Heterocyclic derivative inhibitors, their preparation method and their uses

Abstract

Heterocyclic derivative inhibitors and their preparation methods and uses. Specifically, the present invention relates to compounds represented by general formula (I), their preparation methods, pharmaceutical compositions containing said compounds, and their use as inhibitors for the treatment of cancer, wherein the substituents in general formula (I) are as defined in the specification. JPEG2024514338000215.jpg28170

Description

[Technical field]

[0001] The present invention belongs to the field of biomedical sciences, specifically, to heterocyclic derivative inhibitors, methods for their preparation and their uses. [Background technology]

[0002] Poly(ADP-ribose) polymerase (PARP) is a protein superfamily that catalyzes the ribosylation of protein ADP in eukaryotic cells, including at least 17 protein subtypes. PARP can catalyze the cleavage of the substrate nicotinamide adenine dinucleotide NAD+ to nicotinamide and ADP-ribose, allowing the poly ADP-ribosylation of its target proteins. PARP is located in the nucleus and is a key enzyme in the repair of cellular DNA damage.

[0003] PARP1 is the earliest discovered and most studied PARP subtype, which contains three major domains: an N-terminal DNA binding domain (DBD), an automodification domain (AMD), and a C-terminal catalytic domain. PARP1 is a key functional protein in the process of DNA damage repair and is a sensor of DNA single-strand damage. DNA damage can lead to PARP1 activation, its target proteins, such as poly-ADP-ribosylation modification of histones, and the recruitment of related repair proteins to promote DNA damage repair. PARP1 is crucial for the stability of the genome in normal cells. However, in tumor treatment, PARP1 may antagonize the tumor-killing effect caused by radiotherapy and chemotherapy by repairing the DNA of tumor cells damaged by radiotherapy and chemotherapy. Therefore, PARP1 inhibitors can be developed as sensitizers for tumor radiotherapy and chemotherapy.

[0004] Breast cancer susceptibility gene (BRCA) is an important tumor suppressor gene, mainly including two subtypes, BRCA1 and BRCA2. BRCA plays an important role in repairing double-stranded DNA breaks in DNA homologous recombination. Tumor cells often have BRCA deficiency, which leads to loss of double-stranded DNA break repair function. If PARP1 function is simultaneously lost or inhibited, single-stranded DNA break repair is also lost, which ultimately leads to tumor cell death, resulting in a "synthetic lethal" effect. Therefore, the use of PARP1 inhibitors blocks the repair function of single-stranded DNA breaks, which has a selective killing effect on BRCA-deficient tumors.

[0005] Currently, PARP inhibitors have achieved great success in the precision treatment of tumors, especially tumors with BRCA mutations or defects. Currently marketed PARP inhibitors include olaparib (AZD2281) from AstraZeneca, rucaparib (CO-338) from Clovis, niraparib (MK-4827) from Tesaro, and talazoparib (BMN-673) from Pfizer. Their indications are mainly ovarian and breast cancers with BRCA mutations. There are also many PARP inhibitors in clinical research. In the PARP family, PARP2 has the highest homology with PARP1. Therefore, the majority of PARP inhibitors currently on the market or in clinical stages are non-selective PARP inhibitors, which have strong inhibitory effects on both PARP1 and PARP2 subtypes. Studies have shown that PARP2 plays an important role in regulating red blood cell production. Inhibition of PARP2 is closely associated with clinical side effects of PARP inhibitors, such as hematological toxicity, e.g., anemia. Summary of the Invention [Problem to be solved by the invention]

[0006] The object of the present invention is to provide a compound of formula (I), its stereoisomer or a pharma- ceutically acceptable salt thereof, the structure of the compound of formula (I) being:

[0007] [ka]

[0008] wherein Ring A, Ring B, Ring C, and Ring D are each independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 1 is hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R 11 , -(CH 2 ) n OR 11 , -(CH 2 ) n C(O)R 11 , -(CH 2 ) n C(O)OR 11 , -(CH 2 ) n S(O) m R 11 , -(CH 2 ) n NR 22 R 33 , -(CH 2 ) n NR 22 C(O)OR 33 , -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , -(CH 2 ) n NR 22 C(O)NR 22 R 33 , -(CH 2 ) n C(O)NR 22 (CH 2 ) n1 R 33 , -OC(R 11 R22 ) n (CH 2 ) n1 R 33 and -(CH 2 ) n NR 22 S(O) m R 33 wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted; R 11 , R 22 and R 33 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkyl substituted with cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally further substituted; L 1 , L 2 and L 3 represents a bond, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -(CH 2 ) n -, -(CH 2 ) n C(O)(CR aa R bb ) n1 -, -(CH 2 ) n C(O)NR aa (CH 2 ) n1 -, -(CH 2 ) n (CR aa R bb ) n2 -, -(CR aa R bb )n O(CH 2 ) n1 -, -(CH 2 ) n O(CR aa R bb ) n1 -, -(CR aa R bb ) n3 S(CH 2 ) n4 -, -(CH 2 ) n S(CR aa R bb ) n3 -, -(CR aa R bb ) n3 (CH 2 ) n NR cc -, -(CH 2 ) n NR aa (CR bb R cc ) n -, -(CH 2 ) n NR aa C(O)-, -(CH 2 ) n P(O) p R aa -, -(CH 2 ) n S(O) m -, -(CH 2 ) n S(O) m NR aa - and -(CH 2 ) n NR aa S(O) m - each independently selected from the group consisting of R aa , R bb and R ccare each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally further substituted; Each R a is hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R a1 , -(CH 2 ) n OR a1 , -(CH 2 ) n C(O)R a1 , -(CH 2 ) n C(O)OR a1 , -(CH 2 ) n S(O) m R a1 , -(CH 2 ) n NR a2 R a3 , -(CH 2 ) n NR a2 C(O)OR a3 , -(CH 2 ) n NR a2 C(O)(CH 2 ) n1 R a3 , -(CH 2 ) n NR a2 C(O)NR a2 R a3 , -(CH 2 ) n C(O)NR a2 (CH2 ) n1 R a3 , -OC(R a1 R a2 ) n (CH 2 ) n1 R a3 and -(CH 2 ) n NR a2 S(O) m R a3 wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted; R a1 , R a2 and R a3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally further substituted; Each R b is hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R b1 , -(CH 2 ) n OR b1 , -(CH 2 ) n C(O)R b1 , -(CH 2 ) n C(O)OR b1 , -(CH 2 ) n S(O)m R b1 , -(CH 2 ) n NR b2 R b3 , -(CH 2 ) n NR b2 C(O)OR b3 , -(CH 2 ) n NR b2 C(O)(CH 2 ) n1 R b3 , -(CH 2 ) n NR b2 C(O)NR b2 R b3 , -(CH 2 ) n C(O)NR b2 (CH 2 ) n1 R b3 , -OC(R b1 R b2 ) n (CH 2 ) n1 R b3 and -(CH 2 ) n NR b2 S(O) m R b3 wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted; R b1 , R b2 and R b3are each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally further substituted; Each R c is hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R c1 , -(CH 2 ) n OR c1 , -(CH 2 ) n C(O)R c1 , -(CH 2 ) n C(O)OR c1 , -(CH 2 ) n S(O) m R c1 , -(CH 2 ) n NR c2 R c3 , -(CH 2 ) n NR c2 C(O)OR c3 , -(CH 2 ) n NR c2 C(O)(CH 2 ) n1 R c3 , -(CH 2 ) n NR c2 C(O)NR c2 R c3 , -(CH 2 ) n C(O)NR c2 (CH2 ) n1 R c3 , -OC(R c1 R c2 ) n (CH 2 ) n1 R c3 and -(CH 2 ) n NR c2 S(O) m R c3 wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted; R c1 , R c2 and R c3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally further substituted; Each R d is hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R d1 , -(CH 2 ) n OR d1 , -(CH 2 ) n C(O)R d1 , -(CH 2 ) n C(O)OR d1 , -(CH 2 ) n S(O)m R d1 , -(CH 2 ) n NR d2 R d3 , -(CH 2 ) n NR d2 C(O)OR d3 , -(CH 2 ) n NR d2 C(O)(CH 2 ) n1 R d3 , -(CH 2 ) n NR d2 C(O)NR d2 R d3 , -(CH 2 ) n C(O)NR d2 (CH 2 ) n1 R d3 , -OC(R d1 R d2 ) n (CH 2 ) n1 R d3 and -(CH 2 ) n NR d2 S(O) m R d3 wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted; R d1 , R d2 and R d3are each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally further substituted; w, x, y and z are each independently 1, 2, 3 or 4; each m is independently 0, 1, or 2; each n is independently 0, 1, 2, 3, or 4; each p is independently 0 or 1; n1, n2, n3 and n4 are each independently 0, 1, 2, 3 or 4. [Means for solving the problem]

[0009] In some embodiments of the invention, the compound has formula (III):

[0010] [ka]

[0011] (In the formula,

[0012] [ka]

