Fused lactam ring compound and use thereof

Abstract

The present invention discloses a fused lactam ring compound and the use thereof, and belongs to the technical field of chemical pharmaceuticals. The fused lactam ring compound as represented by formula I provided in the present invention can be used as a PARP1 inhibitor, has the advantages of high activity and high selectivity, and also has excellent pharmacokinetic properties and levels of safety.

Description

Lactam ring compounds and uses thereof Technical Field

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

[0002] As cells grow, their DNA is constantly damaged by various internal and external factors. The most severe types of DNA damage are single-strand breaks and double-strand breaks, with single-strand breaks being more common. If these breaks are not repaired promptly and accurately, they can lead to genomic instability, cancer, and even direct cell death. The repair of single-strand breaks in DNA primarily relies on the enzyme PARP. Double-strand breaks can be repaired through two methods: non-homologous end joining repair and homologous recombination repair. Homologous recombination repair is a high-fidelity, error-free repair method and the primary pathway for double-stranded DNA repair. Numerous proteins are involved in homologous recombination repair, the most well-known of which are the BRCA proteins. Two studies in 2005 (Farmer H, McCabe N, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy [J]. Nature, 2005, 434(7035): 917-921. Bryant, H., Schultz, N., Thomas, H. et al. Specific killing of BRCA2-deficient tumors with inhibitors of poly(ADP-ribose)polymerase. Nature 434, 913–917 (2005)) showed that tumor cells lacking BRCA1 or BRCA2 are selectively inhibited by PARP inhibitors. Based on this research result, scholars proposed the concept of synthetic lethality: the loss of either BRCA or PARP gene is not lethal in itself, but the simultaneous inactivation of both will lead to cell death. Based on the theory of synthetic lethality, PARP inhibitors (PARPi) have been developed to selectively target cancer cells with BRCA1 / 2 mutations.

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

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

[0005] Summary of the Invention

[0006] The purpose of the present invention is to provide a class of heterocyclic compounds and uses thereof to achieve highly selective and efficient prevention or treatment of diseases related to PARP function.

[0007] In a first aspect, the present invention provides a compound represented by Formula I or a pharmaceutically acceptable form thereof, wherein the structure of Formula I is as follows:

[0008] in:

[0009] Structural unit Selected from the following structures: or

[0010] R x1 、Ry1 independently selected from hydrogen, deuterium, halogen, cyano, amino or the following groups optionally substituted with 0-3 substituents: C 1-4 Alkyl, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl; R x1 and R y1 wherein the substituent is selected from the group consisting of: deuterium, halogen, oxo, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Fluoroalkyl, -NH-C 1-4 Alkyl, -N(C 1-4 Alkane)2, -OC 1-4 Alkyl or 3-6 membered cycloalkyl; R x1 and R y1 wherein the 4- to 6-membered heterocycloalkyl group and the 5- to 6-membered heteroaryl group contain 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0011] R x2 is selected from hydrogen, deuterium or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl; R x2 wherein the substituent is selected from the group consisting of: deuterium, halogen, -OH, -NH2, -CN, oxo, C 1-4 Alkyl, C 1-4 Fluoroalkyl, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -OC 1-4 Alkyl or 3-6 membered cycloalkyl; R x2 wherein the 4- to 6-membered heterocycloalkyl group and the 5- to 6-membered heteroaryl group contain 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0012] R7 is selected from hydrogen, deuterium, halogen, hydroxy, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Fluoroalkoxy, -OC 1-4Alkyl, -OC 1-4 Fluorinated alkyl, -OC 1-4 Deuterated alkyl, -NH-C 1-4 Alkyl or -N(C 1-4 At least one of alkyl) 2; n4 is selected from 1, 2, 3, 4, 5, 6;

[0013] R8 is selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Deuterated alkyl or 3-6 membered cycloalkyl;

[0014] Z1 is selected from a bond, O, NR a1 , CR a2 R a3 Or C=Z4;

[0015] Z2 is selected from O, NR b1 or CR b2 R b3 ;

[0016] Z3 is selected from O or CR c1 R c2 ;

[0017] R a1 、R b1 independently selected from hydrogen, deuterium or the following groups optionally substituted with 0-6 substituents: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; R a1 and R b1 wherein the substituent is selected from: deuterium, halogen, -OH, -NH2, -CN or 3-6 membered cycloalkyl; R a1 and R b1 wherein the 4- to 6-membered heterocycloalkyl group and the 5- to 6-membered heteroaryl group contain 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0018] R a2 、R a3 、R b2 、R b3 、R c1 、R c2 independently selected from hydrogen, deuterium, fluorine, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl or C 1-4 Hydroxyl substituted alkyl;

[0019] R1 is selected from hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl or C 1-4 Hydroxyl substituted alkyl;

[0020] R2, R3 are independently selected from hydrogen, deuterium, fluorine, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl or C 1-4 Hydroxyl substituted alkyl, or R2 and R3 together with the atoms to which they are attached form a 3-6 membered alkyl ring;

[0021] Ring A is selected from 4-8 membered heterocycloalkyl; in ring A, the 4-8 membered heterocycloalkyl contains 1-3 N heteroatoms, and one of the N atoms is connected;

[0022] R4 is selected from hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy or C 1-4 At least one of the fluoroalkoxy groups; or any two R4 together with the atoms to which they are attached form a 3-6 membered alkyl ring or a 5-7 membered alkyl heterocycle; when any two R4 together with the atoms to which they are attached form a ring, the 5-7 membered alkyl heterocycle contains 1 to 3 heteroatoms selected from at least one of N and O;

[0023] L is selected from a bond, O, NR L1 or CR L2 R L3 ;

[0024] R L1 Selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl or C 1-4 Hydroxyl substituted alkyl;

[0025] R L2 and R L3 independently selected from hydrogen, deuterium, fluorine, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl or C 1-4 Hydroxyl substituted alkyl;

[0026] Ring B is selected from a 5-10 membered aryl group or a 5-10 membered heteroaryl group; in Ring B, the 5-10 membered heteroaryl group contains 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0027] R5 is selected from hydrogen, deuterium, halogen, cyano, -(CR 5a R 5b ) n3 OR 5c 、-(CR 5a R 5b ) n3 N(R 5c R 5d ), -COOR 5c , -CONH2, -CONHR 5c 、-CON(R 5c R 5d ),-NHCOR 5c 、-SO2R 5c 、-SO2NHR 5c 、-SO2NR 5c R 5d 、 The following groups substituted by one or more R6: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; or two adjacent R5s and the atoms to which they are attached form a 5-6 membered alkyl ring, a 5-6 membered alkyl heterocycle, a benzene ring or a 5-6 membered heteroaryl ring; in R5, the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl contains 1-3 heteroatoms selected from at least one of N, S and O; when two adjacent R5s and the atoms to which they are attached form a ring, the 5-6 membered alkyl heterocycle or 5-6 membered heteroaryl ring contains 1-3 heteroatoms selected from at least one of N, S and O;

[0028] Or R5 and R4 form a 5-7 membered alkyl heterocyclic ring with the atoms to which they are attached; when R5 and R4 form a ring with the atoms to which they are attached, the 5-7 membered alkyl heterocyclic ring contains 1 to 3 heteroatoms selected from at least one of N and O;

[0029] R 5a and R 5b independently selected from hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy or C 1-4 At least one of fluoroalkoxy; or R5a and R 5b Together with the atoms to which they are attached, they form a 3- to 6-membered alkyl ring or a 4- to 6-membered alkyl heterocyclic ring substituted with 0-6 substituents; R 5a and R 5b When forming a ring with the atoms to which they are attached, the substituents are selected from hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy or C 1-4 At least one of the fluoroalkoxy groups; R 5a and R 5b When forming a ring with the atoms to which they are attached, the 5-6 membered alkyl heterocycle contains 1 to 3 heteroatoms selected from at least one of N, S, and O;

[0030] R 5c and R 5d independently selected from hydrogen, deuterium or the following groups substituted with 0-6 substituents: C 1-4 alkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, 3-8 membered cycloalkyl, 6-10 membered spirocycloalkyl, 6-10 membered heterospirocycloalkyl, 6-10 membered bridged cycloalkyl or 6-10 membered heterobridged cycloalkyl; R 5c and R 5d In the embodiment, the substituent is selected from the group consisting of: deuterium, halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Alkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, 3- to 6-membered cycloalkylmethylene, 4- to 6-membered heterocycloalkylmethylene, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -OC 1-6 Alkyl, -CONH2 or -CONH-C 1-6 alkyl;

[0031] R 5c and R 5d wherein the 5- to 10-membered heteroaryl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered heterospirocycloalkyl, and 6- to 10-membered heterobridged cycloalkyl contain 1 to 3 heteroatoms selected from at least one of N, S, and O; R 5c and R 5d In the substituent, the 4- to 6-membered heterocycloalkyl group and the 4- to 6-membered heterocycloalkylmethylene group contain 1 to 3 heteroatoms selected from at least one of N, S, or O;

[0032] Or, R 5a With R 5c 、R 5a With R 5d 、R 5b With R 5c 、R 5b With R 5d or R 5c With R 5d Together with the atoms to which they are attached, they form a 4-6 membered alkane heterocycle substituted by 0-6 substituents selected from hydrogen, deuterium, fluorine, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy or C 1-4 at least one of the fluoroalkoxy groups, wherein the 4-6 membered alkyl heterocycle contains 1 to 3 heteroatoms selected from at least one of N, S or O;

[0033] R6 is selected from H, deuterium, fluorine, C 1-4 Alkyl, C 1-4 Deuterated alkyl or C 1-4 Fluorinated alkyl;

[0034] n1 is selected from 1, 2, 3, 4, 5, 6, 7, 8;

[0035] n2 is selected from 1, 2, 3, 4, 5;

[0036] n3 is selected from 0, 1, 2, 3, 4, 5;

[0037] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled substances, metabolites, or prodrugs.

[0038] In some embodiments of the present invention, R1 is selected from hydrogen, deuterium, fluorine, hydroxyl, amino or C 1-4 alkyl.

[0039] In some preferred embodiments of the present invention, R1 is selected from hydrogen, deuterium, fluorine or methyl.

[0040] In some embodiments of the present invention, R2 and R3 are independently selected from hydrogen, deuterium, fluorine, C 1-4 Alkyl or C 1-4 The alkyl group is substituted with a hydroxy group.

[0041] In some preferred embodiments of the present invention, R2 and R3 are independently selected from hydrogen, deuterium, fluorine, methyl or hydroxymethyl.

[0042] In some embodiments of the present invention, L is selected from a bond, O, NR L1 or CR L2 R L3 ; R L1 is selected from hydrogen, deuterium, methyl, deuterated methyl, fluoromethyl or hydroxymethyl; R L2 and R L3 are independently selected from hydrogen, deuterium, fluorine, hydroxy, amino, methyl, deuterated methyl, fluoromethyl or hydroxymethyl.

[0043] In some preferred embodiments of the present invention, L is selected from a bond, O or NH.

[0044] In some embodiments of the present invention, R4 is selected from at least one of hydrogen, deuterium, fluorine, hydroxyl, amino, methyl, deuterated methyl, fluoromethyl, ethyl, methoxy, deuterated methoxy, fluoromethoxy or hydroxymethyl; or two R4 connected to adjacent C atoms together with the atoms to which they are connected form a 3-5 membered alkyl ring or a 5-6 membered alkyl heterocycle; when two R4 connected to adjacent C atoms form a ring with the atoms to which they are connected, the 5-6 membered alkyl heterocycle contains 1 to 2 heteroatoms selected from at least one of N or O; n1 is selected from 1, 2, 3, or 4.

[0045] In some preferred embodiments of the present invention, R4 is selected from at least one of hydrogen, deuterium, fluorine, hydroxyl, amino, methyl, ethyl, hydroxymethyl, and methoxy; or two R4 connected to adjacent carbon atoms together with the atoms to which they are connected form a 3-5 membered alkyl ring or a 5-6 membered alkyl heterocycle; when two R4 connected to adjacent C atoms form a ring with the atoms to which they are connected, the 5-6 membered alkyl heterocycle contains 1 O heteroatom; n1 is selected from 1 and 2.

[0046] In some embodiments of the present invention, the structural unit Selected from: or (The left ends of these structures are related to the structural units connected to the left and right, and connected to L).

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

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

[0049] In some embodiments of the present invention, ring B is selected from phenyl, pyridyl, imidazolyl, imidazo[1,2-a]pyrazinyl, 1,7-naphthyridinyl, pyridazinyl, pyrazinyl, pyridothiazolyl, pyrazolo[1,5-a]pyrimidinyl, benzopyrazolyl, benzimidazolyl, thiazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, thienyl, furanyl, pyrazolyl, pyridazinopyrrolyl, pyridopyrazolyl, pyridoxazolyl or pyrimidinyl.

[0050] In some preferred embodiments of the present invention, ring B is selected from or (The wavy bond in these structures is connected to L).

[0051] In some embodiments of the present invention, R5 is selected from hydrogen, fluorine, chlorine, bromine, cyano, amino, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Fluorinated alkoxy, 3-6 membered cycloalkyl, C 1-4 Alkyl aminoacyl, C 1-4 Deuterated alkylaminoacyl, C 1-4 Fluoroalkylaminoacyl, C 1-4 Alkoxy-substituted C 1-4 at least one of alkylaminoacyl, 3-6-membered cycloalkylaminoacyl, 3-6-membered fluorocycloalkylaminoacyl, 4-6-membered heterocycloalkylaminoacyl, 6-membered arylaminoacyl or 5-6-membered heteroarylaminoacyl, or two adjacent R5s and the atoms to which they are attached form a 5-6-membered alkyl ring or a 5-6-membered alkyl heterocycle; in R5, the 4-6-membered heterocycloalkylaminoacyl or 5-6-membered heteroarylaminoacyl contains 1-2 heteroatoms selected from at least one of N, S and O; when two adjacent R5s and the atoms to which they are attached form a ring, the 5-6-membered alkyl heterocycle contains 1-2 heteroatoms selected from at least one of N, S and O; and n2 is selected from 1, 2 or 3.

[0052] In some preferred embodiments of the present invention, R5 is selected from hydrogen, fluorine, chlorine, cyano, amino, methyl, deuterated methyl, fluoromethyl, ethyl, deuterated ethyl, fluoroethyl, cyclopropyl, cyclobutyl, methylamino, deuterated methylamino, fluoromethylamino, methylaminoacyl, deuterated methylaminoacyl, fluoromethylaminoacyl, ethylaminoacyl, deuterated ethylaminoacyl, fluoroethylaminoacyl, methoxyethylaminoacyl, cyclopropylaminoacyl, fluorocyclopropylaminoacyl, cyclobutylaminoacyl, fluorocyclobutylaminoacyl or At least one of; n2 is selected from 1, 2.

[0053] In some embodiments of the present invention, the structural unit Selected from: or

[0054] In some embodiments of the present invention, Z3 is selected from O, CH2, CHF or CF2.

[0055] In some preferred embodiments of the present invention, Z3 is selected from O or CH2.

[0056] In some embodiments of the present invention, Z2 is selected from O, NR b1 or CR b2 R b3 ; R b1 is selected from hydrogen, deuterium or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl; R b1 wherein the substituent is selected from: deuterium, fluorine, -OH, -NH2, -CN or a 3-4 membered cycloalkyl group; R b1 wherein the 4-6 membered heterocycloalkyl group contains 1-2 heteroatoms selected from N or O; R b2 and R b3 independently selected from hydrogen, deuterium, fluorine or C 1-4 alkyl.

[0057] In some preferred embodiments of the present invention, Z2 is selected from O, NR b1 or CR b2 R b3 ; R b1 is selected from hydrogen, deuterium or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl or 3-4 membered cycloalkyl; R b1 wherein the substituent is selected from: deuterium, fluorine, -OH, -NH2, -CN or a 3-4 membered cycloalkyl group; R b2 and R b3 are independently selected from hydrogen, deuterium, fluorine or methyl.

[0058] In some more preferred embodiments of the present invention, Z2 is selected from O, CH2, NH, NCH3, NCD3 or N-cyclopropyl.

[0059] In some embodiments of the present invention, when Z1 is selected from a bond, O, NR a1 or CR a2 R a3 When R a1 is selected from hydrogen, deuterium or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl; R a1 wherein the substituent is selected from: deuterium, fluorine, -OH, -NH2, -CN or a 3-4 membered cycloalkyl group; R a1 wherein the 4-6 membered heterocycloalkyl group contains 1-2 heteroatoms selected from N or O; R a2 and R a3 independently selected from hydrogen, deuterium, fluorine or C 1-4 alkyl.

[0060] In some preferred embodiments of the present invention, when Z1 is selected from a bond, O, NR a1 or CR a2 R a3 When R a1 is selected from hydrogen, deuterium or the following groups optionally substituted by 0-3 substituents: C 1-4 Alkyl or 3-4 membered cycloalkyl; R a1 wherein the substituent is selected from: deuterium, fluorine, -OH, -NH2, -CN or a 3-4 membered cycloalkyl group; R a2 and R a3 are independently selected from hydrogen, deuterium, fluorine or methyl.

[0061] In some more preferred embodiments of the present invention, when Z1 is selected from a bond, O, NR a1 or CR a2 R a3 When Z1 is selected from O, CH2, NH, NCH3, NCD3 or N-cyclopropyl.

[0062] In some preferred embodiments of the present invention, R x1 、R y1 independently selected from hydrogen, deuterium, halogen, cyano, amino, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -OC 1-4 Alkyl, -SC 1-4 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered fluorinated cycloalkyl or phenyl;

[0063] R x2 Selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered fluorinated cycloalkyl or phenyl;

[0064] R7 is selected from hydrogen, deuterium, halogen, hydroxy, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Fluoroalkoxy, -NH-C 1-4 Alkyl or -N(C 1-4 At least one of alkyl) 2; n4 is selected from 1, 2, 3, 4;

[0065] R8 is selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 deuterated alkyl or 3-4 membered cycloalkyl.

[0066] In some more preferred embodiments of the present invention, R x1 、R y1 independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, cyclopropyl or fluorocyclopropyl;

[0067] R x2 is selected from hydrogen, deuterium, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, cyclopropyl or fluorocyclopropyl;

[0068] R7 is selected from hydrogen, deuterium, fluorine, chlorine, amino, methylamino, deuterated methylamino, fluoromethylamino, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, cyclopropyl, fluorocyclopropyl, methoxy, deuterated methoxy or fluoromethoxy; n4 is selected from 1, 2;

[0069] R8 is selected from hydrogen, methyl, deuterated methyl or fluoromethyl.

[0070] In some most preferred embodiments of the present invention, the structural unit Selected from:

[0071] The present invention also provides some specific compounds represented by formula I, which are selected from:

[0072] Based on the above-mentioned compound of formula I, the present invention also provides a class of compounds represented by formula I. In some embodiments of the present invention, the structural unit Selected from or (The left ends of these structures are related to the structural units connected to the left and right, and connected to L).

[0073] In some embodiments of the present invention, R5 is selected from hydrogen, fluorine, chlorine, bromine, cyano, amino, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Fluorinated alkoxy, 3-6 membered cycloalkyl, C 1-4 Alkyl aminoacyl, C 1-4 Deuterated alkylaminoacyl, C 1-4 Fluoroalkylaminoacyl, C 1-4 Alkoxy-substituted C 1-4 Alkylaminoacyl, 3-6 membered cycloalkylaminoacyl, 3-6 membered fluorocycloalkylaminoacyl, 4-6 membered heterocycloalkylaminoacyl, 6 membered arylaminoacyl, 5-6 membered heteroarylaminoacyl, C 1-4 Alkoxyaminoacyl, 3-6 membered cycloalkyl substituted C 1-4 At least one of the alkoxyaminoacyl group or the 3-6-membered cycloalkoxyaminoacyl group, or two adjacent R5s and the atoms to which they are attached form a 5-6-membered alkyl ring or a 5-6-membered alkyl heterocycle; in R5, the 4-6-membered heterocycloalkylaminoacyl group or the 5-6-membered heteroarylaminoacyl group contains 1 to 2 heteroatoms selected from at least one of N, S, and O; when two adjacent R5s and the atoms to which they are attached form a ring, the 5-6-membered alkyl heterocycle contains 1 to 2 heteroatoms selected from at least one of N, S, and O; and n2 is selected from 1, 2, and 3.

[0074] In some preferred embodiments of the present invention, R5 is selected from hydrogen, fluorine, chlorine, cyano, amino, methyl, deuterated methyl, fluoromethyl, ethyl, deuterated ethyl, fluoroethyl, cyclopropyl, cyclobutyl, methylamino, deuterated methylamino, fluoromethylamino, methylaminoacyl, deuterated methylaminoacyl, fluoromethylaminoacyl, ethylaminoacyl, deuterated ethylaminoacyl, fluoroethylaminoacyl, methoxyethylaminoacyl, cyclopropylaminoacyl, fluorocyclopropylaminoacyl, cyclobutylaminoacyl, fluorocyclobutylaminoacyl, or At least one of; n2 is selected from 1, 2.

[0075] In some embodiments of the present invention, the structural unit Selected from: or

[0076] In some embodiments of the present invention, R x1 、R y1 independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, cyclopropyl or fluorocyclopropyl;

[0077] R x2 is selected from hydrogen, deuterium, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, cyclopropyl or fluorocyclopropyl;

[0078] R7 is selected from hydrogen, deuterium, fluorine, chlorine, amino, methylamino, deuterated methylamino, fluoromethylamino, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, cyclopropyl, fluorocyclopropyl, methoxy, deuterated methoxy or fluoromethoxy; n4 is selected from 1, 2;

[0079] R8 is selected from hydrogen, methyl, deuterated methyl or fluoromethyl.

[0080] In some preferred embodiments of the present invention, the structural unit Selected from: or In some embodiments of the present invention, the structural unit Replace with:

[0081] The present invention also provides some specific compounds represented by formula I, which are selected from:

[0082] Based on the above-mentioned compound of formula I, the present invention also provides a class of compounds represented by formula I. In some embodiments of the present invention, the structural unit Selected from: or (The left ends of these structures are related to the structural units connected to the left and right, and connected to L).

[0083] In some preferred embodiments of the present invention, the structural unit Selected from: or (The left ends of these structures are related to the structural units connected to the left and right, and connected to L).

[0084] In some more preferred embodiments of the present invention, the structural unit Selected from or (The left ends of these structures are related to the structural units connected to the left and right, and connected to L).

[0085] In some embodiments of the present invention, ring B is selected from phenyl, pyridyl, imidazolyl, imidazo[1,2-a]pyrazinyl, 1,7-naphthyridinyl, pyridazinyl, pyrazinyl, pyridothiazolyl, pyrazolo[1,5-a]pyrimidinyl, benzopyrazolyl, benzimidazolyl, thiazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, pyridazinopyrrolyl, pyridopyrazolyl, pyridoxazolyl or pyrimidinyl.

[0086] In some preferred embodiments of the present invention, ring B is selected from or

[0087] In some embodiments of the present invention, R5 is selected from hydrogen, fluorine, chlorine, bromine, cyano, amino, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Fluorinated alkoxy, 3-6 membered cycloalkyl, C 1-4 Alkyl aminoacyl, C 1-4 Deuterated alkylaminoacyl, C 1-4 Fluoroalkylaminoacyl, C 1-4 Alkoxy-substituted C 1-4 Alkylaminoacyl, 3-6 membered cycloalkylaminoacyl, 3-6 membered fluorocycloalkylaminoacyl, 4-6 membered heterocycloalkylaminoacyl, 6 membered arylaminoacyl, 5-6 membered heteroarylaminoacyl, C 1-4 Alkoxyaminoacyl, 3-6 membered cycloalkyl substituted C 1-4At least one of the alkoxyaminoacyl group or the 3-6-membered cycloalkoxyaminoacyl group, or two adjacent R5s and the atoms to which they are attached form a 5-6-membered alkyl ring or a 5-6-membered alkyl heterocycle; in R5, the 4-6-membered heterocycloalkylaminoacyl group or the 5-6-membered heteroarylaminoacyl group contains 1 to 2 heteroatoms selected from at least one of N, S, and O; when two adjacent R5s and the atoms to which they are attached form a ring, the 5-6-membered alkyl heterocycle contains 1 to 2 heteroatoms selected from at least one of N, S, and O; and n2 is selected from 1, 2, and 3.

