise the temperature to room temperature and react for 2 hours. After the reaction is complete, quench with ice water and extract with ethyl acetate. Wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the crude product by normal phase column chromatography to obtain 2-chloro-7-fluoro-4,8-di((4-methoxybenzyl)oxo)quinazoline (350 mg, yield: 13.21%).

[0291] Preparation Examples

[0292] Example 1: Preparation of 6-fluoro-N-methyl-5-(4-((1-(4-carbonyl-3,4-dihydroquinazolin-2-yl)acetidin-3-yl)methyl)piperazin-1-yl)methylpyridine amide

[0293] Step 1: Dissolve tert-butyl-3-formyl acridine-1-carboxylic acid ester (0.13 mL, 0.84 mmol) in dichloromethane (5 mL), add 6-fluoro-N-methyl-5-(piperazin-1-yl)methylpyridineamide (200 mg, 0.84 mmol), and two drops of acetic acid. Stir at room temperature for 1 hour, then add sodium triacetoxyborohydride (355.80 mg, 1.68 mmol), and continue stirring at room temperature for 16 hours. After the reaction is complete, quench the reaction with saturated sodium bicarbonate aqueous solution (5 mL), extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the crude product by normal phase column chromatography to obtain tert-butyl-3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)acridine-1-carboxylic acid ester (320 mg, yield: 93.554%).

[0294] Step 2: Dissolve tert-butyl 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)acetidine-1-carboxylic acid ester (100 mg, 0.25 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (0.5 mL), and then stir the reaction at room temperature while monitoring. After the reaction is complete, concentrate the reaction solution to obtain 5-(4-(acetidine-3-ylmethyl)piperazin-1-yl)-6-fluoro-N-methylmethylpyridinamide (104.3 mg, purity: 72.320%). This can be used directly in the next step.

[0295] Step 3: 5-(4-(acridin-3-ylmethyl)piperazin-1-yl)-6-fluoro-N-methylmethylpyridine amide (104.3 mg, 0.25 mmol) was dissolved in dimethyl sulfoxide (2 ml), and 2-chloroquinazoline-4(3H)-one (44.32 mg, 0.25 mmol) was added. The mixture was then heated to 90 °C and stirred for 12 hours. After the reaction was complete, the system was cooled to room temperature, and the reaction solution was purified by reverse-phase chromatography to obtain 6-fluoro-N-methyl-5-(4-((1-(4-carbonyl-3,4-dihydroquinazoline-2-yl)acridin-3-yl)methyl)piperazin-1-yl)methylpyridine amide (16.23 mg, yield: 14.648%). ESI-MS [M+H] + :found 452.2. 1 H NMR (400MHz, DMSO-d6) δ11.34(brs,1H),8.40(q,J=4.6Hz,1H),7.90(dd,J=7.9,1. 3Hz,1H),7.87–7.82(m,1H),7.62–7.50(m,2H),7.25(d,J=8.1Hz,1H),7.12(t,J=7 .5Hz,1H),4.17(t,J=8.4Hz,2H),3.77(dd,J=8.6,5.7Hz,2H),3.20–3.12(m,4H),3 .00–2.86(m,1H),2.77(d,J=4.8Hz,3H),2.64(d,J=7.5Hz,2H),2.60–2.52(m,4H).

[0296] Examples 2-5 can be prepared by selecting suitable raw materials according to the synthesis method of Example 1, and their structures are shown in Table 3.

[0297] Table 3. Structural formulas, chemical names, and mass spectrometry data of Examples 2-5

[0298] The NMR data of some of the compounds in the examples are as follows:

[0299] Example 6: Preparation of 6-fluoro-5-(4-((3-hydroxy-1-(4-carbonyl-3,4-dihydroquinazolin-2-yl)acetidin-3-yl)methyl)piperazin-1-yl)-N-methylmethylpyridine amide

[0300] Step 1: To a methanol (10 mL) solution of 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridinecarboxamide (386 mg, 1.62 mmol), tert-butyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylic acid (300 mg, 1.62 mmol) and N,N-diisopropylethylamine (837 mg, 6.5 mmol) were added. After the addition was complete, the mixture was heated to 80 °C and stirred for 16 hours. After the reaction was complete, the reaction solution was concentrated, and the crude product was purified by normal-phase column chromatography to obtain tert-butyl 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3-hydroxyazacyclobutane-1-carboxylic acid (610 mg, yield: 89.05%).

[0301] Steps two and three, respectively, follow the procedures in steps two and three of the synthesis in Example 1, selecting appropriate reagents to prepare 6-fluoro-5-(4-((3-hydroxy-1-(4-carbonyl-3,4-dihydroquinazolin-2-yl)acetidin-3-yl)methyl)piperazin-1-yl)-N-methylmethylpyridinamide. ESI-MS [M+H] + :found 468.3. 1 H NMR (400MHz, DMSO-d6) δ11.46(s,1H),8.41(d,J=4.1Hz,1H),7.90(d,J=7.7Hz,1H),7.84(d,J=8.0Hz,1H),7.65–7.50(m,2H),7.34–7.21( m,1H),7.20–7.07(m,1H),5.76(s,1H),425–3.80(m,4H),3.75–3.45(m,2H),3.25–3.02(m,4H),2.77(d,J=4.8Hz,3H),2.75–2.54(m,4H).

[0302] Examples 7 and 8: Preparation of N-methyl-5-(4-((1r,3r)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)methyl)cyclobutyl)piperazin-1-yl)methylpyridinamide and N-methyl-5-(4-((1s,3s)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)methyl)cyclobutyl)piperazin-1-yl)methylpyridinamide

[0303] Step 1: Methyl 2-(3-carbonylcyclobutyl)acetate (1.0 g, 7.03 mmol) and tert-butylpiperazine-1-carboxylic acid (1.31 g, 7.03 mmol) were dissolved in dichloroethane (50 mL), and two drops of acetic acid were added. After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (2.98 g, 14.07 mmol) was added, and the reaction was continued at room temperature for 16 hours. After the reaction was completed, the reaction was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the crude product was concentrated and separated by normal phase chromatography to obtain tert-butyl-4-(3-(2-methoxy-2-carbonylethyl)cyclobutyl)piperazine-1-carboxylic acid (1.8 g, yield: 81.818%).

[0304] Step 2: Dissolve tert-butyl 4-(3-(2-methoxy-2-carbonylethyl)cyclobutyl)piperazine-1-carboxylic acid ester (1.8 g, 55.76 mmol) in tetrahydrofuran (28 mL) and methanol (7 mL), add a solution of lithium hydroxide (1.21 g, 28.81 mmol) in water (7 mL), and stir at room temperature for 16 hours. After the reaction is complete, add 1 M dilute hydrochloric acid to adjust the acidity of the system to pH 5-6. The mixture is then freeze-dried to obtain 2-(3-(4-(tert-butoxycarbonyl)piperazine-1-yl)cyclobutyl)acetic acid (4.3 g, purity: 40%).

[0305] Step 3: Dissolve 1.4 g (1.88 mmol) of 2-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclobutyl)acetic acid in 20 mL of N,N-dimethylformamide, add 2-aminobenzamide (255.53 mg, 1.88 mmol), triethylamine (0.52 mL, 3.75 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (784.98 mg, 2.06 mmol), and stir at room temperature for 16 hours. After the reaction is complete, dilute with a large amount of dichloromethane, wash three times with saturated brine, and dry with anhydrous sodium sulfate. After filtration and concentration of the filtrate, the crude product was separated by normal phase chromatography to obtain tert-butyl 4-(3-(2-((2-carbamoylphenyl)amino)-2-carbonylethyl)cyclobutyl)piperazine-1-carboxylic acid ester (440 mg, yield: 56.286%).

[0306] Step 4: 440 mg (1.06 mmol) of tert-butyl 4-(3-(2-((2-carbamoylphenyl)amino)-2-carbonylethyl)cyclobutyl)piperazine-1-carboxylic acid ester was dissolved in ethylene glycol dimethyl ether (10 mL), and potassium hydroxide (296.34 mg, 5.28 mmol) was added. The mixture was then heated to 60 °C and stirred for 16 hours. After the reaction was complete, the system was cooled to room temperature and concentrated. The crude product was purified by normal-phase column chromatography to obtain 200 mg (52.260%) of tert-butyl 4-(3-((4-carbonyl-3,4-dihydroquinazolin-2-yl)methyl)cyclobutyl)piperazine-1-carboxylic acid ester.

[0307] Step 5: Dissolve tert-butyl-4-(3-(((4-carbonyl-3,4-dihydroquinazoline-2-yl)methyl)cyclobutyl)piperazine-1-carboxylic acid ester (200 mg, 0.5 mmol) in dichloromethane (2 mL), add 4 M hydrochloric acid (1,4-dioxane solution, 2 mL), and react at room temperature for 1 hour. After the reaction is complete, evaporate the reaction solution directly to dryness to obtain 2-((3-(piperazine-1-yl)cyclobutyl)methyl)quinazoline-4(3H)-one (200 mg, purity: 74.875%).

[0308] Step 6: 200 mg (0.5 mmol) of compound 2-((3-(piperazin-1-yl)cyclobutyl)methyl)quinazolin-4(3H)-one, 120 mg (0.75 mmol) of compound methyl 5-fluoromethylpyridinium ester, and 1 mL of N,N-diisopropylethylamine were dissolved sequentially in dimethyl sulfoxide (10 mL). The reaction mixture was heated to 100 °C and stirred overnight. After the reaction was complete, the mixture was diluted with dichloromethane, washed three times with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the crude product was concentrated and purified by normal-phase column chromatography to obtain methyl 5-(4-(3-((4-carbonyl-3,4-dihydroquinazolin-2-yl)methyl)cyclobutyl)piperazin-1-yl)methylpyridinium ester (160 mg, yield: 74%).

[0309] Step 7: Dissolve methyl 5-(4-(3-((4-carbonyl-3,4-dihydroquinazolin-2-yl)methyl)cyclobutyl)piperazin-1-yl)methylpyridinium ester (160 mg, 0.37 mmol) in methylamine-ethanol solution (20 mL). Stir the reaction mixture at 40 °C for 3 hours. After the reaction is complete, concentrate the solution to obtain the crude product. The crude product was purified by reverse-phase reaction to obtain N-methyl-5-(4-((1r,3r)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)methyl)cyclobutyl)piperazin-1-yl)methylpyridine amide (57.28 mg, yield: 35.8%, purity: 99.204%) and N-methyl-5-(4-((1s,3s)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)methyl)cyclobutyl)piperazin-1-yl)methylpyridine amide (22.07 mg, yield: 13.8%, purity: 97.712%).

[0310] Example 7, N-methyl-5-(4-((1r,3r)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)methyl)cyclobutyl)piperazin-1-yl)methylpyridineamide: ESI-MS [M+H] + :found 433.2. 1 H NMR (400MHz, CDCl3) δ9.93 (s, 1H), 8.27 (d, J = 6.8Hz, 1H), 8.15 (d, J = 2.8Hz, 1H), 8.04 (d, J=8.8Hz,1H),7.81–7.74(m,2H),7.70(d,J=7.8Hz,1H),7.47(t,J=7.5Hz,1H),7.21(dd,J =8.8,3.0Hz,1H),3.37–3.29(m,4H),3.08–3.02(m,1H),3.01(d,J=5.1Hz,3H),2.94(d,J =8.2Hz,2H),2.85–2.73(m,1H),2.55–2.45(m,4H),2.28–2.18(m,2H),2.11–2.01(m,2H).

[0311] Example 8, N-methyl-5-(4-((1s,3s)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)methyl)cyclobutyl)piperazin-1-yl)methylpyridineamide: ESI-MS [M+H] + :found 433.2. 1H NMR (400MHz, CDCl3) δ10.76(s,1H),8.29(d,J=8.0Hz,1H),8.14(d,J=2.3Hz,1H),8.05(d ,J=8.8Hz,1H),7.81–7.74(m,2H),7.69(d,J=8.1Hz,1H),7.47(t,J=7.5Hz,1H),7.20(dd, J=8.8,2.6Hz,1H),3.36–3.27(m,4H),3.01(d,J=5.0Hz,3H),2.89(d,J=7.4Hz,2H),2.77– 2.67(m,1H),2.64–2.54(m,1H),2.53–2.46(m,4H),2.45–2.35(m,2H),1.87–1.75(m,2H).

[0312] Examples 9 and 10: Preparation of N-methyl-5-(4-(((1r,3r)-3-(4-carbonyl-3,4-dihydroquinazoline-2-yl)cyclobutyl)methyl)piperazin-1-yl)methylpyridinamide and N-methyl-5-(4-(((1s,3s)-3-(4-carbonyl-3,4-dihydroquinazoline-2-yl)cyclobutyl)methyl)piperazin-1-yl)methylpyridinamide

[0313] Step 1: Methoxymethyltriphenylphosphine chloride (50 g, 147 mmol) was dissolved in tetrahydrofuran (200 mL), cooled to -65 °C under nitrogen protection, and bis(trimethylsilylaminolithium) (147 mL, 147 mmol) was slowly added dropwise. After reacting at this temperature for half an hour, benzyl 3-carbonylcyclobutane-1-carboxylic acid ester (20 g, 98 mmol) was slowly added dropwise. After the addition was complete, the mixture was slowly brought to room temperature and reacted overnight. After the reaction was completed, the reaction was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the crude product was concentrated and purified by normal-phase column chromatography to obtain benzyl 3-(methoxymethylene)cyclobutane-1-carboxylic acid ester (7.6 g, yield: 33.41%).