[0013] is a single bond or a double bond, L 1 is a bond, -(CH 2 ) n (CR aa R bb ) n2 -, -(CH 2 ) n C(O)(CR aa R bb ) n1-or- aa R bb ) n O(CH 2 ) n1 - and L 2 is a bond or -(CH 2 ) n (CR aa R bb ) n2 - and L 3 is a bond, -(CH 2 ) n C(O)(CR aa R bb ) n1 -, -(CH 2 ) n C(O)NR aa (CH 2 ) n1 -, -(CH 2 ) n (CR aa R bb ) n2 -, -(CR aa R bb ) n O(CH 2 ) n1 - and -(CH 2 ) n NR aa (CR bb R cc ) n - selected from the group consisting of R aa , R bb and R cc are each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, and alkynyl; Or R aa , R bb and R cc any two of the following may be joined to form a cycloalkyl: M 1 is N, C or CR 2 and M 2 is N or CR 3and M 5 HA-CR 6 R 7 -, -CR 6 R 7 -CR 8 R 9 -, -CR 6 =CR 8 -, -CR 6 R 7 -NR 8 -, -NR 8 -C(=O)-, -CR 6 R 7 -O- or -CR 6 =N-, M 6 is N or CR 10 and R 1 is hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R 11 , -(CH 2 ) n OR 11 , -(CH 2 ) n C(O)R 11 , -(CH 2 ) n C(O)OR 11 , -(CH 2 ) n S(O) m R 11 , -(CH 2 ) n NR 22 R 33 , -(CH 2 ) n NR 22 C(O)OR 33 , -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , -(CH 2 ) n NR22 C(O)NR 22 R 33 , -(CH 2 ) n C(O)NR 22 (CH 2 ) n1 R 33 , -OC(R 11 R 22 ) n (CH 2 ) n1 R 33 and -(CH 2 ) n NR 22 S(O) m R 33 wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted; R 11 , R 22 and R 33 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkyl substituted with cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally further substituted; R 2 and R 3 are the same or different and each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino optionally substituted with alkyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, preferably R 2 and R 3are each independently hydrogen, deuterium, halogen, alkyl, or cycloalkyl; R 6 , R 7 , R 8 , R 9 and R 10 are the same or different and each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino optionally substituted with alkyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, preferably R 6 , R 7 , R 8 and R 9 are each independently hydrogen, deuterium, halogen, cyano, alkyl, alkynyl, or cycloalkyl; Or R 6 , R 7 are joined together with adjacent carbon atoms to form a cycloalkyl, which is optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, and amino; Or R 6 , R 8 are joined together with adjacent carbon atoms to form a cycloalkyl, which is optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, and amino; Each R b is hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R b1 , -(CH 2 ) n OR b1 , -(CH 2 ) n C(O)Rb1 , -(CH 2 ) n C(O)OR b1 , -(CH 2 ) n S(O) m R b1 , -(CH 2 ) n NR b2 R b3 , -(CH 2 ) n NR b2 C(O)OR b3 , -(CH 2 ) n NR b2 C(O)(CH 2 ) n1 R b3 , -(CH 2 ) n NR b2 C(O)NR b2 R b3 , -(CH 2 ) n C(O)NR b2 (CH 2 ) n1 R b3 , -OC(R b1 R b2 ) n (CH 2 ) n1 R b3 and -(CH 2 ) n NR b2 S(O) m R b3 wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted; R b1 , R b2 and R b3are each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally further substituted; Each R c is hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R c1 , -(CH 2 ) n OR c1 , -(CH 2 ) n C(O)R c1 , -(CH 2 ) n C(O)OR c1 , -(CH 2 ) n S(O) m R c1 , -(CH 2 ) n NR c2 R c3 , -(CH 2 ) n NR c2 C(O)OR c3 , -(CH 2 ) n NR c2 C(O)(CH 2 ) n1 R c3 , -(CH 2 ) n NR c2 C(O)NR c2 R c3 , -(CH 2 ) n C(O)NR c2 (CH2 ) n1 R c3 , -OC(R c1 R c2 ) n (CH 2 ) n1 R c3 and -(CH 2 ) n NR c2 S(O) m R c3 wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted; R c1 , R c2 and R c3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally further substituted; Each R d is hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R d1 , -(CH 2 ) n OR d1 , -(CH 2 ) n C(O)R d1 , -(CH 2 ) n C(O)OR d1 , -(CH 2 ) n S(O)m R d1 , -(CH 2 ) n NR d2 R d3 , -(CH 2 ) n NR d2 C(O)OR d3 , -(CH 2 ) n NR d2 C(O)(CH 2 ) n1 R d3 , -(CH 2 ) n NR d2 C(O)NR d2 R d3 , -(CH 2 ) n C(O)NR d2 (CH 2 ) n1 R d3 , -OC(R d1 R d2 ) n (CH 2 ) n1 R d3 and -(CH 2 ) n NR d2 S(O) m R d3 wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted; R d1 , R d2 and R d3are each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally further substituted; w, y, and z are each independently 1, 2, 3, or 4; each m is independently 0, 1, or 2; each n is independently 0, 1, 2, 3, or 4; n1 and n2 each independently represent 0, 1, 2, 3, or 4; n5 and n6 each independently represent 0, 1, or 2; M 1 is N and M 2 is N, then ring D is not a monocyclic ring, and ring D is

[0014] [ka]

[0015] If R 1 is not hydrogen, M 2 is N and M 1 is CH and ring D is

[0016] [ka]

[0017] If R 1 is not hydrogen, M 1 is N and M 2 is CH and ring D is

[0018] [ka]

[0019] If R 1 is not hydrogen,

[0020] [ka]

[0021] is a double bond, and M 1 is C and M 2 is N and ring D is phenyl, R 1 is not hydrogen) As further shown in

[0022] In some embodiments of the present invention, the compound of formula (I) is represented by the formula (II):

[0023] [ka]

[0024] It is a compound of the formula:

[0025] In some embodiments of the present invention, the compound of formula (I) is represented by the formula (IV):

[0026] [ka]

[0027] (In the formula, M 1 is N or CR a is) It is a compound of the formula:

[0028] In some embodiments of the invention, Ring C is a 3-10 membered heterocyclyl, preferably Ring C is a 4-8 membered heterocyclyl, wherein the heteroatoms in the 3-10 membered heterocyclyl and the 4-8 membered heterocyclyl are each independently selected from the group consisting of nitrogen, oxygen and sulfur, and the number of heteroatoms is independently 1, 2 or 3, preferably the rings of the 3-10 membered heterocyclyl and the 4-8 membered heterocyclyl are each independently a monocyclic ring, a bridged ring, a spiro ring or a fused ring.

[0029] In some embodiments of the invention, ring C is

[0030] [ka]

[0031] It is.

[0032] In some embodiments of the invention, ring C is

[0033] [ka]

[0034] It is.

[0035] In some embodiments of the invention, ring C is

[0036] [ka]

[0037] It is.

[0038] In some embodiments of the invention, ring D is 6-10 membered heterocyclyl, C 6~10and more preferably, ring D is a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a benzene ring, a 5-membered heteroaromatic ring fused with a 6-membered heteroaromatic ring, a 6-membered heteroaromatic ring fused with a 6-membered heteroaromatic ring, a 6-membered heteroaromatic ring fused with a 6-membered heterocyclic ring, a 6-membered heteroaromatic ring fused with a 5-membered heterocyclic ring, a benzene ring fused with a 5-membered heterocyclic ring, a benzene ring fused with a 6-membered heteroaromatic ring, a benzene ring fused with a 6-membered heterocyclic ring, and the heteroatoms in the 3-14 membered heterocyclyl, the 6-10 membered heterocyclyl, the 5-10 membered heteroaryl, and the 5-14 membered heteroaryl are each independently selected from the group consisting of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3.

[0039] In some embodiments of the invention, Ring D is

[0040] [ka]

[0041] It is.

[0042] In some embodiments of the invention, Ring D is

[0043] [ka]

[0044] is selected from the group consisting of:

[0045] In some embodiments of the invention, ring D is

[0046] [ka]

[0047] It is.

[0048] In some embodiments of the invention, ring D is

[0049] [ka]

[0050] It is.

[0051] In some embodiments of the invention, ring D is

[0052] [ka]

[0053] It is.

[0054] In some embodiments of the present invention, R 1 is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered heteroaryl, -(CH 2 ) n R 11 , -(CH 2 ) n OR 11 , -(CH 2 ) n C(O)R 11 , -(CH 2 ) n C(O)OR 11 , -(CH 2 ) n S(O) m R 11 , -(CH 2 ) n NR 22 R 33 , -(CH 2 ) n NR 22 C(O)OR33 , -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , -(CH 2 ) n NR 22 C(O)NR 22 R 33 , -(CH 2 ) n C(O)NR 22 (CH 2 ) n1 R 33 , -OC(R 11 R 22 ) n (CH 2 ) n1 R 33 and -(CH 2 ) n NR 22 S(O) m R 33 Amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Aryl and 5-12 membered heteroaryl are each optionally selected from hydroxy, halogen, nitro, hydroxy, thiol, cyano, amino, oxo, C 1~6 Alkyl, C 1~6 Alkoxy, C 6~12 It may be further substituted with one or more substituents selected from the group consisting of aryl, 5- to 12-membered heteroaryl, and 3- to 12-membered heterocyclyl.

[0055] In some embodiments of the present invention, R 1 is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered heteroaryl, -(CH 2 ) n R 11 , -(CH 2 ) n OR 11 , -(CH 2 ) n C(O)R 11 , -(CH 2 ) n C(O)OR 11 , -(CH 2 ) n S(O) m R 11 , -(CH 2 ) n NR 22 R 33 , -(CH 2 ) n NR 22 C(O)OR 33 , -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , -(CH 2 ) n NR 22 C(O)NR 22 R 33 , -(CH 2 ) n C(O)NR 22 (CH 2 ) n1 R 33 , -OC(R 11 R 22 ) n (CH 2 ) n1 R 33 and -(CH 2 ) n NR 22 S(O) m R 33Amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Aryl and 5-12 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1~6 It may be further substituted with one or more substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl.