[0088] In some preferred embodiments of the present invention, R5 is selected from hydrogen, fluorine, chlorine, cyano, amino, methyl, deuterated methyl, fluoromethyl, ethyl, deuterated ethyl, fluoroethyl, cyclopropyl, cyclobutyl, methylamino, deuterated methylamino, fluoromethylamino, methylaminoacyl, deuterated methylaminoacyl, fluoromethylaminoacyl, ethylaminoacyl, deuterated ethylaminoacyl, fluoroethylaminoacyl, methoxyethylaminoacyl, cyclopropylaminoacyl, fluorocyclopropylaminoacyl, cyclobutylaminoacyl, fluorocyclobutylaminoacyl, At least one of; n2 is selected from 1, 2.

[0089] In some embodiments of the present invention, the structural unit Selected from: or

[0090] In some embodiments of the present invention, R x1 、R y1 independently selected from hydrogen, deuterium, halogen, cyano, amino, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -OC 1-4 Alkyl, -SC 1-4 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered fluorinated cycloalkyl, vinyl or phenyl;

[0091] R x2 Selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered fluorinated cycloalkyl or phenyl;

[0092] R7 is selected from hydrogen, deuterium, halogen, hydroxy, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Fluoroalkoxy, -NH-C 1-4 Alkyl or -N(C 1-4 At least one of alkyl) 2; n4 is selected from 1, 2, 3, 4;

[0093] R8 is selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 deuterated alkyl or 3-4 membered cycloalkyl.

[0094] In some preferred embodiments of the present invention, R x1 、R y1 independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, cyclopropyl, methoxy, methylthio, vinyl or fluorocyclopropyl;

[0095] R x2 is selected from hydrogen, deuterium, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, cyclopropyl or fluorocyclopropyl;

[0096] R7 is selected from hydrogen, deuterium, fluorine, chlorine, amino, methylamino, deuterated methylamino, fluoromethylamino, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, cyclopropyl, fluorocyclopropyl, methoxy, deuterated methoxy or fluoromethoxy; n4 is selected from 1, 2;

[0097] R8 is selected from hydrogen, methyl, deuterated methyl or fluoromethyl.

[0098] In some more preferred embodiments of the present invention, the structural unit Selected from: or

[0099] In some embodiments of the present invention, the structural unit Replace with: or The present invention also provides some specific compounds represented by formula I, which are selected from:

[0100] The present invention also provides some specific compounds represented by formula I, which are selected from:

[0101] In a second aspect, the present invention provides a pharmaceutical composition comprising the aforementioned compound (Formula I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope-labeled substance, metabolite or prodrug thereof as an active ingredient, supplemented with a pharmaceutically acceptable carrier.

[0102] A further object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, which comprises combining any compound of Formula I or a pharmaceutically acceptable form thereof, or a mixture thereof, with one or more pharmaceutically acceptable carriers.

[0103] The pharmaceutically acceptable carrier that can be used in the pharmaceutical composition of the present invention is a pharmaceutically acceptable carrier. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).

[0104] The pharmaceutical composition can be administered in any form, as long as it prevents, alleviates, prevents or cures the symptoms of a human or animal patient. For example, it can be prepared into various suitable dosage forms according to the route of administration.

[0105] In other embodiments, the administration of the compound or pharmaceutical composition of the present invention can be combined with another treatment method. The other treatment method can be selected from, but not limited to: radiation therapy, chemotherapy, immunotherapy, or a combination thereof.

[0106] The present invention also relates to a pharmaceutical preparation comprising any compound of Formula I or a pharmaceutically acceptable form thereof, or a mixture thereof as an active ingredient, or a pharmaceutical composition of the present invention. In some embodiments, the preparation is in the form of a solid preparation, a semi-solid preparation, a liquid preparation, or a gaseous preparation.

[0107] A further object of the present invention is to provide an article of manufacture, for example, in the form of a kit. As used herein, an article of manufacture is intended to include, but is not limited to, a kit and packaging. The article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition in the first container, wherein the composition comprises: a first therapeutic agent, wherein the first therapeutic agent comprises: any compound comprising Formula I or a pharmaceutically acceptable form thereof, or a mixture thereof; (c) an optional package insert indicating that the pharmaceutical composition can be used to treat a neoplastic condition (as defined below); and (d) a second container.

[0108] The first container is a container for holding a pharmaceutical composition. This container can be used for preparation, storage, transportation and / or individual / bulk sales. The first container is intended to encompass bottles, jars, vials, flasks, syringes, tubes (e.g., for cream products), or any other container for preparing, holding, storing, or dispensing pharmaceutical products.

[0109] The second container is a container for accommodating the first container and optional package insert. Examples of the second container include, but are not limited to, boxes (e.g., paper or plastic boxes), boxes, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The package insert can be physically adhered to the outside of the first container via a cable tie, glue, staples, or other adhesion methods, or it can be placed inside the second container without any physical tool for adhering to the first container. Alternatively, the package insert is located outside the second container. When located outside the second container, it is preferred that the package insert is physically adhered via a cable tie, glue, staples, or other adhesion methods. Alternatively, it can abut or contact the outside of the second container without physical adhesion.

[0110] The package insert is a trademark, label, or indicia that lists information about the pharmaceutical composition within the first container. The information listed is typically determined by the regulatory agency (e.g., the U.S. Food and Drug Administration) that governs the region in which the product is to be sold. Preferably, the package insert specifically lists the indications for which the pharmaceutical composition is approved. The package insert can be made of any material from which the information contained therein or thereon can be read. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper, or plastic, etc.) onto which the desired information can be formed (e.g., printed or applied).

[0111] In a third aspect, the present invention provides the use of the aforementioned compound of formula I, and related specific compounds or pharmaceutically acceptable forms thereof, or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating PARP1 enzyme-related diseases.

[0112] The present invention provides a method for preventing or treating PARP1 enzyme-related diseases, comprising administering a compound of formula I or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention to a subject in need thereof.

[0113] The present invention provides a compound of formula I or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention, for use in preventing or treating PARP1 enzyme-related diseases.

[0114] The present invention provides a method for preventing or treating PARP1 enzyme-related diseases in combination with a compound of Formula I or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention, wherein the additional treatment method includes but is not limited to: radiotherapy, chemotherapy, immunotherapy, or a combination thereof.

[0115] In some embodiments, the PARP1 enzyme-related disease is a disease that is sensitive or responsive to PARP1 enzyme inhibition.

[0116] In some embodiments, the PARP1 enzyme-related disease is a tumor-related disorder.

[0117] In some preferred embodiments, the oncological disorder is deficient in a HR-dependent DNA DSB repair pathway.

[0118] In some preferred embodiments, the neoplastic disorder comprises one or more cancer cells that have a reduced or absent ability to repair DNA DSBs by HR relative to normal cells.

[0119] In some preferred embodiments, the cancer cells have a BRCA1 or BRCA2 deficient phenotype.

[0120] In some embodiments, the PARP1 enzyme-related disease is a tumor-related disorder, including but not limited to solid and hematological malignancies. In further embodiments, the tumor-related disorder includes but is not limited to breast cancer, colorectal cancer, colon cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchioloalveolar cancer) and prostate cancer, as well as bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer and vulvar cancer, as well as leukemia (including chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL) and chronic myeloid leukemia (CML)), multiple myeloma or lymphoma.

[0121] In some preferred embodiments, the PARP1 enzyme-related disease is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer or lung cancer.

[0122] In a further preferred embodiment, the compounds of the present invention can be used in combination with chemoradiotherapy or immunotherapy to prevent or treat cancer.

[0123] The present invention provides the use of the above-mentioned compound or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope-labeled substance, metabolite or prodrug, and the above-mentioned pharmaceutical composition in the preparation of PARP1 inhibitors.

[0124] Beneficial effects of the present invention:

[0125] The present invention provides a novel class of highly active and highly selective PARP1 inhibitors capable of achieving at least one of the following technical effects: (1) high inhibitory activity against PARP1 enzyme; (2) selective inhibition of PARP1 enzyme, with high selectivity for other PARP family enzymes such as PARP2, PARP5a, and PARP5b; (3) strong inhibitory activity against homologous recombination-deficient tumor cells and weak inhibitory effect on non-homologous recombination-deficient cells; (4) excellent pharmacokinetic properties (e.g., good bioavailability, suitable half-life and duration of action); (5) excellent safety (lower toxicity and / or fewer side effects, wider therapeutic window), etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0126] FIG1 is a graph showing the in vivo efficacy of compound 2 on a breast cancer MDA-MB-436 subcutaneous transplanted tumor model in nude mice.

[0127] FIG2 is a graph showing the in vivo efficacy of compound 53 on a breast cancer MDA-MB-436 subcutaneous transplant tumor model in nude mice. DETAILED DESCRIPTION

[0128] The scheme of the present invention will be explained below with reference to the examples. Those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. Where specific techniques or conditions are not specified in the examples, the techniques or conditions described in the literature in this area or the product specifications shall be followed.

[0129] The reagents and raw materials used in the examples of the present invention are all commercially available.

[0130] Table 1 Abbreviations and their meanings in the present invention

[0131] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS). Chemical shifts were measured at 10 -6 The unit is (ppm). MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, signal: 6110).

[0132] HPLC analysis was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfirc C18, 150×4.6 mm, 5 μm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18, 150×4.5 mm, 5 μm column).

[0133] The thin layer chromatography silica gel plate used was Qingdao Ocean GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) had a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products was 0.4mm-0.5mm silica gel plate.

[0134] Column chromatography generally uses Qingdao Ocean 100-200, 200-300 mesh silica gel as the carrier.

[0135] Unless otherwise specified, all reactions in the following examples were conducted under an argon or nitrogen atmosphere. Argon or nitrogen atmosphere refers to the reaction flask being connected to an approximately 1 L argon or nitrogen balloon. Hydrogen atmosphere refers to the reaction flask being connected to an approximately 1 L hydrogen balloon. The hydrogenation reaction was typically performed by evacuating the flask and then filling it with hydrogen, repeating this process three times.

[0136] Intermediate INT1: N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0137] Step 1: Compound INT1a (1 g, 4.6 mmol), INT1b (1.7 g, 5.5 mmol), Pd(dppf)Cl2 (0.3 g, 0.46 mmol), and potassium carbonate (1.6 g, 11.5 mmol) were added to a mixed solvent of 7 ml of dioxane, 3 ml of anhydrous ethanol, and 4 ml of water. The nitrogen atmosphere was then replaced three times and the mixture was reacted at 90°C under nitrogen for 2 h. After TLC analysis of the reaction, the reaction mixture was cooled to room temperature, 30 ml of dichloromethane and 20 ml of water were added, and the layers were separated in a separatory funnel. The aqueous phase was extracted twice with dichloromethane, and the combined organic phases were washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The resulting crude product was purified by column chromatography to yield compound INT1c (1 g, white solid).

[0138] Step 2: Add INT1c (1 g, 3 mmol), aqueous methylamine (5 g, 161.3 mmol), and anhydrous methanol (20 ml) to a 100 ml reaction flask and stir overnight at room temperature. After completion of the reaction as monitored by TLC, the reaction mixture was concentrated under reduced pressure to dryness to yield compound INT1d (0.8 g, white solid).

[0139] Step 3: Compound INT1d (0.5 g, 1.5 mmol) was added to 10 ml of anhydrous methanol, followed by 10 ml of a 4 mol / L hydrochloric acid and dioxane solution. The mixture was stirred at room temperature for 0.5-1 h. After completion of the reaction as monitored by TLC, the reaction solution was concentrated under reduced pressure to dryness to obtain compound INT1 (0.5 g, white solid). MS / ESI [M+H] + =218.1.

[0140] The preparation of intermediates INT2 and INT3 refers to intermediate INT1.

[0141] Table 2 Intermediates INT2~INT3

[0142] Intermediate INT4: N-cyclopropyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0143] Step 1: Weigh INT1c (1.4 g, 4.5 mmol), add 20 mL of MeOH to dissolve, add 5 mL of water, add lithium hydroxide (570 mg, 13.5 mmol), react at room temperature for 12 h, monitor the reaction by TLC, and after the reaction is complete, add 2 M HCl to adjust the pH to 6. Add EA (3 x 25 mL) for extraction, combine the organic phases, dry over anhydrous sodium sulfate, and vacuum dry to obtain the product INT4a (460 mg, light yellow solid).

[0144] Step 2: Weigh INT4a (180 mg, 0.6 mmol), EDCI (144 mg, 0.75 mmol), HOBT (100 mg, 0.75 mmol) 2 mL DMF, N-methylmorpholine (290 mg, 3.2 mmol), and cyclopropylamine (34 mg, 0.6 mmol), and react at room temperature for 12 h. Monitor by TLC. After the raw materials are completely consumed, dilute with water, extract with EA, and wash the organic phase with water 5 times. Dry over anhydrous sodium sulfate and spin dry to obtain the crude product INT4b (180 mg, yellow oily liquid).

[0145] Step 3: Dissolve the crude product of INT4b (171 mg, 0.5 mmol) in methanol (5 mL), then add 4M HCl 1,4-dioxane (0.9 mL) and react at room temperature for 12 h. Monitor the reaction by TLC. After the reaction is complete, add potassium carbonate and stir for 30 minutes. Remove the potassium carbonate by filtration to obtain the crude product of compound INT4 (180 mg, yellow-brown solid). MS / ESI [M+H] + =244.1.

[0146] The preparation of intermediates INT5-INT8 refers to intermediate INT4.

[0147] Table 3 Intermediates INT5-INT8

[0148] Intermediate INT9: N-methyl-5-(piperazin-1-yl)pyridineamide

[0149] Step 1: Compound INT1a (5.66 g, 26.21 mmol, 1.05 eq), compound INT9a (4.65 g, 25.0 mmol, 1.00 eq), Cs2CO3 (16.27 g, 50.0 mmol, 2.00 eq) and RuPhos-Pd-G3 (1.04 g, 1.25 mmol, 0.05 eq) were added to 1,4-dioxane (50 mL) and stirred at 120°C overnight under a nitrogen atmosphere. After the reaction was completed, the mixture was allowed to cool to room temperature after LCMS. The reaction solution was diluted with water (100 mL) and then extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound INT9b (white solid, 4.5 g). MS / ESI[M+H] + =322.1.

[0150] Step 2: Compound INT9b (1.92 g, 6.0 mmol, 1.0 eq) was added to a solution of methylamine (8 mL, 25-30 wt% aqueous solution) in methanol (7 mL) and stirred at room temperature for 3 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with saturated aqueous ammonium chloride solution (30 mL) at room temperature. The resulting mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layer was washed with brine (2 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain compound INT9c (1.65 g) as a light yellow oil. MS / ESI[M+H] + =321.3.

[0151] Step 3: Compound INT9c (482 mg, 1.50 mmol, 1.00 eq) and HCl in 1,4-dioxane (3.7 mL, 15.0 mmol, 10.0 eq, 4.0 M) were stirred at room temperature for 2 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure by LCMS monitoring to obtain compound INT9 (392 mg, crude product) as a yellow solid. The crude product was used directly in the next step without further purification. MS / ESI [M+H] +=221.3.

[0152] The preparation of intermediates INT10 and INT11 refers to intermediate INT9.

[0153] Table 4 Intermediates INT10 and INT11

[0154] Intermediate INT12: N-cyclopropyl-5-(piperazin-1-yl)pyridineamide

[0155] Step 1: Weigh INT9b (1.4 g, 4.5 mmol), add 20 mL of MeOH to dissolve, add 5 mL of water, add lithium hydroxide (570 mg, 13.5 mmol), react at room temperature for 12 h, monitor the reaction by TLC, add 2 M HCl after the reaction is complete to adjust the pH to 6, add EA (3 x 25 mL) to extract, combine the organic phases, dry over anhydrous sodium sulfate, and vacuum dry to obtain the product INT12a (845 mg).

[0156] Step 2: INT12a (180 mg, 0.6 mmol), EDCI (144 mg, 0.75 mmol), HOBT (100 mg, 0.75 mmol), 2 mL DMF, N-methylmorpholine (290 mg, 3.2 mmol), and cyclopropylamine (34 mg, 0.6 mmol) were weighed and reacted at room temperature for 12 h. TLC monitoring was performed. After the starting material was completely consumed, the mixture was diluted with water and extracted with EA. The organic phase was washed with water five times, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain the crude product INT12b (165 mg). MS / ESI [M+H] + =347.2.

[0157] Step 3: Dissolve the crude product of INT12b (150 mg, 0.4 mmol) in 5 mL of MeOH, then add 0.9 mL of 4 M HCl in dioxane solution. React at room temperature for 12 h. Monitor the reaction by TLC. After completion, add potassium carbonate. Stir for 30 minutes, then filter and remove the potassium carbonate to obtain the crude product of compound INT12 (120 mg, yellow-brown solid). MS / ESI [M+H] + =247.1.

[0158] The preparation method of intermediates INT13-INT16 refers to intermediate INT12.

[0159] Table 5 Intermediates INT13-INT16

[0160] Intermediate INT17: 5-fluoro-1',2',3',6'-tetrahydro-2,4'-bipyridine

[0161] Step 1: Compound INT17a (0.5 g, 2.8 mmol), INT1b (0.92 g, 3.4 mmol), Pd(dppf)Cl2 (0.21 g, 0.52 mmol), and potassium carbonate (0.99 g, 13 mmol) were added to a mixed solvent of 7 ml of dioxane, 3 ml of anhydrous ethanol, and 4 ml of water. The nitrogen atmosphere was then replaced three times and the mixture was reacted at 90°C under nitrogen for 2 h. After TLC analysis of the reaction was complete, the reaction mixture was cooled to room temperature, 30 ml of dichloromethane and 20 ml of water were added, and the layers were separated in a separatory funnel. The aqueous phase was extracted twice with dichloromethane, and the combined organic phases were washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The resulting crude product was purified by column chromatography to yield compound INT17b (0.7 g, white solid).

[0162] Step 2: Compound INT17b (0.5 g, 1.8 mmol) was added to 10 ml of anhydrous methanol, followed by 10 ml of a 4 mol / L hydrochloric acid and dioxane solution. The mixture was stirred at room temperature for 0.5-1 h. After completion of the reaction as monitored by TLC, the reaction solution was concentrated under reduced pressure to dryness to obtain compound INT17 (0.3 g, white solid). MS / ESI [M+H] + =179.1.

[0163] The preparation method of intermediates INT18 and INT19 refers to intermediate INT17.

[0164] Table 6 Intermediates INT18 and INT19

[0165] Intermediate INT20: 1-(5-fluoropyridin-2-yl)piperazine

[0166] Step 1: Compound INT17a (1 g, 5.00 mmol) and compound INT9a (838 mg, 4.5 mmol) were dissolved in toluene (15 mL), and palladium acetate (112 mg, 0.5 mmol) and BINAP (311 mg, 0.5 mmol) were added. The reaction flask was replaced with nitrogen and placed in an oil bath at 120 ° C. After 16 h of reaction, water (20 mL) was added to quench the reaction, and ethyl acetate (3×30 mL) was added for extraction. The organic phases were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA=5:1) to obtain compound INT20a (yellow solid, 1.4 g). MS / ESI[M+H] + =282.1.

[0167] Step 2: Compound INT20a (0.5 g, 1.8 mmol) was added to anhydrous methanol (10 ml), followed by a 4 mol / L hydrochloric acid solution in dioxane (10 ml). The mixture was stirred at room temperature for 1 h. After completion of the reaction as monitored by TLC, the reaction solution was concentrated under reduced pressure to yield compound INT20 (0.4 g, white solid). MS / ESI [M+H] + =182.1.

[0168] The preparation methods of intermediates INT21 and INT22 refer to intermediate INT20.

[0169] Table 7 Intermediates INT21 and INT22

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

[0171] Step 1: Compound INT1a (5.66 g, 26.21 mmol, 1.05 eq), compound INT23a (5.00 g, 24.96 mmol, 1.00 eq), Cs2CO3 (16.27 g, 49.93 mmol, 2.00 eq), and RuPhos-Pd-G3 (1.04 g, 1.25 mmol, 0.05 eq) were added to 1,4-dioxane (50 mL) and stirred at 120°C overnight under a nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature after LCMS. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield compound INT23b (white solid, 5.00 g, 59.71%). MS / ESI[M+H] + =336.1.

[0172] Step 2: Compound INT23b (2.00 g, 5.96 mmol, 1.00 eq) was added to a solution of methylamine (8 mL, 25-30 wt% aqueous solution) in methanol (7 mL) and stirred at room temperature for 3 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with saturated aqueous ammonium chloride solution (30 mL) at room temperature. The resulting mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layer was washed with brine (2 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain compound INT23c (1.70 g, 85.25%) as a light yellow oil. MS / ESI[M+H] + =335.3.

[0173] Step 3: Compound INT23c (500 mg, 1.50 mmol, 1.00 eq) and a 1,4-dioxane solution of HCl (3.7 mL, 14.95 mmol, 10.0 eq, 4.0 M) were stirred at room temperature for 2 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure by LCMS to give compound INT23 (400 mg, crude product) as a yellow solid. The crude product was used directly in the next step without further purification. MS / ESI [M+H] + =235.3.

[0174] Intermediate INT24: 7-(Bromomethyl)-3-ethyl-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-2-one

[0175] Step 1: To a suspension of 2-chloro-6-methoxypyridine-3-carboxylic acid INT24a (4.69 g, 25 mmol) and sodium acetate (4.10 g, 50 mmol) in glacial acetic acid (200 ml) was added bromine (16.0 g, 100 mmol) at room temperature. The mixture was heated to 80°C overnight. After the reaction was complete, it was cooled to room temperature and poured into 500 ml of ice water with vigorous stirring. The solid was filtered and washed with water to give compound INT24b (white solid, 5.2 g, 78% yield). 1 H NMR (400MHz, DMSO-d6): δ8.51 (s, 1H), 3.93 (s, 3H). MS / ESI[M+H] + =266.1.

[0176] Step 2: Compound INT24b (2.0 g, 7.50 mmol) was added to a solution of BH3.THF (30.0 mL, 1 mol / L) and stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was quenched with MeOH and then concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography using petroleum ether / ethyl acetate (5 / 1, v / v) to obtain compound INT24c (white solid, 1.4 g, 73%). MS / ESI[M+H] + =251.9.

[0177] Step 3: Compound INT24c (2.5 g, 10 mmol) and imidazole (1.0 g, 15 mmol) were added to DMF (50 mL) and tert-butyldimethylsilyl chloride (1.8 g, 12 mmol). The resulting solution was stirred at room temperature for 24 hours, then diluted with ether and washed with water and brine. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The target compound INT24d (2.3 g) was purified by column chromatography. MS / ESI[M+H] + =366.2.

[0178] Step 4: Compound INT24d (3.65 g, 10 mmol), ethylboronic acid (1.11 g, 15 mmol), cesium carbonate (9.78 g, 30 mmol), and Pd(dppf)Cl2 (0.73 g, 1 mmol) were added to 1,4-dioxane / water (10:1, 50 mL). The mixture was heated to 80°C under nitrogen for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water and ethyl acetate, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The target compound INT24e (1.5 g) was purified by column chromatography. MS / ESI [M+H] + =316.2.

[0179] Step 5: Compound INT24e (3.65 g, 10 mmol), allylboronic acid pinacol ester (2.52 g, 15 mmol), cesium carbonate (9.78 g, 30 mmol), and Pd(dppf)Cl2 (0.73 g, 1 mmol) were added to 1,4-dioxane / water (10:1, 50 mL) and heated to 80°C under nitrogen for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water and ethyl acetate, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The target compound INT24f (2.2 g) was purified by column chromatography. MS / ESI[M+H] + =322.2.

[0180] Step 6: Compound INT24f (1.6 g, 5 mmol) and 48% aqueous HBr solution (1.1 mL) were added to acetic acid (30 mL). The reaction temperature was raised to 70°C and continued with heating and stirring for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated, and then stirred with aqueous K2CO3 solution. The mixture was then extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography to obtain compound INT24g (0.7 g). MS / ESI [M+H] + =194.2.