[0314] Step 2: Benzyl 3-(methoxymethylene)cyclobutane-1-carboxylic acid ester (2.6 g, 11.19 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) and water (1 mL) were added. The reaction system was stirred at room temperature for 1 hour. After the reaction was completed, the organic phase was concentrated to obtain benzyl 3-formylcyclobutane-1-carboxylic acid ester (2.1 g, crude product).

[0315] Step 3: Benzyl 3-formylcyclobutane-1-carboxylic acid ester (1 g, 4.58 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of tert-butylpiperazine-1-carboxylic acid ester (853 mg, 4.58 mmol), one drop of acetic acid, and sodium triacetoxyborohydride (1.94 g, 9.16 mmol). The mixture was stirred overnight at room temperature. After the reaction was complete, the reaction was quenched with water, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the crude product was concentrated and separated by normal-phase chromatography to obtain tert-butyl-4-((3-((benzyloxy)carbonyl)cyclobutyl)methyl)piperazine-1-carboxylic acid ester (1.1 g, yield: 61.8%), which was purified by normal-phase column chromatography.

[0316] Step 4: Dissolve 1.1 g (2.83 mmol) of tert-butyl 4-((3-((benzyloxy)carbonyl)cyclobutyl)methyl)piperazine-1-carboxylic acid ester in methanol (10 mL), and add 10% palladium on carbon (110 mg). After purging with hydrogen three times, react at room temperature for 3 hours. Filter the reaction solution with diatomaceous earth, and concentrate the filtrate to obtain 0.7 g (crude product) of 2-(3-((4-(tert-butoxycarbonyl)piperazine-1-yl)methyl)cyclobutyl)-2-carbonylacetic acid.

[0317] Starting with 2-(3-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)cyclobutyl)-2-carbonylacetic acid, and following the procedures in steps three through seven of Examples 7 and 8, suitable starting materials were selected to prepare Examples 9 and 10. The two compounds could be effectively separated by reverse-phase preparation, but their relative configurations could not be confirmed by two-dimensional NMR spectroscopy.

[0318] Example 9, N-methyl-5-(4-(((1r,3r)-3-(4-carbonyl-3,4-dihydroquinazoline-2-yl)cyclobutyl)methyl)piperazin-1-yl)methylpyridinamide or N-methyl-5-(4-(((1s,3s)-3-(4-carbonyl-3,4-dihydroquinazoline-2-yl)cyclobutyl)methyl)piperazin-1-yl)methylpyridinamide: ESI-MS [M+H] + :found 433.2. 1H NMR (400MHz, CDCl3) δ10.70(s,1H),8.27(dd,J=8.0,1.1Hz,1H),8.16(d,J=2.8Hz,1H),8.05(d,J=8.7Hz,1H),7.83–7.66(m,3H) ,7.50–7.43(m,1H),7.22(dd,J=8.8,2.9Hz,1H),3.61–3.33(m,5H),3.01(d,J=5.1Hz,3H),2.89–2.55(m,9H),2.33–2.21(m,2H).

[0319] Example 10, N-methyl-5-(4-(((1s,3s)-3-(4-carbonyl-3,4-dihydroquinazoline-2-yl)cyclobutyl)methyl)piperazin-1-yl)methylpyridinamide or N-methyl-5-(4-(((1r,3r)-3-(4-carbonyl-3,4-dihydroquinazoline-2-yl)cyclobutyl)methyl)piperazin-1-yl)methylpyridinamide: ESI-MS [M+H] + :found 433.2. 1 H NMR (400MHz, CDCl3) δ9.93(s,1H),8.27(d,J=6.9Hz,1H),8.16(d,J=2.8Hz,1H),8.05(d,J=8.7Hz,1H),7.81–7.72(m,3H),7.50–7.44( m,1H),7.21(dd,J=8.8,2.9Hz,1H),3.60–3.50(m,1H),3.42–3.30(m,4H),3.01(d,J=5.1Hz,3H),2.85–2.57(m,9H),2.32–2.20(m,2H).

[0320] Example 11: Preparation of 6-fluoro-N-methyl-5-(4-((1-(4-carbonyl-3,4-dihydroquinazolin-2-yl)pyrrolidine-3-yl)methyl)piperazin-1-yl)methylpyridine amide

[0321] The first step can be performed by selecting appropriate raw materials to prepare tert-butyl 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrrolidine-1-carboxylic acid ester, referring to the first step of the synthesis in Example 1.

[0322] Step 2: 400 mg (0.950 mmol) of tert-butyl 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)pyrrolidine-1-carboxylic acid ester was dissolved in hydrochloric acid-dioxane solution (4.0 mL, 4 M), and the mixture was stirred for 1 hour. After the reaction was completed, the system was directly concentrated to obtain 6-fluoro-N-methyl-5-(4-(pyrrolidine-3-ylmethyl)piperazin-1-yl)methylpyridine amide (350 mg, crude product).

[0323] Step 3: Dissolve 6-fluoro-N-methyl-5-(4-(pyrrolidone-3-ylmethyl)piperazin-1-yl)methylpyridine amide (130 mg, 0.405 mmol), 4-(tert-butoxy)-2-chloroquinazoline (96 mg, 0.405 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (32 mg, 0.040 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (34 mg, 0.01 mmol), and cesium carbonate (526 mg, 1.620 mmol) in 1,4-dioxane (10 mL). The reaction system was evacuated and purged three times with nitrogen, then heated to 100 °C and stirred overnight. After the reaction was completed, the product was concentrated and purified by normal phase column chromatography to obtain 5-(4-((1-(4-(tert-butoxy)quinazolin-2-yl)pyrrolidine-3-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylmethylpyridineamide (110 mg, yield: 51.89%).

[0324] Step 4: 5-(4-((1-(4-(tert-butoxy)quinazolin-2-yl)pyrrolidine-3-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylmethylpyridine amide (110 mg, 0.210 mmol) was dissolved in hydrochloric acid-dioxane solution (1.1 mL, 4 M) and stirred at room temperature for 1 hour. After the reaction was complete, the system was concentrated, and the crude product was purified by reverse-phase chromatography to obtain 6-fluoro-N-methyl-5-(4-((1-(4-carbonyl-3,4-dihydroquinazolin-2-yl)pyrrolidine-3-yl)methyl)piperazin-1-yl)methylpyridine amide (20.94 mg, yield: 6.51%, purity: 99.839%). ESI-MS [M+H] + :found 466.3. 1H NMR(400MHz, DMSO-d6)δ11.04(s,1H),8.40(q,J=4.6Hz,1H),7.99–7.78(m,2H), 7.68–7.52(m,2H),7.38–7.18(m,1H),7.16–7.02(m,1H),3.72(dd,J=10.8,7.2Hz ,1H),3.66–3.58(m,1H),3.53–3.44(m,1H),3.28–3.12(m,5H),2.77(d,J=4.8Hz, 3H),2.69–2.50(m,5H),2.46–2.36(m,2H),2.16–1.95(m,1H),1.76–1.62(m,1H).

[0325] Example 12: Preparation of 6-fluoro-N-methyl-5-(4-(1-((4-carbonyl-3,4-dihydroquinazolin-2-yl)methyl)acetidin-3-yl)piperazin-1-yl)methylpyridine amide

[0326] The first and second steps were performed by selecting the appropriate reagents according to the first and second steps of the synthesis in Example 11, respectively, to prepare 5-(4-(acididin-3-yl)piperazin-1-yl)-6-fluoro-N-methylmethylpyridine amide.

[0327] Step 3: Add 2-(chloromethyl)quinazoline-4(3H)-one (117 mg, 0.51 mmol) and potassium carbonate (323 mg, 2.3 mmol) to a 5 mL ethanol solution of 5-(4-(acridin-3-yl)piperazin-1-yl)-6-fluoro-N-methylmethylpyridineamide (0.51 mmol). Heat to 80 °C and stir for 16 hours. Cool to room temperature, concentrate the reaction solution, dissolve the residue in a small amount of acetonitrile, filter, concentrate the filtrate, and purify the crude product by reverse-phase chromatography: 6-fluoro-N-methyl-5-(4-(1-((4-carbonyl-3,4-dihydroquinazoline-2-yl)methyl)acridin-3-yl)piperazin-1-yl)methylpyridineamide (19.3 mg, yield: 8.39%, purity: 95.95%). ESI-MS [M+H] + :found 452.4. 1H NMR (400MHz, DMSO-d6) δ11.97 (brs, 1H), 8.40 (q, J = 4.5Hz, 1H), 8.09 (d, J = 7. 1Hz,1H),7.94–7.75(m,2H),7.63(d,J=8.0Hz,1H),7.60–7.52(m,1H),7.49(t ,J=7.2Hz,1H),3.55(s,2H),3.50(t,J=6.3Hz,2H),3.20–3.12(m,4H),3.08( t,J=6.6Hz,2H),3.03–2.96(m,1H),2.76(d,J=4.7Hz,3H),2.46–2.38(m,4H).

[0328] Examples 13 and 14: Preparation of 6-fluoro-N-methyl-5-(4-((1r,3r)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)methyl)cyclobutyl)piperazin-1-yl)methylpyridinamide and 6-fluoro-N-methyl-5-(4-((1s,3s)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)methyl)cyclobutyl)piperazin-1-yl)methylpyridinamide

[0329] Step 1: Ethyl 2-(diethoxyphospho)acetate (20.3 g, 90.5 mmol) was dissolved in tetrahydrofuran (100 mL). NaH (2.7 g, 68.1 mmol) was added in portions at 0 °C, and the mixture was stirred for 1 hour. Then, 3-(benzyloxy)cyclobutane-1-one (10 g, 56.7 mmol) was added. After the addition was complete, the mixture was slowly brought to room temperature and stirred for 3 hours. After the reaction was complete, saturated ammonium chloride solution was added to quench the reaction, and the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain ethyl 2-(3-(benzyloxy)cyclobutylene)acetate (6.11 g, yield: 87.57%).

[0330] Step 2: Ethyl 2-(3-(benzyloxy)cyclobutylene)acetate (6 g, 24.36 mmol) was dissolved in methanol (50 mL), and palladium on carbon (600 mg) was added. The system was evacuated and purged three times with hydrogen, and the reaction was stirred under hydrogen atmosphere for 1 hour. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to obtain ethyl 2-(3-(benzyloxy)cyclobutylene)acetate (4.79 g, yield: 79.19%).

[0331] Step 3: Ethyl 2-(3-(benzyloxy)cyclobutyl)acetic acid ester (2.7 g, 10.887 mmol) and lithium hydroxide monohydrate (2.3 g, 54.435 mmol) were dissolved in tetrahydrofuran (20 mL), methanol (5 mL), and water (5 mL), and stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with water and adjusted to pH 2-3 with N HCl. The system was extracted three times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain 2-(3-(benzyloxy)cyclobutyl)acetic acid (2.0 g, yield: 63.33%).

[0332] Step 4: Dissolve 2-(3-(benzyloxy)cyclobutyl)acetic acid (1.7 g, 7.727 mmol) in N,N-dimethylformamide (20 mL), then add 2-aminobenzamide (1.1 g, 7.727 mmol), triethylamine (1.6 g, 15.455 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (2.9 g, 7.727 mmol) sequentially. Stir the mixture at room temperature for 2 hours. After the reaction is complete, dilute with water and extract with ethyl acetate. Wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the crude product by normal-phase column chromatography to obtain 2-(2-(3-(benzyloxy)cyclobutyl)acetamido)benzamide (2.0 g, yield: 76.92%).

[0333] Step 5: Dissolve 2-(2-(3-(benzyloxy)cyclobutyl)acetamido)benzamide (2 g, 5.917 mmol) and potassium hydroxide (1.7 g, 29.588 mmol) in ethylene glycol dimethyl ether (30 mL), heat to 60 °C and stir overnight. After the reaction is complete, cool the system to room temperature and concentrate directly. The crude product is purified by normal phase column chromatography to obtain 2-((3-(benzyloxy)cyclobutyl)methyl)quinazolin-4(3H)-one (1.2 g, yield: 63.49%).

[0334] Step 6: Dissolve 2-((3-(benzyloxy)cyclobutyl)methyl)quinazolin-4(3H)-one (900 mg, 2.813 mmol) in dichloromethane (20 mL), add boron trichloride (28 mL, 28.125 mmol) at 0 °C, and stir for 30 minutes. After the reaction is complete, quench the reaction with ice water (40 mL), and extract with ethyl acetate. Wash the organic phase with saturated brine and dry with anhydrous sodium sulfate. Filter and concentrate. The crude product is purified by normal phase column chromatography to obtain 2-((3-hydroxycyclobutyl)methyl)quinazolin-4(3H)-one (450 mg, yield: 69.55%).

[0335] Step 7: Dissolve 2-((3-hydroxycyclobutyl)methyl)quinazolin-4(3H)-one (430 mg, 1.870 mmol) in dichloromethane (10 mL), add Dess-Martin periodinane (1.6 g, 3.739 mmol), and stir overnight at room temperature. After the reaction is complete, quench the reaction with saturated sodium bicarbonate solution and extract with ethyl acetate. Wash the organic phase with saturated brine and dry with anhydrous sodium sulfate. Filter, concentrate the filtrate to give 2-((3-carbonylcyclobutyl)methyl)quinazolin-4(3H)-one (305 mg, yield: 70.93%).

[0336] Step 8: Dissolve 6-fluoro-N-methyl-5-(piperazin-1-yl)methylpyridine amide (104 mg, 0.439 mmol) and triethylamine (44 mg, 0.439 mmol) in 1,2-dichloroethane (10 mL) and stir at room temperature for 10 minutes. Then add 2 drops of acetic acid and 2-((3-carbonylcyclobutyl)methyl)quinazolin-4(3H)-one (100 mg, 0.439 mmol) and stir at room temperature for 1 hour. Finally, add sodium triacetoxyborohydride (185 mg, 0.877 mmol) and continue stirring for 2 hours. After the reaction was completed, 5 mL of saturated sodium bicarbonate aqueous solution was added to quench the reaction. The product was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered, and the crude product was purified by reverse-phase preparative column chromatography to obtain Example 43 (18.34 mg, yield: 9.28%, purity: 99.740%) and Example 44 (30.43 mg, yield: 15.40%, purity: 99.342%).