[0056] In some embodiments of the present invention, R 11 , R 22 and R 33 are optionally deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl and C 3~12 cycloalkyl, substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, cyano substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered heteroaryl, -O(CH 2 ) n1 R 66 , -OC(R 44 R 55 ) m1 (CH 2 ) n1 R 66 , -NR 44 (CH 2 )n1 R 66 , -(CH 2 ) n1 -, -(CH 2 ) n1 R 66 , -(CH 2 ) n1 OR 66 , -(CH 2 ) n1 S.R. 66 , -(CH 2 ) n1 C(O)R 66 , -(CH 2 ) n1 C(O)OR 66 , -(CH 2 ) n1 S(O) m1 R 66 , -(CH 2 ) n1 NR 44 R 55 , -(CH 2 ) n1 C(O)NR 44 R 55 , -(CH 2 ) n1 NR 44 C(O)R 66 and -(CH 2 ) n1 NR 44 S(O) m1 R 66 are each independently selected from the group consisting of:

[0057] In some embodiments of the present invention, R 44 , R 55 and R 66 are optionally deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl and C 3~12 cycloalkyl, substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, cyano substituted C 1~6 Alkyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 are each independently selected from the group consisting of aryl and 5-12 membered heteroaryl.

[0058] In some embodiments of the present invention, R 1 Each of them may optionally be hydroxy, halogen, amino, C 1~6 may be further substituted by one or more substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 It is selected from the group consisting of aryl and 5-12 membered heteroaryl.

[0059] In some embodiments of the present invention, R 1 is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 It is selected from the group consisting of aryl and 5-12 membered heteroaryl.

[0060] In some embodiments of the present invention, R1 Each of them may optionally be hydroxy, halogen, amino, C 1~3 may be further substituted by one or more substituents selected from the group consisting of alkyl and 3- to 6-membered heterocyclyl; 1~3 Deuterated alkyl, C 1~3 Alkyl, C 1~3 Alkoxy, C 3~6 It is selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl.

[0061] In some embodiments of the present invention, R 1 is hydrogen, deuterium, C 1~3 Deuterated alkyl, C 1~3 Alkyl, C 3~6 It is selected from the group consisting of cycloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, and 4- to 6-membered heterocyclyl substituted with oxo.

[0062] In some embodiments of the present invention, R 1 is hydrogen, deuterium, C 1~6 Deuterated alkyl, C 1~6 Alkyl, C 3~12 It is selected from the group consisting of cycloalkyl and 3- to 12-membered heterocyclyl.

[0063] In some embodiments of the present invention, R 1 is hydrogen, -CH 3 , -CD 3 , -CH 2 CN, ethyl, methoxy, cyano, cyclopropyl,

[0064] [ka]

[0065] is selected from the group consisting of:

[0066] In some embodiments of the present invention, R 1 is hydrogen, -CH 3 , -CD 3, ethyl, methoxy, cyano, cyclopropyl,

[0067] [ka]

[0068] is selected from the group consisting of:

[0069] In some embodiments of the present invention, R 1 is hydrogen, -CH 3 , -CD 3 , cyclopropyl,

[0070] [ka]

[0071] is selected from the group consisting of:

[0072] In some embodiments of the present invention, each R a is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, oxo, cyano, amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered heteroaryl, -(CH 2 ) n R a1 , -(CH 2 ) n OR a1 , -(CH 2 ) n C(O)R a1 , -(CH 2 ) n C(O)OR a1 , -(CH 2 ) n S(O) m Ra1 , -(CH 2 ) n NR a2 R a3 , -(CH 2 ) n NR a2 C(O)OR a3 , -(CH 2 ) n NR a2 C(O)(CH 2 ) n1 R a3 , -(CH 2 ) n NR a2 C(O)NR a2 R a3 , -(CH 2 ) n C(O)NR a2 (CH 2 ) n1 R a3 , -OC(R a1 R a2 ) n (CH 2 ) n1 R a3 and -(CH 2 ) n NR a2 S(O) m R a3 Independently selected from the group consisting of amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Aryl and 5-12 membered heteroaryl are each optionally selected from hydroxy, nitro, thiol, oxo, cyano, halogen, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, Amino, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6Alkynyl, C 3~8 Cycloalkyl, C 6~10 It may be further substituted with one or more substituents selected from the group consisting of aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl.

[0073] In some embodiments of the present invention, each R a is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, oxo, cyano, amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered heteroaryl, -(CH 2 ) n R a1 , -(CH 2 ) n OR a1 , -(CH 2 ) n C(O)R a1 , -(CH 2 ) n C(O)OR a1 , -(CH 2 ) n S(O) m R a1 , -(CH 2 ) n NR a2 R a3 , -(CH 2 ) n NR a2 C(O)OR a3 , -(CH 2 ) n NR a2 C(O)(CH 2 ) n1 R a3 , -(CH 2 ) n NR a2 C(O)NR a2 R a3 , -(CH2 ) n C(O)NR a2 (CH 2 ) n1 R a3 , -OC(R a1 R a2 ) n (CH 2 ) n1 R a3 and -(CH 2 ) n NR a2 S(O) m R a3 Independently selected from the group consisting of amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Aryl and 5-12 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1~6 It may be further substituted with one or more substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl.

[0074] In some embodiments of the present invention, each R a is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, oxo, cyano, amino, C 1~3 Alkyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 2~3 Alkenyl, C 2~3 Alkynyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, -(CH 2 ) n R a1 , -(CH 2 ) n ORa1 , -(CH 2 ) n C(O)R a1 , -(CH 2 ) n C(O)OR a1 , -(CH 2 ) n S(O) m R a1 , -(CH 2 ) n NR a2 R a3 , -(CH 2 ) n NR a2 C(O)OR a3 , -(CH 2 ) n NR a2 C(O)(CH 2 ) n1 R a3 , -(CH 2 ) n NR a2 C(O)NR a2 R a3 , -(CH 2 ) n C(O)NR a2 (CH 2 ) n1 R a3 , -OC(R a1 R a2 ) n (CH 2 ) n1 R a3 and -(CH 2 ) n NR a2 S(O) m R a3 Independently selected from the group consisting of amino, C 1~3 Alkyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 2~3 Alkenyl, C 2~3 Alkynyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10The aryl and 5-10 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1~3 It may be further substituted with one or more substituents selected from the group consisting of alkyl and 3- to 6-membered heterocyclyl.

[0075] In some embodiments of the present invention, R a1 , R a2 and R a3 is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 aryl and 5-12 membered heteroaryl; 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Aryl and 5-12 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1~6 It may be further substituted with one or more substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl.

[0076] In some embodiments of the present invention, each R a In some cases, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkyl, C 1~3 Alkoxy, C 2~4 Alkynyl and C 3~6Independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, substituted by cycloalkyl.

[0077] In some embodiments of the present invention, each R a is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, oxo, cyano, amino, C 1~3 Haloalkyl, C 1~3 Alkyl and C 3~6 cycloalkyl.

[0078] In some embodiments of the present invention, each R a is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, oxo, cyano, amino, C 1~3 Alkyl and C 3~6 cycloalkyl.

[0079] In some embodiments of the present invention, each R a is independently selected from the group consisting of hydrogen, ethyl, oxo, cyclopropyl, methyl, methoxy, ethynyl, propynyl, trifluoromethyl and cyano.

[0080] In some embodiments of the present invention, each R a is independently selected from the group consisting of hydrogen, ethyl, oxo, cyclopropyl, methyl, methoxy, ethynyl, trifluoromethyl, and cyano.

[0081] In some embodiments of the present invention, each R a is independently selected from the group consisting of hydrogen, ethyl, oxo, cyclopropyl, methyl, trifluoromethyl, and cyano.

[0082] In some embodiments of the present invention, each R a is independently selected from the group consisting of hydrogen, ethyl, oxo, cyclopropyl, and methyl.

[0083] In some embodiments of the invention, x is 1, 2 or 3.

[0084] In some embodiments of the present invention, each R b is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, oxo, cyano, amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered heteroaryl, -(CH 2 ) n R b1 , -(CH 2 ) n OR b1 , -(CH 2 ) n C(O)R b1 , -(CH 2 ) n C(O)OR b1 , -(CH 2 ) n S(O) m R b1 , -(CH 2 ) n NR b2 R b3 , -(CH 2 ) n NR b2 C(O)OR b3 , -(CH 2 ) n NR b2 C(O)(CH 2 ) n1 R b3 , -(CH 2 ) n NR b2 C(O)NR b2 R b3 , -(CH 2 ) n C(O)NR b2 (CH 2 ) n1 R b3 , -OC(R b1 Rb2 ) n (CH 2 ) n1 R b3 and -(CH 2 ) n NR b2 S(O) m R b3 Independently selected from the group consisting of amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Aryl and 5-12 membered heteroaryl are each optionally selected from hydroxy, nitro, thiol, oxo, cyano, halogen, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, Amino, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, C 6~10 It may be further substituted with one or more substituents selected from the group consisting of aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl.