[0181] Step 7: Compound INT24g (3.5 g, 18 mmol) was added to dry dichloromethane (50 mL) at 0°C, and N-bromosuccinimide (NBS, 3.56 g, 20.0 mmol) was added portionwise. The reaction mixture was warmed to room temperature and stirred for 12 hours. The solvent was removed by concentration under reduced pressure. The residue was purified by column chromatography to obtain compound INT24 (2.7 g). MS / ESI [M+H] + =272.2.

[0182] Intermediate INT25: 7-(iodomethyl)-2-methoxy-3-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine

[0183] Step 1: Compound INT25a (25 g, 124.4 mmol), allylboronic acid pinacol ester (31.3 g, 186.6 mmol), Pd(dppf)Cl2 (9.1 g, 12.4 mmol) and potassium phosphate (66.0 g, 310.9 mmol) were added to a mixed solvent of 250 ml of tetrahydrofuran and 25 ml of water, and then the nitrogen atmosphere was replaced three times. The reaction was carried out at 90 ° C for 3 hours under nitrogen protection. After TLC detection, the reaction was cooled to room temperature, ethyl acetate and water were added, and the layers were separated in a separatory funnel. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined and then washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by column chromatography to obtain compound INT25b (24.0 g, colorless oily liquid). LC-MS: ESI [M+H] + =208.1.

[0184] Step 2: Compound INT25b (24.0 g, 115.9 mmol) was added to 240 ml of anhydrous tetrahydrofuran, followed by the addition of 290 ml of 1 mol / L lithium diisobutylaluminum hydride solution, and stirred at room temperature for 3 h. After TLC monitoring, the reaction was quenched by adding saturated ammonium chloride, ethyl acetate and water were added, and the layers were separated in a separatory funnel. The aqueous phase was extracted 2-3 times with ethyl acetate, and the organic phases were combined and then washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by column chromatography to obtain compound INT25c (17.2 g, colorless oily liquid). LC-MS: ESI [M+H] + =180.1.

[0185] Step 3: Compound INT25c (17.2 g, 96.1 mmol), I2 (58.6 g, 230.6 mmol), and sodium bicarbonate (19.4 g, 230.6 mmol) were added to 200 ml of anhydrous acetonitrile and stirred at room temperature for 18 h. After the reaction was complete, a saturated sodium thiosulfate solution was added, followed by ethyl acetate and water, and the mixture was separated in a separatory funnel. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined and then washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by column chromatography to obtain compound INT25d (6.2 g, white solid). LC-MS: ESI[M+H] + =306.1.

[0186] Step 4: Add compound INT25d (6.2 g, 20.3 mmol), NBS (5.8 g, 32.5 mmol), and dichloroacetic acid (0.26 g, 2.0 mmol) to 50 ml of glacial acetic acid, react at 90 ° C for 3 hours, and after TLC monitoring, add saturated sodium thiosulfate solution, add ethyl acetate and water, and separate them in a separatory funnel. The aqueous phase is extracted twice with ethyl acetate, and the organic phases are combined and then washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product is purified by column chromatography to obtain compound INT25e (3.1 g, yellow solid). LC-MS: ESI [M + H] + =384.1.

[0187] Step 5: Compound INT25e (1 g, 2.6 mmol), methylboric acid (0.31 g, 5.2 mmol), Pd(dppf)Cl2 (0.19 g, 0.26 mmol) and potassium carbonate (0.90 g, 6.5 mmol) were added to a mixed solvent of 10 ml of toluene and 1 ml of water, and then the nitrogen was replaced three times. The reaction was allowed to proceed at 90°C overnight under nitrogen protection. After TLC detection showed that the reaction was complete, the reaction was cooled to room temperature, 30 ml of ethyl acetate and 50 ml of water were added, and the layers were separated in a separatory funnel. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined and then washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by column chromatography to obtain compound INT25 (0.6 g, white solid). LC-MS: ESI[M+H] + =320.1.

[0188] Intermediate INT26: 3-cyclopropyl-7-(iodomethyl)-2-methoxy-7,8-dihydro-5H-pyrano[4,3-b]pyridine

[0189] Preparation of 3-cyclopropyl-7-(iodomethyl)-2-methoxy-7,8-dihydro-5H-pyrano[4,3-b]pyridine: Reference intermediate INT25. LC-MS: ESI[M+H] + =346.1.

[0190] Intermediate INT27: 3-(difluoromethyl)-7-(iodomethyl)-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-2-one

[0191] Step 1: INT25e (1.0 g, 2.6 mmol), (tributyltin)methanol (1.0 g, 3.1 mmol), and RuPhos Pd G3 (0.22 g, 0.26 mmol) were added to a 10 ml dioxane solution. The nitrogen atmosphere was then replaced three times and the mixture was allowed to react overnight at 90°C under nitrogen protection. After TLC detection, the reaction mixture was cooled to room temperature, 30 ml of ethyl acetate and 50 ml of water were added, and the layers were separated in a separatory funnel. The aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The resulting crude product was purified by column chromatography to obtain compound INT27a (0.5 g, white solid).

[0192] Step 2: INT27a (0.5 g, 1.5 mmol) and DMP (0.76 g, 1.8 mmol) were added to a 5 mL dichloromethane solution and stirred at room temperature for 2 h. After completion of the reaction, saturated sodium bicarbonate solution was added, followed by 30 mL of ethyl acetate and 50 mL of water. The layers were separated in a separatory funnel. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. Purification by column chromatography afforded compound INT27b (0.4 g, white solid).

[0193] Step 3: INT27b (0.4 g, 1.2 mmol) and DAST (0.23 g, 1.4 mmol) were added to a 5 mL dichloromethane solution and stirred at room temperature for 8 h. After completion of the reaction by LC-MS, saturated sodium bicarbonate was added to quench the reaction. 30 mL of ethyl acetate and 50 mL of water were added, and the layers were separated in a separatory funnel. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by column chromatography to yield compound INT27c (0.3 g, white solid).

[0194] Step 4: Add INT27c (0.3 g, 0.84 mmol) and 0.5 ml of 48% aqueous hydrobromic acid to 5 ml of dioxane, heat to 80°C, and stir for 1 hour. After the reaction is complete as determined by LC-MS, add saturated sodium bicarbonate solution, 30 ml of ethyl acetate, and 50 ml of water, and separate the layers in a separatory funnel. The aqueous phase is extracted twice with ethyl acetate, and the combined organic phases are washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. Purification by column chromatography yields compound INT27 (0.12 g, white solid). LC-MS: ESI [M+H] + =342.1.

[0195] Intermediate INT28: N-(cyclopropylmethoxy)-5-(piperazin-1-yl)picolinamide

[0196] Preparation of N-(cyclopropylmethoxy)-5-(piperazin-1-yl)picolinamide reference intermediate INT12. LC-MS: ESI [M+H] + =277.2.

[0197] Intermediate INT29: 6-Fluoro-N-methyl-5-(piperidin-4-yl)picolinamide

[0198] Compound INT2 (0.2 g, 0.84 mmol) was dissolved in DCM (20 mL) and Pd / C (10%, 0.1 g) was added. After hydrogen replacement three times, the mixture was stirred at 25°C under a hydrogen atmosphere for 12 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain compound INT29 (0.2 g, crude). LC-MS: ESI [M+H] + =238.2.

[0199] Intermediate INT30: 7-(Bromomethyl)-3-chloro-2-methoxy-7,8-dihydro-5H-pyrano[4,3-b]pyridine

[0200] Step 1: Compound INT25c (17.2 g, 96.1 mmol), NBS (34.2 g, 192.2 mmol), and sodium bicarbonate (19.4 g, 230.6 mmol) were added to 200 ml of anhydrous acetonitrile and stirred at room temperature for 18 h. After the reaction was complete, a saturated sodium thiosulfate solution was added, followed by ethyl acetate and water, and the mixture was separated in a separatory funnel. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined and then washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by column chromatography to obtain compound INT30a (3.2 g, white solid). LC-MS: ESI[M+H] +=258.1;

[0201] Step 2: Add compound INT30a (3.2 g, 12.5 mmol), NCS (3.3 g, 24.9 mmol), and dichloroacetic acid (0.26 g, 2.0 mmol) to 50 ml of glacial acetic acid, react at 90 ° C for 3 hours, and after TLC monitoring, add saturated sodium thiosulfate solution, add ethyl acetate and water, and separate them in a separatory funnel. The aqueous phase is extracted twice with ethyl acetate, and the organic phases are combined and then washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried. The crude product is purified by column chromatography to obtain compound INT30 (1.1 g, yellow solid). LC-MS: ESI [M + H] + =292.1.

[0202] Intermediate INT31: 7-(iodomethyl)-3-vinyl-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-2-one

[0203] Compound INT25e (0.85 g, 2.3 mmol), tributyl vinyl tin (1.09 g, 3.5 mmol), and Ruphos Pd G3 (0.19 g, 0.23 mmol) were added to a 10 ml dioxane solution, heated to 100°C, and stirred for 2 h. After the reaction was complete as determined by LC-MS, 30 ml of ethyl acetate and 50 ml of water were added, and the layers were separated in a separatory funnel. The aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. Purification by column chromatography afforded compound INT31 (0.35 g, white solid). LC-MS: ESI [M+H] + =318.1;

[0204] Intermediate INT32: 2-chloro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0205] The preparation method of 2-chloro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide refers to intermediate INT1. MS / ESI[M+H] + =252.1.

[0206] Intermediate INT33: 6-chloro-N-methyl-5-(piperazin-1-yl)picolinamide

[0207] The preparation method of 6-chloro-N-methyl-5-(piperazin-1-yl)picolinamide refers to intermediate INT9. MS / ESI[M+H]+ =255.3.

[0208] Intermediate INT34: 6-cyano-N-methyl-5-(piperazin-1-yl)picolinamide

[0209] The preparation method of 6-cyano-N-methyl-5-(piperazin-1-yl)picolinamide refers to intermediate INT9. MS / ESI[M+H] + =246.3.

[0210] Intermediate INT35: (S)-6-Fluoro-N-methyl-5-(3-methylpiperazin-1-yl)picolinamide

[0211] The preparation method of (S)-6-fluoro-N-methyl-5-(3-methylpiperazin-1-yl)picolinamide refers to intermediate INT23. MS / ESI[M+H] + =235.3.

[0212] Intermediate INT36: (R)-6-Fluoro-N-methyl-5-(3-methylpiperazin-1-yl)picolinamide

[0213] The preparation method of (R)-6-fluoro-N-methyl-5-(3-methylpiperazin-1-yl)picolinamide refers to intermediate INT23. MS / ESI[M+H] + =235.3.

[0214] Intermediate INT37: 6-Fluoro-N-(1-methyl-1H-pyrazol-4-yl)-5-(piperazin-1-yl)picolinamide

[0215] The preparation method of 6-fluoro-N-(1-methyl-1H-pyrazol-4-yl)-5-(piperazin-1-yl)picolinamide refers to intermediate INT12. MS / ESI[M+H] + =305.3.

[0216] Intermediate INT38: 6-Fluoro-N-(3-methoxycyclobutyl)-5-(piperazin-1-yl)picolinamide

[0217] The preparation method of 6-fluoro-N-(3-methoxycyclobutyl)-5-(piperazin-1-yl)picolinamide refers to intermediate INT12. MS / ESI[M+H] + =309.3.

[0218] Intermediate INT39: 5-((1S, 6R)-2,5-diazabicyclo[4.2.0]octan-2-yl)-6-fluoro-N-methylpicolinamide

[0219] The preparation method of 5-((1S,6R)-2,5-diazabicyclo[4.2.0]octan-2-yl)-6-fluoro-N-methylpicolinamide refers to intermediate INT23. MS / ESI[M+H] + =265.3.

[0220] Intermediate INT40: Preparation of (R)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazolidine-9-carboxamide hydrochloride

[0221] Step 1: (R)-tert-Butyl 3-(hydroxymethyl)piperazine-1-carboxylate (5 g, 23.118 mmol) was added to DMF (50 mL), followed by p-methoxybenzyl chloride (3.62 g, 23.118 mmol) and potassium carbonate (9.58 g, 69.355 mmol). The mixture was heated to 60°C for 24 h. After completion of the reaction, water was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was washed three times with water and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) to obtain compound INT40b (6 g, yield: 77.14%). LCMS = 337.4; 1 H NMR(400MHz,Chloroform-d)δ7.14(d,J=8.3Hz,2H),6.79(d,J=8.3Hz,2H),3.88(d,J=13.2Hz,1H),3.81–3.76(m,1H),3.72(s,3H), 3.60(m,1H),3.51(m,2H),3.28(d,J=13.1Hz,2H),3.07(s,1H),2.69(d,J=12.3Hz,1H),2.56–2.42(m,1H),2.18(m,1H),1.38(s,9H).

[0222] Step 2: Compound INT40b (6 g, 17.834 mmol) and 6-bromo-2-(bromomethyl)-3-fluoropyridine (4.80 g, 17.834 mmol) were added to DMF (100 mL), cooled to 0°C, and sodium hydroxide (1.07 g, 26.751 mmol) was added. The reaction was allowed to react at room temperature for 12 h. After the reaction was complete, water was added to quench the reaction, and ethyl acetate was added for extraction. The organic phase was washed three times with water and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1) to obtain compound INT40d (4.2 g). LCMS = 525.4. 1 H NMR(400MHz,Chloroform-d)δ7.37-7.34(m,1H),7.23-7.19(m,1H),7.16–7.10(m,2H),6.79–6.73(m,2H),4.66–4.51(m,2H),3.84(s,1H), 3.72(s,3H),3.59-3.55(m,2H),3.43(d,J=13.1Hz,1H),3.29(d,J=13.3Hz,1H),3.11(s,2H),2.61-2.53(m,2H),2.09(s,1H),1.37(s,9H).

[0223] Step 3: Compound INT40d (4.2 g, 8.009 mmol), PdCl2(PPh3)2 (1.12 g, 1.602 mmol), and DIEA (3.11 g, 24.026 mmol) were added to DMF (30 mL) and ethanol (30 mL). Under carbon monoxide protection, the temperature was raised to 90°C for 12 h. The reaction solution was added to water and extracted with ethyl acetate. The organic phase was washed three times with water and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1 to 2:1) to obtain compound INT40e (2 g, yield: 48.25%). LCMS = 518.2.

[0224] Step 4: Compound INT40e (500 mg, 0.966 mmol) was added to acetonitrile (10 mL) and water (10 mL). The temperature was lowered to 0°C, and ceric ammonium nitrate (2.647 g, 4.83 mmol) was added. The mixture was stirred at room temperature for 12 hours. After the reaction, the reaction solution was added to saturated aqueous sodium bicarbonate solution to adjust the pH to 8-9. Ethyl acetate was added for extraction, and the organic phase was washed three times with water. The organic phase was concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 8:1) to obtain crude compound INT40f (100 mg, yield: 26.05%). LCMS = 398.2.

[0225] Step 5: Compound INT40f (85 mg, 0.214 mmol) and DIEA (82.93 mg, 0.642 mmol) were added to NMP (3 mL), heated to 180°C, and stirred for 6 hours. After the reaction, the reaction solution was added to water and extracted with ethyl acetate. The organic phase was washed three times with water and concentrated under reduced pressure to obtain compound INT40g (80 mg, yield: 99.11%). LCMS = 378.2.

[0226] Step 6: Compound INT40g (80 mg, 0.212 mmol) and methylamine alcohol solution (2 mL) were added to methanol (2 mL), stirred at room temperature for 1 h, and after completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude compound INT40h (80 mg, yield: 100%). LCMS = 363.4.

[0227] Step 7: Add compound INT40h (80 mg, 0.221 mmol) to dioxane (2 mL), add dioxane hydrochloride (1 mL), and stir at room temperature for 1 hour. After the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain compound INT40 (hydrochloride 80 mg), LCMS = 263.2.

[0228] Intermediate INT41: N,6-dimethyl-5-(piperidin-4-yl)picolinamide

[0229] The preparation method of N,6-dimethyl-5-(piperidin-4-yl)picolinamide refers to intermediate INT29. LC-MS:ESI[M+H] + =234.2.

[0230] Intermediate INT42: 6-chloro-N-cyclopropyl-5-(piperazin-1-yl)picolinamide

[0231] The preparation method of 6-chloro-N-cyclopropyl-5-(piperazin-1-yl)picolinamide refers to intermediate INT12. LC-MS:ESI[M+H] + =281.2.

[0232] Example 1

[0233] 5-(4-(((3-ethyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0234] Step 1: Add INT9 (0.13 g, 0.6 mmol), DIEA (0.4 g, 3.2 mmol), INT24 (0.17 g, 0.6 mmol), and KI (0.01 g, 0.06 mmol) to 5 ml of acetonitrile, raise the temperature to 80°C and stir for 48 h. After the reaction is complete as detected by LC-MS, add 5 ml of saturated sodium bicarbonate solution, extract with ethyl acetate, and purify by spin-drying column chromatography to obtain compound 1a (0.08 g, light yellow solid).

[0235] Step 2: 1a (0.08 g, 0.19 mmol) and 0.5 ml of 48% aqueous hydrobromic acid solution were added to 4 ml of dioxane, and the mixture was heated to 80°C and stirred for 2 h. After the reaction was complete as determined by LC-MS, saturated sodium bicarbonate solution was added, stirred, filtered, and purified by spin column chromatography to obtain compound 1 (0.024 g, white solid); LC-MS: ESI [M+H] + =412.2; 1 H NMR (400MHz, DMSO-d6) δ11.46(s,1H),8.47(q,J=4.8Hz,1H),8.33(d,J=2.9Hz,1H),7.89 (d,J=8.8Hz,1H),7.46(dd,J=8.8,2.9Hz,1H),7.05(s,1H),4.57–4.43(m,2H),3.91(dq, J=10.2,5.0Hz,1H),3.35(m,J=3.2Hz,4H),2.84(d,J=4.8Hz,3H),2.67(m,J=6.6Hz,4H), 2.62–2.58(m,2H),2.50(d,J=11.5Hz,2H),2.41(q,J=7.4Hz,2H),1.12(t,J=7.4Hz,3H).

[0236] The preparation methods of compounds 2 to 38 of Examples 2 to 38 can be referred to Example 1.

[0237] Table 8 Compounds 2 to 38

[0238] Example 39

[0239] 6-Fluoro-N-methyl-5-(4-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)picolinamide

[0240] Step 1: To 5 ml of acetonitrile were added INT10 (0.14 g, 0.6 mmol), DIEA (0.4 g, 3.2 mmol), INT25 (0.2 g, 0.6 mmol), and KI (0.01 g, 0.06 mmol), and the temperature was raised to 80°C and stirred for 48 h. After the reaction was complete as detected by LC-MS, 5 ml of saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The mixture was purified by spin-drying column chromatography to obtain compound 39a (0.07 g, light yellow solid).

[0241] Step 2: 39a (0.08 g, 0.19 mmol) and 0.5 ml of 48% aqueous hydrobromic acid solution were added to 4 ml of dioxane, and the mixture was heated to 80°C and stirred for 2 h. After the reaction was complete as determined by LC-MS, saturated sodium bicarbonate solution was added, the mixture was stirred and filtered, and the mixture was purified by spin column chromatography to obtain compound 39 (0.014 g, white solid); LC-MS: ESI [M+H] + =416.2; 1 H NMR (400MHz, DMSO-d6) δ11.42(s,1H),8.41(q,J=4.8Hz,1H),7.85(dd,J=8.1,1.4Hz ,1H),7.57(dd,J=10.6,8.1Hz,1H),7.04(d,J=1.3Hz,1H),4.49-4.36(m,2H),3.88-3 .79(m,1H),3.15(t,J=4.9Hz,4H),2.77(d,J=4.8Hz,3H),2.64(d,J=4.3Hz,2H),2.6 2(d,J=5.0Hz,2H),2.57(dd,J=13.1,6.3Hz,1H),2.45(t,J=8.3Hz,2H),1.93(s,3H).

[0242] Example 40

[0243] 5-(4-((3-Bromo-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0244] Preparation of 5-(4-((3-bromo-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide Reference Example 39. LC-MS: ESI [M+H] + =480.3; 1H NMR (400MHz, DMSO-d6) δ12.03(s,1H),8.41(q,J=4.7Hz,1H),7.85(dd,J=8.0,1.4Hz,1H),7.71(s,1H),7.57(dd,J=10.6,8.1Hz,1H),4.61-4.31(m,2H) ,3.85(q,J=4.8Hz,1H),3.16(t,J=4.8Hz,4H),2.77(d,J=4.7Hz,3H),2.63( hept,J=6.6,6.1Hz,4H),2.58-2.53(m,2H),2.44(dd,J=17.5,10.0Hz,2H).

[0245] Example 41

[0246] N-Cyclopropyl-6-fluoro-5-(4-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)picolinamide

[0247] Preparation of N-cyclopropyl-6-fluoro-5-(4-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)picolinamide Reference Example 39. LC-MS: ESI [M+H] + =442.3; 1 H NMR (400MHz, DMSO-d6) δ11.42(s,1H),8.36(d,J=4.9Hz,1H),7.85(dd,J=8.0,1 .4Hz,1H),7.57(dd,J=10.6,8.1Hz,1H),7.04(d,J=1.3Hz,1H),4.50-4.37(m,2H ),3.89-3.77(m,1H),3.16(d,J=4.2Hz,4H),2.91-2.79(m,1H),2.64(s,3H),2.4 9-2.36(m,2H),1.93(s,3H),1.26(q,J=6.1Hz,3H),0.66(tt,J=6.3,2.1Hz,4H).

[0248] Example 42

[0249] 5-(4-(((3-cyclopropyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0250] Preparation of 5-(4-(((3-cyclopropyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide Reference Example 39. LC-MS: ESI [M+H] + =442.3; 1 HNMR (400MHz, DMSO-d6) δ11.41(s,1H),8.41(q,J=4.7Hz,1H),7.85(dd,J=8.0,1.4 Hz,1H),7.57(dd,J=10.6,8.1Hz,1H),6.71(s,1H),4.51-4.27(m,2H),3.87-3.74(m,1H),3.15(t,J=4.8Hz,4H),2.77(d,J=4. 7Hz, 3H), 2.63 (q, J = 4.9, 4.5Hz, 4H), 2.56 (t, J = 6.5Hz, 3H), 2.48-2.35 (m, 2H), 0.80 (dd, J = 8.4, 2.3Hz, 2H), 0.62-0.50 (m, 2H).

[0251] Example 43

[0252] 5-(4-((3-(difluoromethyl)-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0253] Preparation of 5-(4-((3-(difluoromethyl)-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide Reference Example 1. LC-MS: ESI [M+H] + =452.3; 1 HNMR (400MHz, DMSO-d6) δ12.23(s,1H),8.53(q,J=4.7Hz,1H),7.96(dd,J=8.1,1.3Hz,1H),7.75(dd,J=10.6,8.0Hz,1H),7.65(s,1H),6.8 9(s,1H),4.73(d,J=14.4Hz,1H),4.65(d,J=14.4Hz,1H),4.26(s,1H),3.23(t,4H),2.84(d,J=4.8Hz,4H),2.68-2.59(m,3H),2.58(s,4H).

[0254] Example 44

[0255] N-(Cyclopropylmethoxy)-5-(4-((3-ethyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)-6-fluoropicolinamide

[0256] Preparation of N-(cyclopropylmethoxy)-5-(4-((3-ethyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)-6-fluoropicolinamide Reference Example 1. LC-MS: ESI [M+H] + =486.3; 1 H NMR (400MHz, DMSO-d6) δ11.42(s,1H),8.24(s,1H),7.60(d,J=8.0Hz,1H),7.41(s,1H),6.79(s,1H),4.28(s,2H),3.87(s,1H),3.44( d,J=7.2Hz,4H),2.89(dd,J=7.4,4.1Hz,3H),2.22(d,J=11.5Hz,3H),2.12(q,J=7.3Hz,3H),0.83(t,J=7.4Hz,4H),0.32-0.23(m,2H).

[0257] Example 45

[0258] (S)-6-Fluoro-N-methyl-5-(4-((2-methyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0259] Step 1: Dissolve compound 45a (15.0 g, 52.2 mmol) in DCM (200 mL), add DIPEA (43.0 mL, 261 mmol), and slowly add MOMCl (15.0 g, 130.5 mmol) dropwise at 0°C. The temperature was slowly raised to 25°C and stirred for 4 h. The reaction mixture was slowly poured into 200 mL of saturated sodium bicarbonate solution for quenching. The mixture was extracted with DCM (4 x 50 mL) and dried over sodium sulfate to afford compound 45b (17.0 g, crude).