[0337] Example 13: 6-Fluoro-N-methyl-5-(4-((1r,3r)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)methyl)cyclobutyl)piperazin-1-yl)methylpyridinamide or 6-fluoro-N-methyl-5-(4-((1s,3s)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)methyl)cyclobutyl)piperazin-1-yl)methylpyridinamide, ESI-MS [M+H] + :found 451.3, 1H NMR (400MHz, DMSO-d6) δ10.75(s,1H),8.40(q,J=4.6Hz,1H),8.08(dd,J=7.9,1.3H z,1H),7.89–7.82(m,1H),7.80–7.73(m,1H),7.61(d,J=8.0Hz,1H),7.55(dd,J=10. 6,8.2Hz,1H),7.49–7.43(m,1H),3.20–3.10(m,4H),2.97–2.89(m,1H),2.83–2.73( m,5H),2.71–2.60(m,1H),2.46–2.37(m,4H),2.08–1.99(m,2H),1.95–1.85(m,2H).

[0338] Example 14: 6-Fluoro-N-methyl-5-(4-((1s,3s)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)methyl)cyclobutyl)piperazin-1-yl)methylpyridinamide or 6-fluoro-N-methyl-5-(4-((1r,3r)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)methyl)cyclobutyl)piperazin-1-yl)methylpyridinamide, ESI-MS [M+H] + :found 451.3. 1 H NMR (400MHz, DMSO-d6) δ12.12(s,1H),8.40(q,J=4.4Hz,1H),8.07(d,J=7.1H z,1H),7.84(d,J=7.8Hz,1H),7.80–7.73(m,1H),7.63–7.52(m,2H),7.45(t,J =7.5Hz,1H),3.20–3.09(m,4H),2.76(d,J=4.8Hz,3H),2.70(d,J=7.4Hz,2H) ,2.65–2.59(m,1H),2.48–2.35(m,5H),2.25–2.15(m,2H),1.68–1.55(m,2H).

[0339] Example 15: Preparation of 6-fluoro-N-methyl-5-(4-(((1s,3s)-3-(4-carbonyl-3,4-dihydroquinazolin-2-yl)cyclobutyl)methyl)piperazin-1-yl)methylpyridine amide

[0340] Step 1: Methyl 3-(hydroxymethyl)cyclobutane-1-carboxylic acid ester (10 g, 69.36 mmol) was dissolved in DMF (100 mL), and TBDPSCl (19.07 g, 69.36 mmol) and imidazole (7.08 g, 104.04 mmol) were added at room temperature. The reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with aqueous solution (100 mL), and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and the reaction solution was filtered. The crude product was concentrated and purified by normal phase column chromatography to obtain methyl 3-(((tert-butyldiphenylsilyl)oxo)methyl)cyclobutane-1-carboxylic acid ester (19 g, yield: 71.6%).

[0341] Steps two through four can be performed by referring to steps three through five of the synthesis in Examples 13 and 14, selecting appropriate starting materials to react and obtain 2-(3-(((tert-butyldiphenylsilyl)oxo)methyl)cyclobutyl)quinazolin-4(3H)-one.

[0342] Step 5: Dissolve 1.3 g (2.78 mmol) of 2-(3-(((tert-butyldiphenylsilyl)oxo)methyl)cyclobutyl)quinazolin-4(3H)-one in tetrahydrofuran (10 mL), add tetrabutylammonium fluoride (3.33 mL, 3.33 mmol, 1 M tetrahydrofuran solution), and react at room temperature for 1 hour. After the reaction is complete, quench the reaction with water (100 mL), and extract with ethyl acetate. Wash the organic phase with saturated brine and dry with anhydrous sodium sulfate. Filter, concentrate the filtrate, and purify the crude product by normal-phase column chromatography to obtain 2-(3-(hydroxymethyl)cyclobutyl)quinazolin-4(3H)-one (550 mg, yield: 85.6%).

[0343] Steps six and seven can be performed with suitable starting materials, referring to steps seven and eight in the syntheses of Examples 13 and 14, to obtain 6-fluoro-N-methyl-5-(4-(((1s,3s)-3-(4-carbonyl-3,4-dihydroquinazoline-2-yl)cyclobutyl)methyl)piperazin-1-yl)methylpyridineamide. Step seven only yielded one product, the disubstituted four-membered ring of which was tentatively identified as cis-substituted by two-dimensional NMR spectroscopy; however, the determined configuration needs further confirmation by other methods. ESI-MS [M+H] + :found 451.2. 1H NMR (400MHz, DMSO-d6) δ12.11(s,1H),8.41(q,J=4.5Hz,1H),8.23(s,1H),8.07(d d,J=7.9,1.2Hz,1H),7.84(d,J=7.4Hz,1H),7.81–7.75(m,1H),7.64(d,J=8.0Hz,1 H),7.60–7.52(m,1H),7.47(d,J=7.8Hz,1H),3.45–3.33(m,1H),3.20–3.12(m,4H ),2.77(d,J=4.8Hz,3H),2.60–2.50(m,5H),2.48–2.34(m,4H),2.15–2.03(m,2H).

[0344] Examples 16 and 17: Preparation of 6-fluoro-N-methyl-5-(4-((1r,3r)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)amino)cyclobutyl)piperazin-1-yl)methylpyridinamide and 6-fluoro-N-methyl-5-(4-((1s,3s)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)amino)cyclobutyl)piperazin-1-yl)methylpyridinamide

[0345] In the first and second steps, the corresponding reagents were selected and reacted according to the first and second steps of the synthesis in Example 11 to prepare 5-(4-(3-aminocyclobutyl)piperazin-1-yl)-6-fluoro-N-methylmethylpyridine amide, wherein the cyclobutane was a mixture of cis and trans substitutions and the two isomers were not separated.

[0346] Step 3: 5-(4-(3-aminocyclobutyl)piperazin-1-yl)-6-fluoro-N-methylmethylpyridine amide (200 mg, 0.97 mmol) was dissolved in sulfoxide (4 mL), and diisopropylethylamine (335.4 mg, 2.6 mmol) and 2-chloroquinazoline-4(3H)-one (117.3 mg, 0.97 mmol) were added. The mixture was heated to 90 °C and stirred for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was directly purified by reverse-phase preparation to obtain Example 16 (21.63 mg, purity: 99.319%) and Example 17 (17.69 mg, purity: 98.141%).

[0347] Example 16: 6-Fluoro-N-methyl-5-(4-((1r,3r)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)amino)cyclobutyl)piperazin-1-yl)methylpyridinamide or 6-fluoro-N-methyl-5-(4-((1s,3s)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)amino)cyclobutyl)piperazin-1-yl)methylpyridinamide, ESI-MS [M+H] + :found 452.3. 1 H NMR (400MHz, DMSO-d6) δ10.72 (s, 1H), 8.40 (q, J = 4.7Hz, 1H), 7.91–7.85 (mm 2H),7.62–7.51(m,2H),7.25(d,J=8.1Hz,1H),7.10(t,J=7.3Hz,1H),6.70(s,1H),4.41–4.31m,1H),3.24–3. 16(m,4H),2.94–2.85(m,1H),2.77(d,J=4.8Hz,3H),2.49–2.44(m,4H),2.37–2.28(m,2H),2.10–2.00(m,2H).

[0348] Example 17: 6-Fluoro-N-methyl-5-(4-((1s,3s)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)amino)cyclobutyl)piperazin-1-yl)methylpyridinamide or 6-fluoro-N-methyl-5-(4-((1r,3r)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)amino)cyclobutyl)piperazin-1-yl)methylpyridinamide, ESI-MS [M+H] + :found 452.3. 1 H NMR (400MHz, DMSO-d6) δ10.70(s,1H),8.40(q,J=4.6Hz,1H),7.91–7.82(m,2H),7.62–7.53(m,2H),7.24(d,J=8.1Hz,1H),7.10(t,J=7.4H z,1H),6.52(s,1H),4.22–4.08(m,1H),3.20–3.13(m,4H),2.77(d,J=4.8Hz,3H),2.58–2.50(m,3H),2.49–2.41(m,4H),1.82–1.68(m,2H).

[0349] Examples 18-19 can be prepared by selecting suitable raw materials according to the synthesis methods of Examples 16 and 17, and their structures are shown in Table 4.

[0350] Table 4. Structural formulas, chemical names, and mass spectrometry data of Examples 18-19

[0351] The NMR data of some of the compounds in the examples are as follows:

[0352] Example 20: Preparation of 6-fluoro-N-methyl-5-(4-((1s,3s)-3-((4-carbonyl-3,4-dihydroquinazolin-2-yl)oxo)cyclobutyl)piperazin-1-yl)methylpyridine amide

[0353] Step 1: 6-fluoro-N-methyl-5-(piperazin-1-yl)methylpyridine amide (1.0 g, 4.2 mmol) was dissolved in dichloroethane (20 mL), and triethylamine (0.7 mL) was added. After stirring for 5 minutes, 3-(benzyloxy)cyclobutane-1-one (740 mg, 4.2 mmol) and 3 drops of acetic acid were added. The mixture was heated to 50 °C and stirred for 0.5 hours. Then, sodium borohydride acetate (2.67 g, 12.6 mmol) was added. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain 5-(4-((1s,3s)-3-(benzyloxy)cyclobutyl)piperazin-1-yl)-6-fluoro-N-methylmethylpyridine amide (760 mg, yield: 45.5%).

[0354] Step 2: 5-(4-((1s,3s)-3-(benzyloxy)cyclobutyl)piperazin-1-yl)-6-fluoro-N-methylmethylpyridinamide (685 mg, 1.72 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 °C, and boron tribromide (2 M, 2.6 mL, 5.16 mmol) was added. The mixture was stirred for 0.5 hours. After the reaction was complete, a small amount of water was added dropwise to quench the reaction. The reaction system was directly concentrated, and the crude product was purified by reverse-phase separation to obtain 6-fluoro-5-(4-((1s,3s)-3-hydroxycyclobutyl)piperazin-1-yl)-N-methylmethylpyridinamide (140 mg, yield: 26.4%).

[0355] Step 3: Dissolve 6-fluoro-5-(4-((1s,3s)-3-hydroxycyclobutyl)piperazin-1-yl)-N-methylmethylpyridine amide (140 mg, 0.455 mmol) in 1,4-dioxane (15 mL), add 4-(tert-butoxy)-2-chloroquinazoline (139 mg, 0.591 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (38 mg, 0.045 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (42 mg, 0.09 mmol), and cesium carbonate (296 mg, 0.910 mmol). The system is evacuated and purged three times with nitrogen, then heated to 100 °C and stirred overnight. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by normal phase column chromatography to obtain 5-(4-((1s,3s)-3-((4-(tert-butoxy)quinazolin-2-yl)oxo)cyclobutyl)piperazin-1-yl)-6-fluoro-N-methylmethylpyridine amide (105 mg, yield: 45.5%).

[0356] Step 4: 5-(4-((1s,3s)-3-((4-(tert-butoxy)quinazolin-2-yl)oxo)cyclobutyl)piperazin-1-yl)-6-fluoro-N-methylmethylpyridine amide (105 mg, 0.207 mmol) was dissolved in 5 mL of 1,4-dioxane hydrochloride solution and stirred at room temperature for 10 minutes. After the reaction was complete, the product was concentrated, and the crude product was purified by reverse-phase chromatography to obtain 6-fluoro-N-methyl-5-(4-((1s,3s)-3-((4-carbonyl-3,4-dihydroquinazolin-2-yl)oxo)cyclobutyl)piperazin-1-yl)methylpyridine amide (34.18 mg, yield: 36.8%, purity: 99.793%). ESI-MS [M+H] + :found 453.3. 1 H NMR (400MHz, DMSO-d6) δ12.27(s,1H),8.40(q,J=4.7Hz,1H),8.00(d,J=7.9Hz,1H),7 .85(d,J=8.1Hz,1H),7.73–7.66(m,1H),7.57(dd,J=10.6,8.2Hz,1H),7.42(d,J=8.1H z,1H),7.32(t,J=7.5Hz,1H),5.05(p,J=7.4Hz,1H),3.21–3.14(m,4H),2.77(d,J=4. 8Hz,3H),2.73–2.64(m,2H),2.59–2.54(m,1H),2.50–2.43(m,4H),2.02–1.90(m,2H).

[0357] Examples 21-48 can be prepared by selecting suitable raw materials according to the synthesis method of Example 20, and their structures are shown in Table 5.

[0358] Table 5. Structural formulas, chemical names, and mass spectrometry data of Examples 21-48

[0359] The NMR data of some of the compounds in the examples are as follows:

[0360] Examples 49 and 50: Preparation of 6-fluoro-N-methyl-5-(4-((1s,3s)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)thio)cyclobutyl)piperazin-1-yl)methylpyridinamide and 6-fluoro-N-methyl-5-(4-((1r,3r)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)thio)cyclobutyl)piperazin-1-yl)methylpyridinamide

[0361] Step 1: 3-(benzyloxy)cyclobutane-1-ol (2 g, 11.221 mmol) was dissolved in dichloromethane (40 mL), and 4-dimethylaminopyridine (0.14 g, 1.122 mmol), triethylamine (4.679 mL, 33.664 mmol), and p-toluenesulfonyl chloride (3.21 g, 16.832 mmol) were added. The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain 3-(benzyloxy)cyclobutyl-4-methylbenzenesulfonate (3.1 g, yield: 83.11%).