[0085] In some embodiments of the present invention, each R b is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, oxo, cyano, amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12Aryl, 5-12 membered heteroaryl, -(CH 2 ) n R b1 , -(CH 2 ) n OR b1 , -(CH 2 ) n C(O)R b1 , -(CH 2 ) n C(O)OR b1 , -(CH 2 ) n S(O) m R b1 , -(CH 2 ) n NR b2 R b3 , -(CH 2 ) n NR b2 C(O)OR b3 , -(CH 2 ) n NR b2 C(O)(CH 2 ) n1 R b3 , -(CH 2 ) n NR b2 C(O)NR b2 R b3 , -(CH 2 ) n C(O)NR b2 (CH 2 ) n1 R b3 , -OC(R b1 R b2 ) n (CH 2 ) n1 R b3 and -(CH 2 ) n NR b2 S(O) m R b3 Independently selected from the group consisting of amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Aryl and 5-12 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1~6 It may be further substituted with one or more substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl.

[0086] In some embodiments of the present invention, each R b is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, oxo, cyano, amino, C 1~3 Alkyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 2~3 Alkenyl, C 2~3 Alkynyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, -(CH 2 ) n R b1 , -(CH 2 ) n OR b1 , -(CH 2 ) n C(O)R b1 , -(CH 2 ) n C(O)OR b1 , -(CH 2 ) n S(O) m R b1 , -(CH 2 ) n NR b2 R b3 , -(CH 2 ) n NR b2 C(O)OR b3 , -(CH 2 ) n NR b2 C(O)(CH 2 ) n1 R b3 , -(CH 2 )n NR b2 C(O)NR b2 R b3 , -(CH 2 ) n C(O)NR b2 (CH 2 ) n1 R b3 , -OC(R b1 R b2 ) n (CH 2 ) n1 R b3 and -(CH 2 ) n NR b2 S(O) m R b3 Independently selected from the group consisting of amino, C 1~3 Alkyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 2~3 Alkenyl, C 2~3 Alkynyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 The aryl and 5-10 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1~3 It may be further substituted with one or more substituents selected from the group consisting of alkyl and 3- to 6-membered heterocyclyl.

[0087] In some embodiments of the present invention, R b1 , R b2 and R b3 is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12aryl and 5-12 membered heteroaryl; 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Aryl and 5-12 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1~6 It may be further substituted with one or more substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl.

[0088] In some embodiments of the present invention, each R b is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, oxo, cyano, amino, C 1~3 Alkyl, C 1~3 Haloalkyl and C 3~6 cycloalkyl.

[0089] In some embodiments of the present invention, each R b is hydrogen, F, -CF 3 , cyano, methyl and cyclopropyl.

[0090] In some embodiments of the invention, y is 1.

[0091] In some embodiments of the present invention, each R c is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, oxo, cyano, amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered heteroaryl, -(CH 2 ) n R c1 , -(CH 2 ) n OR c1 , -(CH 2 ) n C(O)R c1 , -(CH 2 ) n C(O)OR c1 , -(CH 2 ) n S(O) m R c1 , -(CH 2 ) n NR c2 R c3 , -(CH 2 ) n NR c2 C(O)OR c3 , -(CH 2 ) n NR c2 C(O)(CH 2 ) n1 R c3 , -(CH 2 ) n NR c2 C(O)NR c2 R c3 , -(CH 2 ) n C(O)NR c2 (CH 2 ) n1 R c3 , -OC(R c1 R c2 ) n (CH 2 ) n1 R c3 and -(CH 2 ) n NR c2 S(O) m R c3 Independently selected from the group consisting of amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Aryl and 5-12 membered heteroaryl are each optionally selected from hydroxy, nitro, thiol, oxo, cyano, halogen, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, Amino, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, C 6~10 It may be further substituted with one or more substituents selected from the group consisting of aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl.

[0092] In some embodiments of the present invention, each R c is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, oxo, cyano, amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered heteroaryl, -(CH 2 ) n R c1 , -(CH 2 ) n OR c1 , -(CH 2 ) n C(O)R c1 , -(CH 2 ) n C(O)OR c1 , -(CH 2 ) n S(O) m R c1 , -(CH2 ) n NR c2 R c3 , -(CH 2 ) n NR c2 C(O)OR c3 , -(CH 2 ) n NR c2 C(O)(CH 2 ) n1 R c3 , -(CH 2 ) n NR c2 C(O)NR c2 R c3 , -(CH 2 ) n C(O)NR c2 (CH 2 ) n1 R c3 , -OC(R c1 R c2 ) n (CH 2 ) n1 R c3 and -(CH 2 ) n NR c2 S(O) m R c3 Independently selected from the group consisting of amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Aryl and 5-12 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1~6 It may be further substituted with one or more substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl.

[0093] In some embodiments of the present invention, each R c is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, oxo, cyano, amino, C1~3 Alkyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 2~3 Alkenyl, C 2~3 Alkynyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, -(CH 2 ) n R c1 , -(CH 2 ) n OR c1 , -(CH 2 ) n C(O)R c1 , -(CH 2 ) n C(O)OR c1 , -(CH 2 ) n S(O) m R c1 , -(CH 2 ) n NR c2 R c3 , -(CH 2 ) n NR c2 C(O)OR c3 , -(CH 2 ) n NR c2 C(O)(CH 2 ) n1 R c3 , -(CH 2 ) n NR c2 C(O)NR c2 R c3 , -(CH 2 ) n C(O)NR c2 (CH 2 ) n1 R c3 , -OC(R c1 R c2 ) n (CH 2 ) n1 R c3 and -(CH 2 ) n NRc2 S(O) m R c3 Independently selected from the group consisting of amino, C 1~3 Alkyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 2~3 Alkenyl, C 2~3 Alkynyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 The aryl and 5-10 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1~3 It may be further substituted with one or more substituents selected from the group consisting of alkyl and 3- to 6-membered heterocyclyl.

[0094] In some embodiments of the present invention, R c1 , R c2 and R c3 is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 aryl and 5-12 membered heteroaryl; 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Aryl and 5-12 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1~6It may be further substituted with one or more substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl.

[0095] In some embodiments of the present invention, each R c In some cases, C 1~3 Alkyl, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 3~6 Independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, substituted by cycloalkyl.

[0096] In some embodiments of the present invention, each R c is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, oxo, cyano, amino, C 1~3 Alkyl, C 1~3 Haloalkyl and C 3~6 cycloalkyl.

[0097] In some embodiments of the present invention, each R c are independently selected from the group consisting of hydrogen, deuterium, F, chlorine, hydroxy, methyl, methoxy, oxo, and cyano.

[0098] In some embodiments of the present invention, each R c are independently selected from the group consisting of hydrogen, deuterium, F, hydroxy, methyl, methoxy, oxo, and cyano.

[0099] In some embodiments of the present invention, each R c is independently selected from the group consisting of hydrogen, F, hydroxy, methyl, methoxy, oxo, and cyano.

[0100] In some embodiments of the present invention, each R c is independently selected from the group consisting of hydrogen, F, methyl, oxo, and cyano.

[0101] In some embodiments of the present invention, each R c is independently selected from the group consisting of hydrogen, F, methyl and oxo.

[0102] In some embodiments of the invention, z is 1 or 2.

[0103] In some embodiments of the present invention, each R d is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, oxo, cyano, amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered heteroaryl, -(CH 2 ) n R d1 , -(CH 2 ) n OR d1 , -(CH 2 ) n C(O)R d1 , -(CH 2 ) n C(O)OR d1 , -(CH 2 ) n S(O) m R c1 , -(CH 2 ) n NR d2 R d3 , -(CH 2 ) n NR d2 C(O)OR d3 , -(CH 2 ) n NR d2 C(O)(CH 2 ) n1 R d3 , -(CH 2 ) n NR d2 C(O)NR d2 Rd3 , -(CH 2 ) n C(O)NR d2 (CH 2 ) n1 R d3 , -OC(R d1 R d2 ) n (CH 2 ) n1 R d3 and -(CH 2 ) n NR d2 S(O) m R d3 Independently selected from the group consisting of amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Aryl and 5-12 membered heteroaryl are each optionally selected from hydroxy, nitro, thiol, oxo, cyano, halogen, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, Amino, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, C 6~10 It may be further substituted with one or more substituents selected from the group consisting of aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl.

[0104] In some embodiments of the present invention, each R d is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, oxo, cyano, amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Aryl, 5-12 membered heteroaryl, -(CH 2 ) n R d1 , -(CH 2 ) n OR d1 , -(CH 2 ) n C(O)R d1 , -(CH 2 ) n C(O)OR d1 , -(CH 2 ) n S(O) m R c1 , -(CH 2 ) n NR d2 R d3 , -(CH 2 ) n NR d2 C(O)OR d3 , -(CH 2 ) n NR d2 C(O)(CH 2 ) n1 R d3 , -(CH 2 ) n NR d2 C(O)NR d2 R d3 , -(CH 2 ) n C(O)NR d2 (CH 2 ) n1 R d3 , -OC(R d1 R d2 ) n (CH 2 ) n1 R d3 and -(CH 2 ) n NR d2 S(O) m R d3 Independently selected from the group consisting of amino, C 1~6Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Aryl and 5-12 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1~6 It may be further substituted with one or more substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl.