[0260] Step 2: Compound 45b (17.0 g, 52.2 mmol) was dissolved in anhydrous THF (300 mL). Solid lithium aluminum hydride (3.0 g, 78.3 mmol) was slowly added at 0°C and stirred at 0°C for 2 h. The reaction was quenched with H2O / THF (1 / 10, 30 mL). NaOH (1.0 M, 20 mL) was added and stirred until a solid precipitated. The filtrate was collected by filtration and concentrated under reduced pressure to afford compound 45c (13.0 g, 45 mmol, 87% yield).

[0261] Step 3: Dissolve compound 45c (13.0 g, 45.0 mmol) in DCM (100 mL), add TEA (18.0 mL, 135 mmol), and slowly add BzCl (7.8 mL, 67.47 mmol) dropwise at 0°C. The temperature is slowly raised to 25°C and stirred for 14 h. The reaction mixture is slowly poured into 100 mL of saturated sodium bicarbonate solution for quenching. Extract with 4 x 40 mL of DCM, dry with sodium sulfate, and column chromatography (EA / PE = 1 / 3) yields compound 45d (17.0 g, 45 mmol, 100%). LC-MS: ESI [M+H] + =394.2.

[0262] Step 4: Dissolve compound 45d (17.0 g, 45.0 mmol) in HCl / MeOH (4.0 M, 30 mL) and stir at 25°C for 12 h. Concentrate under reduced pressure to give compound 45e (12.36 g, 42 mmol, 94%). LC-MS: ESI [M+H] + =250.1.

[0263] Step 5: Compound 45e (5.0 g, 17.54 mmol) was dissolved in DMF (50 mL), and 2-((tert-butoxycarbonyl)amino)propionic acid (3.7 g, 19.29 mmol), DIPEA (13.0 mL, 70.16 mmol), and HOBT (2.8 g, 21.05 mmol) were added. The mixture was stirred at 25°C for 10 min, and EDCI (4.0 g, 21.05 mmol) was added. Stirring was continued at 25°C for 2 h. The reaction mixture was slowly poured into 100 mL of saturated ammonium chloride solution for quenching. The mixture was extracted with 4 x 40 mL of EA, dried over sodium sulfate, and purified by column chromatography (EA) to afford compound 45f (4.94 g, 11.76 mmol, 67%). LC-MS: ESI [M+H] + =421.2.

[0264] Step 6: Dissolve compound 45f (4.94 g, 11.76 mmol) in DCM (50 mL), add solid sodium bicarbonate (5.0 g, 58.8 mmol), and add DMP (15.03 g, 35.29 mmol) at 0°C. Stir at 25°C for 12 h. The reaction mixture is slowly poured into 200 mL of saturated sodium bicarbonate solution to quench the mixture. Extract with 4 x 50 mL of DCM and dry with sodium sulfate to obtain compound 45g (4.0 g, crude). LC-MS: ESI [M-56+H] + =363.1.

[0265] Step 7: Dissolve compound 45g (4.0 g, 9.57 mmol) in HCl / MeOH (4.0 M, 40 mL) and stir at 25°C for 1 h. After concentration under reduced pressure, add pyridine (20 mL), stir at 70°C for 2 h, concentrate under reduced pressure, and purify by column chromatography (EA) to give compound 45h (1.0 g, 3.34 mmol, 35%). LC-MS: ESI [M+H] + =299.1.

[0266] Step 8: Compound 45h (1.0 g, 3.34 mmol) was dissolved in MeOH / DCM (30 / 5 mL), potassium carbonate (0.9 g, 6.68 mmol) was added, and the mixture was stirred at 25°C for 12 h. After concentration under reduced pressure, the reaction was quenched by addition of saturated ammonium chloride solution (10 mL). The mixture was extracted with 4 x 30 mL of DCM, dried over sodium sulfate, and concentrated under reduced pressure. Prep-TLC (DCM / MeOH = 5 / 1) was used to purify compound 45i (0.37 g, crude). LC-MS: ESI [M+H] + =195.2.

[0267] Step 9: Compound 45i (0.1 g, 0.51 mmol) was dissolved in DCM (20 mL). TEA (0.35 mL, 2.55 mmol) and MsCl (0.2 mL, 1.53 mmol) were added dropwise at 0°C. The mixture was heated to 25°C and stirred for 1 h. 20 mL of saturated sodium bicarbonate solution was slowly poured into the reaction mixture to quench the mixture. The mixture was extracted with 30 mL of DCM, dried over sodium sulfate, and filtered and concentrated under reduced pressure to afford compound 45j (0.17 g, crude). LC-MS: ESI [M+H] + =351.2.

[0268] Step 10: Compound 45j (0.17 g, 0.51 mmol) was dissolved in ACN (10 mL), and DIPEA (0.5 mL, 2.80 mmol), KI (0.05 g), and compound INT10 (0.12 g, 0.51 mmol) were added. The mixture was stirred at 80°C for 24 h. 20 mL of saturated ammonium chloride solution was slowly poured into the reaction mixture for quenching. The mixture was extracted with 4 x 30 mL of DCM, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Prep-TLC (DCM / MeOH = 20 / 1) was used to obtain compound 45k (0.05 g, 0.10 mmol, 20%). LC-MS: ESI [M+H] + =493.2.

[0269] Step 11: Compound 45k (0.05 g, 0.10 mmol) was dissolved in MeOH (5 mL), and KOH (5 mL, 3.0 M) was added, followed by stirring at 25°C for 1 h. The reaction mixture was slowly poured into 30 mL of saturated ammonium chloride solution to quench the mixture. The mixture was extracted with 4 x 30 mL of EA, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by prep-TLC (DCM / MeOH = 15 / 1) afforded Compound 45 (7.5 mg, 0.018 mmol, 18% yield) as a white solid. LC-MS: ESI [M+H] + =415.1. 1 H NMR (400MHz, CDCl3) δ7.99(d,J=7.9Hz,1H),7.49(d,J=4.8Hz,1H),7.34–7.26(m,1H),3.21(d,J=4.1Hz,4H),2.98( t,J=9.2Hz,3H),2.79–2.53(m,7H),2.42(s,3H),2.38(d,J=7.1Hz,3H),2.03(s,2H),1.48(dd,J=22.2,18.4Hz,1H).

[0270] Example 46

[0271] (S)-2-Fluoro-N-methyl-1'-(2-methyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)-1'-,2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0272] Preparation of (S)-2-fluoro-N-methyl-1'-(2-methyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)-1'-, 2', 3', 6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide Reference Example 45. LC-MS: ESI [M+H] + =412.1.1 HNMR (400MHz, CDCl3) δ8.05(d,J=6.7Hz,1H),7.84(t,J=8.8Hz,1H),7.65(d,J=5.0Hz,1H),6.21(s,1H),3.21(s,2H),3.02( d,J=5.0Hz,3H),2.75–2.69(m,4H),2.57(s,2H),2.46(d,J=7.2Hz,2H),2.42(s,3H),2.15–1.96(m,3H),1.55-1.42(m,2H).

[0273] Example 47

[0274] (S)-N,6-Dimethyl-5-(4-((2-methyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0275] Preparation of (S)-N,6-dimethyl-5-(4-((2-methyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide Reference Example 45. LC-MS: ESI [M+H] + =411.2. 1 H NMR (400MHz, DMSO) δ12.22(s,1H),8.59(q,J=4.5Hz,1H),8.12–7.97(m,1H ),7.94–7.79(m,1H),4.67(t,J=8.8Hz,2H),3.58(s,2H),3.46–3.39(m,4H ),2.95(d,J=11.3Hz,2H),2.77(d,J=4.8Hz,3H),2.70(dt,J=11.8,3.8Hz, 1H), 2.50 (s, 3H), 2.42 (s, 3H), 2.14 (t, J = 10.5Hz, 2H), 1.82–1.59 (m, 4H).

[0276] Example 48

[0277] (S)-5-(4-((2-ethyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0278] Preparation of (S)-5-(4-((2-ethyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide Reference Example 45. LC-MS: ESI [M+H] + =429.2. 1 H NMR (400MHz, DMSO-d6) δ11.76 (s, 1H), 8.41 (q, J = 4.7Hz, 1H), 7.85 (dd, J = 8.0, 1.4Hz, 1H), 7.57 (dd, J=10.6,8.1Hz,1H),3.17(t,J=5.0Hz,4H),2.77(d,J=4.8Hz,3H),2.65–2.58(m,4H),2.56(s,4H),2.52(s,1H),2.35–2. 26(m,2H),2.20(dd,J=17.5,9.6Hz,1H),2.01(s,1H),1.90(d,J=12.9Hz,1H),1.45–1.33(m,1H),1.10(t,J=7.5Hz,3H).

[0279] Example 49

[0280] N-(2,2-difluoroethyl)-5-(4-(((3-ethyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)-6-fluoropicolinamide

[0281] Preparation of N-(2,2-difluoroethyl)-5-(4-(((3-ethyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)-6-fluoropicolinamide Reference Example 1. LC-MS: ESI [M+H] + =480.2. 1H NMR (400MHz, DMSO-d6) δ11.41(s,1H),8.73(t,J=6.2Hz,1H),7.89(dd,J=8.1,1.4H z,1H),7.59(dd,J=10.6,8.1Hz,1H),7.00(s,1H),6.11(tt,J=56.2,4.1Hz,1H),4. 51–4.37(m,2H),3.89–3.82(m,1H),3.72–3.63(m,2H),3.17(d,J=5.2Hz,4H),2.64 (q,J=4.7Hz,3H),2.59–2.51(m,4H),2.35(q,J=7.5Hz,2H),1.06(t,J=7.4Hz,3H).

[0282] Example 50

[0283] 2-Fluoro-N-methyl-1'-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-1'-, 2', 3', 6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0284] Preparation of 2-fluoro-N-methyl-1'-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-1'-, 2', 3', 6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide Reference Example 39. LC-MS: ESI [M+H] + =413.2. 1 H NMR(400MHz,DMSO-d6)δ11.41(s,1H),8.64(d,J=4.9Hz,1H),8.09(dd,J=9.9,7.7Hz, 1H),7.93(dd,J=7.7,1.8Hz,1H),7.05(d,J=1.2Hz,1H),6.25(s,1H),4.44(d,J=5.2H z,2H),3.87(dd,J=10.0,5.2Hz,1H),3.22(q,J=2.9Hz,2H),2.80(d,J=4.8Hz,3H),2. 76–2.68(m,2H),2.68–2.54(m,2H),2.48(s,3H),2.41(d,J=17.2Hz,1H),1.94(s,3H).

[0285] Example 51

[0286] 1'-((3-cyclopropyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0287] Preparation of 1'-((3-cyclopropyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide Reference Example 39. LC-MS: ESI [M+H] + =439.2. 1 H NMR (400MHz, DMSO-d6) δ11.41(s,1H),8.64(q,J=4.8Hz,1H),8.08(dd,J=9.9,7.7Hz,1H),7.92( dd,J=7.7,1.8Hz,1H),6.71(s,1H),6.28–6.21(m,1H),4.48–4.34(m,2H),3.85(q,J=4.7Hz,1H) ,3.21(t,J=3.1Hz,2H),2.80(d,J=4.8Hz,3H),2.72(td,J=5.7,3.9Hz,2H),2.60(qd,J=12.9,5. 7Hz,2H),2.50–2.35(m,4H),1.93(tt,J=8.4,5.3Hz,1H),0.86–0.72(m,2H),0.64–0.50(m,2H).

[0288] Example 52

[0289] 1'-((3-(difluoromethyl)-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0290] Preparation of 1'-((3-(difluoromethyl)-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide Reference Example 1. LC-MS: ESI [M+H] + =449.2; 1H NMR (400MHz, DMSO-d6) δ12.02(s,1H),8.64(q,J=4.8Hz,1H),8.08(dd,J=9.9 ,7.7Hz,1H),7.92(dd,J=7.7,1.8Hz,1H),7.52(s,1H),6.81(t,J=55.3Hz,1H) ,6.24(d,J=3.7Hz,1H),4.62–4.42(m,2H),3.94–3.87(m,1H),3.24-3.21(m,2 H),2.80(d,J=4.8Hz,3H),2.77–2.71(m,2H),2.70-2.55(m,4H),2.48(s,1H).

[0291] Example 53

[0292] (S)-1'-((2-ethyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4-bipyridine]-6-carboxamide

[0293] Preparation of (S)-1'-((2-ethyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4-bipyridine]-6-carboxamide Reference Example 45. LC-MS: ESI [M+H] + =426.3; 1 HNMR(400MHz,DMSO-d6)δ11.78(s,1H),8.64(q,J=4.8Hz,1H),8.09(dd,J=9.9,7.7 Hz,1H),7.92(dd,J=7.7,1.8Hz,1H),6.26(d,J=3.7Hz,1H),3.14(qd,J=17.7,3. 2Hz,2H),2.80(d,J=4.8Hz,3H),2.66(d,J=5.8Hz,2H),2.61(d,J=4.5Hz,2H),2. 58(d,J=7.6Hz,4H),2.51(s,1H),2.40–2.30(m,2H),2.21(dd,J=17.5,9.7Hz,1H ), 2.04 (s, 1H), 1.90 (d, J = 13.0Hz, 1H), 1.45–1.31 (m, 1H), 1.10 (t, J = 7.4Hz, 3H).

[0294] Example 54

[0295] (S)-5-(1-((2-ethyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)piperidin-4-yl)-6-fluoro-N-methylpicolinamide

[0296] Preparation of (S)-5-(1-((2-ethyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)piperidin-4-yl)-6-fluoro-N-methylpicolinamide Reference Example 45. LC-MS: ESI [M+H] + =427.2; 1 H NMR (400MHz, DMSO-d6) δ11.65(s,1H),8.61(q,J=4.7Hz,1H),8.06(dd,J=9.7,7.7Hz, 1H),7.91(dd,J=7.7,1.6Hz,1H),3.03–2.95(m,2H),2.79(d,J=4.8Hz,3H),2.64–2.5 5(m,4H),2.54(d,J=4.9Hz,1H),2.33–2.22(m,2H),2.22–2.15(m,1H),2.08–1.96(m, 3H), 1.95–1.86 (m, 1H), 1.82–1.65 (m, 4H), 1.43–1.29 (m, 1H), 1.10 (t, J = 7.5Hz, 3H).

[0297] Example 55

[0298] (S)-1'-((2-ethyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4-bipyridine]-6-carboxamide

[0299] Preparation of (S)-1'-((2-ethyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4-bipyridine]-6-carboxamide Reference Example 45. LC-MS: ESI [M+H] + =426.1; 1H NMR (400MHz, DMSO-d6) δ11.52(s,1H),8.40(q,J=4.8Hz,1H),8.27(d,J=2.9Hz,1H),7.83(d,J=8.8Hz ,1H),7.40(dd,J=8.9,2.9Hz,1H),3.31–3.23(m,4H),2.78(d,J=4.8Hz,3H),2.67–2.61(m,1H),2.59 (d,J=7.5Hz,2H),2.57–2.52(m,4H),2.47(d,J=4.8Hz,1H),2.36–2.22(m,2H),2.20(dd,J=17.4,9.7 Hz,1H),2.01(s,1H),1.96–1.86(m,1H),1.37(ddt,J=12.8,10.5,8.1Hz,1H),1.10(t,J=7.4Hz,3H).

[0300] Example 56

[0301] (S)-1'-((2-cyclopropyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4-bipyridine]-6-carboxamide

[0302] Preparation of (S)-1'-((2-cyclopropyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4-bipyridine]-6-carboxamide Reference Example 45. LC-MS: ESI [M+H] + =438.2; 1 H NMR(400MHz,DMSO-d6)δ11.75(s,1H),8.64(q,J=4.7Hz,1H),8.09(dd,J=9.9,7.7Hz,1H), 7.92(dd,J=7.8,1.8Hz,1H),6.26(d,J=3.6Hz,1H),3.22–3.06(m,2H),2.80(d,J=4.8Hz,3 H),2.68(dd,J=11.4,5.5Hz,1H),2.63–2.57(m,2H),2.50–2.45(m,3H),2.44–2.39(m,1H) ,2.24–2.12(m,1H),2.01(s,1H),1.91–1.83(m,1H),1.40–1.30(m,1H),0.94–0.75(m,4H).

[0303] Example 57

[0304] (S)-5-(4-((2-cyclopropyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0305] Preparation of (S)-5-(4-((2-cyclopropyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide Reference Example 45. LC-MS: ESI [M+H] + =441.3; 1 H NMR (400MHz, DMSO-d6) δ8.41(q,J=4.7Hz,1H),7.85(dd,J=8.0,1.4Hz,1H),7.57(dd,J=10 .7,8.1Hz,1H),3.16(t,J=5.1Hz,4H),2.77(d,J=4.8Hz,3H),2.62(d,J=5.1Hz,1H),2.58– 2.54(m,2H),2.52(d,J=2.1Hz,2H),2.49–2.45(m,2H),2.42(dd,J=8.0,4.9Hz,1H),2.02– 1.94(m,1H),1.93–1.82(m,1H),1.41–1.27(m,1H),0.90–0.84(m,2H),0.82–0.78(m,2H).

[0306] Example 58

[0307] (S)-5-(4-((2-cyclopropyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0308] Preparation of (S)-5-(4-((2-cyclopropyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide Reference Example 45. LC-MS: ESI [M+H] + =423.1; 1H NMR (400MHz, DMSO-d6) δ11.70(s,1H),8.44–8.33(m,1H),8.27(d,J=2.8Hz,1H),7.83(d,J=8.7Hz,1H),7. 40(dd,J=8.9,2.9Hz,1H),3.32(t,J=5.2Hz,4H),2.78(d,J=4.8Hz,3H),2.66–2.59(m,1H),2.58–2.53(m,1 H),2.51(d,J=2.4Hz,2H),2.48(d,J=7.2Hz,5H),2.42(dd,J=8.1,4.9Hz,1H),2.35–2.23(m,2H),2.21–2. 13(m,1H),2.05–1.94(m,1H),1.92–1.83(m,1H),1.42–1.27(m,1H),0.91–0.86(m,2H),0.84–0.80(m,2H).

[0309] Example 59

[0310] 6-Fluoro-N-methyl-5-(1-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperidin-4-yl)picolinamide

[0311] Preparation of 6-fluoro-N-methyl-5-(1-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperidin-4-yl)picolinamide Reference Example 39. LC-MS: ESI [M+H] + =415.2; 1 H NMR(400MHz,DMSO-d6)δ11.40(s,1H),8.61(q,J=4.8Hz,1H),8.06(dd,J=9.7,7.6Hz,1H), 7.90(dd,J=7.6,1.6Hz,1H),7.03(d,J=1.3Hz,1H),4.48–4.35(m,2H),3.81(dq,J=10.2,5 .3Hz,1H),3.04(td,J=7.5,3.7Hz,2H),2.79(d,J=4.8Hz,3H),2.59–2.53(m,1H),2.47–2. 36(m,1H),2.14(dtd,J=14.4,11.3,3.4Hz,2H),1.93(s,3H),1.73(qt,J=8.7,4.9Hz,4H).

[0312] Example 60

[0313] 5-(1-((3-ethyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperidin-4-yl)-6-fluoro-N-methylpicolinamide

[0314] Preparation of 5-(1-((3-ethyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperidin-4-yl)-6-fluoro-N-methylpicolinamide Reference Example 39. LC-MS: ESI [M+H] + =428.3; 1 H NMR(400 MHz, DMSO-d6) δ11.38(s,1H),8.61(q,J=4.8Hz,1H),8.06(dd,J=9.7,7.6Hz,1H),7.90 (dd,J=7.6,1.6Hz,1H),6.99(s,1H),4.50–4.37(m,2H),3.85–3.78(m,1H),3.08–3.00 (m,2H),2.79(d,J=4.7Hz,3H),2.76–2.70(m,1H),2.58–2.52(m,1H),2.50–2.41(m,1H ), 2.35 (q, J = 7.3Hz, 2H), 2.19–2.09 (m, 2H), 1.77–1.64 (m, 4H), 1.06 (t, J = 7.4Hz, 3H).

[0315] Example 61

[0316] 5-(1-((3-cyclopropyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperidin-4-yl)-6-fluoro-N-methylpicolinamide

[0317] Preparation of 5-(1-((3-cyclopropyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperidin-4-yl)-6-fluoro-N-methylpicolinamide Reference Example 39. LC-MS: ESI [M+H] + =441.2; 1H NMR (400MHz, DMSO-d6) δ11.39(s,1H),8.61(q,J=4.7Hz,1H),8.06(dd,J=9.7,7.7Hz,1H),7.90(d d,J=7.6,1.6Hz,1H),6.69(s,1H),4.39(d,J=8.5Hz,2H),3.80(dd,J=9.9,5.0Hz,1H),3.03(s,2H) ,2.79(d,J=4.7Hz,3H),2.78–2.70(m,1H),2.57–2.52(m,1H),2.48–2.31(m,3H),2.13(q,J=11.4H z,2H),1.97–1.90(m,1H),1.73(d,J=10.0Hz,4H),0.79(dd,J=8.4,2.2Hz,2H),0.62–0.50(m,2H).

[0318] Example 62

[0319] 6-Chloro-N-cyclopropyl-5-(4-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)picolinamide

[0320] Preparation of 6-chloro-N-cyclopropyl-5-(4-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)picolinamide Reference Example 39. LC-MS: ESI [M+H] + =458.2; 1 H NMR (400MHz, DMSO-d6) δ11.41(s,1H),8.37(d,J=4.9Hz,1H),7.93(d,J=8.1Hz,1H),7.66(d,J=8.2Hz,1H),7.03(s,1H),4.50-4.36(m,2H),3.89- 3.78(m,1H),3.09(t,J=4.7Hz,4H),2.91-2.80(m,1H),2.71-2.59(m,4H ),2.60-2.51(m,2H),2.49-2.40(m,2H),1.93(s,3H),0.72-0.63(m,4H).

[0321] Example 63

[0322] 1'-((3-chloro-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-2-fluoro-N-methyl-1', 2', 3', 6'-tetrahydro-[3,4-bipyridine]-6-carboxamide

[0323] Preparation of 1'-((3-chloro-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4-bipyridine]-6-carboxamide Reference Example 39. LC-MS: ESI [M+H] + =433.1; 1 H NMR (400MHz, DMSO-d6) δ12.08(s,1H),8.64(q,J=4.8Hz,1H),8.12–8.04(m,1H),7.92(dd,J=7.7,1.8Hz,1H),7.54(s,1H),6.28–6 .21(m,1H),4.56–4.36(m,2H),3.91–3.85(m,1H),3.22–3.21(m,2H),2.79(d,J=4.8Hz,3H),2.75–2.67(m,4H),2.66–2.50(m,4H).

[0324] Example 64

[0325] 5-(4-((3-chloro-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0326] Preparation of 5-(4-((3-chloro-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide Reference Example 39. LC-MS: ESI [M+H] + =436.1; 1H NMR (400MHz, DMSO-d6) δ12.08(s,1H),8.40(q,J=4.7Hz,1H),7.84(dd,J=8.0,1.4Hz,1H),7.61–7.51(m,2H),4.54–4.38(m,2H),3.88–3.8 2(m,1H),3.15(t,J=4.9Hz,4H),2.76(d,J=4.8Hz,3H),2.63(q,J=4.5Hz,4H),2.56(d,J=6.3Hz,1H),2.55–2.52(m,2H),2.47–2.40(m,1H).

[0327] Example 65 and Example 66

[0328] (S)-5-(4-((3-ethyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide and (R)-5-(4-((3-ethyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0329] Compound 2 was separated and purified by supercritical fluid chromatography (SFC) (Column: CHIRALPAK IE 250 mm x 20 mm, 5 μm, 40% EtOH (0.2% NHOH) to obtain two compounds 65 and 66:

[0330] Example 65 (t R =3.489), MS / ESI[M+H] + =430.2; 1 H NMR (400MHz, DMSO-d6) δ11.40 (s, 1H), 8.40 (q, J = 4.7Hz, 1H), 7.85 (dd, J = 8. 1,1.4Hz,1H),7.57(dd,J=10.6,8.1Hz,1H),6.99(s,1H),4.51-4.37(m,2H), 3.90-3.79(m,1H),3.16(t,J=4.9Hz,4H),2.77(d,J=4.8Hz,3H),2.64(q,J= 4.8Hz, 4H), 2.61-2.40 (m, 4H), 2.35 (q, J = 7.5Hz, 2H), 1.07 (t, J = 7.4Hz, 3H).