[0362] Step 2: 3-(benzyloxy)cyclobutyl 4-methylbenzenesulfonate (3.1 g, 9.326 mmol) was dissolved in anhydrous N,N-dimethylformamide (30 mL), and potassium thioacetate (4.26 g, 37.303 mmol) was added. The mixture was stirred overnight at 100 °C. After the reaction was complete, the solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain S-(3-(benzyloxy)cyclobutyl)ethyl sulfate (1.88 g, yield: 85.30%).

[0363] Step 3: S-(3-(benzyloxy)cyclobutyl)ethyl sulfate (1.88 g, 7.955 mmol) was dissolved in methanol (30 mL), and potassium carbonate (3.30 g, 23.865 mmol) was added. The mixture was stirred at 70 °C for 1 hour. After the reaction was complete, the solution was diluted with water, adjusted to neutral with 1N dilute hydrochloric acid, and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain 3-(benzyloxy)cyclobutane-1-thiol (1.2 g, yield: 77.64%).

[0364] Step 4: Dissolve 3-(benzyloxy)cyclobutane-1-thiol (1.2 g, 6.176 mmol) in anhydrous N,N-dimethylformamide (15 mL), add 4-(tert-butoxy)-2-chloroquinazoline (1.46 g, 6.176 mmol) and potassium tert-butoxide (1.39 g, 12.353 mmol), heat to 100 °C and stir for 2 hours. After the reaction is complete, dilute with water and extract with ethyl acetate. Wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the crude product by normal phase column chromatography to obtain 2-((3-(benzyloxy)cyclobutyl)thio)-4-(tert-butoxy)quinazoline (1.1 g, yield: 48%).

[0365] Step 5: Dissolve 2-((3-(benzyloxy)cyclobutyl)thio)-4-(tert-butoxy)quinazoline (1.1 g, 2.8 mmol) in anhydrous dichloromethane (150 mL), cool to 0 °C, and then add a dichloromethane solution of boron tribromide (2 M, 4.2 mL, 8.4 mmol). After the addition is complete, maintain this temperature and stir the reaction for 1 hour. After the reaction is complete, quench with methanol. The crude product after concentration is purified by normal-phase column chromatography to obtain 2-((3-hydroxycyclobutyl)thio)quinazoline-4(3H)-one (550 mg, yield: 80%).

[0366] Step 6: Dissolve 2-((3-hydroxycyclobutyl)thio)quinazolin-4(3H)-one (550 mg, 2.2 mmol) in anhydrous N,N-dimethylformamide (20 mL), add potassium carbonate (911 mg, 6.6 mmol) and 4-methoxybenzyl chloride (288 mg, 1.8 mmol), and stir overnight at room temperature. After the reaction is complete, dilute with water and extract with ethyl acetate. Wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the crude product by normal phase column chromatography to obtain 3-((4-((4-methoxybenzyl)oxo)quinazolin-2-yl)thio)cyclobutane-1-ol (680 mg, yield: 84%).

[0367] Step 7: Dissolve 3-((4-(((4-methoxybenzyl)oxo)quinazolin-2-yl)thio)cyclobutane-1-ol (480 mg, 1.303 mmol) in acetonitrile (30 mL), and add 2-iodobenzoic acid (729.59 mg, 2.606 mmol). Heat to 80 °C and stir for 1 hour. After the reaction is complete, filter, concentrate the filtrate, and purify the crude product by normal phase column chromatography to obtain 3-((4-(((4-methoxybenzyl)oxo)quinazolin-2-yl)thio)cyclobutane-1-one (150 mg, yield: 31.42%).

[0368] Step 8: 3-((4-(((4-methoxybenzyl)oxo)quinazolin-2-yl)thio)cyclobutane-1-one (150 mg, 0.409 mmol) and 6-fluoro-N-methyl-5-(piperazin-1-yl)methylpyridine amide (195.07 mg, 0.819 mmol) were dissolved in methanol (10 mL), and sodium cyanoborohydride (77.17 mg, 1.228 mmol) was added. The mixture was heated to 60 °C and stirred for 1 hour. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by normal-phase column chromatography to obtain 6-fluoro-5-(4-(3-((4-(((4-methoxybenzyl)oxo)quinazolin-2-yl)thio)cyclobutyl)piperazin-1-yl)-N-methylmethylpyridine amide (160 mg, yield: 66.39%).

[0369] Step 9: 6-Fluoro-5-(4-(3-((4-(((4-methoxybenzyl)oxo)quinazolin-2-yl)thio)cyclobutyl)piperazin-1-yl)-N-methylmethylpyridine amide (150 mg, 0.255 mmol) was dissolved in trifluoroacetic acid (3 mL), and trifluoromethanesulfonic acid (0.5 mL) was added. The mixture was heated to 60 °C and stirred for 20 minutes. After the reaction was completed, the mixture was cooled to room temperature, and the system was directly concentrated. The crude product was purified by reverse-phase reaction to obtain Example 49 (1.02 mg, 0.85%) and Example 50 (9.69 mg, 7.39%).

[0370] Example 49: 6-Fluoro-N-methyl-5-(4-((1s,3s)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)thio)cyclobutyl)piperazin-1-yl)methylpyridinamide or 6-fluoro-N-methyl-5-(4-((1r,3r)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)thio)cyclobutyl)piperazin-1-yl)methylpyridinamide, ESI-MS [M+H] + :found 469.1. 1H NMR (400MHz, DMSO-d6) δ8.40(brs,1H),7.99(d,J=7.9Hz,1H),7.85(d,J=8.1Hz,1H),7.66(d,J=7.1Hz,1H),7.62–7.53(m,1H),7.44(d,J=8. 0Hz,1H),7.33(t,J=7.0Hz,1H),4.30–4.17(m,1H),3.23–3.14(m,4H), 3.10–3.05(m,1H),2.76(s,3H),2.50–2.40(m,6H),2.22–2.10(m,2H).

[0371] Example 50: 6-Fluoro-N-methyl-5-(4-((1r,3r)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)thio)cyclobutyl)piperazin-1-yl)methylpyridinamide or 6-fluoro-N-methyl-5-(4-((1s,3s)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)thio)cyclobutyl)piperazin-1-yl)methylpyridinamide, ESI-MS [M+H] + :found 469.1. 1 H NMR (400MHz, DMSO-d6) δ8.43–8.38(m,2H),8.01–7.95(m,1H),7.84(d,J=8.0H z,1H),7.71–7.64(m,1H),7.57(dd,J=10.6,8.2Hz,1H),7.45(d,J=8.1Hz,1H), 7.36–7.30(m,1H),4.15–4.06(m,1H),3.20–3.13(m,4H),2.86–2.80(m,1H),2 .76(d,J=4.8Hz,3H),2.72–2.62(m,2H),2.48–2.41(m,4H),1.98–1.86(m,2H).

[0372] Example 51: Preparation of 5-(4-((1s,3s)-3-((7-acetyl-4-carbonyl-3,4,5,6,7,8-hexahydropyridino[3,4-d]pyrimidin-2-yl)oxo)cyclobutyl)piperazin-1-yl)-6-fluoro-N-methylmethylpyridine amide

[0373] Step 1: 1.2 g (2.922 mmol) of tert-butyl-2-chloro-4-((4-methoxybenzyl)oxo)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid ester, 6-fluoro-5-(4-((1s,3s)-3-hydroxycyclobutyl)piperazin-1-yl)-N-methylmethylpyridine amide (600 mg, 1.948 mmol), and 2-dicyclohexyl methanesulfonic acid were added. Phospho-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (163 mg, 0.195 mmol), 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl (182 mg, 0.398 mmol), and cesium carbonate (1.3 g, 3.896 mmol) were dissolved in 1,4-dioxane (20 mL). The system was evacuated and purged three times with nitrogen, then heated to 100 °C and stirred for 16 hours. After the reaction was completed, the reaction solution was filtered, and the crude product was concentrated by normal phase column chromatography to obtain tert-butyl 2-((1s,3s)-3-(4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclobutoxy)-4-((4-methoxybenzyl)oxo)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid ester (600 mg, yield: 46.28%).

[0374] Step 2: 500 mg (0.739 mmol) of tert-butyl 2-((1s,3s)-3-(4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclobutoxy)-4-((4-methoxybenzyl)oxo)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid ester was dissolved in dichloromethane (5.0 mL), and 1.0 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the system was concentrated to obtain 6-fluoro-N-methyl-5-(4-((1s,3s)-3-((4-carbonyl-3,4,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-2-yl)oxo)cyclobutyl)piperazin-1-yl)methylpyridineamide (600 mg, crude product).

[0375] Step 3: 6-Fluoro-N-methyl-5-(4-((1s,3s)-3-((4-carbonyl-3,4,5,6,7,8-hexahydropyridino[3,4-d]pyrimidin-2-yl)oxo)cyclobutyl)piperazin-1-yl)methylpyridine amide (100 mg, 0.219 mmol), methyl chloroformate (19 mg, 0.241 mmol), and triethylamine (44 mg, 0.438 mmol) were dissolved in dichloromethane (5 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated to obtain the crude product. The crude product was purified by reverse-phase reaction to give 5-(4-((1s,3s)-3-((7-acetyl-4-carbonyl-3,4,5,6,7,8-hexahydropyridano[3,4-d]pyrimidin-2-yl)oxo)cyclobutyl)piperazin-1-yl)-6-fluoro-N-methylmethylpyridine amide (27.67 mg, yield: 25.39%, purity: 97.231%). ESI-MS [M+H] + :found 500.1. 1 H NMR(400MHz,DMSO-d6)δ8.40(q,J=4.4Hz,1H),8.22(s,0.78H,FA),7.84(d,J=7.9H z,1H),7.56(dd,J=10.5,8.3Hz,1H),4.97–4.85(m,1H),4.25(d,J=10.0Hz,2H),3.6 3–3.55(m,2H),3.19–3.12(m,4H),2.76(d,J=4.8Hz,3H),2.68–2.58(m,2H),2.57– 2.50(m,2H),2.48–2.34(m,5H),2.32–2.24(m,1H),2.07(s,3H),1.96–1.84(m,2H).

[0376] Examples 52-54 can be prepared by selecting suitable raw materials according to the synthesis method of Example 51, and their structures are shown in Table 6.

[0377] Table 6. Structural formulas, chemical names, and mass spectrometry data of Examples 52-54

[0378] The NMR data of some of the compounds in the examples are as follows:

[0379] Example 55: Preparation of 6-fluoro-N-methyl-5-(4-((1s,3s)-3-((4-carbonyl-3,4,5,6,7,8-hexahydropyridino[2,3-d]pyrimidin-2-yl)oxo)cyclobutyl)piperazin-1-yl)methylpyridine amide

[0380] The synthesis of Example 55 can be carried out by referring to the first and second steps of the synthesis of Example 51, selecting appropriate principles for preparation. ESI-MS [M+H] + :found 458.1. 1 H NMR (400MHz, DMSO-d6) δ11.10(s,1H),8.40(q,J=4.6Hz,1H),7.84(dd,J=8.0,1.2Hz,1H),7.56(dd,J=10.6,8.2Hz,1H),6.61(s,1H),4.80(p,J=7.5H z,1H),3.20–3.11(m,6H),2.76(d,J=4.8Hz,3H),2.63–2.54(m,2H),2.49– 2.40(m,5H),2.24(t,J=6.1Hz,2H),1.92–1.80(m,2H),1.72–1.60(m,2H).

[0381] Example 56: Preparation of 5-(4-((1s,3s)-3-((8-amino-4-carbonyl-3,4-dihydroquinazolin-2-yl)oxo)cyclobutyl)piperazin-1-yl)-6-fluoro-N-methylmethylpyridine amide

[0382] Step 1: Dissolve 8-bromo-2,4-dichloroquinazoline (9g, 32.37mmol) in tetrahydrofuran (100mL). o Potassium tert-butoxide solution (39 mL, 38.84 mmol) was slowly added dropwise at C. After the addition was complete, the reaction was stirred at 0 °C for 16 hours. The reaction was quenched with water after completion and extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was purified by normal-phase column chromatography to give 8-bromo-4-(tert-butoxy)-2-chloroquinazoline (6.8 g, 66.47%).

[0383] Step 2: 8-Bromo-4-(tert-butoxy)-2-chloroquinazoline (8.6 g, 27.39 mmol) was dissolved in dioxane (160 mL), and 3-(benzyloxy)cyclobutane-1-ol (4.88 g, 27.39 mmol) and potassium tert-butoxide (6.14 g, 54.78 mmol) were added sequentially. The reaction system was heated to 100 °C and stirred for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, and extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by normal-phase column chromatography to obtain 2-(3-(benzyloxy)cyclobutoxy)-8-bromo-4-(tert-butoxy)quinazoline (5.2 g, 41.53%).

[0384] Step 3: 2-(3-(benzyloxy)cyclobutoxy)-8-bromo-4-(tert-butoxy)quinazoline (5.2 g, 11.38 mmol) was dissolved in dioxane (100 mL), followed by the addition of tert-butylcarbamate (1.33 g, 11.38 mmol), tris(diphenylmethyleneacetone)dipalladium (1.04 g, 1.14 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (1.32 g, 2.28 mmol), and cesium carbonate (11.13 g, 34.14 mmol). The system was purged with nitrogen three times and then heated to 100 °C with stirring for 16 hours. After the reaction was completed and cooled to room temperature, the crude product was concentrated and purified by normal phase column chromatography to obtain tert-butyl(2-(3-(benzyloxy)cyclobutoxy)-4-(tert-butoxy)quinazolin-8-yl)carbamate (930 mg, 16.58%).