[0105] In some embodiments of the present invention, each R d is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, oxo, cyano, amino, C 1~3 Alkyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 2~3 Alkenyl, C 2~3 Alkynyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, -(CH 2 ) n R d1 , -(CH 2 ) n OR d1 , -(CH 2 ) n C(O)R d1 , -(CH 2 ) n C(O)OR d1 , -(CH 2 ) n S(O) m R c1 , -(CH 2 ) n NR d2 R d3 , -(CH 2 ) n NR d2 C(O)ORd3 , -(CH 2 ) n NR d2 C(O)(CH 2 ) n1 R d3 , -(CH 2 ) n NR d2 C(O)NR d2 R d3 , -(CH 2 ) n C(O)NR d2 (CH 2 ) n1 R d3 , -OC(R d1 R d2 ) n (CH 2 ) n1 R d3 and -(CH 2 ) n NR d2 S(O) m R d3 Independently selected from the group consisting of amino, C 1~3 Alkyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 2~3 Alkenyl, C 2~3 Alkynyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 The aryl and 5-10 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1~3 It may be further substituted with one or more substituents selected from the group consisting of alkyl and 3- to 6-membered heterocyclyl.

[0106] In some embodiments of the present invention, R d1 , R d2 and R d3 is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 aryl and 5-12 membered heteroaryl; 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Aryl and 5-12 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1~6 It may be further substituted with one or more substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl.

[0107] In some embodiments of the present invention, each R d In some cases, C 1~3 Alkyl, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 3~6 Independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, substituted by cycloalkyl.

[0108] In some embodiments of the present invention, each R d is hydrogen, deuterium, cyclopropyl, isopropyl, cyano, F, Cl, methyl, -CD 3 , -NHCH 3 , -NHCD 3 , methoxy and oxo.

[0109] In some embodiments of the present invention, each R d is hydrogen, cyclopropyl, cyano, F, Cl, methyl, -NHCH3 , methoxy and oxo.

[0110] In some embodiments of the present invention, each R d is hydrogen, cyclopropyl, cyano, F, methyl, -NHCH 3 , methoxy and oxo.

[0111] In some embodiments of the present invention, each R d is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, oxo, cyano, amino, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl and C 3~6 cycloalkyl.

[0112] In some embodiments of the present invention, each R d is independently selected from the group consisting of hydrogen, cyclopropyl, cyano, F, methyl, methoxy and oxo.

[0113] In some embodiments of the invention, w is 1 or 2.

[0114] In some embodiments of the invention, w is 1.

[0115] In some embodiments of the present invention, the compound of formula (I) has the formula (VII)

[0116] [ka]

[0117] (In the formula, L 2 is a bond or O,

[0118] [ka]

[0119] is a single bond or a double bond, M 1 is C or CR 2 and M 2 is N or CR 3 and M 3 is N or CR 4 and M 4 is N or CR 5 and M 5 HA-CR 6 R 7 -, -CR 6 R 7 -CR 8 R 9 -, -CR 6 =CR 8 -, -CR 6 R 7 -NR 8 -, -NR 8 -C(=O)-, -CR 6 R 7 -O- or -CR 6 =N-, M 6 is N or CR 10 and R 1 is C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, -(CH 2 ) n R 11 , -(CH 2 ) n OR 11 , -(CH 2 ) n C(O)R 11 , -(CH 2 ) n C(O)OR 11 , -(CH 2 ) n NR 22 R 33 and -(CH 2 ) n NR 22 C(O)OR33 is selected from the group consisting of R 11 , R 22 and R 33 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 are each independently selected from the group consisting of aryl and 5-12 membered heteroaryl; R 2 , R 3 , R 4 and R 5 are the same or different, and optionally C 1~3 Alkyl, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, and amino, each of which is substituted with aryl and 5-12 membered heteroaryl, preferably R 2 , R 3 , R 4 and R 5 are each independently hydrogen, deuterium, halogen, C 1~3 Alkyl or C 3~6 is cycloalkyl, R b In some cases, C 1~3 Alkyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6Alkoxy and C 3~6 selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, substituted by cycloalkyl; R c In some cases, C 1~3 Alkyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy and C 3~6 selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, substituted by cycloalkyl; R d In some cases, C 1~3 Alkyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy and C 3~6 selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, substituted by cycloalkyl; R 6 , R 7 , R 8 , R 9 and R 10 are the same or different, and optionally C 1~3 Alkyl, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, and amino, each of which is substituted with aryl and 5-12 membered heteroaryl, preferably R 6 , R 7 , R 8 and R 9 are each independently hydrogen, deuterium, halogen, cyano, C 1~3 Alkyl or C3~6 cycloalkyl, or Or R 6 , R 7 is bonded together with the adjacent carbon atom to form C 3~6 Forms a cycloalkyl, C 3~6 Cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, and amino; Or R 6 , R 8 is bonded together with the adjacent carbon atom to form C 3~6 Forms a cycloalkyl, C 3~6 cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, and amino; n5 and n6 each independently represent 0, 1, or 2; w is 1 or 2; y is 1 or 2; z is 1 or 2; n is 0, 1, 2 or 3. It is a compound of the formula:

[0120] In some embodiments of the present invention, M 6 is N or C-CN.

[0121] In some embodiments of the present invention, the compound of formula (I) is represented by the formula (VI):

[0122] [ka]

[0123] (In the formula, L 2 is a bond or O,

[0124] [ka]

[0125] is a single bond or a double bond, M 1 is C or CR 2 and M 2 is N or CR 3 and M 3 is N or CR 4 and M 4 is N or CR 5 and M 5 HA-CR 6 R 7 -, -CR 6 R 7 -CR 8 R 9 -, -CR 6 =CR 8 -, -CR 6 R 7 -NR 8 -, -NR 8 -C(=O)-, -CR 6 R 7 -O- or -CR 6 =N-, R 1 is C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, -(CH 2 ) n R 11 , -(CH 2 ) n OR 11 , -(CH 2 ) n C(O)R 11 , -(CH 2 ) n C(O)OR 11 , -(CH 2 ) n NR 22 R 33 and -(CH 2 ) n NR 22 C(O)OR 33 is selected from the group consisting of R11 , R 22 and R 33 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 are each independently selected from the group consisting of aryl and 5-12 membered heteroaryl; R 2 , R 3 , R 4 and R 5 are the same or different, and optionally C 1~3 Alkyl, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, and amino, each of which is substituted with aryl and 5-12 membered heteroaryl, preferably R 2 , R 3 , R 4 and R 5 are each independently hydrogen, deuterium, halogen, C 1~3 Alkyl or C 3~6 is cycloalkyl, R c In some cases, C 1~3 Alkyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy and C 3~6selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, substituted by cycloalkyl; R d In some cases, C 1~3 Alkyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy and C 3~6 selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, substituted by cycloalkyl; R 6 , R 7 , R 8 and R 9 are the same or different, and optionally C 1~3 Alkyl, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 Each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, and amino, each of which is substituted with aryl and 5-12 membered heteroaryl, preferably R 6 , R 7 , R 8 and R 9 are each independently hydrogen, deuterium, halogen, C 1~3 Alkyl or C 3~6 cycloalkyl, or Or R 6 , R 7 is bonded together with the adjacent carbon atom to form C 3~6 Forms a cycloalkyl, C 3~6 Cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, and amino; Or R6 , R 8 is bonded together with the adjacent carbon atom to form C 3~6 Forms a cycloalkyl, C 3~6 cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, and amino; n5 and n6 each independently represent 0, 1, or 2; w is 1 or 2; z is 1 or 2; n is 0, 1, 2 or 3. It is a compound of the formula:

[0126] In some embodiments of the present invention, M 3 is N, CH or CF.

[0127] In some embodiments of the present invention, M 1 is CH or C.

[0128] In some embodiments of the present invention, M 1 is CH or CD.

[0129] In some embodiments of the present invention, R 6 , R 7 , R 8 and R 9 are each independently hydrogen, methyl, ethyl, methoxy, ethynyl, propynyl, or cyclopropyl, or R 6 , R 7 is bonded together with the adjacent carbon atom to form a cyclopropyl, or R 6 , R 8 is attached together with the adjacent carbon atom to form a cyclopropyl.

[0130] In some embodiments of the present invention, R 6 , R 7 , R 8 and R 9 are each independently hydrogen, methyl, ethyl, methoxy, ethynyl, or cyclopropyl, or R6 , R 7 is bonded together with the adjacent carbon atom to form a cyclopropyl, or R 6 , R 8 is attached together with the adjacent carbon atom to form a cyclopropyl.

[0131] In some embodiments of the present invention, R 1 Ha-NHCH 3 Or -NH-cyclopropyl.

[0132] In some embodiments of the present invention, R d is hydrogen, fluorine, chlorine or cyclopropyl.

[0133] In some embodiments of the present invention, R d is hydrogen or cyclopropyl.

[0134] In some embodiments of the present invention, the compound of formula (I) has the formula (V):

[0135] [ka]

[0136] (In the formula,

[0137] [ka]

[0138] is a single bond or a double bond, M 1 is C or CR 2 and M 2 is N or CR 3 and M 3 is N or CR 4 and M 4 is N or CR 5 and R 1 is C 1~6Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, -(CH 2 ) n R 11 , -(CH 2 ) n OR 11 , -(CH 2 ) n C(O)R 11 , -(CH 2 ) n C(O)OR 11 , -(CH 2 ) n NR 22 R 33 and -(CH 2 ) n NR 22 C(O)OR 33 or selected from the group consisting of Or R 1 is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 aryl and 5-12 membered heteroaryl, preferably R 1 is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, C 1~3 Alkyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 cycloalkyl, 3- to 10-membered heterocyclyl, more preferably R 1is selected from the group consisting of hydrogen, deuterium, cyano, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and 3-8 membered heterocyclyl containing 1-3 oxygen, nitrogen, or sulfur atoms, each of which is optionally further substituted; R 11 , R 22 and R 33 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Hydroxyalkyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 are each independently selected from the group consisting of aryl and 5-12 membered heteroaryl; R 2 , R 3 , R 4 and R 5 are the same or different and are hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 aryl and 5-12 membered heteroaryl, preferably R 2 , R 3 , R 4 and R5 are each independently hydrogen, deuterium, halogen, C 1~3 Alkyl or C 3~6 is cycloalkyl, R c is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, oxo, cyano, amino, C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 cycloalkyl; z is 1 or 2; n is 0, 1, 2 or 3. It is a compound of the formula:

[0139] In some embodiments of the present invention, M 1 is C or CH.