[0331] Example 66 (t R =4.696), MS / ESI[M+H]+ =430.2; 1 H NMR (400MHz, DMSO-d6) δ11.40 (s, 1H), 8.40 (q, J = 4.7Hz, 1H), 7.85 (dd, J = 8. 1,1.4Hz,1H),7.57(dd,J=10.6,8.1Hz,1H),6.99(s,1H),4.51-4.37(m,2H), 3.90-3.79(m,1H),3.16(t,J=4.9Hz,4H),2.77(d,J=4.8Hz,3H),2.64(q,J= 4.8Hz, 4H), 2.61-2.40 (m, 4H), 2.35 (q, J = 7.5Hz, 2H), 1.07 (t, J = 7.4Hz, 3H).

[0332] Example 67

[0333] 6-Fluoro-N-methyl-5-(4-((2-oxo-3-vinyl-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)picolinamide

[0334] Preparation of 6-fluoro-N-methyl-5-(4-((2-oxo-3-vinyl-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)picolinamide Reference Example 1. LC-MS: ESI [M+H] + =427.2; 1 H NMR (400MHz, DMSO-d6) δ11.67(s,1H),8.41(d,J=4.9Hz,1H),7.85(dd,J=8.0,1.5Hz,1H) ,7.57(dd,J=10.6,8.1Hz,1H),7.34(s,1H),6.65(dd,J=17.7,11.4Hz,1H),6.06(dd,J=1 7.7,2.2Hz,1H),5.20(dd,J=11.3,2.2Hz,1H),4.48(d,J=13.8Hz,2H),3.86(d,J=5.1Hz, 1H), 3.16 (t, J=4.9Hz, 4H), 2.77 (d, J=4.8Hz, 3H), 2.69–2.59 (m, 4H), 2.58–2.52 (m, 4H).

[0335] Example 68

[0336] 2-Fluoro-N-methyl-1'-((2-oxo-3-vinyl-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0337] Preparation of 2-fluoro-N-methyl-1'-((2-oxo-3-vinyl-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide Reference Example 1. LC-MS: ESI [M+H] + =425.2.

[0338] Example 69

[0339] 2-Chloro-1'-((3-cyclopropyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0340] Preparation of 2-chloro-1'-((3-cyclopropyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide Reference Example 39. LC-MS: ESI [M+H] + =455.1; 1 H NMR (400MHz, DMSO-d6) δ11.41(s,1H),8.61(d,J=4.9Hz,1H),7.97(d,J=7.7Hz ,1H),7.89(d,J=7.7Hz,1H),6.71(s,1H),5.85(s,1H),4.41(d,J=6.3Hz,2H), 3.91–3.80(m,1H),3.20–3.17(m,2H),2.81(d,J=4.8Hz,3H),2.77–2.53(m,4H ),2.49–2.36(m,4H),1.96–1.91(m,1H),0.82–0.78(m,2H),0.59–0.55(m,2H).

[0341] Example 70

[0342] 2-Chloro-N-methyl-1'-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0343] Preparation of 2-chloro-N-methyl-1'-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide Reference Example 39. LC-MS: ESI [M+H] + =429.2; 1 H NMR (400MHz, DMSO-d6) δ11.51(s,1H),8.70(d,J=4.9Hz,1H),8.12–7.91(m,2H),7.13(d,J=1.3Hz,1H),5.94(d,J=1.7Hz,1H),4.63–4.43(m,2H), 4.02–3.89(m,1H),3.29–3.27(m,2H),2.95(t,J=5.1Hz,1H),2.90(d,J= 4.8Hz, 3H), 2.85–2.64 (m, 4H), 2.58–2.47 (m, 4H), 2.03 (d, J = 3.1Hz, 3H).

[0344] Example 71

[0345] (S)-6-Fluoro-N-methyl-5-(4-(1-(2-methyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)ethyl)piperazin-1-yl)picolinamide

[0346] Step 1: Compound 45c (25.0 g, 87.1 mmol) was dissolved in DCM (500 mL). DMP (74.0 g, 35.29 mmol) was added at 0°C and stirred at 25°C for 2 h. The reaction solution was slowly poured into 500 mL of saturated sodium bicarbonate solution to quench the mixture. The mixture was extracted with DCM (5 x 50 mL), dried over sodium sulfate, and purified by column chromatography (EA / PE = 1:1) to afford compound 71a (21.0 g, 73.6 mmol, 85%).

[0347] Step 2: Dissolve compound 71a (21.0 g, 73.6 mmol) in anhydrous THF (500 mL). Slowly add methylmagnesium bromide (61.0 mL, 184.0 mmol, 3.0 M) at 0°C and stir at 0°C for 1 h. Slowly add dropwise to saturated ammonium chloride solution, extract with 50 mL of EA, dry with sodium sulfate, and concentrate under reduced pressure to obtain compound 71b (20.0 g, crude).

[0348] Step 3: Dissolve compound 71b (20.0 g, 73.6 mmol) in DCM (100 mL), add TEA (28.0 mL, 220.8 mmol), and slowly add BzCl (9 mL, 73.6 mmol) dropwise at 0°C. Slowly raise the temperature to 25°C and stir for 1 h. The reaction mixture is slowly poured into 100 mL of saturated sodium bicarbonate solution to quench. Extract with 4 x 40 mL of DCM, dry with sodium sulfate, and column chromatography (EA / PE = 1 / 3) to afford compound 71c (26.0 g, crude). LC-MS: ESI [M+Na] + =430.2.

[0349] Step 4: Dissolve compound 71c (26.0 g, 64.0 mmol) in HCl / MeOH (4.0 M, 50 mL) and stir at 25°C for 1 h. Concentrate under reduced pressure to give compound 71d (17 g, 64.0 mmol, 100%). LC-MS: ESI [M+H] + =264.2.

[0350] Step 5: Compound 71d (17.0 g, 64.0 mmol) was dissolved in DCM (300 mL), and 2-((tert-butoxycarbonyl)amino)propanoic acid (14.0 g, 71.59 mmol), DIPEA (53.0 mL, 325 mmol), and HATU (37.0 g, 97.5 mmol) were added. The mixture was stirred at 25°C for 1 h. The reaction solution was slowly poured into 200 mL of saturated ammonium chloride solution to quench the mixture. The mixture was extracted with 4 x 50 mL of EA, dried over sodium sulfate, and purified by column chromatography (EA) to afford compound 71e (13.0 g, 29.88 mmol, 47%). LC-MS: ESI [M+H] + =435.2.

[0351] Step 6: Compound 71e (13.0 g, 29.88 mmol) was dissolved in DCM (500 mL). DMP (38.0 g, 89.65 mmol) was added at 0°C and stirred at 25°C for 12 h. The reaction solution was slowly poured into 500 mL of saturated sodium bicarbonate solution for quenching. The mixture was extracted with 4 x 50 mL of DCM, dried over sodium sulfate, and purified by column chromatography (EA / PE = 1 / 1) to afford compound 71f (5.5 g, 12.73 mmol, 43%). LC-MS: ESI [M+H] + =433.2.

[0352] Step 7: Dissolve compound 71f (5.5 g, 12.7 mmol) in HCl / MeOH (4.0 M, 40 mL) and stir at 25°C for 1 h. After concentration under reduced pressure, add pyridine (20 mL), stir at 80°C for 1 h, concentrate under reduced pressure, and analyze by column chromatography (DCM / MeOH = 50 / 1) to obtain compound 71g (1.8 g, 5.75 mmol, 45.3%). LC-MS: ESI [M+H] + =313.2.

[0353] Step 8: Compound 71g (1.8 g, 5.75 mmol) was dissolved in MeOH (30 mL), and lithium hydroxide (0.4 g, 17.25 mmol) was added. The mixture was stirred at 25°C for 12 h. After concentration under reduced pressure, the reaction was quenched by addition of saturated ammonium chloride solution (10 mL). The mixture was extracted with 4 x 30 mL of DCM, dried over sodium sulfate, and concentrated under reduced pressure. The mixture was purified by column chromatography (DCM / MeOH = 20 / 1) to afford compound 71h (0.7 g). LC-MS: ESI [M+H] + =209.2.

[0354] Step 9: Dissolve compound 71h (0.4 g, 1.92 mmol) in DCM (20 mL). Add TEA (1.4 mL, 9.6 mmol) and MsCl (0.65 mL, 5.76 mmol) dropwise at 0°C. Heat the temperature to 25°C and stir for 0.5 h. Slowly pour 20 mL of saturated sodium bicarbonate solution into the reaction mixture to quench. Extract with 30 mL of DCM, dry with sodium sulfate, and filter and concentrate under reduced pressure to obtain compound 71i (0.7 g, crude). LC-MS: ESI [M+H] + =365.2.

[0355] Step 10: Dissolve compound 71i (0.7 g, 1.92 mmol) in ACN (10 mL), add DIPEA (1.3 mL, 7.80 mmol), KI (0.05 g), and compound 8 (0.5 g, 1.92 mmol), and stir at 80°C for 24 h. Slowly pour 20 mL of saturated ammonium chloride solution into the reaction mixture to quench. Extract with 4 x 30 mL of DCM, dry with sodium sulfate, filter, concentrate under reduced pressure, and purify by column chromatography (DCM / MeOH = 20 / 1) to obtain compound 71j (1.1 g, crude). LC-MS: ESI [M+H] + =507.2.

[0356] Step 11: Compound 71j (1.1 g, 2.17 mmol) was dissolved in MeOH (10 mL), and NaOH (10 mL, 2.0 M) was added, followed by stirring at 25°C for 1 h. The reaction mixture was slowly poured into 30 mL of saturated ammonium chloride solution to quench the mixture. The mixture was extracted with 4 x 30 mL of EA, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by prep-TLC (DCM / MeOH = 10 / 1) afforded Compound 71 (5 mg) as a white solid. LC-MS: ESI [M+H] + =429.2; 1 H NMR (400MHz, CDCl3) δ7.99(d,J=7.9Hz,1H),7.50(d,J=4.8Hz,1H),7.35–7.29(m,1H),3.21(s,4H),2.99(d,J=4. 9Hz, 3H), 2.78 (d, J = 4.2Hz, 4H), 2.68-2.50 (m, 4H), 2.39 (s, 3H), 2.02 (s, 2H), 1.83 (s, 2H), 1.07 (d, J = 6.3Hz, 3H).

[0357] Example 72

[0358] 5-((3S)-4-((3-ethyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-3-methylpiperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0359] Preparation of 5-((3S)-4-((3-ethyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-3-methylpiperazin-1-yl)-6-fluoro-N-methylpicolinamide Reference Example 39. LC-MS: ESI [M+H] + =444.2; 1H NMR (400MHz, DMSO-d6) δ11.37(s,1H),8.40(q,J=4.8Hz,1H),7.85(d,J=7.9Hz,1 H),7.57(dd,J=10.6,8.1Hz,1H),6.99(s,1H),4.57–4.38(m,2H),3.83(d,J=5.6H z,1H),3.32(s,3H),3.05–2.93(m,2H),2.92–2.82(m,1H),2.77(d,J=4.7Hz,3H) ,2.72–2.53(m,4H),2.47–2.43(m,1H),2.35(q,J=7.3Hz,2H),1.13–1.01(m,6H).

[0360] Example 73

[0361] 6-Chloro-5-(4-((3-cyclopropyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0362] Preparation of 6-chloro-5-(4-((3-cyclopropyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide Reference Example 39. LC-MS: ESI [M+H] + =458.3; 1 H NMR (400MHz, DMSO-d6) δ11.43(s,1H),8.44(q,J=4.8Hz,1H),7.94(d,J=8.2Hz,1H ),7.67(d,J=8.2Hz,1H),6.71(s,1H),4.49–4.27(m,2H),3.87–3.81(m,1H),3.11( t,J=4.8Hz,4H),2.80(d,J=4.8Hz,3H),2.73–2.64(m,4H),2.62–2.54(m,2H),2.4 8–2.37(m,2H),1.94(tt,J=8.5,5.3Hz,1H),0.89–0.70(m,2H),0.62–0.47(m,2H).

[0363] Example 74

[0364] 6-Chloro-N-methyl-5-(4-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)picolinamide

[0365] Preparation of 6-chloro-N-methyl-5-(4-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)picolinamide Reference Example 39. LC-MS: ESI [M+H] + =432.2; 1 H NMR (400MHz, DMSO-d6) δ11.42(s,1H),8.44(q,J=4.7Hz,1H),7.94(d,J=8.2Hz,1H),7.67(d,J=8.2Hz,1H),7.04(s,1H),4.50–4.37(m,2H), 3.89–3.79(m,1H),3.10(t,J=4.7Hz,4H),2.80(d,J=4.8Hz,3H),2.72–2.62(m,4H),2.61–2.53(m,2H),2.46(t,J=7.9Hz,2H),1.94(s,3H).

[0366] Example 75

[0367] 5-((3R)-4-((3-ethyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-3-methylpiperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0368] Preparation of 5-((3R)-4-((3-ethyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-3-methylpiperazin-1-yl)-6-fluoro-N-methylpicolinamide Reference Example 39. LC-MS: ESI [M+H] + =444.2; 1 H NMR (400MHz, DMSO-d6) δ11.38(s,1H),8.40(q,J=4.8Hz,1H),7.84(d,J=7.9Hz,1H),7.56(dd,J=10.6,8.5Hz,1H),6.99(s,1H),4.53–4.35(m,2H ),3.87–3.77(m,1H),3.04–2.83(m,3H),2.77(d,J=4.8Hz,3H),2.74–2. 54(m,3H),2.49–2.40(m,2H),2.35(q,J=7.3Hz,2H),1.16–0.99(m,6H).

[0369] Example 76

[0370] 6-Cyano-N-methyl-5-(4-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)picolinamide

[0371] Preparation of 6-cyano-N-methyl-5-(4-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)picolinamide Reference Example 39. LC-MS: ESI [M+H] + =423.3; 1 H NMR (400MHz, DMSO-d6) δ11.42(s,1H),8.57(q,J=4.7Hz,1H),8.11(d,J=8.8Hz,1H),7.74(d,J=8.9Hz,1H),7.03(d,J=1.3Hz,1H),4.49–4.36( m,2H),3.90–3.79(m,1H),3.36(d,J=2.7Hz,4H),2.79(d,J=4.8Hz,3H) ,2.73–2.63(m,4H),2.62–2.53(m,2H),2.49–2.36(m,2H),1.93(s,3H).

[0372] Example 77

[0373] 6-Fluoro-N-(1-methyl-1H-pyrazol-4-yl)-5-(4-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)picolinamide

[0374] Preparation of 6-fluoro-N-(1-methyl-1H-pyrazol-4-yl)-5-(4-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)picolinamide Reference Example 39. LC-MS: ESI [M+H] + =482.3; 1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),10.51(s,1H),8.04(s,1H), 7.93(dd,J=8.1,1.5Hz,1H),7.70(s,1H),7.61(dd,J=10.6,8.1Hz,1H),7.03(d,J=1.3Hz,1H),4.49–4.36(m,2H),3.88–3.8 0(m,1H),3.81(s,3H),3.19(t,J=4.9Hz,4H),2.65(d,J=5.2Hz,4H),2.53(d,J=4.8Hz,2H),2.49–2.36(m,2H),1.93(s,3H).

[0375] Example 78

[0376] 5-(4-((3-ethyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-(1-methyl-1H-pyrazol-4-yl)picolinamide

[0377] Preparation of 5-(4-((3-ethyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-(1-methyl-1H-pyrazol-4-yl)picolinamide Reference Example 39. LC-MS: ESI [M+H] + =496.1; 1 H NMR (400MHz, DMSO-d6) δ11.49(s,1H),10.60(s,1H),8.13(s,1H),8.02(dd,J=8.1 ,1.4Hz,1H),7.79(s,1H),7.70(dd,J=10.6,8.2Hz,1H),7.08(s,1H),4.60–4.47(m ,2H),3.98–3.91(m,1H),3.90(s,3H),3.28(t,J=4.9Hz,4H),2.78–2.69(m,4H),2 .68–2.61(m,2H),2.58–2.50(m,2H),2.44(d,J=7.4Hz,2H),1.15(t,J=7.4Hz,3H).

[0378] Example 79

[0379] 6-Fluoro-N-(3-methoxycyclobutyl)-5-(4-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)picolinamide

[0380] Preparation of 6-fluoro-N-(3-methoxycyclobutyl)-5-(4-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)picolinamide Reference Example 39. LC-MS: ESI [M+H] + =486.2; 1 H NMR(400MHz,DMSO-d6)δ11.41(s,1H),8.65–8.57(m,1H),7.90–7.78(m,1H),7.59–7.54(m ,1H),7.03(d,J=1.3Hz,1H),4.50–4.36(m,2H),4.07–3.92(m,1H),3.85–3.81(m,1H),3.64 –3.53(m,1H),3.19–3.12(m,4H),3.13(s,2H),2.65–2.56(m,4H),2.59–2.51(m,2H),2.44( t,J=7.7Hz,2H),2.33(d,J=1.8Hz,2H),2.38–2.16(m,2H),2.07–2.00(m,2H),1.93(s,3H).

[0381] Example 80

[0382] (S)-6-Fluoro-N-methyl-5-(1-((2-methyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)piperidin-4-yl)picolinamide

[0383] Preparation of (S)-6-fluoro-N-methyl-5-(1-((2-methyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)piperidin-4-yl)picolinamide Reference Example 45. LC-MS: ESI [M+H] + =414.1. 1H NMR (400MHz, CDCl3) δ12.45(s,1H),8.04(d,J=7.5Hz,1H),7.85–7.76(m,1H),7.65(d,J=4.9Hz,1H),3.02(t,J=9.7H z,5H),2.88–2.61(m,4H),2.43(s,3H),2.39–2.30(m,3H),2.18–1.96(m,4H),1.88–1.74(m,4H),1.55–1.40(m,1H).

[0384] Example 81

[0385] (S)-N-Cyclopropyl-6-fluoro-5-(4-((2-methyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0386] Preparation of (S)-N-cyclopropyl-6-fluoro-5-(4-((2-methyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide Reference Example 45. LC-MS: ESI [M+H] + =441.1. 1 H NMR(400MHz, CDCl3) δ7.99(d,J=7.8Hz,1H),7.53(d,J=3.3Hz,1H),7.29(dd, J=10.0,8.2Hz,1H),3.23(t,J=4.6Hz,4H),2.89(tq,J=7.4,3.8Hz,1H),2.82– 2.57(m,7H),2.42(s,3H),2.37(d,J=17.5Hz,2H),2.05(d,J=10.9Hz,2H),1. 55–1.45(m,1H),1.42(t,J=5.1Hz,1H),0.90–0.79(m,2H),0.68–0.58(m,2H).

[0387] Example 82

[0388] (S)-6-Fluoro-N-(methyl-d3)-5-(4-((2-methyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0389] Preparation of (S)-6-fluoro-N-(methyl-d3)-5-(4-((2-methyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide Reference Example 45. LC-MS: ESI [M+H] + =418.1. 1 H NMR (400MHz, DMSO) δ11.85 (s, 1H), 8.39 (s, 1H), 7.85 (d, J = 8.0Hz, 1H), 7.59 (s, 1H), 4. 14(dd,J=9.9,4.8Hz,8H),2.70–2.52(m,6H),2.38–2.22(m,2H),2.21(d,J=7.8Hz,4H).

[0390] Example 83

[0391] (S)-6-Fluoro-N-methyl-5-(4-((2-methyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl-d2)piperazin-1-yl)picolinamide

[0392] Preparation of (S)-6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl-d2)piperazin-1-yl)picolinamide Reference Example 45. LC-MS: ESI [M+H] + =443.1. 1 H NMR (400MHz, DMSO) δ11.81(s,1H),8.35(d,J=4.9Hz,1H),7.84(d,J=7.9Hz,1H),7.56(dd,J=10.5,8.2Hz,1H),3.15(d,J=4.4Hz,4H),2.85(dd, J=11.4,6.6Hz,1H),2.65–2.52(m,7H),2.25–2.14(m,4H),1.99(d,J=9.9Hz,1H),1.92–1.79(m,1H),1.43–1.29(m,1H),0.65(d,J=7.2Hz,4H).

[0393] Example 84

[0394] (S)-6-Fluoro-N-(methyl-d3)-5-(4-((2-methyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl-d2)piperazin-1-yl)picolinamide

[0395] Preparation of (S)-6-fluoro-N-(methyl-d3)-5-(4-((2-methyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl-d2)piperazin-1-yl)picolinamide Reference Example 45. LC-MS: ESI [M+H] + =420.1. 1 H NMR (400MHz, DMSO) δ11.81(s,1H),8.37(s,1H),7.84(d,J=8.0Hz,1H),7.56(dd,J=10.5,8.2Hz,1H),3.15(t,J=4.5Hz ,4H),2.64–2.52(m,7H),2.24–2.11(m,4H),1.99(d,J=10.0Hz,1H),1.92–1.80(m,1H),1.36(dq,J=13.2,8.1Hz,1H).

[0396] Example 85

[0397] (S)-6-Chloro-N-methyl-5-(4-(2-methyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl-d2)piperazin-1-yl)picolinamide

[0398] Preparation of (S)-6-chloro-N-methyl-5-(4-(2-methyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl-d2)piperazin-1-yl)picolinamide Reference Example 45. LC-MS: ESI [M+H] + =433.1. 1 H NMR (400MHz, DMSO) δ11.82(s,1H),8.43(q,J=4.6Hz,1H),7.66(dd,J=8.2,4.4Hz,1H),3.10(s,4H),2.79(d,J =4.8Hz,3H),2.65–2.51(m,10H),2.20(s,3H),1.99(t,J=11.3Hz,1H),1.93–1.83(m,1H),1.43–1.31(m,1H).

[0399] Example 86

[0400] 5-(4-((7-chloro-6-oxo-3,4,5,6-tetrahydro-2H-pyrano[3,2-b]pyridin-3-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0401] Step 1: Compound 86a (14 g, 11.2 mmol) was dissolved in anhydrous acetonitrile (150 ml), and NBS (22 g, 12.3 mmol) was added. The reaction was allowed to react at room temperature overnight. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the desired product 86b (18 g). LC-MS: ESI [M+H] + =203.9.

[0402] Step 2: Compound 86b (5 g, 25 mmol), potassium ethylene trifluoroborate (5 g, 37 mmol), Pd(dppf)Cl2 (1.8 g, 2.5 mmol), and potassium carbonate (10.4 g, 75 mmol) were dissolved in dioxane (50 ml) and water (5 ml). The atmosphere was replaced with nitrogen and the reaction was carried out at 100°C for 5 h. The mixture was filtered, mixed with silica gel, and purified by column chromatography to obtain the target compound 86c (2 g). LC-MS: ESI [M+H] + =152.1.

[0403] Step 3: Compound 86c (302 mg, 2 mmol), compound 86d (88 mg, 3 mmol), and triphenylphosphine (786 mg, 3 mmol) were dissolved in anhydrous THF (10 ml). The system was replaced with a nitrogen atmosphere, the temperature was lowered to 0°C, and DIAD (606 mg, 3 mmol) was added dropwise. The mixture was then brought to room temperature and allowed to react overnight. Silica gel was added and the sample was mixed. Column chromatography afforded the title compound 86e (500 mg). LC-MS: ESI [M+H] + =222.1.

[0404] Step 4: Compound 86e (500 mg, 2.3 mmol) and Grubbs' second-generation catalyst (98 mg, 0.23 mmol) were dissolved in anhydrous DCM (20 ml), replaced with a nitrogen atmosphere, and reacted at room temperature overnight. Silica gel was added and the sample was stirred. Column chromatography gave the desired product 86f (450 mg). LC-MS: ESI [M+H] + =194.1.