[0385] Step 4: Dissolve tert-butyl(2-(3-(benzyloxy)cyclobutoxy)-4-(tert-butoxy)quinazoline-8-yl)carbamate (930 mg, 1.89 mmol) in methanol (20 mL), then add palladium on carbon (460 mg). Stir the reaction mixture at room temperature for 16 hours. After the reaction is complete, filter the mixture, and wash the filter cake with methanol. Combine the filtrates and concentrate to obtain tert-butyl(4-(tert-butoxy)-2-(3-hydroxycyclobutoxy)quinazoline-8-yl)carbamate (560 mg, 73.49%).

[0386] Step 5: Dissolve tert-butyl(4-(tert-butoxy)-2-(3-hydroxycyclobutoxy)quinazoline-8-yl)carbamate (500 mg, 1.239 mmol) in dichloromethane (20 mL), add Dys-Martin oxidant (1.05 g, 2.478 mmol), and stir at room temperature for 16 hours. After the reaction is complete, quench the reaction with saturated sodium bicarbonate, and extract with dichloromethane. Wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the crude product by normal phase column chromatography to obtain tert-butyl(4-(tert-butoxy)-2-(3-oxocyclobutoxy)quinazoline-8-yl)carbamate (200 mg, 40.20%).

[0387] Step 6: Dissolve tert-butyl (4-(tert-butoxy)-2-(3-oxocyclobutoxy)quinazolin-8-yl)carbamate (200 mg, 0.498 mmol) in methanol (8.0 mL), then add 6-fluoro-N-methyl-5-(piperazin-1-yl)methylpyridine amide (118.70 mg, 0.498 mmol) and sodium cyanoborohydride (63 mg, 0.996 mmol) sequentially. Heat to 50 °C and stir for 1 hour. After the reaction is complete, quench the reaction with water and extract three times with ethyl acetate. Wash the organic phase with saturated brine and dry with anhydrous sodium sulfate. After filtration and concentration of the filtrate, the crude product was purified by normal phase column chromatography to obtain tert-butyl(4-(tert-butoxy)-2-((1s,3s)-3-(4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclobutoxy)quinazolin-8-yl)carbamate (220 mg, 77.80%).

[0388] Step 7: 50 mg (0.080 mmol) of tert-butyl(4-(tert-butoxy)-2-((1s,3s)-3-(4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclobutoxy)quinazoline-8-yl)carbamate was dissolved in dioxane hydrochloride (1.0 mL), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the system was directly concentrated, and the crude product was purified by reverse-phase chromatography to obtain 5-(4-((1s,3s)-3-((8-amino-4-carbonyl-3,4-dihydroquinazoline-2-yl)oxo)cyclobutyl)piperazin-1-yl)-6-fluoro-N-methylmethylpyridinamide (7.90 mg, yield: 19.18%, purity: 98.554%). ESI-MS [M+H] + :found 468.1. 1 H NMR (400MHz, DMSO-d6) δ12.10(s,1H),8.40(d,J=4.8Hz,1H),8.29(s,1H),7.85(d,J=8. 0Hz,1H),7.57(dd,J=10.5,8.2Hz,1H),7.15(dd,J=7.8,1.4Hz,1H),7.01(t,J=7.8Hz,1 H),6.90(dd,J=7.7,1.4Hz,1H),5.44(s,2H),5.09(dd,J=14.6,7.4Hz,1H),3.17(s,4H) ,2.76(t,J=6.4Hz,5H),2.57(d,J=5.5Hz,1H),2.47(d,J=4.3Hz,4H),2.02–1.91(m,2H).

[0389] Example 57: Preparation of 6-fluoro-N-methyl-5-(4-((1s,3s)-3-((5-methyl-4-carbonyl-3,4,5,6,7,8-hexahydropyridino[3,2-d]pyrimidin-2-yl)oxo)cyclobutyl)piperazin-1-yl)methylpyridine amide

[0390] 6-Fluoro-N-methyl-5-(4-((1s,3s)-3-((4-carbonyl-3,4,5,6,7,8-hexahydropyridino[3,2-d]pyrimidin-2-yl)oxo)cyclobutyl)piperazin-1-yl)methylpyridine amide (200 mg, 0.437 mmol) was dissolved in methanol (8.0 mL), and then formaldehyde aqueous solution (0.087 mL, 0.874 mmol) and sodium cyanoborohydride (55 mg, 0.874 mmol) were added sequentially. The mixture was heated to 50 °C and stirred for 1 hour. After the reaction was completed, the product was concentrated, and the crude product was purified by reverse-phase synthesis to obtain 6-fluoro-N-methyl-5-(4-((1s,3s)-3-((5-methyl-4-carbonyl-3,4,5,6,7,8-hexahydropyrido[3,2-d]pyrimidin-2-yl)oxo)cyclobutyl)piperazin-1-yl)methylpyridineamide (17.23 mg, yield: 9.70%, purity: 96.951%). ESI-MS [M+H] + :found 472.1. 1 H NMR (400MHz, DMSO-d6) δ12.05(s,1H),8.40(d,J=4.8Hz,1H),8.19(s,1H),7.84(d,J=7.9Hz,1H),7.56(dd,J=10.4,8.3Hz,1H),4.84(p,J=7.1Hz, 1H),3.16(s,4H),2.86(s,2H),2.76(d,J=4.7Hz,3H),2.69(s,3H),2.59 (d,J=6.6Hz,3H),2.42(d,J=15.7Hz,6H),1.93–1.80(m,2H),1.72(s,2H)

[0391] Examples 58-60 can be prepared by selecting suitable raw materials according to the synthesis method of Example 57, and their structures are shown in Table 7.

[0392] Table 7. Structural formulas, chemical names, and mass spectrometry data of Examples 58-60

[0393] The NMR data of some of the compounds in the examples are as follows:

[0394] Examples 61 and 62: Preparation of 6-fluoro-5-(4-((1r,3r)-3-((5-fluoro-4-carbonyl-3,4-dihydroquinazoline-2-yl)oxo)cyclobutyl)piperazin-1-yl)-N-methylmethylpyridinamide and 6-fluoro-5-(4-((1s,3s)-3-((5-fluoro-4-carbonyl-3,4-dihydroquinazoline-2-yl)oxo)cyclobutyl)piperazin-1-yl)-N-methylmethylpyridinamide

[0395] Step 1: 10 g (53.76 mmol) of tert-butylpiperazine-1-carboxylic acid ester was dissolved in 100 mL of methanol. 3-(benzyloxy)cyclobutane-1-one (9.46 g, 53.76 mmol), sodium cyanoborohydride (9.99 g, 161.29 mmol), and acetic acid (0.2 mL) were added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated and quenched with water. The mixture was extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the crude product was purified by normal-phase column chromatography to obtain tert-butyl-4-(3-(benzyloxy)cyclobutyl)piperazine-1-carboxylic acid ester (3.0 g, yield: 16.13%, cis-trans mixture).

[0396] Step 2: 3.0 g (8.67 mmol) of tert-butyl-4-(3-(benzyloxy)cyclobutyl)piperazine-1-carboxylic acid ester was dissolved in 30 mL of 1,4-dioxane hydrogen chloride solution, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the product was concentrated to obtain 1-(3-(benzyloxy)cyclobutyl)piperazine (3.0 g, yield: 100%). The crude product was used directly in the next step of the reaction.

[0397] Step 3: Methyl 5-bromo-6-fluoromethylpyridinium ester (1.33 g, 5.68 mmol) was dissolved in 1,4-dioxane (80 mL), and 1-(3-(benzyloxy)cyclobutyl)piperazine (1.5 g, 5.68 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (712 mg, 0.85 mmol), and cesium carbonate (7.41 mg, 22.72 mmol) were added. The system was evacuated and purged with nitrogen three times, then heated to 100 °C and stirred overnight. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by normal phase column chromatography to obtain methyl 5-(4-(3-(benzyloxy)cyclobutyl)piperazin-1-yl)-6-fluoromethylpyridinium ester (1.3 g, yield: 57.4%).

[0398] Step 4: Methyl 5-(4-(3-(benzyloxy)cyclobutyl)piperazin-1-yl)-6-fluoromethylpyridinium ester (1.3 g, 3.26 mmol) was dissolved in methylamine-ethanol (30 mL) and stirred at room temperature for 45 minutes. After the reaction was complete, the system was directly concentrated to give 5-(4-(3-(benzyloxy)cyclobutyl)piperazin-1-yl)-6-fluoro-N-methylmethylpyridinamide (1.2 g, yield: 92.3%). The crude product was used directly in the next step of the reaction.

[0399] Step 5: 5-(4-(3-(benzyloxy)cyclobutyl)piperazin-1-yl)-6-fluoro-N-methylmethylpyridinamide (1.93 g, 4.85 mmol) was dissolved in dichloromethane (20 mL), cooled to 0 °C, and boron tribromide (7.3 mL, 14.55 mmol, 2 M dichloromethane solution) was added. The mixture was stirred for 0.5 hours. After the reaction was complete, a small amount of water was added dropwise to quench the reaction, and the mixture was directly concentrated. The crude product was purified by reverse-phase separation to obtain 6-fluoro-5-(4-(3-hydroxycyclobutyl)piperazin-1-yl)-N-methylmethylpyridinamide (550 mg, yield: 36.8%).

[0400] Step 6: Dissolve 6-fluoro-5-(4-(3-hydroxycyclobutyl)piperazin-1-yl)-N-methylmethylpyridine amide (550 mg, 1.79 mmol) in 1,4-dioxane (30 mL), and add 4-(tert-butoxy)-2-chloro-5-fluoroquinazoline (680 mg, 2.68 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (149 mg, 0.18 mmol), 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl (167 mg, 0.36 mmol), and cesium carbonate (1.16 g, 3.58 mmol). The system is evacuated and purged three times with nitrogen, then heated to 100 °C and stirred for 16 hours. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by normal phase column chromatography to obtain 5-(4-(3-((4-(tert-butoxy)-5-fluoroquinazolin-2-yl)oxo)cyclobutyl)piperazin-1-yl)-6-fluoro-N-methylmethylpyridine amide (660 mg, yield: 70.0%).

[0401] Step 7: Dissolve 660 mg (1.25 mmol) of 5-(4-(3-((4-(tert-butoxy)-5-fluoroquinazolin-2-yl)oxo)cyclobutyl)piperazin-1-yl)-6-fluoro-N-methylmethylpyridine amide in 5 mL of 1,4-dioxane hydrochloride solution and stir at room temperature for 30 minutes. After the reaction is complete, concentrate to obtain the crude product. The crude product was purified by reverse-phase preparation to obtain 6-fluoro-5-(4-((1r,3r)-3-((5-fluoro-4-carbonyl-3,4-dihydroquinazoline-2-yl)oxo)cyclobutyl)piperazin-1-yl)-N-methylmethylpyridine amide (41.14 mg, yield: 7.0%, purity: 99.422%) and 6-fluoro-5-(4-((1s,3s)-3-((5-fluoro-4-carbonyl-3,4-dihydroquinazoline-2-yl)oxo)cyclobutyl)piperazin-1-yl)-N-methylmethylpyridine amide (31.25 mg, yield: 5.3%, purity: 99.588%).

[0402] Example 61: 6-Fluoro-5-(4-((1r,3r)-3-((5-fluoro-4-carbonyl-3,4-dihydroquinazolin-2-yl)oxo)cyclobutyl)piperazin-1-yl)-N-methylmethylpyridinamide, ESI-MS [M+H] + :found 471.2. 1 H NMR (400MHz, DMSO-d6) δ12.32(s,1H),8.41(q,J=4.5Hz,1H),7.86(d,J=7.9Hz,1H),7.70–7.52(m,2H),7.24(d,J=8.2Hz,1H),7.05(dd,J =10.8,8.3Hz,1H),5.36–5.24(m,1H),3.26–3.15(m,4H),3.04–2.94(m,1H),2.77(d,J=4.7Hz,3H),2.50–2.40(m,6H),2.31–2.21(m,2H).

[0403] Example 62: 6-Fluoro-5-(4-((1s,3s)-3-((5-fluoro-4-carbonyl-3,4-dihydroquinazoline-2-yl)oxo)cyclobutyl)piperazin-1-yl)-N-methylmethylpyridinamide, ESI-MS [M+H] + :found 471.2. 1H NMR (400MHz, DMSO-d6) δ12.31 (s, 1H), 8.40 (q, J = 4.4Hz, 1H), 7.84 (d, J = 8.1 Hz,1H),7.70–7.62(m,1H),7.60–7.52(m,1H),7.23(d,J=8.2Hz,1H),7.10– 7.01(m,1H),5.10–4.98(m,1H),3.22–3.13(m,4H),2.76(d,J=4.7Hz,3H),2 .73–2.64(m,2H),2.60–2.52(m,1H),2.50–2.42(m,4H),2.03–1.91(m,2H).

[0404] Example 63: Preparation of N-ethyl-6-fluoro-5-(4-((1s,3s)-3-((4-carbonyl-3,4-dihydroquinazolin-2-yl)oxo)cyclobutyl)piperazin-1-yl)methylpyridine amide

[0405] Step 1: Methyl 5-(4-(3-(benzyloxy)cyclobutyl)piperazin-1-yl)-6-fluoromethylpyridinium ester (1.3 g, 3.26 mmol) was dissolved in methanol (30 mL), palladium on carbon was added, and the mixture was purged three times with hydrogen gas. The mixture was then stirred at room temperature under atmospheric hydrogen pressure (using a balloon) for 10 h. After the reaction was complete, the mixture was directly filtered, and the filtrate was concentrated to obtain methyl 6-fluoro-5-(4-(3-hydroxycyclobutyl)piperazin-1-yl)methylpyridinium ester (0.8 g, crude product, yield: 82.3%). This was used directly in the next step of the reaction.