[0140] In some embodiments of the present invention, M 2 is CH.

[0141] In some embodiments of the present invention, M 4 is CH.

[0142] In some embodiments of the present invention, M 3 is N or CF.

[0143] In some embodiments of the present invention, R 1 is C 1~3 Alkyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, -(CH 2 ) n R 11 , -(CH 2 ) n OR 11 , -(CH 2 ) n C(O)R 11 , (CH 2 ) n C(O)OR 11 , -(CH 2 ) n NR22 R 33 and -(CH 2 ) n NR 22 C(O)OR 33 is selected from the group consisting of:

[0144] In some embodiments of the present invention, R 11 , R 22 and R 33 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~3 Alkyl, C 2~3 Alkenyl, C 2~3 Alkynyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, C 1~3 Hydroxyalkyl, C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 Each is independently selected from the group consisting of aryl and 5-10 membered heteroaryl.

[0145] In some embodiments of the present invention, R 1 -NHCH 3 ,

[0146] [ka]

[0147] It is.

[0148] In some embodiments of the present invention, the compound represented by formula (V) (In the formula,

[0149] [ka]

[0150] is a double bond, M 1 is C, M 2is N or CH, M 3 is N or CH, M 4 is N or CH, R 1 is C 1~3 Alkyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl, C 1~3 Alkoxy, -R 11 , -OR 11 , -C(O)R 11 , -C(O)OR 11 , -NR 22 R 33 and -(CH 2 ) n NR 22 C(O)OR 33 is selected from the group consisting of R 11 , R 22 and R 33 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1~3 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, C 1~3 Hydroxyalkyl, C 3~6 are each independently selected from the group consisting of cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl; R c is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, oxo, cyano, amino, C 1~3 Alkyl, C 1~3 Haloalkyl and C 3~3 cycloalkyl; z is 1 or 2) or a stereoisomer or a pharma- ceutically acceptable salt thereof.

[0151] In some embodiments of the invention, the compound has formula (IX):

[0152] [ka]

[0153] (Wherein, ring D is a 9-10 membered heterocyclyl, C 6~10 aryl or 9-10 membered heteroaryl, preferably a 6-membered heteroaromatic ring fused with a 6-membered heteroaromatic ring, a 6-membered heteroaromatic ring fused with a 6-membered heterocyclic ring, or a 6-membered heteroaromatic ring fused with a 5-membered heterocyclic ring, more preferably

[0154] [ka]

[0155] is) As further shown in

[0156] In some embodiments of the present invention, the compound of formula (I) has the formula (VII)

[0157] [ka]

[0158] (In the formula,

[0159] [ka]

[0160] represents a single bond or a double bond, M 1 is N, C or CR 2 and M 2 is N or CR 3 and M 6 is N or CR 10 and M7 is CR 12or N, M8 is CR 13 or O, preferably

[0161] [ka]

[0162] teeth

[0163] [ka]

[0164] and R 2 , R 3 , R 10 , R 12 and R 13 are the same or different, and optionally one or more C 1~3 Alkyl, C 1~6 Alkyl, C 1~6 Deuterated alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~12 Cycloalkyl, 3-12 membered heterocyclyl, C 6~12 R is independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, and amino substituted with aryl and 5-12 membered heteroaryl, and preferably R 2 , R 3 , R 10 , R 12 and R 13 are the same or different, and optionally one or more C 1~3 Alkyl, C 1~3 Alkyl, C 1~3 Deuterated alkyl, C 1~3 Haloalkyl, C 1~3 Hydroxyalkyl and C 1~3each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, and amino substituted with alkoxy; R b may be one or more C 1~3 Alkyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy and C 3~6 Hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, preferably optionally one or more C substituted with cycloalkyl 1~3 Alkyl, C 1~3 Alkyl, C 1~3 Haloalkyl and C 1~3 selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, substituted by alkoxy; R c may be one or more C 1~3 Alkyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy and C 3~6 Hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, preferably optionally one or more C substituted with cycloalkyl 1~3 Alkyl, C 1~3 Alkyl, C 1~3 Haloalkyl and C 1~3 selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, substituted by alkoxy; R d may be one or more C 1~3 Alkyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy and C 3~6 Hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, preferably optionally one or more C substituted with cycloalkyl 1~3 Alkyl, C1~3 Alkyl, C 1~3 Haloalkyl and C 1~3 selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, substituted by alkoxy; w, y and z are each independently 1, 2, 3 or 4. It is a compound of the formula:

[0165] In formula (VIII),

[0166] [ka]

[0167] is preferably

[0168] [ka]

[0169] It is.

[0170] In formula (VIII), M 2 is preferably CH.

[0171] In formula (VIII), M 6 is preferably N or CH.

[0172] In formula (VIII), M 7 is preferably CH or N.

[0173] In formula (VIII),

[0174] [ka]

[0175] is preferably

[0176] [ka]

[0177] It is.

[0178] In formula (VIII), R b is preferably hydrogen, deuterium or F.

[0179] In formula (VIII), R c is preferably hydrogen.

[0180] In formula (VIII), R d is preferably hydrogen, deuterium, F, Cl, methyl, -CD 3 , -NHCH 3 It is.

[0181] In formula (VIII), w is preferably 1 or 2.

[0182] In formula (VIII), y is preferably 1.

[0183] The present invention also relates to a method for preparing a compound, its stereoisomer or its pharma- ceutically acceptable salt, wherein the compound is as shown in formula (III), and a compound of formula (III-1) and a compound of formula (III-2) are reacted by the following reaction:

[0184] [ka]

[0185] wherein X is a halogen, preferably fluorine, chlorine, bromine or iodine; Preferably, the reaction is carried out in the presence of a base and a catalyst, the base is preferably DIPEA and the catalyst is preferably potassium iodide;

[0186] [ka]

[0187] , M1 , M 2 , M 5 , M 6 , R b , R c , R d , L 1 , L 2 , L 3 , R 1 , ring D, n5, n6, y, z and w are as defined above. To provide a method for receiving the same.

[0188] The present invention also relates to a compound represented by formula (III-2)

[0189] [ka]

[0190] (In the formula,

[0191] [ka]

[0192] , M 1 , M 2 , R c , R d , L 2 , L 3 , R 1 , ring D, n5, n6, z and w are as defined above. The present invention provides a compound of the formula:

[0193] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), its stereoisomers or any one of its pharma-ceutically acceptable salts, and one or more pharma-ceutically acceptable carriers, diluents or excipients.

[0194] The present invention further relates to the use of any one of the compounds of formula (I), its stereoisomers or its pharma- ceutically acceptable salts, or a pharmaceutical composition comprising same, in the preparation of a PARP inhibitor medicament, wherein the PARP is preferably PARP1.

[0195] The present invention further relates to the use of a compound of formula (I), its stereoisomer or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising same, in the preparation of a medicament for treating cancer, an ischemic disease or a neurodegenerative disease, wherein the cancer is preferably selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematological cancer, gastric cancer, colorectal cancer, gastrointestinal cancer and lung cancer.

[0196] The present invention further relates to a method for treating cancer, an ischemic disease or a neurodegenerative disease with a compound of formula (I), its stereoisomer or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising same.

[0197] The present invention also relates to a method for preventing and / or treating ischemic diseases, neurodegenerative diseases, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematological cancer, gastrointestinal cancer or lung cancer, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising same. Preferably, the gastrointestinal cancer is selected from the group consisting of gastric cancer and colorectal cancer.

[0198] The present invention also provides methods for treating disease conditions by using the compounds or pharmaceutical compositions of the present invention, including but not limited to conditions associated with PARP kinase dysfunction, wherein PARP is preferably PARP1 or PARP2.

[0199] The present invention also relates to a method for treating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention or a pharma- ceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

[0200] In some embodiments of the invention, the methods relate to the treatment of a condition, such as cancer, an ischemic disease, or a neurodegenerative disease.

[0201] In some embodiments of the invention, the method relates to the treatment of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematological cancer, gastrointestinal cancer or lung cancer, preferably the gastrointestinal cancer is selected from the group consisting of gastric cancer and colorectal cancer.

[0202] In some embodiments of the invention, the methods relate to the treatment of ovarian cancer or breast cancer.

[0203] In some embodiments of the invention, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer.

[0204] definition Unless otherwise stated, terms used in the specification and claims have the meanings set forth below.

[0205] The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 8 carbon atoms, more preferably an alkyl group having from 1 to 6 carbon atoms, and most preferably an alkyl group having from 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, Examples of dimethylpentyl include 3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof.More preferably, the alkyl is a lower alkyl having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available point of attachment. The substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy, and alkoxycarbonyl. The alkyl of the present invention is preferably selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0206] The term "alkylene" refers to an alkyl further substituted with a hydrogen atom, for example, "methylene" is -CH 2 -, and "ethylene" is -(CH 2 ) 2 -, and "propylene" refers to -(CH 2 ) 3 -, and "butylene" is -(CH 2 ) 4The term "alkenyl" refers to an alkyl, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as, for example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. An alkenyl can be substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocyclylthio.