[0405] Step 5: Compound 86f (450 mg) was dissolved in methanol (10 ml), 10% Pd / C (45 mg) was added, the system was replaced with a hydrogen atmosphere, and the reaction was allowed to proceed overnight at room temperature. The reaction solution was filtered through a pad of celite and concentrated under reduced pressure to obtain the target compound 86g (430 mg). LC-MS: ESI [M+H] + =196.1.

[0406] Step 6: Compound 86g (200 mg, 1 mmol) and triethylamine (0.417 mL, 3 mmol) were dissolved in DCM (10 mL), and benzoyl chloride (0.17 g, 1.2 mmol) was added. The mixture was allowed to react at room temperature overnight. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, extracted three times with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and mixed with silica gel. Column chromatography afforded the desired product 86h (193 mg). LC-MS: ESI [M+H] + =300.1.

[0407] Step 7: Compound 86h (140 mg, 0.47 mmol) was dissolved in anhydrous DMF (5 ml), and NCS (75 mg, 0.56 mmol) was added. The reaction was allowed to react at room temperature overnight. The reaction was quenched with saturated sodium bicarbonate aqueous solution, extracted three times with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and mixed with silica gel. Column chromatography afforded the desired product 86i (90 mg). LC-MS: ESI [M+H] + =334.1.

[0408] Step 8: Compound 86i (90 mg, 0.27 mmol) was dissolved in methanol (5 ml), and lithium hydroxide (19.37 mg, 0.81 mmol) was added. The mixture was reacted at room temperature overnight. Silica gel was added and the sample was mixed. Column chromatography was performed to obtain the target product 86j (65 mg). LC-MS: ESI [M+H] + =230.1.

[0409] Step 9: Compound 86j (65 mg, 0.28 mmol) and triethylamine (0.12 mL, 0.85 mmol) were dissolved in anhydrous DCM (5 mL), cooled to 0°C, and MsCl (65 mg, 0.57 mmol) was added dropwise. The mixture was allowed to react at room temperature for 2 h. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of the target compound 86k (77 mg). LC-MS: ESI [M+H] + =308.0.

[0410] Step 10: Compound 86k (77 mg, 0.25 mmol), compound INT10 (66 mg, 0.28 mmol), potassium iodide (83 mg, 0.5 mmol), and DIEA (97 mg, 0.75 mmol) were dissolved in anhydrous ACN (5 ml) and reacted at 80°C overnight. Silica gel was added and the sample was stirred. Column chromatography gave the desired product 86l (45 mg). LC-MS: ESI [M+H] + =450.2.

[0411] Step 11: Compound 861 (40 mg, 0.09 mmol) was dissolved in ACN (5 ml), and hydrogen bromide acetic acid solution (1 ml) was added. The reaction was allowed to proceed at 80°C for 1 h. LC-MS confirmed the complete reaction of the starting material. The mixture was cooled to room temperature, diluted with water, and extracted three times with EA to remove some organic impurities. The aqueous phase was adjusted to a weak base with solid sodium bicarbonate and extracted three times with 10% MeOH in DCM. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Preparative TLC isolated the desired product 86 (21 mg). LC-MS: ESI [M+H] + =436.1, 1 H NMR (400MHz, DMSO) δ11.83(s,1H),8.41(q,J=4.6Hz,1H),7.85(dd,J=8.0,1.3Hz,1H),7.57(dd,J= 10.6,8.2Hz,1H),7.47(s,1H),4.10(d,J=10.9Hz,1H),3.75(dd,J=9.9,4.9Hz,1H),3.20–3.12(m, 4H), 2.77 (d, J = 4.8Hz, 2H), 2.71–2.63 (m, 1H), 2.59–2.53 (m, 4H), 2.42–2.25 (m, 2H).

[0412] Example 87

[0413] N,6-Dimethyl-5-(4-((3-(methylthio)-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)picolinamide

[0414] Step 1: Compound INT25e (500 mg, 1.31 mmol), compound INT11 (367 mg, 1.57 mmol), and N,N-diisopropylethylamine (337 mg, 2.61 mmol) were added to 15 ml of acetonitrile and stirred at 80°C for 12 hours. After the reaction was complete as monitored by TLC, 15 ml of saturated aqueous sodium bicarbonate solution was added and the mixture was extracted three times with 30 ml of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and oven-dried. The resulting crude product was purified by column chromatography to yield compound 87a (400 mg, light yellow solid). LC-MS: ESI [M+H] + =490.2;

[0415] Step 2: Compound 87a (400 mg, 0.82 mmol), 2-ethylhexyl 3-mercaptopropionate (267.5 mg, 1.23 mmol), Xantphos (96.7 mg, 0.16 mmol), Pd2(dba)3 (75 mg, 0.082 mmol), and DIPEA (221 mg, 1.6 mmol) were added to anhydrous toluene and heated to 110°C under a nitrogen atmosphere for 12 hours. After completion of the reaction as monitored by TLC, water and 30 ml of ethyl acetate were added and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and oven-dried. The resulting crude product was purified by column chromatography to yield compound 87c (300 mg, white solid). LC-MS: ESI [M+H] + =628.4;

[0416] Step 3: Compound 87c (300 mg, 0.92 mmol) was dissolved in ethanol, and sodium ethoxide (124.8 mg, 1.8 mmol) was added. The mixture was stirred at 25°C for 2 h. After completion of the reaction as monitored by TLC, the reaction solution was slowly poured into HCl (0.5 M, 10 ml) for quenching. Water and ethyl acetate were added, and the mixture was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and oven-dried. The resulting crude product was purified by column chromatography to yield compound 87d (150 mg, white solid). LC-MS: ESI [M+H] + =444.2;

[0417] Step 4: Compound 87d (150 mg, 0.35 mmol), iodomethane (52 mg, 0.37 mmol), and cesium carbonate (165.5 mg, 0.51 mmol) were added to anhydrous acetonitrile and stirred at 25°C for 1 hour. After completion of the reaction as monitored by TLC, the reaction solution was poured into saturated ammonium chloride for quenching. Water and ethyl acetate were added and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and oven-dried to obtain crude compound 87e (100 mg, yellow oil). LC-MS: ESI [M+H] + =458.2;

[0418] Step 5: Add crude compound 87e (100 mg, 0.22 mmol) and 0.5 ml of 48% aqueous hydrobromic acid to the dioxane solution, heat to 80°C, and stir for 2 h. After the reaction is complete as determined by LC-MS, add saturated sodium bicarbonate solution, 30 ml of ethyl acetate, and 50 ml of water, and separate the layers in a separatory funnel. The aqueous phase is extracted twice with ethyl acetate, and the combined organic phases are washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. Purification by column chromatography yields compound 87 (33 mg, white solid). LC-MS: ESI [M+H] + =444.3; 1H NMR (400MHz, DMSO-d6) δ11.65(s,1H),8.42(q,J=4.8Hz,1H),7.80(d,J=8.2Hz,1H),7.48(d,J=8.3Hz,1H),6.89(s,1H),4.57–4.41(m,2H ),3.89–3.81(m,1H),2.94(t,J=4.7Hz,4H),2.80(d,J=4.9Hz,3H),2.65(s,4H),2.57(dt,J=11.8,5.8Hz,2H),2.49(s,3H),2.27(s,3H).

[0419] Example 88

[0420] (S)-N-Cyclopropyl-6-fluoro-5-(4-((2-methyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl-d2)piperazin-1-yl)picolinamide

[0421] Preparation of (S)-N-cyclopropyl-6-fluoro-5-(4-((2-methyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl-d2)piperazin-1-yl)picolinamide Reference Example 45. LC-MS: ESI [M+H] + =443.1. 1 H NMR (400MHz, DMSO) δ11.81(s,1H),8.35(d,J=4.9Hz,1H),7.84(d,J=7.9Hz,1H),7.56(dd,J=10.5,8.2Hz,1H),3.15(d,J=4.4Hz,4H),2.85(dd, J=11.4,6.6Hz,1H),2.65–2.52(m,7H),2.25–2.14(m,4H),1.99(d,J=9.9Hz,1H),1.92–1.79(m,1H),1.43–1.29(m,1H),0.65(d,J=7.2Hz,4H).

[0422] Example 89

[0423] 6-Fluoro-N-methyl-5-((1S,6R)-5-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)picolinamide

[0424] Preparation of 6-fluoro-N-methyl-5-((1S,6R)-5-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)picolinamide Reference Example 39. LC-MS: ESI [M+H] + =442.3; 1 H NMR (400MHz, DMSO-d6) δ11.49(s,1H),8.44(q,J=4.7Hz,1H),7.90(dt,J=8.1,1.7Hz,1H ),7.53–7.43(m,1H),7.12(s,1H),4.59–4.44(m,2H),4.30–4.18(m,1H),3.97–3.86(m,1 H),3.60–3.51(m,1H),3.34–3.19(m,1H),3.07(t,J=8.2Hz,1H),2.85(d,J=4.8Hz,3H),2 .57–2.39(m,2H),2.02(s,3H),1.93–1.76(m,2H),1.46–1.26(m,4H),0.99–0.90(m,2H).

[0425] Example 90

[0426] 6-Fluoro-N-methyl-5-((1S,6R)-5-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)picolinamide

[0427] Preparation of 6-fluoro-N-methyl-5-((1S,6R)-5-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)picolinamide Reference Example 39. LC-MS: ESI [M+H] + =442.3; 1H NMR (400MHz, DMSO-d6) δ11.49(s,1H),8.44(q,J=4.7Hz,1H),7.90(dt,J=8.1,1.7Hz,1H ),7.53–7.43(m,1H),7.12(s,1H),4.59–4.44(m,2H),4.30–4.18(m,1H),3.97–3.86(m,1 H),3.60–3.51(m,1H),3.34–3.19(m,1H),3.07(t,J=8.2Hz,1H),2.85(d,J=4.8Hz,3H),2 .57–2.39(m,2H),2.02(s,3H),1.93–1.76(m,2H),1.46–1.26(m,4H),0.99–0.90(m,2H).

[0428] Example 91

[0429] (4aR)-3-((3-ethyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazolidine-9-carboxamide

[0430] Preparation of (4aR)-3-((3-ethyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazolidine-9-carboxamide Reference Example 39. LC-MS: ESI [M+H] + =454.5. 1 H NMR(400MHz,DMSO-d6)δ11.39(s,1H),8.40(d,J=5.2Hz,1H),7.82(dd,J=8.5,1.9Hz,1H), 7.50(d,J=8.5Hz,1H),6.99(s,1H),4.95(dd,J=14.0,4.4Hz,1H),4.73(dd,J=14.0,2.5Hz ,1H),4.46-4.39(m,2H),4.01-3.94(m,1H),3.87-3.76(m,2H),3.53-3.43(m,1H),3.30(s ,2H),2.79(d,J=4.8Hz,3H),2.76-2.52(m,5H),2.49-2.30(m,5H),1.06(t,J=7.4Hz,3H).

[0431] Example 92

[0432] (4aR)-N-methyl-3-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazolidine-9-carboxamide

[0433] Preparation of (4aR)-N-methyl-3-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazolidine-9-carboxamide Reference Example 39. LC-MS: ESI [M+H] + =440.5. 1 H NMR (400MHz, DMSO-d6) δ11.16(s,1H),8.40(d,J=5.1Hz,1H),7.81(d,J=8.4Hz,1H),7.50 (d,J=8.5Hz,1H),7.00(s,1H),4.96(dd,J=14.1,1.7Hz,1H),4.73(d,J=13.9Hz,1H),4.10 -3.96(m,2H),3.82(dd,J=12.2,3.9Hz,1H),3.75-3.64(m,1H),3.50(d,J=7.5Hz,1H),3.3 1-3.27(m,2H),2.79(d,J=4.8Hz,3H),2.70-2.53(m,4H),2.39-2.23(m,5H),1.92(s,3H).

[0434] Example 93

[0435] (R)-N-Methyl-3-(((S)-2-methyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazolidine-9-carboxamide

[0436] Preparation of (R)-N-methyl-3-(((S)-2-methyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazolidine-9-carboxamide Reference Example 45. LC-MS: ESI [M+H]+ =439.5.

[0437] Example 94 and Example 95

[0438] (S)-6-Chloro-N-methyl-5-(4-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)picolinamide and (R)-6-chloro-N-methyl-5-(4-((3-methyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)picolinamide

[0439] Compound 74 was separated and purified by supercritical fluid chromatography (SFC) (Column: CHIRALPAK IG 250 mm x 20 mm, 5 μm, 70% EtOH (NH 3 H 2 O 0.1%) to give two compounds 94 and 95:

[0440] Example 94 (t R =1.971), MS / ESI[M+H] + =432.2; 1 H NMR (400MHz, DMSO-d6) δ11.42(s,1H),8.44(q,J=4.7Hz,1H),7.94(d,J=8.2Hz,1H),7.67(d,J=8.2Hz,1H),7.04(s,1H),4.50-4.37(m,2H), 3.89-3.79(m,1H),3.10(t,J=4.7Hz,4H),2.80(d,J=4.8Hz,3H),2.72-2.62(m,4H),2.61-2.53(m,2H),2.46(t,J=7.9Hz,2H),1.94(s,3H).

[0441] Example 95 (t R =2.895), MS / ESI[M+H] + =430.2; 1H NMR (400MHz, DMSO-d6) δ11.42(s,1H),8.44(q,J=4.7Hz,1H),7.94(d,J=8.2Hz,1H),7.67(d,J=8.2Hz,1H),7.04(s,1H),4.50-4.37(m,2H), 3.89-3.79(m,1H),3.10(t,J=4.7Hz,4H),2.80(d,J=4.8Hz,3H),2.72-2.62(m,4H),2.61-2.53(m,2H),2.46(t,J=7.9Hz,2H),1.94(s,3H).

[0442] Example 96

[0443] 6-Fluoro-N-methyl-5-(4-((3-(methylthio)-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)picolinamide

[0444] Preparation of 6-fluoro-N-methyl-5-(4-((3-(methylthio)-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)picolinamide Reference Example 87. LC-MS: ESI [M+H] + =448.3; 1 H NMR (400MHz, DMSO-d6) δ11.64(s,1H),8.40(d,J=4.9Hz,1H),7.85(dd,J=8.0,1.4Hz,1H),7.57(dd,J=10.6,8.1Hz,1H),6.89(s,1H),4.56-4.41 (m,3H),3.91-3.77(m,1H),3.16(t,J=5.0Hz,4H),2.86-2.77(m,1H),2. 76(d,J=4.8Hz,3H),2.68-2.60(m,4H),2.59-2.52(m,3H),2.27(s,3H).

[0445] Example 97

[0446] N,6-Dimethyl-5-(1-((3-(methylthio)-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperidin-4-yl)picolinamide

[0447] Preparation of N,6-dimethyl-5-(1-((3-(methylthio)-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperidin-4-yl)picolinamide Reference Example 87. LC-MS: ESI [M+H] + =443.2; 1 H NMR (400MHz, DMSO-d6) δ11.64(s,1H),8.72-8.39(m,1H),7.79(d,J=2.9Hz,2H),6.89( s,1H),4.59-4.37(m,2H),3.88-3.78(m,1H),3.10-3.00(m,2H),2.81(d,J=4.9Hz,3H), 2.76-2.66(m,1H),2.58(s,3H),2.58-2.52(m,1H),2.49-2.44(m,2H), 2.45-2.37(m,1H),2.27(s,3H),2.23-2.08(m,2H),1.76-1.57(m,4H).

[0448] Example 98

[0449] (R)-5-(4-((1,7-dimethyl-6-oxo-2,3,5,6-tetrahydro-1H-pyrido[2,3-b][1,4]oxazin-3-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0450] Step 1: 98a (25 g, 162.2 mmol) was added to a round-bottom flask, followed by CAN (200 mL). Stirring did not dissolve the mixture. TEA (33.8 mL, 243.3 mmol) was added and stirred for 10 min until the mixture dissolved. The mixture was cooled to 0-10°C and pivaloyl chloride (21.6 mL, 175.2 mmol) was added dropwise. The mixture was slowly allowed to return to room temperature and stirred for 4 h. After the reaction was complete, the mixture was dried and the residue was purified by column chromatography with EA / PE = 0-20% to afford 98b (36 g) as an off-white solid. LC-MS: [M+H] + =239.2.

[0451] Step 2: 98b (37.5 g, 157.4 mmol) was added to a round-bottom flask, followed by methanol (600 mL) and palladium carbon (4.0 g, 37.6 mmol). The mixture was replaced with hydrogen three times and stirred overnight under a hydrogen atmosphere. The mixture was filtered and dried. The residue was purified by column chromatography with MeOH / DCM = 0-2% to give 98c (24 g) as an off-white solid. LC-MS: [M+H] + =209.3.

[0452] Step 3: Compound 98c (24.0 g, 115.2 mmol) was added to a round-bottom flask, and CAN (300 mL) was added to dissolve the mixture. The temperature was lowered to 0°C, and NBS (21.5 g, 121.0 mmol) was added. The mixture was stirred for 30 min until the reaction was complete. The residue was dried and purified by column chromatography with EA / PE = 0-20% to obtain compound 98d (20 g) as an off-white solid. LC-MS: [M+H] + =287.2,289.2.

[0453] Step 4: Compound 98d (20.0 g, 69.6 mmol) was added to a round-bottom flask and dissolved in DMF (200 mL). The mixture was cooled to -10-0°C, and iodomethane (6.95 mL, 111.6 mmol) was added. The mixture was stirred for 10 min, and sodium methoxide (5.31 g, 98.297 mmol) was added. The mixture was stirred at -10-0°C for 1.5 h, then returned to room temperature and stirred for 3 h. TLC (PE / EA = 10:1) indicated that the reaction had reached equilibrium. 800 mL of ice water was added to the system, and the mixture was extracted with EA. The organic phase was washed with water and brine, dried, and spin-dried. The residue was purified by column chromatography using EA / PE = 0-10% to afford compound 98e (3.43 g) as an off-white solid. LC-MS: [M+H] + =301.2,303.2.

[0454] Step 5: Compound 98e (2.9 g, 9.6 mmol) was added to a round-bottom flask and dissolved in hexafluoroisopropanol (50 mL). (R)-benzyloxymethyloxirane (6.33 g, 38.5 mmol) was added, the atmosphere was replaced with nitrogen, and the temperature was raised to 75°C with stirring for 9 h. The system was then spin-dried to dryness. The residue was purified by column chromatography with 0-25% EA / PE to afford compound 98e (2.7 g) as a pale yellow-green oil. LC-MS: [M+H] + =467.2,469.2.

[0455] Step 6: Compound 98g (2.7g, 5.8mmol) was added to a round-bottom flask and dissolved in methanol (50mL). A solution of sodium hydroxide (0.7g, 17.4mmol) and water (20mL) was added and stirred at room temperature for 30min. The mixture was cooled to 0-10°C and the pH was adjusted to 4-6 with HCl (2N). The mixture was extracted with EA, dried, and spin-dried to obtain a crude product of compound 98h (2.32g) as a brown oil. LC-MS: [M+H] + =383.1,385.1.

[0456] Step 7: Compound 98h (2.34 g, 6.1 mmol) was added to a round-bottom flask and dissolved in DMF (50 mL). Potassium carbonate (1.1 g, 7.98 mmol) and p-methoxybenzyl chloride (1 mL, 7.365 mmol) were added, and the temperature was raised to 60°C and stirred for 3 h. The reaction solution was poured into ice water and extracted with EA. The organic phase was washed with water, dried over Na2SO4, and dried by spin drying. The residue was purified by EA / PE = 0-25% column chromatography to obtain compound 98i (2.2 g) as a colorless oil. LC-MS: [M+H] + =503.2,505.2.

[0457] Step 8: Compound 98i (2.2 g, 4.4 mmol) was added to a round-bottom flask and dissolved in DME (50 mL). The temperature was lowered to 0-10°C, and sodium hydroxide (0.614 g, 15.4 mmol, 60% dispersion in mineral oil) was added portionwise under N2 protection. The temperature was raised to 85°C and stirred for 2 h. The reaction solution was poured into ice water and extracted with EA. The organic phase was dried and spin-dried. The residue was purified by column chromatography with EA / PE = 0-25% to obtain compound 98j (1.72 g) as a colorless oil. LC-MS: [M+H] + =421.2.

[0458] Step 9: Compound 98j (1.72 g, 4.09 mmol) was added to a round-bottom flask and dissolved in methanol (20 mL). Palladium carbon (150 mg) was added and H2 was replaced. The mixture was stirred under H2 atmosphere for 1 h. DCM (20 mL) was added to the reaction solution, filtered, and dried to obtain a crude product of compound 98k (1.12 g) as a white solid. LC-MS: [M+H] + =301.2.

[0459] Step 10: Compound 98k (0.56 g, 1.864 mmol) was added to a round-bottom flask and dissolved in DMSO (12 mL). Potassium hydroxide (9.34 mg, 0.166 mmol) and water (3 mL) were added, and the mixture was stirred at room temperature for 30 min. Dimethyl sulfate (0.177 mL, 1.864 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was poured into cold water and extracted with EA. The organic phase was dried and spin-dried. The residue was purified by column chromatography with EA / PE = 0-25% to obtain compound 98l (130 mg) as a colorless oil. 1H NMR (400MHz, DMSO) δ7.40-7.26(m,5H),7.03(s,1H),4.56(s,2H),4.51-4.44(m,1H),3.71(s,3H),3.65(dq,J=10. 4,5.2Hz,2H),3.19(dd,J=11.7,2.5Hz,1H),2.91(dd,J=11.7,7.7Hz,1H),2.73(s,3H),2.04(s,3H), LC-MS:[M+H] + =315.2.

[0460] Step 11: Compound 98l (130 mg, 0.414 mmol) was added to a round-bottom flask and dissolved in methanol (6 mL). Palladium on carbon (30 mg, 0.282 mmol) and palladium hydroxide (30 mg, 0.414 mmol) were added. H2 was replaced three times and hydrogenated overnight. Most of the starting material remained. The catalyst was filtered to remove the catalyst, and H2 was added again. H2 was replaced and hydrogenated for 10 h. The reaction was completed. The product was filtered and dried to obtain 80 mg of crude compound 98m as an oil. LC-MS: [M+H] + = 225.1. It was used directly in the next step without further purification.

[0461] Step 12: Compound 98m (80 mg, 0.357 mmol) was added to a round-bottom flask and dissolved in DCM (10 mL). TEA (0.1 mL, 0.713 mmol) was added and the temperature was lowered to 0-10°C. MsCl (0.03 mL, 0.39 mmol) was added and stirred for 30 min. Water was added to the reaction solution and extracted with DCM. The organic phase was dried and spin-dried to obtain a crude product of compound 98n (130 mg) as an oil. LC-MS: [M+H] + = 303.1. It was used directly in the next step without further purification.

[0462] Step 13: Compound 98n (130 mg, 0.43 mmol), compound INT10 (133.80 mg, 0.43 mmol), TEA (0.3 mL, 2.15 mmol), potassium iodide (71.37 mg, 0.43 mmol) were added to a round-bottom flask and dissolved in DMF (8 mL). The mixture was replaced with nitrogen and heated to 100°C with stirring overnight. The mixture was filtered and dried. The residue was purified by column chromatography with MeOH / DCM = 0-6% to obtain compound 98o (17 mg) as a white solid. LC-MS: [M+H] + =445.3.

[0463] Step 14: Compound 98o (17 mg, 0.038 mmol) was added to a round-bottom flask and dissolved in ACN (5 mL). A 33% w / w (45% w / v) hydrobromic acid solution in acetic acid (1 mL) was added, and the temperature was raised to 80°C and stirred for 2 h. The reaction solution was spin-dried and the residue was adjusted to pH 7-9 with NaHCO3 (aq). The residue was extracted with DCM, and the organic phase was dried and spin-dried. The residue was purified by Prep-TLC to obtain compound 98 (10 mg) as an off-white solid. 1 H NMR (400MHz, DMSO) δ9.81(s,1H),8.41(d,J=4.8Hz,1H),7.85(d,J=7.8Hz,1H),7.57(dd,J=10.5,8.2Hz,1H),6.95(s,1H),4.48(d,J=5.4Hz,1H),3 .30(s,1H),3.22-3.10(m,5H),2.83(dd,J=11.7,7.6Hz,1H),2.76(d,J=4 .8Hz,3H),2.72(s,4H),2.62(d,J=6.1Hz,4H),2.00(s,3H), LC-MS:[M+H] + =431.2.