[0406] Step 2: Methyl 6-fluoro-5-(4-(3-hydroxycyclobutyl)piperazin-1-yl)methylpyridinium ester (550 mg, 1.79 mmol) was dissolved in 1,4-dioxane (30 mL), and 4-(tert-butoxy)-2-chloroquinazoline (680 mg, 2.68 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (149 mg, 0.18 mmol), 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl (167 mg, 0.36 mmol), and cesium carbonate (1.16 g, 3.58 mmol) were added. The system was evacuated and purged with nitrogen three times, then heated to 100 °C and stirred overnight. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by normal phase column chromatography to obtain methyl 5-(4-(3-((4-(tert-butoxy)quinazolin-2-yl)oxo)cyclobutyl)piperazin-1-yl)-6-fluoromethylpyridinium ester (660 mg, yield: 70.0%).

[0407] Step 3: Methyl 5-(4-(3-((4-(tert-butoxy)quinazolin-2-yl)oxo)cyclobutyl)piperazin-1-yl)-6-fluoromethylpyridine ester (660 mg, 1.25 mmol) was dissolved in a water-tetrahydrofuran (1 / 5 mL) solution, and lithium hydroxide (120 mg, 5 mmol) was added. The mixture was stirred at room temperature for 4 h. After the reaction was complete, the solution was diluted with water, and then the pH was adjusted to 6 with 1 N HCl. The mixture was extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 5-(4-(3-((4-(tert-butoxy)quinazolin-2-yl)oxo)cyclobutyl)piperazin-1-yl)-6-fluoroo-o-pyridinecarboxylic acid (530 mg, yield: 80.1%).

[0408] Step 4: Dissolve 5-(4-(3-((4-(tert-butoxy)quinazolin-2-yl)oxo)cyclobutyl)piperazin-1-yl)-6-fluoroo-o-pyridinecarboxylic acid (200 mg, 0.40 mmol) in N,N-dimethylformamide (5 mL), then add N,N-diisopropylethylamine (0.20 mL), ethylamine hydrochloride (36 mg, 0.80 mmol), and 2-(7-azaphenyltriazole)-N,N,N ’ N ’ -Tetramethylurea hexafluorophosphate (153 mg, 0.40 mmol) was reacted with stirring at room temperature for 30 minutes. After the reaction was complete, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the crude product was concentrated and purified by normal phase to give 5-(4-(3-((4-(tert-butoxy)quinazolin-2-yl)oxo)cyclobutyl)piperazin-1-yl)-N-ethyl-6-fluoromethylpyridineamide (150 mg, yield: 71.12%).

[0409] Step 5: 5-(4-(3-((4-(tert-butoxy)quinazolin-2-yl)oxo)cyclobutyl)piperazin-1-yl)-N-ethyl-6-fluoromethylpyridine amide (150 mg, 0.28 mmol) was dissolved in a hydrogen chloride-dioxane solution (2 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated, and the crude product was purified by reverse-phase chromatography to obtain N-ethyl-6-fluoro-5-(4-((1s,3s)-3-((4-carbonyl-3,4-dihydroquinazolin-2-yl)oxo)cyclobutyl)piperazin-1-yl)methylpyridine amide (40.26 mg, yield: 30.07%, purity: 98.801%). ESI-MS [M+H] + :found 467.1. 1H NMR(400MHz,DMSO-d6)δ12.27(s,1H),8.44(t,J=6.0Hz,1H),8.00(dd,J=7.9,1.3Hz,1H), 7.88–7.80(m,1H),7.75–7.67(m,1H),7.57(dd,J=10.6,8.2Hz,1H),7.42(d,J=8.1Hz,1H) ,7.36–7.30(m,1H),5.06(p,J=7.3Hz,1H),3.32–3.24(m,2H),3.22–3.13(m,4H),2.74–2. 64(m,2H),2.60–2.54(m,1H),2.50–2.43(m,4H),2.02–1.92(m,2H),1.09(t,J=7.1Hz,3H).

[0410] Examples 64-65 can be prepared by selecting suitable raw materials according to the synthesis method of Example 63, and their structures are shown in Table 8.

[0411] Table 8. Structural formulas, chemical names, and mass spectrometry data of Examples 64-65

[0412] The NMR data of some of the compounds in the examples are as follows:

[0413] Examples 66 and 67: Preparation of 1-(6-fluoro-5-(4-((1s,3s)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)oxo)cyclobutyl)piperazin-1-yl)pyridin-2-yl)-3-methylurea and 1-(6-fluoro-5-(4-((1r,3r)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)oxo)cyclobutyl)piperazin-1-yl)pyridin-2-yl)-3-methylurea

[0414] Steps one through three can be performed by selecting appropriate raw materials, referring to steps two, four, and five of the synthesis in Example 56, to prepare 2-(3-carbonylcyclobutoxy)quinazolin-4(3H)-one.

[0415] Step 4: Sodium hydride (1.57 g, 39.48 mmol) was added in portions to a tetrahydrofuran (50 mL) solution of 5-bromo-6-fluoropyridine-2-amine (2.5 g, 13.16 mmol) at 0 °C. After stirring for 1 hour, 4-methoxybenzyl chloride (6.15 g, 39.48 mmol) was added. The reaction mixture was slowly brought to room temperature and stirred for 16 hours. The reaction was quenched with saturated ammonium chloride solution, and the mixture was extracted three times with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the crude product was concentrated and purified by normal-phase column chromatography to obtain 5-bromo-6-fluoro-N,N-di(4-methoxybenzyl)pyridine-2-amine (3.9 g, yield: 68.90%).

[0416] Step 5: At room temperature, tert-butylpiperazine-1-carboxylic acid ester (1.91 g, 10.28 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.98 g, 1.58 mmol), tris(dibenzylacetone)dipalladium (0.72 g, 0.79 mmol), and sodium tert-butoxide (1.14 g, 11.87 mmol) were added to a toluene (50 mL) solution of 5-bromo-6-fluoro-N,N-bis(4-methoxybenzyl)pyridine-2-amine (3.4 g, 7.91 mmol) at room temperature. The system was evacuated and purged with nitrogen three times, then heated to 80 °C and stirred for 16 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated. The crude product was purified by normal phase column chromatography to obtain tert-butyl 4-(6-(di(4-methoxybenzyl)amino)-2-fluoropyridin-3-yl)piperazine-1-carboxylic acid ester (2.6 g, yield: 61.32%).

[0417] Step 6: Add 2.5 mL of trifluoroacetic acid to tert-butyl 4-(6-(di(4-methoxybenzyl)amino)-2-fluoropyridin-3-yl)piperazine-1-carboxylic acid ester (2.5 g, 4.66 mmol), heat the system to 70 °C and stir for 30 minutes. After the reaction is complete, cool to room temperature, concentrate the system to give 6-fluoro-5-(piperazine-1-yl)pyridin-2-amine (1.25 g, yield: 100%).

[0418] Step 7: At 0°C, di-tert-butyl dicarbonate (1.34 g, 6.12 mmol) was added to a solution of 6-fluoro-5-(piperazin-1-yl)pyridin-2-amine (1 g, 5.1 mmol) and triethylamine (2.06 g, 20.41 mmol) in dichloromethane (20 mL). After the addition was complete, the mixture was stirred at room temperature for 2 hours. The crude product was directly concentrated and purified by normal-phase column chromatography to give tert-butyl-4-(6-amino-2-fluoropyridin-3-yl)piperazin-1-carboxylic acid ester (610 mg, yield: 40.39%).

[0419] Step 8: At room temperature, 1,8-diazabicyclo[5.4.0]undec-7-ene (13.2 mg, 0.87 mmol) and methylaminomethyl chloride (15.8 mg, 1.69 mmol) were added to a solution of tert-butyl 4-(2-fluoro-6-(3-methylureido)pyridin-3-yl)piperazine-1-carboxylate (100 mg, 0.34 mmol) in dioxane (0.5 mL). After addition, the mixture was heated to 80 °C and stirred for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, and the reaction was quenched with saturated sodium bicarbonate. The mixture was extracted three times with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the product was purified by normal-phase column chromatography to give tert-butyl 4-(2-fluoro-6-(3-methylureido)pyridin-3-yl)piperazine-1-carboxylate (70 mg, yield: 58.33%).

[0420] Step 9: Add a solution of dioxane in hydrochloric acid (4M, 1.5mL) to a solution of tert-butyl-4-(2-fluoro-6-(3-methylureo)pyridin-3-yl)piperazine-1-carboxylic acid (70mg, 0.20mmol) in dioxane (1.5mL). After the addition is complete, stir the mixture at room temperature for 60 minutes. After the reaction is complete, concentrate the system directly to obtain 1-(6-fluoro-5-(piperazine-1-yl)pyridin-2-yl)-3-methylurea (54mg, crude product).

[0421] Step 10: Dissolve 1-(6-fluoro-5-(piperazin-1-yl)pyridin-2-yl)-3-methylurea (54 mg, 0.235 mmol) in methanol (3 mL), add 2-(3-carbonylcyclobutoxy)quinazolin-4(3H)-one (72 mg, 0.281 mmol) and sodium cyanoborohydride (30 mg, 0.469 mmol), heat to 50 °C and stir for 2 hours. After the reaction is complete, cool to room temperature, concentrate the system directly, and purify the crude product by reverse-phase preparation to obtain Example 66 (4.55 mg, yield: 8.30%, purity: 97.038%) and Example 67 (5.87 mg, yield: 10.71%, purity: 96.667%).

[0422] Example 66: 1-(6-fluoro-5-(4-((1s,3s)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)oxo)cyclobutyl)piperazin-1-yl)pyridin-2-yl)-3-methylurea, ESI-MS [M+H] + :found 468.2. 1H NMR (400MHz, MeOD-d4) δ8.11(d,J=7.8Hz,1H),7.75–7.67(m,1H),7.56(dd,J=10.5,8.6Hz,1H),7.48(d,J=8.2Hz,1H),7.36(t,J=7.5Hz,1H),7.20 (d,J=8.5Hz,1H),5.52–5.42(m,1H),3.82–3.70(m,1H),3.28–3.20(m,4H ),3.18–3.05(m,4H),2.83(s,3H),2.80–2.72(m,2H),2.68–2.60(m,2H).

[0423] Example 67: 1-(6-fluoro-5-(4-((1r,3r)-3-((4-carbonyl-3,4-dihydroquinazoline-2-yl)oxo)cyclobutyl)piperazin-1-yl)pyridin-2-yl)-3-methylurea, ESI-MS [M+H] + :found 468.2. 1 H NMR (400MHz, MeOD-d4) δ8.10(d,J=6.9Hz,1H),7.75–7.69(m,1H),7.54(dd,J=10.5,8.6Hz,1H),7.49(d,J=7.5Hz,1H),7.36(t,J =7.7Hz,1H),7.19(d,J=8.4Hz,1H),5.19(p,J=7.2Hz,1H),3.27–3.18(m,5H),3.16–2.96(m,6H),2.83(s,3H),2.40–2.28(m,2H).

[0424] Example 68 can be prepared by selecting appropriate raw materials according to the synthesis methods of Examples 66 and 67, and its structure is shown in Table 9.

[0425] Table 9. Structural formulas, chemical names, and mass spectrometry data of Example 68

[0426] The NMR data of some of the compounds in the examples are as follows:

[0427] Biological testing evaluation

[0428] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0429] PARP Trapping test

[0430] This experiment tested the DNA capture inhibitory activity of the compounds of this invention against PARP1 and PARP2. This test can be performed using PARPtrap. TM The Assay Kit for PARP1 / 2 (BPS, 80584-1 / 78296-1) was used. First, the test compounds were prepared as 10 mM stock solutions in DMSO, and then serially diluted with assay buffer to obtain working solutions. Recombinant GST-labeled PARP1 / 2 protein was diluted with assay buffer to obtain 0.5 ng / µL PARP1 / 2 protein working solutions. Fluorescent labeled DNA was prepared as Master Mix using assay buffer and deionized water in a specific ratio. 20 µL of Master Mix, 5 µL of the test compound working solutions, and 20 µL of PARP1 / 2 protein working solutions were added to the wells of a 96-well plate and incubated at room temperature for 45 minutes; then 5 µL of 5X NAD+ working solution was added and incubated at room temperature for 1 hour. With test compound or solvent controls available, fluorescence signal values ​​were detected using an Envision 2105 microscope. The experimental results were input into GraphPad Prism 7.0 software, and the IC50 values ​​for each compound were calculated through fitting. 50 Some test results are shown in Table 10. Among them, IC... 50 In the numerical value, "A" represents IC. 50 ≤10nM, where “B” indicates 10nM <IC 50 ≤100nM, where "C" represents 100nM <IC 50 ≤500nM, “D” indicates 500nM <IC 50 ≤2.5uM, “E” indicates 2.5uM <IC 50 The selectivity of PARP1 / 2 is determined by PARP2 IC. 50 / PARP1 IC 50 The calculations show that "+" indicates selectivity < 100, "++" indicates selectivity > 100 (500 > 100), and "+++" indicates selectivity > 500. The Yangshen compound is the compound from Example 4 of patent WO2021013735 A1, and its structure is as follows:

[0431] Table 10. DNA Trapping Test Results of Compound PARP1 / 2 in Some Examples Note: "ND" is an abbreviation for "Not Determined," meaning it has not yet been tested.