[0207] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. Polycyclic cycloalkyls include cycloalkyls having spiro rings, fused rings, or bridged rings. Cycloalkyls are preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0208] The term "spirocycloalkyl" refers to a 5-20 membered polycyclic group in which the individual rings are bonded through one shared carbon atom (called a spiro atom) and the rings may have one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Spirocycloalkyls are preferably 6-14 membered spirocycloalkyls, and more preferably 7-10 membered spirocycloalkyls. According to the number of spiro atoms shared between the rings, spirocycloalkyls can be divided into mono-spirocycloalkyls, di-spirocycloalkyls, or poly-spirocycloalkyls, and spirocycloalkyls are preferably mono-spirocycloalkyls or di-spirocycloalkyls, and more preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered mono-spirocycloalkyls. Non-limiting examples of spirocycloalkyls include:

[0209] [ka]

[0210] The following are some of the reasons: Also included are spirocycloalkyls in which cycloalkyl and heterocyclyl are attached through a spiro atom, non-limiting examples of which include

[0211] [ka]

[0212] Examples include:

[0213] The term "fused cycloalkyl" refers to a 5-20 membered all carbon polycyclic group in which each ring in the system shares adjacent pairs of carbon atoms with another ring, and one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Fused cycloalkyls are preferably 6-14 membered fused cycloalkyls, and more preferably 7-10 membered fused cycloalkyls. According to the number of membered rings, fused cycloalkyls can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyls, and fused cycloalkyls are preferably bicyclic or tricyclic fused cycloalkyls, and more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused cycloalkyls. Non-limiting examples of fused cycloalkyls include:

[0214] [ka]

[0215] Examples include:

[0216] The term "bridged cycloalkyl" refers to a 5-20 membered all carbon polycyclic group in which every two rings in the system share two unbonded carbon atoms, and the rings may have one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Bridged cycloalkyls are preferably 6-14 membered bridged cycloalkyls, and more preferably 7-10 membered bridged cycloalkyls. According to the number of membered rings, bridged cycloalkyls can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, and bridged cycloalkyls are preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyls, and more preferably bicyclic or tricyclic bridged cycloalkyls. Non-limiting examples of bridged cycloalkyls include:

[0217] [ka]

[0218] Examples include:

[0219] A cycloalkyl ring can be fused to an aryl, heteroaryl or heterocyclyl ring, where the ring attached to the parent structure is a cycloalkyl. Non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. A cycloalkyl can be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy, and alkoxycarbonyl.

[0220] The term "heterocyclyl" refers to a heterocyclic ring in which one or more ring atoms are nitrogen, oxygen, and S(O) m (wherein m is an integer of 0 to 2), except that -OO-, -OS- or -SS- in the ring are excluded, and the remaining ring atoms are carbon atoms, and the ring atoms are further selected from the group consisting of boron or P(O) p(wherein p is an integer from 0 to 2). Preferably, the heterocyclyl has 3 to 12 ring atoms, of which 1 to 4 atoms are heteroatoms, more preferably 3 to 8 ring atoms, and most preferably 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, preferably tetrahydrofuryl, pyrazolidinyl, morpholinyl, piperazinyl, and pyranyl. Polycyclic heterocyclyls include heterocyclyls having spiro rings, fused rings, or bridged rings. Heterocyclyls having spiro, fused or bridged rings are optionally bonded to other groups through a single bond or further bonded to other cycloalkyls, heterocyclyls, aryls and heteroaryls through any two or more atoms of the ring.

[0221] Non-limiting examples of heterocyclyl include:

[0222] [ka]

[0223] Examples include:

[0224] The term "spiroheterocyclyl" refers to a heterocyclic ring in which the individual rings are joined through one shared atom (called a spiroatom) and one or more of the ring atoms are selected from the group consisting of nitrogen, oxygen, and S(O). m(wherein m is an integer from 0 to 2), the remaining ring atoms are carbon atoms, and the ring may have one or more double bonds, but none of the rings has a fully conjugated π-electron system. Spiroheterocyclyl is preferably 6-14 membered spiroheterocyclyl, and more preferably 7-10 membered spiroheterocyclyl. According to the number of spiro atoms shared between the rings, spiroheterocyclyl can be divided into mono-spiroheterocyclyl, di-spiroheterocyclyl, or poly-spiroheterocyclyl, and spiroheterocyclyl is preferably mono-spiroheterocyclyl or di-spiroheterocyclyl, and more preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered mono-spiroheterocyclyl. Non-limiting examples of spiroheterocyclyl include:

[0225] [ka]

[0226] Examples include:

[0227] The term "fused heterocyclyl" refers to a ring in which each ring in the system shares adjacent pairs of atoms with another ring, one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and one or more of the ring atoms is selected from the group consisting of nitrogen, oxygen, and S(O). m (wherein m is an integer of 0 to 2), and the remaining ring atoms are carbon atoms. The fused heterocyclyl is preferably a 6-14 membered fused heterocyclyl, and more preferably a 7-10 membered fused heterocyclyl. According to the number of ring members, the fused heterocyclyl can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, and is preferably a bicyclic or tricyclic fused heterocyclyl, and more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl. Non-limiting examples of fused heterocyclyl include:

[0228] [ka]

[0229] Examples include:

[0230] The term "bridged heterocyclyl" refers to any two rings in the system that share two unbonded atoms, and the rings may have one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and one or more of the ring atoms is a nitrogen, oxygen, or S(O) m (wherein m is an integer of 0 to 2), and the remaining ring atoms are carbon atoms. The bridged heterocyclyl is preferably a 6-14 membered bridged heterocyclyl, and more preferably a 7-10 membered bridged heterocyclyl. According to the number of membered rings, the bridged heterocyclyl can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, and the bridged heterocyclyl is preferably a bicyclic, tricyclic or tetracyclic bridged heterocyclyl, and more preferably a bicyclic or tricyclic bridged heterocyclyl. Non-limiting examples of bridged heterocyclyl include:

[0231] [ka]

[0232] Examples include:

[0233] The heterocyclyl ring can be fused to an aryl, heteroaryl, or cycloalkyl ring, where the ring attached to the parent structure is a heterocyclyl. Non-limiting examples include:

[0234] [ka]

[0235] etc.

[0236] A heterocyclyl can be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy, and alkoxycarbonyl.

[0237] The term "aryl" refers to a 6-14 membered all carbon monocyclic or polycyclic fused ring having a conjugated pi electron system (i.e., each ring in the system shares adjacent pairs of carbon atoms with another ring in the system), preferably a 6-10 membered aryl, such as phenyl and naphthyl. An aryl is more preferably a phenyl. An aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is an aryl ring. Non-limiting examples include:

[0238] [ka]

[0239] Examples include:

[0240] Aryl can be substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, and alkoxycarbonyl.

[0241] The term "heteroaryl" refers to a 5-14 membered heteroaromatic system having 1-4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. Heteroaryl is preferably a 5-10 membered heteroaryl, and more preferably a 5 or 6 membered heteroaryl, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl, and more preferably triazolyl, pyrrolyl, thienyl, thiazolyl and pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring. Non-limiting examples thereof include:

[0242] [ka]

[0243] Examples include:

[0244] Heteroaryl can be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, and alkoxycarbonyl.

[0245] The term "alkoxy" refers to an -O-(alkyl) or -O-(unsubstituted cycloalkyl) group, where alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. An alkoxy can be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, and alkoxycarbonyl.

[0246] "Haloalkyl" refers to alkyl substituted with one or more halogens, where alkyl is defined above.

[0247] "Haloalkoxy" refers to an alkoxy substituted with one or more halogens, where alkoxy is defined above.

[0248] "Hydroxyalkyl" refers to alkyl substituted with hydroxy, where alkyl is defined above.

[0249] "Alkenyl" refers to an olefinic chain, also known as an alkene group. Alkenyls can be further substituted with other related groups such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, or alkoxycarbonyl.

[0250] "Alkynyl" refers to (CH≡C-). Alkynyl can be further substituted with other related groups such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, or alkoxycarbonyl.

[0251] "Hydroxy" refers to the group --OH.

[0252] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0253] "Amino" is -NH 2 Refers to the base.

[0254] "Cyano" refers to the radical -CN.

[0255] "Nitro" is -NO 2 Refers to the base.

[0256] "Carboxy" refers to the group -C(O)OH.

[0257] "THF" refers to tetrahydrofuran.

[0258] "EtOAc" refers to ethyl acetate.

[0259] "MeOH" refers to methanol.

[0260] "DMF" refers to N,N-dimethylformamide.

[0261] "DIPEA" refers to diisopropylethylamine.

[0262] "TFA" refers to trifluoroacetic acid.

[0263] "MeCN" refers to acetonitrile.

[0264] "DMA" refers to N,N-dimethylacetamide;

[0265] "Et 2 "O" refers to diethyl ether.

[0266] "DCE" refers to 1,2-dichloroethane.

[0267] "DIPEA" refers to N,N-diisopropylethylamine.

[0268] "NBS" refers to N-bromosuccinimide.

[0269] "NIS" refers to N-iodosuccinimide.

[0270] "Cbz-Cl" refers to benzyl chloroformate;

[0271] "Pd 2 (dba) 3 " refers to tris(dibenzylideneacetone)dipalladium.

[0272] "Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.

[0273] "HATU" refers to 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0274] "KHMDS" refers to potassium hexamethyldisilazide.