[0464] Example 99

[0465] 5-(4-((3,4-dimethyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0466] Step 1: Add compound 99a (25.0 g, 297.336 mmol), compound 99b (42.87 g, 297.336 mmol), and methanol (200 mL) to a round-bottom flask and stir to dissolve. Add potassium hydroxide (25 g, 446.0 mmol) and methanol (200 mL) solution, heat the system to 65-70°C and react for 4 hours, then return to room temperature and stir overnight. Filter, wash the filter cake with a small amount of methanol, add the resulting solid to 700 mL of water, stir for 30 minutes, then adjust the pH to 1-2 with HCl (6N), stir for 30 minutes, cool to 10-20°C, continue stirring for 30 minutes, and filter. The solid is dried to obtain compound 99c (35 g) as a white powder. 1 H NMR (400MHz, DMSO) δ2.18 (s, 3H), 1.87 (s, 3H), LC-MS: [M+H] + =165.1.

[0467] Step 2: Compound 99c (5.0 g, 30.458 mmol) and phosphorus oxychloride (10 mL) were added to a sealed tube, sealed, and heated to 180°C for 5 h. The mixture was then cooled to room temperature. TLC (PE / EA = 5:1) indicated that the reaction was complete. The reaction solution was added to stirred ice water and extracted with EA. The organic phase was dried and spin-dried. The residue was purified by column chromatography using EA / EA = 0-10 to obtain compound 99d (5.46 g) as a white solid. LC-MS: [M+H] + =201.2,203.2.

[0468] Step 3: Compound 99d (3.0 g, 14.922 mmol) was added to a round-bottom flask and dissolved in sulfuric acid (15 mL). Nitric acid (2.4 mL, mmol) was added and the temperature was raised to 110°C. The mixture was stirred for 2 h. The reaction solution was poured into ice water and extracted with EA. The organic phase was dried and spin-dried to obtain crude compound 99e (3.28 g) as a white solid. LC-MS: [M+H] + =220.2,222.2.

[0469] Step 4: Compound 99e (3.28 g, 14.91 mmol) was added to a round-bottom flask and dissolved in DMF (40 mL). Potassium carbonate (3.09 g, 22.359 mmol) and iodomethane (1.86 mL, 29.8 mmol) were added and stirred at room temperature for 2 h. Water (200 mL) was added to the reaction solution and extracted with EA. The organic phase was dried and spin-dried. The residue was purified by EA / PE = 0-20% column chromatography to obtain compound 99f (3.4 g) as a colorless oil. LC-MS: [M+H] + =234.2,236.2.

[0470] Step 5: Compound 99f (7.36 g, 31.44 mmol), Pd2(dba)3 (1.44 g, 1.57 mmol), Xantphos (1.82 g, 3.144 mmol), TEA (21.85 mL, 157.21 mmol), and dioxane (75 mL) were added to a round-bottom flask and dissolved. Sodium methoxide (3.4 g, 62.88 mmol) was added, and the atmosphere was replaced with N2 three times. The temperature was raised to 60°C and stirred for 3 days. The reaction solution was filtered and dried. The residue was purified by column chromatography with EA / PE = 0-5% to obtain compound 99g (1.05 g) as an off-white solid. 1 H NMR (400MHz, DMSO) δ3.88 (d, J = 5.0Hz, 6H), 2.18 (s, 3H), 2.09 (s, 3H); LC-MS: [M+H] + =230.1.

[0471] Step 6: Compound 99g (0.92 g, 4.0 mmol), compound 99h (4.04 g, 24.04 mmol), Pd(dppf)2Cl2 (0.29 g, 0.40 mmol), potassium carbonate (0.83 g, 6.0 mmol), water (1.6 mL), and dioxane (80 mL) were added to a round-bottom flask and replaced with N2 three times. The temperature was raised to 100°C and stirred overnight. The reaction solution was cooled to room temperature, filtered, and dried. The residue was purified by EA / PE = 0-5% column chromatography to obtain compound 99i (0.84 g) as a colorless oil. 1 H NMR (400MHz, DMSO) δ5.94 (dd, J=17.0, 10.2Hz, 1H), 5.08-4.96 (m, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 3.38 (d, J = 6.7Hz, 2H), 2.14 (s, 3H), 2.07 (s, 3H); LC-MS: [M+H] + =236.1.

[0472] Step 7: Compound 99i (0.84 g, 3.57 mmol) was added to a round-bottom flask and dissolved in THF (10 mL). DIBAL-H (21.42 mL, 21.42 mmol) was added dropwise and stirred at room temperature for 2 h. The reaction solution was cooled to 0-10°C and 60 mL of 10% KOH (aq) was added dropwise. The mixture was extracted with EA. The organic phase was dried and spin-dried. The residue was purified by column chromatography with EA / PE = 0-25% to obtain compound 99j (0.72 g) as a colorless oil. LC-MS: [M+H] + =208.2.

[0473] Step 8: Compound 99j (0.72 g, 3.47 mmol) was added to a round-bottom flask and dissolved in ACN (80 mL). N-iodosuccinimide (1.95 g, 8.68 mmol) was added and stirred for 2 h. The reaction solution was poured into water and extracted with EA. The organic phase was washed with NaHCO3 (aq), dried, and spin-dried. The residue was purified by column chromatography with EA / PE = 0-10% to obtain compound 99k (0.55 g) as a white solid. 1H NMR (400MHz, DMSO) δ4.80(d,J=14.8Hz,1H),4.59(d,J=14.8Hz,1H),3.81(s,3H),3.63(ddd,J=10.2,6.9,3.6Hz,1H),3.53(dd,J=10.4,4.1 Hz,1H),3.39(dd,J=10.4,6.6Hz,1H),2.78(dd,J=16.6,2.8Hz,1H),2.63(dd,J=16.6,10.4Hz,1H),2.05(s,3H),2.02(s,3H); LC-MS:[M+H] + =334.2.

[0474] Step 9: Compound 99k (195 mg, 0.585 mmol) and compound INT10 (182.13 mg, 0.585 mmol) were added to a round-bottom flask and dissolved in DMF (25 mL). DIEA (0.41 mL, 2.34 mmol) was added and the mixture was heated to 80-100°C and stirred for 2 days. The solvent was then concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography using MeOH / DCM = 0-8% to obtain 120 mg of crude product. This was then purified by Prep-TLC using DCM / MeOH = 10:1 to obtain compound 99l (35 mg) as a white solid. LC-MS: [M+H] + =444.3.

[0475] Step 10: Compound 99l (35 mg, 0.079 mmol) was added to a round-bottom flask and dissolved in ACN (6 mL). A 33% w / w (45% w / v) hydrobromic acid solution in acetic acid (1 mL) was added, and the temperature was raised to 80°C and stirred for 3 h. The solvent was removed by concentration under reduced pressure. NaHCO3 (aq) was added to the residue to adjust the pH to 7-9, and the mixture was extracted with DCM / MeOH = 10:1. The organic phase was dried and spin-dried. The residue was purified by Prep-TLC using DCM / MeOH = 10:1 to obtain compound 99 (28 mg) as a white solid. 1 HNMR(400MHz,DMSO)δ11.28(s,1H),8.40(q,J=4.6Hz,1H),7.89-7.79(m,1H) ,7.57(dd,J=10.6,8.2Hz,1H),4.55(d,J=14.2Hz,1H),4.40(d,J=14.3Hz,1H ),3.87-3.74(m,1H),3.16(t,J=4.6Hz,4H),2.76(d,J=4.8Hz,3H),2.70-2.5 9(m,4H),2.59-2.51(m,2H),2.43(d,J=9.2Hz,2H),1.92(s,6H); LC-MS:[M+H]+ =430.2.

[0476] Example 100

[0477] 6-Chloro-5-(4-(3,4-dimethyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0478] Reference Example 99 was used to prepare 6-chloro-5-(4-(3,4-dimethyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide. 1 H NMR (400MHz, DMSO) δ11.28(s,1H),8.42(dd,J=8.9,4.8Hz,1H),7.95(dd,J=8.1,5.2Hz,1H),7.65(dd,J=12.4,8.2Hz,1H),4.56(d,J=14.2Hz,1H ),4.41(d,J=14.3Hz,1H),3.81(d,J=3.6Hz,1H),3.10(s,4H),2.84-2.75(m,3H),2.64(d,J=19.6Hz,4H),2.56(dd,J=11.4,5.4Hz,2H),2.45(s, 2H),1.93(s,6H); LC-MS:[M+H] + =446.2.

[0479] Example 101

[0480] 6-Fluoro-N-methyl-5-(4-((7-methyl-6-oxo-3,4,5,6-tetrahydro-2H-pyrano[3,2-b]pyridin-3-yl)methyl)piperazin-1-yl)picolinamide

[0481] Step 1: Dissolve compound 101a (1.7 g, 12.2 mmol) in anhydrous ACN (20 ml) and add NBS (2.4 g, 13.4 mmol). Allow to react at room temperature overnight. Quench the reaction with saturated sodium bicarbonate solution. Extract three times with ethyl acetate. Combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and column chromatography to obtain the desired product 101b (2.2 g). LC-MS: [M+H] + =217.9.

[0482] Step 2: Dissolve compound 101b (1.2 g, 5.5 mmol), potassium vinyl trifluoroborate (1.47 g, 11 mmol), Pd(dppf)Cl2 (0.4 g, 0.55 mmol), and triethylamine (1.67 g, 16.5 mmol) in dioxane (30 ml). Replace the system with a nitrogen atmosphere and react at 100°C for 3 h. Filter the reaction mixture, add silica gel, and column chromatography to obtain the target compound 101c (650 mg). LC-MS: [M+H] + =166.1.

[0483] Step 3: Dissolve compound 101c (650 mg, 3.9 mmol), 2-methylene-1,3-propanediol (520 mg, 5.9 mmol), and triphenylphosphine (1.55 g, 5.9 mmol) in anhydrous THF (10 ml). Replace the system with a nitrogen atmosphere, cool to 0°C, and add DIAD (1.2 g, 5.9 mmol) dropwise. Transfer the mixture to room temperature and allow to react overnight. After the reaction is complete, add silica gel to the reaction solution and purify by column chromatography to obtain the target compound 101d (893 mg). LC-MS: [M+H] + =236.1.

[0484] Step 4: Compound 101d (893 mg, 3.8 mmol) and Grubbs second-generation catalyst (322 mg, 0.38 mmol) were dissolved in anhydrous DCM (25 ml), replaced with nitrogen atmosphere, and reacted at room temperature overnight. Silica gel was added and the sample was mixed. Column chromatography was used for purification to obtain the desired product 101e (400 mg). LC-MS: [M+H] + =208.1.

[0485] Step 5: Compound 101e (400 mg) was dissolved in methanol (10 ml), 10% Pd / C (40 mg) was added, the system was replaced with a hydrogen atmosphere, and the reaction was allowed to proceed overnight at room temperature. The reaction mixture was filtered through a pad of celite and concentrated under reduced pressure to obtain the target compound 101f (169 mg). LC-MS: [M+H] + =210.1.

[0486] Step 6: Compound 101f (169 mg, 0.81 mmol) and triethylamine (0.34 mL, 2.4 mmol) were dissolved in anhydrous DCM (10 ml), cooled to 0°C, and MsCl (185 mg, 1.6 mmol) was added dropwise. The mixture was then allowed to react at room temperature for 2 h. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of the title compound 101 g (255 mg). LC-MS: [M+H] + =288.1, which was used directly in the next reaction.

[0487] Step 7: Dissolve compound 101g (162 mg, 0.56 mmol), compound INT10 (170 mg, 0.62 mmol), potassium iodide (187 mg, 1.13 mmol), and DIEA (219 mg, 1.69 mmol) in anhydrous ACN (10 ml) and react at 80°C overnight. Add silica gel and stir. Column chromatography yields the desired product 101h (90 mg). LC-MS: [M+H] + =430.2

[0488] Step 8: Compound 101h (90 mg, 0.2 mmol) was dissolved in ACN (15 ml), and hydrogen bromide in acetic acid (2 ml) was added. The mixture was reacted at 80°C for 3 h. LC-MS analysis showed that the reaction was complete. The mixture was cooled to room temperature, diluted with water, and extracted once with EA to remove some organic impurities. The aqueous phase was adjusted to a weak base with solid sodium bicarbonate and extracted three times with 10% MeOH in DCM. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Preparative TLC separation gave the title compound 101 (48 mg). LC-MS: [M+H] + =416.2, 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),8.41(q,J=4.7Hz,1H),7.85(d,J=8.0Hz,1H),7.57(dd,J=10.6,8.1Hz,1H),7.01(s,1H),4.24-3 .96(m,1H),3.70(dd,J=10.7,6.4Hz,1H),3.24-3.10(m,4H),2.77(d,J=4.7Hz,3H),2.62-2.51(m,5H),2.38-2.16(m,4H),1.93(s,3H).

[0489] Example 102

[0490] 6-Chloro-N-methyl-5-(4-((7-methyl-6-oxo-3,4,5,6-tetrahydro-2H-pyrano[3,2-b]pyridin-3-yl)methyl)piperazin-1-yl)picolinamide

[0491] Preparation of 6-chloro-N-methyl-5-(4-((7-methyl-6-oxo-3,4,5,6-tetrahydro-2H-pyrano[3,2-b]pyridin-3-yl)methyl)piperazin-1-yl)picolinamide Reference Example 101. LC-MS: [M+H] + =432.2; 1H NMR (400MHz, DMSO-d6) δ11.13(s,1H),8.50-8.38(m,1H),7.95(dd,J=8.2,5.2Hz,1H),7.65(dd,J=12.3,8.2Hz,1H),7.01(s,1H),4.07(d,J=1 1.1Hz,1H),3.70(dd,J=10.7,6.7Hz,1H),3.15-3.04(m,4H),2.79(dd,J=4.8,1.8Hz,3H),2.68-2.53(m,5H),2.38-2.23(m,4H),1.93(s,3H).

[0492] Example 103

[0493] 6-Fluoro-N-methyl-5-(4-((7-methyl-6-oxo-5,6-dihydro-2H-pyrano[3,2-b]pyridin-3-yl)methyl)piperazin-1-yl)picolinamide

[0494] Step 1: Dissolve compound 101d (893 mg, 3.8 mmol) and Grubbs second-generation catalyst (322 mg, 0.38 mmol) in anhydrous DCM (25 ml), replace the system with nitrogen atmosphere, and react at room temperature overnight. Add silica gel and stir. Purify by column chromatography to obtain the target product 103a (108 mg). LC-MS: [M+H] + =206.1.

[0495] Step 2: Compound 103a (138 mg, 0.58 g) was dissolved in methanol (10 ml), and triethylamine (80 mg, 0.8 mmol) and acetic acid (63 mg, 1.1 mmol) were added. Compound INT10 (108 mg, 0.53 mmol) was then added and stirred at room temperature for 1 h. Sodium cyanoborohydride (99 mg, 1.58 mmol) was then added and the mixture was allowed to react overnight at room temperature. Silica gel was added and the sample was mixed. The target product 103b (230 mg) was obtained by column chromatography. LC-MS: [M+H] + =428.2.

[0496] Step 3: Compound 103b (60 mg, 0.14 mmol) was dissolved in ACN (10 ml), and hydrogen bromide acetic acid solution (2 ml) was added. The reaction was allowed to proceed at 80°C for 3 h. LC-MS monitoring showed that the reaction of the raw material was complete. After cooling to room temperature, the mixture was diluted with water and extracted once with EA to remove some organic impurities. The aqueous phase was adjusted to a weak alkaline state with solid sodium bicarbonate and extracted three times with 10% MeOH in DCM. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Preparative TLC separation and purification gave the target compound 103 (9.5 mg). LC-MS: [M+H] + =414.2; 1 H NMR (400MHz, DMSO-d6) δ11.22(s,1H),8.40(q,J=4.6Hz,1H),7.85(d,J=8.0Hz,1H),7.57(dd,J=10.6,8.1Hz,1H),7.06( s,1H),6.24(s,1H),4.63(s,2H),3.21-3.14(m,4H),3.11(s,2H),2.76(d,J=4.7Hz,3H),2.58-2.52(m,4H),1.97(s,3H).

[0497] Example 104

[0498] (4aR)-N-Methyl-3-((7-methyl-6-oxo-3,4,5,6-tetrahydro-2H-pyrano[3,2-b]pyridin-3-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazolidine-9-carboxamide

[0499] Preparation of (4aR)-N-methyl-3-((7-methyl-6-oxo-3,4,5,6-tetrahydro-2H-pyrano[3,2-b]pyridin-3-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazolidine-9-carboxamide Reference Example 101. LC-MS: [M+H] + = =440.5; 1H NMR (400MHz, DMSO-d6) δ11.41 (s, 1H), 8.44-8.35 (m, 1H), 7.82 (dd, J = 8.4, 1.6Hz, 1H), 7.50 (d,J=8.5Hz,1H),7.03(s,1H),4.95(dd,J=13.8,3.9Hz,1H),4.73(d,J=13.9Hz,1H),4.47- 4.36(m,2H),4.01-3.94(m,1H),3.83-3.79(m,2H),3.53-3.41(m,1H),3.31-3.26(m,2H),2 .79(d,J=4.9Hz,3H),2.75-2.59(m,2H),2.58-2.52(m,2H),2.49-2.30(m,4H),1.93(s,3H).

[0500] Example 105

[0501] (R)-3-(((S)-2-ethyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazolidine-9-carboxamide

[0502] Preparation of (R)-3-(((S)-2-ethyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazolidine-9-carboxamide Reference Example 45. LC-MS: ESI [M+H] + =453.4. 1H NMR (400MHz, DMSO-d6) δ11.79(s,1H),8.40(q,J=4.8Hz,1H),7.82(d,J=8.4Hz,1H),7.51(d,J=8.5Hz,1H) ,4.96(d,J=13.9Hz,1H),4.77–4.66(m,1H),4.07–3.93(m,1H),3.87–3.74(m,1H),3.54–3.43(m,1H),3.2 4(s,1H),2.79(d,J=4.8Hz,3H),2.70–2.58(m,4H),2.61–2.52(m,4H),2.28(d,J=7.5Hz,3H),2.25–2.14( m,1H),2.06–1.95(m,1H),1.92–1.82(m,1H),1.43–1.32(m,1H),1.29–1.20(m,1H),1.10(t,J=7.4Hz,3H).

[0503] Example 106

[0504] (S)-6-Chloro-N-methyl-5-(4-(2-methyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0505] Preparation of (S)-6-chloro-N-methyl-5-(4-(2-methyl-3-oxo-3,4,5,6,7,8-hexahydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide Reference Example 45. LC-MS: ESI [M+H] + =431.1. 1 H NMR (400MHz, DMSO) δ11.82(s,1H),8.43(q,J=4.5Hz,1H),7.94(d,J=8.2Hz,1H),7.67(d,J=8.2Hz,1H),3.11(s,4H),2.79(d,J= 4.8Hz,3H),2.68–2.52(m,7H),2.35-2.27(m,2H),2.25–2.14(m,4H),2.21-1.95(m,1H),1.93-1.87(m,1H),1.48–1.28(m,1H).

[0506] Biological activity test:

[0507] 1. PARP enzyme assay

[0508] Experimental materials: PARP1 protein (BPS, Cat. No. 80501), PARP2 protein (BPS, Cat. No. 80502), PARP5A protein (BPS, Cat. No. 80504), Biotin-NAD+ (R&D, Cat. No. 6573), Strep-HRP (Thermo Pierce, Cat. No. 21127), NAD+ (TCI, Cat. No. D0919-5G), quantitative enhanced chemiluminescence HRP substrate kit (Thermo Pierce, Cat. No. 15159), histone (Active Motif, Cat. No. 81167), activated DNA (Genscript, Cat. No. L05182-01&02&03), anti-rabbit IgG, HRP-linked Antibody (CST, Cat. No. 7074P2), anti-Poly / Mono-ADP Ribose (E6F6A) Rabbit mAb (CST, Cat. No. 83732S), SuperSignal ELISA Femto Substrate (THERMO PIERCE, Cat. No. 37074).

[0509] 1.1 PARP1 enzyme assay

[0510] 1.1.1 Buffer preparation: PBST: 1X PBS, 0.05% Tween-20, blocking solution: 1X PBS, 0.05% Tween-20, 5% BSA, reaction buffer: 50 mM Tris-HCl (pH 7.5), 0.005% Tween-20, 0.01% BSA.

[0511] 1.1.2 Coating: Prepare 50 ng / mL Histone coating solution in 1xPBS, transfer 25 μL of the coating solution to a 384-well reaction plate, and coat overnight at 4°C.

[0512] 1.1.3 Washing: After coating, discard the coating solution and wash with PBST solution. Transfer 50uL PBST to a 384-well reaction plate, let it stand for 5 minutes, discard the wash solution, refill the plate, and repeat the washing process three times. Finally, pat the reaction plate dry and wait for the next step of blocking.

[0513] 1.1.4 Blocking: Transfer 50 μL of blocking solution to a 384-well reaction plate and let it stand for 1 hour.

[0514] Washing: After blocking, discard the blocking solution and wash the plate three times with PBST solution according to step 2. Finally, pat the reaction plate dry.

[0515] 1.1.5 Prepare a 1000-fold dilution of the compound, transfer 1 μL of the compound to 199 μL of reaction buffer in a 96-well plate, mix thoroughly, and transfer 5 μL of the mixed compound to a 384-well reaction plate.

[0516] 1.1.6 Prepare a 25 / 10x PARP1-DNA solution using reaction buffer. Transfer 10 μL of PARP1-DNA solution to a 384-well reaction plate. For the negative control wells, transfer 10 μL of DNA solution. The final concentration of PARP1 is 0.02 nM, and the final concentration of DNA is 0.8 nM.

[0517] 1.1.7 Prepare a 25 / 10x NAD+ solution in reaction buffer. Transfer 10 μL of NAD+ solution to a 384-well reaction plate. The final NAD+ concentration is 3.5 μM. Incubate at room temperature for 60 minutes.

[0518] 1.1.8 Prepare a 25 / 10x NAD+ solution in reaction buffer. Transfer 10 μL of NAD+ solution to a 384-well reaction plate. The final NAD+ concentration is 3.5 μM. Incubate at room temperature for 60 minutes.

[0519] 1.1.9 Washing: After the reaction is completed, discard the reaction solution and wash the plate three times with PBST solution according to the method in step 2. Finally, pat the reaction plate dry.

[0520] 1.1.10 Dilute the primary antibody (anti-Poly / Mono-ADP Ribose Rabbit mAb) 2000-fold with blocking buffer, add 20 μL of primary antibody, and incubate at room temperature for 1.5 hours.

[0521] 1.1.11 Washing: Discard the primary antibody and wash the plate three times with PBST solution according to the method in step 2. Finally, pat the reaction plate dry.

[0522] 1.1.12 Dilute the secondary antibody (anti-rabbit IgG, HRP-linked Antibody) 2000-fold with blocking solution, add 20 μL of secondary antibody, and incubate at room temperature for 1 hour.

[0523] 1.1.13 Washing: Discard the secondary antibody and wash the plate three times with PBST solution according to step 2. Finally, pat the reaction plate dry.

[0524] 1.1.14 Color development: Mix Femto-ECL Substrate A and Femto-ECL Substrate B in a 1:1 ratio and transfer 25 μL to a 384-well reaction plate.

[0525] 1.1.15 Reading: Use Envision to read the chemiluminescence value RLU.

[0526] The test results are shown in Table 9 below:

[0527] Table 9 PARP-1 enzyme test results

[0528] +++ indicates IC 50 Less than or equal to 50nM

[0529] ++ indicates IC 50 Between 50nM and 500nM;

[0530] + indicates IC 50 Greater than 500nM

[0531] Conclusion: The compounds of the present invention have good inhibitory activity against PARP1 enzyme.

[0532] 1.2 PARP family enzyme selectivity test

[0533] Experimental materials: Compounds Olaparib (catalog number: HY-10162, batch number: 136925) and XAV-939 (catalog number: HY-15147, batch number: 112781) were purchased from Shanghai MCE Company.

[0534] Table 10 Reagent materials

[0535] Experimental method: The PARP enzyme reaction buffer formula is shown in Table 11, the PARP enzyme formula is shown in Table 12, the substrate formula is shown in Table 13, and the detection formula is shown in Table 14.