[0432] PARP1 / 2 polyribosylation chemiluminescence assay

[0433] The inhibitory activity of the compounds provided in this invention against PARP1 and PARP2 polyribosylation can be detected using the PARP1 / 2 Chemiluminescent Assay Kit (BPS, 80569 / 80552). In summary, the process begins with overnight coating of a 96-well plate with Histone Mixture. Next, the test compounds are prepared as 10 / 50 μM stock solutions in DMSO, and then serially diluted with assay buffer at ten different concentration levels (three-fold dilution). Master Mix is ​​prepared by mixing PARP Substrate Mixture and Activated DNA with Assay Buffer, deionized water, and DTT solution in a specific ratio. Recombinant GST-labeled PARP1 / 2 protein is diluted with Assay Buffer to obtain a 0.6 ng / μL PARP1 / 2 protein working solution. 12.5 μL of Master Mix, 2.5 μL of the test compound working solution, and 10 μL of PARP1 / 2 protein working solution are added to each well of the coated 96-well plate and incubated at room temperature for 60 minutes, followed by washing three times with PBST solution. 25 μL of diluted Streptavidin-HRP is added to each well and incubated at room temperature for 30 minutes, followed by washing three times with PBST solution. Finally, 50 μL of HRP is added to each well. The chemiluminescent substrate was immediately used, and the emission signal value was detected using a luminometer. The experimental results were input into GraphPad Prism 7.0 software, and the IC50 of each compound was obtained through fitting calculation. 50 Some test results are shown in Table 11. Among them, IC... 50 In the numerical value, "A" represents IC. 50 ≤10nM, where “B” indicates 10nM <IC 50 ≤100nM, where "C" represents 100nM <IC 50 ≤500nM, “D” indicates 500nM <IC 50 ≤2.5uM, “E” indicates 2.5uM <IC 50 The selectivity of PARP1 / 2 is determined by PARP2 IC. 50 / PARP1 IC 50 The calculations show that "+" indicates selectivity < 5, "++" indicates selectivity > 50, and "+++" indicates selectivity > 50. The Yangshen compound is the compound from Example 4 of patent WO2021013735 A1.

[0434] Table 11. Experimental results of DNA pyrrolization inhibition of compounds PARP1 / 2 in some examples.

[0435] Screening for antiproliferative activity of BRCA2(- / -)DLD1 cells

[0436] This study used the CellTiter-Glo (CTG) cell viability assay kit (Promega, G7571) to analyze the cytotoxicity of BRCA2(- / -)DLD1 human colorectal adenocarcinoma epithelial cells after seven days of compound treatment. The BRCA2(- / -)DLD1 cell line was purchased from Horizon and cultured in 1640 medium (Gibco, 12633020) at 37°C in a Thermo Scientific, BB150 cell culture incubator (Thermo Scientific, BB150). In this experiment, the compound was dissolved in DMSO to an initial concentration of 500 μM, and then triple-diluted in DMSO for a total of ten concentration points, with a final DMSO concentration of 0.1%. BRCA2(- / -)DLD1 cells were seeded in white 384-well plates, with 30 μL of cell suspension per well containing 500 BRCA2(- / -)DLD1 cells. Cell culture plates were incubated overnight in a CO2 incubator. Then, 10 nL of a gradient solution of different concentrations of the compound was added to each well of the 384-well plate, and the plates were incubated for 7 days. An additional well containing 0.1% DMSO was prepared in the 386-well plates; the signal value on the day of drug addition was recorded as the maximum value (Max value in the equation below) for data analysis. After 7 days of incubation, 40 μL of CellTiter-Glo reagent was added to each well of this cell culture plate, and the plates were incubated at room temperature for 30 minutes to stabilize the luminescence signal. Readings were performed using a microplate reader (PerkinElmer, Ensight). The raw data were converted into inhibition rate (IC50) using the equation (100 - (Sample-Min) / (Max-Min)) * 100%. 50 The values ​​can be obtained by curve fitting using GraphPad Prism software. Min: Culture medium wells; Max: Day 0 0.1% DMSO cell wells. Some test results are shown in Table 12. Among them, IC50... 50 In the numerical value, "A" represents IC. 50 ≤30nM, where “B” indicates 30nM <IC 50 ≤300nM, where “C” indicates 300nM <IC 50 The compound in question is the compound described in Example 4 of patent WO2021013735 A1.

[0437] Table 12. Results of antitumor proliferative activity tests of compounds from some examples.

[0438] Efficacy study of a mouse subcutaneous xenograft model of human breast cancer MDA-MB-436 cells

[0439] Male CB-17SCID mice (18-22g, 6-8 weeks old) were selected and housed in individual ventilated cages (IVC) under constant temperature and humidity, with no more than 5 mice per cage, and provided with normal food and water. MDA-MB-436 tumor cells were cultured in monolayers in DMEM medium supplemented with 10% fetal bovine serum at 37°C, with a CO2 concentration of 5% in the incubator. Tumor cells were routinely passaged twice weekly after trypsin treatment. Cells in the exponential growth phase were collected, counted, and used for tumor inoculation. Human breast cancer MDA-MB-436 tumor cells were collected under aseptic conditions and the cell density was adjusted to 1×10⁻⁶ cells / mL with sterile physiological saline. 7 The dose was administered subcutaneously to the right side of each mouse, in 100 μL of ice-cold PBS and 100 μL of matrix gel. After 21 days, when the tumor had grown to 200 mm, the dose was administered to the right side of each mouse. 3 Animals were randomly assigned to a blank control group and a test compound group, and drug administration began on day 0. The test compound group was administered the solvent containing the test drug orally via gavage, while the blank control group received a blank solvent without the drug. During the drug administration period, mice were weighed twice a week, and the length and width of the tumors were measured using calipers. After 28 days of drug administration, the mice were euthanized by cervical dislocation, and the tumor tissue was dissected and weighed. Finally, the tumor inhibition rate was calculated to evaluate the intensity of the antitumor effect.

[0440] Drug preparation: The compound of the test example was dissolved in a certain volume of dimethyl sulfoxide according to the dosage, and then 19 times the volume of dimethyl sulfoxide used was added in a mixed solvent (mixed solvent composition: 0.5% (w / v) hydroxypropyl methylcellulose (HPMC) / 0.1% Tween 80 / water, and the pH of the system was adjusted to 3.0-3.2 using methanesulfonic acid (MSA). After vortexing and mixing evenly, the final drug solution was obtained.

[0441] The method used to calculate the efficacy in the experiment:

[0442] Tumor volume (TV) on day t: V t =1 / 2×a×b 2 , where a and b represent the length and width of the tumor, respectively.

[0443] Relative tumor volume RTV = V t / V0.

[0444] Relative tumor growth rate (T / C): T / C = RTV treatment / RTV vehicle ×100%.

[0445] Tumor growth inhibition rate (TGI): TGI = (1 - T / C) × 100%.

[0446] Conclusion: Example 20 demonstrated a highly significant tumor-suppressive effect at doses as low as 0.3 mpk, with a TGI of 98.4%. Mice maintained normal body weight and showed no significant toxic side effects during the administration period.

[0447] Conclusion: The compounds of this invention exhibit good inhibitory activity against PARP1 protein, while showing weaker inhibitory activity against PARP2 protein, demonstrating very high selectivity and effectively avoiding the potential toxic side effects of PARP2 inhibition. Simultaneously, the compounds of this invention also exhibit excellent in vitro and in vivo antitumor proliferative activity. Overall, the compounds of this invention have good development potential.

[0448] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of formula (I), its stereoisomers, tautomers, deuterated derivatives, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, X is CR a Or N; Q is CR b W is CR c ; R a and R c One of them is selected from the following group: H, D, halogen, cyano, C. 1-8 Alkyl, C 2-8 alkenyl, C 2-8 Alkyne group, SF5, OR 7 -COOR 8 -P(O)(R 8 2. NR 10 R 11 -CONR 12 R 13 -N(R) 30 CONR 12 R 13 -S(O)2R 8 -S(O)2NR 12 R 13 -N(R) 30 )S(O)2NR 12 R 13 C 3-10 Carbocyclic group, 4-12 membered heterocyclic group, C 6-12 Aryl, 5-12-membered heteroaryl, wherein each of the above-mentioned groups may optionally be further replaced by one or more groups selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, oxo groups (=O), -S(O)2C 1-6 Alkyl, -COC 1-6 Alkyl groups are substituted; R a and R c Another R b The atoms bonded to it together form C 4-10 Carbon rings, 4-12 membered heterocycles, C 6-12 Aromatic rings, 5-12 member heteroaryl rings, or 8-12 member fused bicyclic rings; Or R a R b R c The atoms bonded to it together form 8-16 member fused bicyclic rings; The carbon rings, heterocycles, aromatic rings, heteroaromatic rings, or fused bicyclic rings formed by the above cyclization may optionally be further bonded by 1-5 R groups. d replace; Each R d Each is independently selected from the following groups: halogen, cyano, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 Alkyne group, SF5, OR 7 -COOR 8 -COR 8 -P(O)(R 8 2. SR 9 NR 31 R 32 -CONR 33 R 34 -S(O)2R 8 -S(O)2NR 33 R 34 -N(R) 30 )S(O)2NR 33 R 34 Oxide group (=O), C 3-10 Carbocyclic group, 4-12 membered heterocyclic group, C 6-12 Aryl, 5-12-membered heteroaryl, wherein each of the above-mentioned groups may optionally be further replaced by one or more groups selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, oxo groups (=O), -S(O)2C 1-6 Alkyl, -COC 1-6 Alkyl groups are substituted; Alternatively, two R atoms connected to two adjacent carbon atoms d The two carbon atoms bonded to it together form a carbon-carbon double bond; Z is CR e Or N; R e Selected from the following groups: H, D, halogen, cyano, hydroxyl, NR 14 R 15 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups; Ring A is C 6-14 Aryl or 5-12 membered heteroaryl rings, and ring A can be connected to Z through any possible ring atom; Each R 1 Independently selected from the following groups: H, halogen, cyano, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 Alkyne group, SF5, OR 7 -COOR 8 -P(O)(R 8 2. SR 9 NR 16 R 17 -CONR 18 R 19 -N(R) 30 CONR 18 R 19 -N(R) 30 COOR 8 -S(O)2R 8 -S(O)2NR 18 R 19 -N(R) 30 )S(O)2NR 18 R 19 , O group (=O), -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4-8-membered heterocyclic groups, wherein each of the above-mentioned groups may optionally be further surrounded by 1, 2, 3 or 4 R groups. i replace; Each R i Independently selected from the following groups: halogen, cyano, hydroxyl, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O)2C 1-6 Alkyl, -COC 1-6 alkyl; B is Furthermore, B is connected to a nitrogen atom through ring C and Y is connected to a carbon atom, or Y is connected to a nitrogen atom and ring C is connected to a carbon atom. The carbon ring (C) is selected from the following group: 4-10 membered carbon rings and 4-10 membered heterocycles; Y is selected from the following group: -C(R) 4a )2-、-NR 4b -, -O-, -S-, -S(O)-, -S(O)2-; Each R 4 Each element is independently selected from the following groups: H, D, halogen, hydroxyl, C. 1-6 Alkyl, C 1-6 Alkoxy, -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkyl-4-8-membered heterocyclic group, oxo group (=O), the above groups may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O)2C 1-6 alkyl; Alternatively, two R atoms connected to two adjacent carbon atoms 4 The two carbon atoms bonded to it together form a carbon-carbon double bond; Each R 4a Each is independently selected from the following groups: H, D, halogens, C 1-6 Alkyl, -C 1-4 Hydroxyalkyl, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4-8-membered heterocyclic group, wherein the above-described groups may optionally be further substituted with one or more halogens; Or, two Rs 4a Together with the carbon atoms attached to it, they form C=O; Or, two Rs 4a Together with the carbon atom attached thereto, they form a 3-8 membered carbon ring or a 4-8 membered heterocycle, which may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, =O, -COC 1-6 Alkyl group, -S(O)2C 1-6 alkyl; R 4b Selected from the following groups: H, C 1-6 Alkyl, -C 2-4 Hydroxyalkyl, -C 2-4 Alkylene-C 1-6 Alkoxy, -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4-8-membered heterocyclic group, wherein the above-described groups may optionally be further substituted with one or more halogens; Each R 5 and each R 6 Each is independently selected from the following groups: H, D, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkyl-4-8-membered heterocyclic group, wherein the above-described groups may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O)2C 1-6 alkyl; Or, R e With an R 5 And the two carbon atoms they are attached to together form a carbon-carbon double bond; Alternatively, two R atoms attached to the same carbon atom 5 Together form = O; Or, two Rs 5 All atoms bonded to it further form a 3-8 membered carbon ring or a 4-8 membered heterocycle, which may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, =O, -COC 1-6 Alkyl group, -S(O)2C 1-6 alkyl; Or, two Rs 6 All atoms bonded to it further form a 3-8 membered carbon ring or a 4-8 membered heterocycle, which may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, =O, -COC 1-6 Alkyl group, -S(O)2C 1-6 alkyl; Or, any R 5 Any R 6 The atoms bonded to it together form a 3-8 membered carbon ring or a 4-8 membered heterocycle, which may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, =O, -COC 1-6 Alkyl group, -S(O)2C 1-6 alkyl; Each R 7 Independently selected from the following groups: H, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkyl-4-8-membered heterocyclic group, -C 0-4 Alkylene-OC 3-10 cycloalkyl, -C 0-4 alkylene-O-4-10-membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, and each of the above groups may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O)2(C 1-6 alkyl), -CO(C) 1-6 Alkyl group), =O; Each R 8 Independently selected from the following groups: H, C 1-6 Alkyl, -C 2-4 Hydroxyalkyl, -C 2-4 Alkylene-C 1-6 Alkoxy, -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkyl-4-8-membered heterocyclic group, -C 0-4 Alkylphenylene, wherein each of the above-described groups may optionally be further substituted with one or more halogens; Each R 9 Select independently from the following group: C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-12 Aryl, 5-12 heteroaryl; Each R 10 R 11 R 14 R 15 R 16 R 17 R 31 and R 32 Each is independently selected from the following groups: H, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-10 cycloalkyl, -C 0-4 Alkyl-4-10 heterocyclic group, -C 0-4 Alkylene-OC 3-10 cycloalkyl, -C 0-4 Alkylene-O-4-10-membered heterocyclic group, -S(O)2(C 1-6 alkyl), -CO(C) 1-6 Alkyl groups, wherein each of the above-described groups may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups; Each R 12 R 13 R 18 R 19 R 33 and R 34 Each is independently selected from the following groups: H, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-10 cycloalkyl, -C 0-4 Alkyl-4-10 heterocyclic group, -C 0-4 Alkylene-OC 3-10 cycloalkyl, -C 0-4 Alkylene-O-4-10-membered heterocyclic group, wherein each of the above-described groups may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O)2C 1-6 alkyl; Or, R attached to the same nitrogen atom 10 and R 11 R 12 and R 13 R 14 and R 15 R 16 and R 17 Or R 18 and R 19 The nitrogen atom attached to it forms a 4-10 membered heterocycle, which may optionally be further substituted by one or more substituents selected from the group consisting of halogens, hydroxyl groups, C, and so on. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, -S(O)2C 1-6 Alkyl, -CO(C) 1-6 Alkyl group), =O; Each R 30 Each is independently selected from the following groups: H, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-10 cycloalkyl, -C 0-4 Alkyl-4-10 heterocyclic group, -C 0-4 Alkylene-OC 3-10 cycloalkyl, -C 0-4 Alkylene-O-4-10-membered heterocyclic group, wherein each of the above-described groups may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups; s and t are each independently 0, 1, 2, 3, 4, 5 or 6; Unless otherwise specified, the heteroaryl or heterocyclic group is an aromatic cyclic group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S on a cyclic skeleton; the heterocyclic group or heterocycle is a saturated or partially unsaturated cyclic group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S that is not aromatic, and it is a monocyclic, fused, bridged or spirocyclic group.

2. The compound, its stereoisomers, tautomers, deuterated derivatives, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as claimed in claim 1, characterized in that, X is CR a Or N; Q is CR b W is CR c ; R a and R c One of them is selected from the following group: H, D, halogen, cyano, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, SF5, OR 7 -COOR 8 -P(O)(R 8 2. NR 10 R 11 -CONR 12 R 13 -N(R) 30 CONR 12 R 13 -S(O)2R 8 -S(O)2NR 12 R 13 -N(R) 30 )S(O)2NR 12 R 13 C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 4-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, and each of the above groups may optionally be further surrounded by one or more elements selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, oxo groups (=O), -S(O)2C 1-6 Alkyl, -COC 1-6 Alkyl groups are substituted; R a and R c Another R b The atoms bonded to it together form C 4-8 Carbon rings, 4-10 membered heterocycles, C 6-10 Aromatic rings, 5-10 member heteroaryl rings, or 8-12 member densely packed bicyclic rings; Or R a R b R c The atoms bonded to it together form 8-14 member fused bicyclic rings; The carbon rings, heterocycles, aromatic rings, heteroaromatic rings, or fused bicyclic rings formed by the above cyclization may optionally be further bonded by 1-5 R groups. d replace; Each R d Each is independently selected from the following groups: halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, SF5, OR 7 -COOR 8 -COR 8 -P(O)(R 8 2. SR 9 NR 31 R 32 -CONR 33 R 34 -S(O)2R 8 -S(O)2NR 33 R 34 -N(R) 30 )S(O)2NR 33 R 34 Oxide group (=O), C 3-8 Carbocyclic group, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-10 heteroaryl, and each of the above groups may optionally be further surrounded by one or more elements selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, oxo groups (=O), -S(O)2C 1-6 Alkyl, -COC 1-6 Alkyl groups are substituted; Alternatively, two R atoms connected to two adjacent carbon atoms d The two carbon atoms bonded to it together form a carbon-carbon double bond; R 7 R 8 R 10 R 11 R 12 R 13 R 30 R 31 R 32 R 33 R 34 The definition is as described in claim 1.

3. The compound, its stereoisomers, tautomers, deuterated derivatives, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as described in claim 1, characterized in that, Each R 1 Independently selected from the following groups: H, halogen, cyano, C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, SF5, OR 7 -COOR 8 -P(O)(R 8 2. SR 9 NR 16 R 17 -CONR 18 R 19 -N(R) 30 CONR 18 R 19 -N(R) 30 COOR 8 -S(O)2R 8 -S(O)2NR 18 R 19 -N(R) 30 )S(O)2NR 18 R 19 , O group (=O), -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 Alkylene-4-6-membered heterocyclic groups, wherein each of the above-mentioned groups may optionally be further surrounded by 1, 2, 3 or 4 R groups. i replace; R 7 R 8 R 9 R 16 R 17 R 18 R 19 R 30 R i The definition is as described in claim 1.

4. The compound of claim 1, its stereoisomers, tautomers, deuterated derivatives, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, characterized in that, Ring A is selected from the following group: C 6-10 Aryl, containing 1-4 5-10 membered heteroaryl rings selected from N, O or S heteroatoms; Preferably, ring A is selected from the group consisting of: benzene rings, 5-6 membered heteroaromatic rings containing 1-4 heteroatoms optionally selected from N, O or S; More preferably, ring A is selected from the group consisting of: benzene ring, furan, pyrrole, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazolium, pyridine, pyrimidine, pyridazine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetraazine; More preferably, ring A is selected from the group consisting of: benzene ring, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazolium, pyridine, pyrimidine, pyridazine, and pyrazine. More preferably, ring A is selected from the group consisting of: benzene ring, imidazole, pyrazole, pyridine, pyrimidine, pyridazine, and pyrazine.

5. The compound of claim 1, its stereoisomers, tautomers, deuterated derivatives, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, characterized in that, Z is CR e Or N; R e Selected from the following groups: H, D, halogen, cyano, hydroxyl, NR 14 R 15 C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups; Each R 5 and each R 6 Each is independently selected from the following groups: H, D, halogens, C 1-4 Alkyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-2 Alkyl-4-6-membered heterocyclic group, wherein the above-described groups may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, -S(O)2C 1-4 alkyl; Or, R e With an R 5 And the two carbon atoms they are attached to together form a carbon-carbon double bond; Or, two Rs 5 All atoms bonded to it further form a 3-6 membered carbon ring or a 4-6 membered heterocycle, which may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, =O, -COC 1-4 Alkyl group, -S(O)2C 1-4 alkyl; Or, two Rs 6 All atoms bonded to it further form a 3-6 membered carbon ring or a 4-6 membered heterocycle, which may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, =O, -COC 1-4 Alkyl group, -S(O)2C 1-4 alkyl; Or, any R 5 Any R 6 The atoms bonded to it together form a 3-6 membered carbon ring or a 4-6 membered heterocycle, which may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, =O, -COC 1-4 Alkyl group, -S(O)2C 1-4 alkyl.

6. The compound of claim 1, its stereoisomers, tautomers, deuterated derivatives, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, characterized in that, B is Furthermore, B is connected to the nitrogen atom through ring C and Y is connected to the carbon atom, or it can also be connected to the nitrogen atom through Y and the carbon atom through ring C; The C ring is selected from the following group: 4-6 member monocyclic carbon ring, 5-8 member bicyclic carbon ring, 4-6 member monocyclic heterocyclic ring, and 5-8 member bicyclic heterocyclic ring; Y is selected from the following group: -C(R) 4a )2-、-NR 4b -, -O-, -S-, -S(O)-, -S(O)2-; Each R 4 Each element is independently selected from the following groups: H, D, halogen, hydroxyl, C. 1-4 Alkyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-4 Alkyl-4-6-membered heterocyclic group, oxo group (=O), the above groups may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, -S(O)2C 1-4 alkyl; Alternatively, two R atoms connected to two adjacent carbon atoms 4 The two carbon atoms bonded to it together form a carbon-carbon double bond; Each R 4a Each is independently selected from the following groups: H, D, halogens, C 1-6 Alkyl, -C 1-4 Hydroxyalkyl, -C 1-4 Alkylene-C 1-4 Alkoxy, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 Alkylene-4-6-membered heterocyclic groups, wherein the groups described above may optionally be further substituted with one or more halogens; Or, two Rs 4a Together with the carbon atoms attached to it, they form C=O; Or, two Rs 4a Together with the carbon atom attached thereto, they form a 3-6 membered carbon ring or a 4-6 membered heterocycle, which may optionally be further substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, =O, -COC 1-4 Alkyl group, -S(O)2C 1-4 alkyl; R 4b Selected from the following groups: H, C 1-4 Alkyl, -C 2-4 Hydroxyalkyl, -C 2-4 Alkylene-C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-2 Alkylene-4-6-membered heterocyclic groups, wherein the groups described above may optionally be further substituted with one or more halogens; The definition of s is as described in claim 1.

7. The compound of claim 1, its stereoisomers, tautomers, deuterated derivatives, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, characterized in that, The compound has the structure shown in formula (II) or formula (III). Where m and n are each independently 0, 1, 2, 3, 4 or 5; Each R 2 Each is independently selected from the following groups: H, halogen, cyano, C. 1-8 Alkyl, C 2-8 alkenyl, C 2-8 Alkyne group, SF5, OR 7 -COOR 8 -P(O)(R 8 2. SR 9 NR 16 R 17 -S(O)2R 8 -S(O)2NR 18 R 19 -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4-8-membered heterocyclic groups, wherein each of the above-mentioned groups may optionally be further surrounded by 1, 2, 3 or 4 R groups. i replace; Ring D is selected from the following group: C 4-8 Carbon rings, 4-8 membered heterocycles, C 6-10 Aromatic rings, 5-10 member heteroaryl rings, or 8-12 member densely packed bicyclic rings; A, B, Z, R 5 R 6 R 18 R 19 R a R d and R i The definition is as described in claim 1.

8. The compound of claim 1, its stereoisomers, tautomers, deuterated derivatives, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, characterized in that, The compound has the following structure: In the formula, ring C is a 4-5 membered carbon ring or a 4-6 membered heterocycle, and the heterocycle has 1-2 heteroatoms selected from the group consisting of N and O; Y is -C(R) 4a )2-、-NR 4b -, -O-, or -S-, where each R 4a Each is independently selected from the following groups: H, D, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl; or, two Rs 4a Together with the carbon atoms attached to it, they form a 3-5 membered carbon ring; R 4b For H or C 1-6 alkyl; Other substituents are defined as before.

9. The compound of claim 1, its stereoisomers, tautomers, deuterated derivatives, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, characterized in that, The compound has the structure shown in formula (IV) or formula (V). Where m1 is 0, 1, or 2; n1 is 0, 1, 2, 3, 4, or 5; Each R 2a R 3a Each is independently selected from the following groups: H, halogen, cyano, C. 1-8 Alkyl, C 2-8 alkenyl, C 2-8 Alkyne group, SF5, OR 7 -COOR 8 -P(O)(R 8 2. SR 9 NR 16 R 17 -S(O)2R 8 -S(O)2NR 18 R 19 -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4-8-membered heterocyclic groups, wherein each of the above-mentioned groups may optionally be further surrounded by 1, 2, 3 or 4 R groups. i replace; Ring D is selected from the following group: C 4-8 Carbon rings, 4-8 membered heterocycles, C 6-10 Aromatic rings, 5-10 member heteroaryl rings, or 8-12 member densely packed bicyclic rings; B, Z, R 5 R 6 R 18 R 19 R a R d and R i The definition is as described in claim 1.

10. The compound of claim 1, its stereoisomers, tautomers, deuterated derivatives, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, characterized in that, The compound has the following structure: In the formula, ring C is a 4-5 membered carbon ring or a 4-6 membered heterocycle, and the heterocycle has 1-2 heteroatoms selected from the group consisting of N and O; Y is -C(R) 4a )2-、-NR 4b -, -O-, or -S-, where each R 4a Each is independently selected from the following groups: H, D, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl; or, two Rs 4a Together with the carbon atoms attached to it, they form a 3-5 membered carbon ring; R 4b For H or C 1-6 alkyl; Other substituents are defined as before.

11. The compound of claim 1, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, characterized in that, The compounds are selected from the group consisting of:

12. A pharmaceutical composition, characterized in that, The composition comprises: (i) The compound, stereoisomer, tautomer, deuterated form, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug as claimed in any one of claims 1-11; and (ii) Pharmaceutically acceptable carriers, excipients or excipients.

13. The use of the compound, stereoisomer, tautomer, deuterated form, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug as claimed in any one of claims 1-11, or the pharmaceutical composition as claimed in claim 12, characterized in that, Used to prepare treatments and / or preventative measures for PARP1-related diseases; Preferably, the PARP1-related disease is cancer; More preferably, the PARP1-related diseases are selected from the group consisting of: breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, colorectal cancer, lung cancer, kidney cancer, liver cancer, cervical cancer, endometrial cancer, myeloma, leukemia, lymphoma, acoustic neuroma, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, bronchial cancer, sarcoma, chordoma, choriocarcinoma, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, hemangioendothelioma, ependymoma, epithelial carcinoma, esophageal cancer, and primary hemangioblastoma. Thrombocytosis, Ewing's tumor, testicular cancer, glioma, heavy chain disease, angioblastoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, neuroblastoma, NUT midline carcinoma, glioma, bone cancer, nasopharyngeal carcinoma, oral cancer, thyroid cancer, pineal tumor, polycythemia vera, retinoblastoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, synovial malformation, sweat gland carcinoma, Waldenström macroglobulinemia, Wilms' tumor; More preferably, the cancer is selected from the group consisting of: breast cancer, ovarian cancer, endometrial cancer, prostate cancer, gastric cancer, colorectal cancer, and lung cancer.

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