[0536] Table 11 PARP enzyme reaction buffer formula

[0537] Table 12 PARP enzyme formula

[0538] Table 13 Substrate formulation

[0539] Table 14 Detection formula

[0540] Experimental steps:

[0541] 1) Dilute the 5× histone mixture 5-fold with PBS, add 25 μL of 1× histone mixture to each well of the assay plate, and incubate at 4°C overnight.

[0542] 2) The test plate was washed three times with 100 μL PBST buffer (5 min / time), and 25 μL blocking buffer was added and incubated at room temperature for 90 min.

[0543] 3) Wash the assay plate three times with 100 μL PBST buffer (5 min / time).

[0544] 4) 100 nL of the diluted compound was transferred to a 384-well plate using acoustic liquid transport technology (Echo 655) and centrifuged at 1000 rpm for 1 min.

[0545] 5) Add 5 μL of PARP enzyme solution to each well and centrifuge at 1000 rpm for 1 min.

[0546] 6) Add 5 μL of substrate mixture solution to each well, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 1 h.

[0547] 7) Wash the test plate three times with 100 μL PBST buffer (5 min / time).

[0548] 8) Add 25 μL of St-HRP diluted in blocking buffer (dilution ratio is 1:2000) to each well and incubate at room temperature for 30 minutes.

[0549] 9) Wash the test plate three times with 100 μL PBST buffer (5 min / time).

[0550] 10) Add 25 μL of ELISA ECL Sub A and ELISA ECL Sub B mixture (mix equal volumes) to each well.

[0551] 11) Use a BMG microplate reader to read the luminescence signal value.

[0552] The test results are shown in Table 15 below:

[0553] Table 15 PARP family enzyme selectivity test results

[0554] Conclusion: The compounds of the present invention selectively inhibit PARP1 enzyme and have high selectivity for other enzymes in the PARP family.

[0555] 2. Cell anti-proliferation activity test:

[0556] BRCA mutant cells MDA-MB-436 cells were cultured in DMEM medium containing 10% fetal bovine serum, 100U / mL penicillin, and 100μg / mL streptomycin, and cultured in a 5% saturated CO2 incubator at 37°C. When the cells grew to 80% confluence, the cells were collected, centrifuged at 300g for 10 minutes, and plated on a 96-well plate at 1200 cells / well. After 24 hours, different final concentrations of PARPi (0, 0.01, 0.1, 1, 10, 100, 1000nM) were added and cultured for 72 hours. The cells were treated with a new medium (PARPi was re-added with the same final concentration) and cultured for 96 hours. The 96-well plate was removed, and the OD value at a wavelength of 450nM was detected by CCK8, and the cell inhibition rate was calculated:

[0557] Inhibition rate %=1-(average OD value of the drug administration group-average OD value of the Blank group) / (average OD value of the Control group-average OD value of the Blank group)*100%.

[0558] BRCA wild-type cells DLD-1 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum, 100U / mL penicillin, and 100μg / mL streptomycin, and cultured in a 5% saturated CO2 incubator at 37°C. When the cells grew to 80% confluence, the cells were collected, centrifuged at 300g for 10 minutes, and plated on a 96-well plate at 1000 cells / well. After 24 hours, different final concentrations of PARPi (0, 1, 10μM) were added and cultured for 72 hours. The cells were treated with a new medium (PARPi was re-added with the same final concentration) and cultured for 96 hours. The 96-well plate was removed, and the OD value at a wavelength of 450nM was detected by CCK8, and the cell inhibition rate was calculated:

[0559] Inhibition rate %=1-(average OD value of the drug administration group-average OD value of the Blank group) / (average OD value of the Control group-average OD value of the Blank group)*100%.

[0560] The test results are shown in Table 16 below:

[0561] Table 16 Cell antiproliferative activity test results

[0562] Conclusion: The compounds of the present invention have a significant inhibitory effect on BRCA mutant MDA-MB-436 cells, but have no significant inhibitory effect on BRCA wild-type DLD-1 cells, indicating that the compounds of the present invention specifically inhibit tumor cells with homologous recombination defects.

[0563] 3. Inhibition experiment of compounds on hERG potassium channels

[0564] Cell culture and treatment: CHO cells stably expressing hERG were cultured in a cell culture flask at 37°C in a 5% CO2 incubator. When the cell density reached 60-80%, the cell culture medium was removed, the cells were washed once with PBS, and then digested with Detachin. After digestion was complete, the cells were neutralized with culture medium, centrifuged, and the supernatant was removed. The cells were then resuspended in culture medium to adjust the cell density to 2-5×10 6 / mL for future use.

[0565] Compound Preparation: Dilute the compound stock solution with 100% DMSO by adding 10 μL of compound stock solution to 20 μL of DMSO and serially diluting the solution 3-fold to six concentrations. Add 4 μL of each of the six concentrations to 396 μL of extracellular fluid, achieving a 100-fold dilution to obtain six intermediate concentrations. Then, add 80 μL of each of the six intermediate concentrations to 320 μL of extracellular fluid, achieving a 5-fold dilution to the desired final concentration. The highest concentration tested was 40 μM, followed by six concentrations of 40, 13.33, 4.44, 1.48, 0.49, and 0.16 μM. The DMSO content in the final test concentration did not exceed 0.2%, as this concentration has no effect on hERG potassium channels. Compound preparation was performed using the Bravo instrument throughout the entire dilution process.

[0566] Electrophysiological recordings: Single-cell high-impedance sealing and whole-cell pattern formation were automated by the Qpatch instrument. After acquiring whole-cell recording mode, cells were clamped at -80 mV. A 50-millisecond pre-depolarization of -50 mV was applied before a 5-second depolarization of +40 mV. The cells then repolarized to -50 mV for 5 seconds before returning to -80 mV. This voltage was applied every 15 seconds. After recording for 2 minutes, extracellular solution was added for 5 minutes. Drug administration then began. Compound concentrations were administered for 2.5 minutes at each test concentration, starting with the lowest tested concentration. After all concentrations were administered, the positive control compound, 3 μM Cisapride, was administered. At least three cells were tested for each concentration (n ≥ 3).

[0567] Data processing: Data analysis and processing were performed using GraphPad Prism 5.0 and Excel software. Compound IC50 was calculated using GraphPad Prism 5 software by fitting the following equation:

[0568] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0569] Where X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0570] Table 17 Inhibition results of compounds on hERG potassium channels

[0571] Conclusion: Compounds 2, 6, 45, 62, 67, 74, 83 and 87 of the present invention have weak inhibitory effects on hERG potassium channels.

[0572] 4. Pharmacokinetic evaluation of the compound in Balb / c mice

[0573] Experimental purpose: To understand the pharmacokinetics of the compound.

[0574] Experimental basis: Technical Guidelines for Nonclinical Pharmacokinetic Studies of Chemical Drugs, 2014.

[0575] Experimental plan: The pharmacokinetics of the compound were investigated by intravenous administration (1 mg·kg-1) and oral administration (1 mg·kg-1) to Balb / c mice.

[0576] Sample preparation: weigh about 0.2 mg of the compound, add 10 μL of DMSO to dissolve it, and then add sodium chloride solution for injection to make a 0.1 mg·mL-1 compound solution for administration.

[0577] Sample collection: 6 male Balb / c mice (Chengdu Dashuo Experimental Animal Co., Ltd., license number: SCXK (Chuan) 2020-030), 3 were intravenously administered (IV) at 1 mg·kg-1, and 3 were gavage administered (PO) at 1 mg·kg-1. Approximately 0.05 mL of blood was collected 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, and 48 h after administration. The collected blood was centrifuged at 3500 rpm for 15 min, the supernatant plasma was collected, and frozen at -40 ° C for testing. The plasma concentration was quantitatively analyzed by LC-MS / MS analysis, and pharmacokinetic parameters such as peak time (Cmax), area under the concentration-time curve (AUC(0-t)), and half-life (T) were calculated. 1 / 2 ), clearance (CL), tissue distribution (Vdss), bioavailability (F), etc.

[0578] Table 18 Pharmacokinetic test results of the compounds in Balb / c mice

[0579] Conclusion: The compounds of the present invention have good pharmacokinetic properties in Balb / c mice.

[0580] 5. Evaluation of compound distribution in cerebrospinal fluid and plasma

[0581] Experimental steps: Weigh the compound and add a small amount of DMSO, then add sodium chloride solution for injection to make 5 mg mL -1 The compound solution is ready for administration. Rats, male rats, 5 mg kg -1 After intravenous administration, cerebrospinal fluid and whole blood were collected 0.25 h and 2 h after administration (n=1). The whole blood was centrifuged at 3500 rpm for 15 min, and the supernatant plasma was collected. 10 μL of plasma and 10 μL of cerebrospinal fluid were placed in a centrifuge tube and 40 μL of 20 ng·ml -1 The internal standard SAHA was precipitated with acetonitrile, vortexed for 30 seconds, centrifuged at 13000 rpm for 15 minutes, and the supernatant was transferred to a sample vial for testing. Standard curve range: 1-1000 ng ml -1 .

[0582] Table 19 Results of the test on the distribution of the compound in rat cerebrospinal fluid and plasma after administration

[0583] Conclusion: Some compounds of the present invention have good brain penetration potential, especially compounds 39, 43, 47, 51, 64, 74, 82, 83 and 101, which have higher distribution concentrations in cerebrospinal fluid.

[0584] 6. Test of compound selectivity for PARP6

[0585] The main instruments and reagents are shown in Table 20:

[0586] Table 20 Main instruments and reagents for PARP6 testing

[0587] Experimental steps: PARP6 enzyme activity was detected by ELISA. First, substrate coating and blocking were performed: 5× histone mixture was diluted 5-fold with PBS, 25 μL of histone mixture was added to each well of the assay plate, and incubated overnight at 4°C; the assay plate was washed three times with 100 μL PBST buffer (5 min / time), 25 μL of blocking buffer was added, and the plate was incubated for 90 min; the assay plate was washed three times with 100 μL PBST buffer (5 min / time). Then, PARP6 enzyme activity was detected by adding 100 nL of compound to each well of the reaction plate and centrifuging at 1000 rpm for 1 min; then, 5 μL of PARP enzyme was added to each well and centrifuged at 1000 rpm for 1 min; then, 5 μL of substrate mixture was added to each well, centrifuged at 1000 rpm for 1 min, and incubated at 25°C for 1 h. Finally, the experimental signal detection was performed: the detection plate was washed three times with 100 μL PBST buffer (5 min / time); 25 μL of St-HRP diluted in blocking solution (dilution ratio is 1:2000) was added to each well and incubated at 25°C for 30 min; the detection plate was washed three times with 100 μL PBST buffer (5 min / time); 25 μL of ELISA ECL Sub A and ELISA ECL Sub B mixture (equal volume mixture) was added to each well. Luminescence signal values ​​were read using a BMG microplate reader. The IC value of the compound was calculated using the nonlinear fitting formula in GraphPad software. 50 The inhibition rate is calculated as follows:

[0588] Inhibition rate (% Inh) = (Signal compound - Signal negative control) / (Signal positive control - Signal negative control) * 100%. Negative control: DMSO (maximum signal value); Positive control: highest tested concentration of positive control compound (minimum signal value). Reference compounds AZD5305 and Olaparib were purchased from Shanghai MedChemExpress.

[0589] Experimental results: as shown in Table 21.

[0590] Table 21 Test results of PARP6 enzymatic activity of compounds

[0591] Conclusion: Compounds 2, 43, etc. of the present invention have weak inhibition on PARP6 and are highly selective.

[0592] 7. Hematological toxicity assay

[0593] CD34+ hematopoietic stem and progenitor cells (hmPB34-P-SC) were cultured overnight at 37°C in 5% CO2 in RPMI 1640 complete medium supplemented with 25 ng / mL IL-3, 25 ng / mL IL-6, 25 ng / mL SCF, and 10% fetal bovine serum. The next day, cells were resuspended and seeded at 1000 cells per well in 96-well plates. Drug treatments were added at various concentrations in triplicate. After 5 days of culture, the number of viable cells in each well was determined using the CellTiter-Glo 2.0 kit and analyzed by microplate reader.

[0594] Table 22 Compounds' inhibitory activity test results on CD34+ hematopoietic stem cell hmPB34-P-SC

[0595] Conclusion: The compounds of the present invention have weak inhibitory effects on CD34+ hematopoietic stem and progenitor cells hmPB34-P-SC, especially compounds 51, 67, 74, 81, 85 and 106, which have a weak inhibitory effect on hmPB34-P-SC. 50 The value was greater than 1000nM, which was significantly better than the positive drug Olaparib.

[0596] 8. In vivo pharmacodynamic study of compound 2 on breast cancer MDA-MB-436 subcutaneous transplanted tumor model in nude mice

[0597] Experimental Procedure: Twenty-four female NOD / SCID mice were randomly divided into four groups, each consisting of six mice, each receiving a blank control group, a 3 mg / kg dose of compound 21, and a 100 mg / kg dose of the reference compound, olaparib. All mice were orally administered once daily. Body weights were measured every two days, and tumor length and width were measured with a vernier caliper. After 30 days of dosing, tumor-bearing mice were anesthetized and sacrificed. Tumor tissue was excised, weighed, and photographed for calculation of tumor inhibition rates.

[0598] Experimental Conclusion: The experimental results are shown in Figure 1. After cell inoculation, each treatment group was administered for 30 consecutive days. Compared with the blank control group, each treatment group (Olaparib 100 mg / kg and Compound 2 1 and 3 mg / kg) showed significant inhibitory effects on tumor growth in a NOD / SCID mouse subcutaneous tumor model of human breast cancer cell line MM436. The tumor inhibition rates of each treatment group were 65.81%, 92.61%, and 95.74%, respectively. The relative tumor growth rate (T / C%) values ​​were 29.23%, 9.03%, and 6.02%, respectively. Among the treatment groups, the Compound 2 3 mg / kg group showed the greatest tumor inhibition effect, and the tumor inhibition effect of the Compound 2 3 mg / kg group was significantly superior to that of the reference drug Olaparib 100 mg / kg group.

[0599] 9. In vivo pharmacodynamic study of compound 53 on breast cancer MDA-MB-436 subcutaneous transplanted tumor model in nude mice

[0600] Experimental procedure: 18 female NOD / SCID mice were randomly divided into a blank control group, a compound AZD9574 (3 mg / kg) group, and a compound 53 (1 mg / kg) group, with a total of 3 groups, 6 mice in each group, all of which were orally administered once a day. At the same time, the body weight was weighed every 2 days and the length and width of the tumor were measured with a vernier caliper. After 30 days of administration, the tumor-bearing mice were anesthetized and sacrificed, the tumor tissue was removed, weighed, and photographed, and the tumor inhibition rate was calculated. Compound AZD9574 was synthesized according to the synthesis method of Example 20 of patent WO2021260092.

[0601] Conclusion: The experimental results are shown in Figure 2. After cell inoculation, each treatment group was administered for 30 consecutive days. Compared with the blank control group, the compound AZD9574 (3 mg / kg) group and the compound 53 (1 mg / kg) group showed significant inhibitory effects on tumor growth in the human breast cancer cell line MM436 subcutaneous tumor model in NOD / SCID mice. The anti-tumor effect of the compound 53 1 mg / kg group was superior to that of the AZD9574 3 mg / kg group.

Claims

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

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

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

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

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

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

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

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

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

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

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

15. The compound according to any one of claims 1 to 5, characterized in that: Structural unit Selected from Selected from or 16. The compound according to any one of claims 1 to 5, 7 or 15, characterized in that: R5 is selected from hydrogen, fluorine, chlorine, bromine, cyano, amino, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Fluorinated alkoxy, 3-6 membered cycloalkyl, C 1-4 Alkyl aminoacyl, C 1-4 Deuterated alkylaminoyl, C 1-4 Fluoroalkylaminoacyl, C 1-4 Alkoxy substituted C 1-4 alkylaminoacyl, 3-6 membered cycloalkylaminoacyl, 3-6 membered fluorinated cycloalkylaminoacyl, 4-6 membered heterocycloalkylaminoacyl, 6 membered arylaminoacyl, 5-6 membered heteroarylaminoacyl, C 1-4 Alkoxyaminoacyl, 3-6 membered cycloalkyl substituted C 1-4 At least one of the alkoxyaminoacyl group or the 3-6-membered cycloalkoxyaminoacyl group, or two adjacent R5s and the atoms to which they are attached form a 5-6-membered alkyl ring or a 5-6-membered alkyl heterocycle; in R5, the 4-6-membered heterocycloalkylaminoacyl group and the 5-6-membered heteroarylaminoacyl group contain 1 to 2 heteroatoms selected from at least one of N, S, and O; when two adjacent R5s and the atoms to which they are attached form a ring, the 5-6-membered alkyl heterocycle contains 1 to 2 heteroatoms selected from at least one of N, S, and O; n2 is selected from 1, 2, and 3; Preferably, R5 is selected from hydrogen, fluorine, chlorine, cyano, amino, methyl, deuterated methyl, fluoromethyl, ethyl, deuterated ethyl, fluoroethyl, cyclopropyl, cyclobutyl, methylamino, deuterated methylamino, fluoromethylamino, methylaminoacyl, deuterated methylaminoacyl, fluoromethylaminoacyl, ethylaminoacyl, deuterated ethylaminoacyl, fluoroethylaminoacyl, methoxyethylaminoacyl, cyclopropylaminoacyl, fluorocyclopropylaminoacyl, cyclobutylaminoacyl, fluorocyclobutylaminoacyl, or At least one of; n2 is selected from 1, 2.

17. The compound according to any one of claims 1 to 5, 7, 15 or 16, characterized in that: Structural unit Selected from: or 18. The compound according to any one of claims 1 to 5, 7, 10 to 12 or 15 to 17, characterized in that: R x1 , R y1 are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, cyclopropyl or fluorocyclopropyl; R x2 is selected from hydrogen, deuterium, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, cyclopropyl or fluorocyclopropyl; R7 is selected from hydrogen, deuterium, fluorine, chlorine, amino, methylamino, deuterated methylamino, fluoromethylamino, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, cyclopropyl, fluorocyclopropyl, methoxy, deuterated methoxy or fluoromethoxy; n4 is selected from 1, 2; R8 is selected from hydrogen, methyl, deuterated methyl or fluoromethyl; Preferably, the structural unit Selected from: or 19. The compound according to any one of claims 1 to 3, 10 to 12 or 15 to 18, characterized in that: The structural unit Replace with:

20. The compound according to any one of claims 1 to 5, 7, 10 to 12 or 15 to 19, characterized in that: The compound is selected from:

21. The compound according to any one of claims 1 to 5, characterized in that: Structural unit Selected from: or Preferably, the structural unit Selected from: or More preferably, the structural unit Selected from Selected from or 22. The compound according to any one of claims 1 to 5 or 21, characterized in that: Ring B is selected from phenyl, pyridyl, imidazolyl, imidazo[1,2-a]pyrazinyl, 1,7-naphthypyridinyl, pyridazinyl, pyrazinyl, pyridothiazolyl, pyrazolo[1,5-a]pyrimidinyl, benzopyrazolyl, benzimidazolyl, thiazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, pyridazinopyrrolyl, pyridopyrazolyl, pyridoxazolyl or pyrimidinyl; Preferably, ring B is selected from or 23. The compound according to any one of claims 1 to 5 or 21 to 22, characterized in that: R5 is selected from hydrogen, fluorine, chlorine, bromine, cyano, amino, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Fluorinated alkoxy, 3-6 membered cycloalkyl, C 1-4 Alkyl aminoacyl, C 1-4 Deuterated alkylaminoyl, C 1-4 Fluoroalkylaminoacyl, C 1-4 Alkoxy substituted C 1-4 alkylaminoacyl, 3-6 membered cycloalkylaminoacyl, 3-6 membered fluorinated cycloalkylaminoacyl, 4-6 membered heterocycloalkylaminoacyl, 6 membered arylaminoacyl, 5-6 membered heteroarylaminoacyl, C 1-4 Alkoxyaminoacyl, 3-6 membered cycloalkyl substituted C 1-4 At least one of the alkoxyaminoacyl group or the 3-6-membered cycloalkoxyaminoacyl group, or two adjacent R5s and the atoms to which they are attached form a 5-6-membered alkyl ring or a 5-6-membered alkyl heterocycle; in R5, the 4-6-membered heterocycloalkylaminoacyl group and the 5-6-membered heteroarylaminoacyl group contain 1 to 2 heteroatoms selected from at least one of N, S, and O; when two adjacent R5s and the atoms to which they are attached form a ring, the 5-6-membered alkyl heterocycle contains 1 to 2 heteroatoms selected from at least one of N, S, and O; n2 is selected from 1, 2, and 3; Preferably, R5 is selected from hydrogen, fluorine, chlorine, cyano, amino, methyl, deuterated methyl, fluoromethyl, ethyl, deuterated ethyl, fluoroethyl, cyclopropyl, cyclobutyl, methylamino, deuterated methylamino, fluoromethylamino, methylaminoacyl, deuterated methylaminoacyl, fluoromethylaminoacyl, ethylaminoacyl, deuterated ethylaminoacyl, fluoroethylaminoacyl, methoxyethylaminoacyl, cyclopropylaminoacyl, fluorocyclopropylaminoacyl, cyclobutylaminoacyl, fluorocyclobutylaminoacyl, At least one of; n2 is selected from 1, 2.

24. The compound according to any one of claims 1 to 5 or 21 to 23, characterized in that: Structural unit Selected from: or 25. The compound according to any one of claims 1 to 5, 10 to 12 or 21 to 24, characterized in that: R x1 , R y1 are independently selected from hydrogen, deuterium, halogen, cyano, amino, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -OC 1-4 Alkyl, -SC 1-4 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered fluorinated cycloalkyl, vinyl or phenyl; R x2 Selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered fluorinated cycloalkyl or phenyl; R7 is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Fluoroalkoxy, -NH-C 1-4 Alkyl or -N(C 1-4 alkyl)2; n4 is selected from 1, 2, 3, 4; R8 is selected from hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyl substituted alkyl, C 1-4 Deuterated alkyl or 3-4 membered cycloalkyl; Preferably, R x1 , R y1 independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, cyclopropyl, methoxy, methylthio, vinyl or fluorocyclopropyl; R x2 is selected from hydrogen, deuterium, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, cyclopropyl or fluorocyclopropyl; R7 is selected from hydrogen, deuterium, fluorine, chlorine, amino, methylamino, deuterated methylamino, fluoromethylamino, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, cyclopropyl, fluorocyclopropyl, methoxy, deuterated methoxy or fluoromethoxy; n4 is selected from 1, 2; R8 is selected from hydrogen, methyl, deuterated methyl or fluoromethyl; More preferably, the structural unit Selected from: or 26. The compound according to any one of claims 1 to 3, 10 to 12 or 21 to 25, characterized in that: The structural unit Replace with: or 27. The compound according to any one of claims 1 to 5 or 21 to 26, characterized in that: The compound is selected from:

28. A compound or a pharmaceutically acceptable form thereof, characterized in that: The compound structure is as follows:

29. A pharmaceutical composition, characterized in that: The active ingredient is a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug thereof, supplemented with a pharmaceutically acceptable carrier.

30. Use of the compound according to any one of claims 1 to 28 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope-labeled substance, metabolite or prodrug, and the pharmaceutical composition according to claim 29 in the preparation of a medicament for preventing and / or treating PARP1 enzyme-related diseases.

31. The use according to claim 30, characterized in that: The PARP1 enzyme-related disease is a tumor-related disease.

32. The use according to claim 31, characterized in that: The tumor-like disorders are deficient in the HR-dependent DNA DSB repair pathway.

33. The use according to claim 32, characterized in that: The neoplastic disorder comprises one or more cancer cells having a reduced or absent ability to repair DNA DSBs by HR relative to normal cells.

34. The use according to claim 33, characterized in that: The cancer cells have a BRCA1 or BRCA2 deficient phenotype.

35. The use according to any one of claims 31 to 34, characterized in that: The tumor-like disease is breast cancer, ovarian cancer, primary peritoneal cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, glioblastoma or lung cancer.

36. Use of the compound according to any one of claims 1 to 28 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope-labeled substance, metabolite or prodrug, and the pharmaceutical composition according to claim 29 in the preparation of a PARP1 inhibitor.

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