[0275] "LiHMDS" refers to lithium bis(trimethylsilyl)amide;

[0276] "MeLi" refers to methyllithium.

[0277] "n-BuLi" refers to n-butyllithium.

[0278] "NaBH(OAc) 3 " refers to sodium triacetoxyborohydride.

[0279] Different expressions such as "X is selected from the group consisting of A, B or C", "X is selected from the group consisting of A, B and C", "X is A, B or C", "X is A, B and C" have the same meaning, i.e., X can be any one or more of A, B and C.

[0280] The hydrogen atoms of the present invention can be replaced by their isotopes, deuterium. Any of the hydrogen atoms in the example compounds of the present invention can be replaced by a deuterium atom.

[0281] "Optionally" or "optionally" means that the subsequently described event or circumstance may occur but need not occur, and such a description includes situations in which the event or circumstance occurs or does not occur. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group may be present but need not be present, and such a description includes situations in which the heterocyclyl is substituted with alkyl and situations in which the heterocyclyl is not substituted with alkyl.

[0282] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to 5, and more preferably 1-3 hydrogen atoms, independently substituted with a corresponding number of substituents. Needless to say, the substituents are present only in their possible chemical positions. Those skilled in the art can determine whether substitution is possible or not by experiment or theory without excessive effort. For example, the combination of amino or hydroxyl having free hydrogen and carbon atom having unsaturated bond (e.g. olefinic) may be unstable.

[0283] "Pharmaceutical composition" refers to a mixture of one or more compounds according to the invention or their physiologically / pharmaceutical acceptable salts or prodrugs with other chemical components, such as physiologically / pharmaceutical acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism, which aids in the absorption of the active ingredient to exert its biological activity.

[0284] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is safe and effective in mammals and possesses the desired biological activity. [Brief description of the drawings]

[0285] [Figure 1] Inhibition of PAR within 24 hours after a single dose of Example 1 in the MDA-MB-436 model. [Diagram 2] Inhibition of PAR within 24-72 hours after a single dose of Example 1 in the MDA-MB-436 model. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0286] The present invention is further described with reference to the following examples, which should not be construed as limiting the scope of the invention. EXAMPLES

[0287] The structures of the compounds of the present invention were identified by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR shifts (δ) are given in parts per million (ppm). NMR is determined on a Bruker AVANCE-400 instrument. The solvent for determination was deuterated dimethylsulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ) and the internal standard is tetramethylsilane (TMS).

[0288] Liquid chromatography-mass spectrometry (LC-MS) was performed on an Agilent 1200 Infinity Series mass spectrometer. High performance liquid chromatography (HPLC) was performed on an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6 mm column).

[0289] Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates were used as thin-layer silica gel chromatography (TLC) plates. The size of the silica gel plates used in TLC was 0.15mm-0.2mm, and the size of the silica gel plates used in product purification was 0.4mm-0.5mm. Yantai Huanghai 200-300 mesh silica gel was used as the carrier for column chromatography throughout.

[0290] The starting materials used in the examples of the present invention are known and commercially available or can be synthesized by or according to methods known in the art.

[0291] Unless otherwise indicated, all reactions of this invention are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, solvents are dry, and reaction temperatures are in degrees Celsius.

[0292] Example 1 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0293] [ka]

[0294] Step 1: Preparation of ethyl 6-formyl-5-nitronicotinate

[0295] [ka]

[0296] Selenium dioxide (3.96 g, 35.68 mmol) was added to a solution of ethyl 6-methyl-5-nitronicotinate (5.0 g, 23.8 mmol) in 1,4-dioxane (25 mL). The reaction solution was heated to 110° C. and stirred for 20 hours. The reaction solution was cooled to room temperature and filtered through diatomaceous earth under reduced pressure. The filtrate was concentrated under reduced pressure to remove the organic solvent, and the resulting residue was purified by column chromatography to obtain a brown oily compound ethyl 6-formyl-5-nitronicotinate (4.8 g, 90%). MS m / z(ES + ):224.1 [M] + .

[0297] Step 2: Preparation of ethyl (E)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nitronicotinate

[0298] [ka]

[0299] In an ice bath, triethyl 2-phosphonobutyrate (12.8 g, 50.6 mmol) was slowly added dropwise to a solution of NaH (60 wt%, 2.0 g, 50.6 mmol) in tetrahydrofuran (30 mL). The reaction solution was stirred in an ice bath for 0.5 h, then warmed to room temperature and stirred for 0.5 h, then heated to 40° C. and stirred for 10 min. The reaction solution was cooled to −78° C. and a solution of ethyl 6-formyl-5-nitronicotinate (4.8 g, 21 mmol) in tetrahydrofuran (20 mL) was slowly added dropwise and stirred at −78° C. for 1 h. The reaction solution was quenched with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The organic phases were combined and washed with saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, and the resulting residue was purified by column chromatography to give the title compound ethyl (E)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nitronicotinate (5.1 g, 75%). MS m / z(ES + ):322.2 [M] + .

[0300] Step 3: Preparation of ethyl 7-ethyl-6-oxo-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxylate

[0301] [ka]

[0302] Palladium on carbon (1.86 g, 1.76 mmol) was added to a solution of ethyl (E)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nitronicotinate (3.76 g, 11.6 mmol) in ethanol (50 mL). The reaction solution was purged with nitrogen for 5 minutes, placed under a hydrogen atmosphere, and stirred at room temperature overnight. The reaction solution was filtered through diatomaceous earth under reduced pressure. The filtrate was concentrated under reduced pressure to give the crude product ethyl 7-ethyl-6-oxo-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxylate (2.8 g), which was used directly in the next step. MS m / z(ESI):249.2 [M+H] + .

[0303] Step 4: Preparation of ethyl 7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate

[0304] [ka]

[0305] DDQ (2.85 g, 12.5 mmol) was added to a solution of ethyl 7-ethyl-6-oxo-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxylate (2.8 g, 11.3 mmol) in 1,4-dioxane (50 mL), heated to 110° C., and stirred for 4 hours. The reaction solution was cooled to room temperature and filtered through diatomaceous earth under reduced pressure. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography to obtain the compound ethyl 7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate (2.1 g, 76%). MS m / z(ESI):247.2 [M+H] + .

[0306] Step 5: Preparation of 3-ethyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one

[0307] [ka]

[0308] In an ice bath, a solution of lithium aluminum hydride in THF (2M, 8.5 mL, 17.0 mmol) was slowly added to a solution of 7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate (2.1 g, 8.5 mmol) in THF (30 mL) and stirred for 2 hours under ice bath. The reaction solution was quenched with sodium sulfate decahydrate and filtered through diatomaceous earth under reduced pressure. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography to obtain the compound 3-ethyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one (1.5 g, 86%). MS m / z(ESI):205.2 [M+H] + .

[0309] Step 6: Preparation of 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one

[0310] [ka]

[0311] In an ice bath, thionyl chloride (3.2 mL, 44.1 mmol) was added to a solution of 3-ethyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one (1.5 g, 7.4 mmol) in dichloromethane (30 mL). DMF (0.06 mL, 0.77 mmol) was added and the reaction solution was stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure to remove the organic solvent to give the crude product 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (1.61 g), which was used directly in the next step. MS m / z(ESI):223.1 [M+H] + .

[0312] Step 7: Preparation of 1'-(tert-butyl) 6-methyl 3',6'-dihydro-[3,4'-bipyridine]-1',6(2'H)-dicarboxylate

[0313] [ka]

[0314] At room temperature, methyl 5-bromopicolinate (1.0 g, 4.6 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.6 g, 5.1 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (146 mg, 0.2 mmol) and potassium carbonate (1.6 g, 11.6 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction solution was purged with nitrogen for 1 min, heated to 140° C. and reacted under microwave for 30 min. Water was added to the reaction and extracted with ethyl acetate. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, and the resulting residue was purified by column chromatography to obtain a brown oily compound 1'-(tert-butyl) 6-methyl 3',6'-dihydro-[3,4'-bipyridine]-1',6(2'H)-dicarboxylate (620 mg, 42%). MS m / z(ES + ):319.1 [M+H] + .

[0315] Step 8: Preparation of tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate

[0316] [ka]

[0317] At room temperature, a solution of methylamine in alcohol (30 wt%, 2.0 g, 19.5 mmol) was added to a solution of 1'-(tert-butyl) 6-methyl 3',6'-dihydro-[3,4'-bipyridine]-1',6(2'H)-dicarboxylate (620 mg, 1.9 mmol) in methanol (8 mL) and stirred at room temperature for 4 h. The reaction solution was concentrated under reduced pressure, saturated aqueous ammonium chloride solution was added, and extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to give the crude product tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (600 mg), which was used directly in the next step without further purification. MS m / z(ESI):318.2 [M+H] + .

[0318] Step 9: Preparation of N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0319] [ka]

[0320] In an ice bath, trifluoroacetic acid (1 mL) was added to a solution of tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (200 mg, 0.6 mmol) in dichloromethane (5 mL) and stirred at room temperature for 4 h. The reaction solution was concentrated under reduced pressure to remove the organic solvent to give the crude product N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (155 mg), which was used directly in the next step without further purification. MS m / z(ESI):218.2 [M+H] + .

[0321] Step 10: Preparation of 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0322] [ka]

[0323] DIPEA (58 mg, 0.45 mmol) and potassium iodide (3 mg, 0.02 mmol) were added to a solution of 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (20 mg, 0.09 mmol) and N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (52 mg, 0.24 mmol) in acetonitrile (3 mL). The reaction solution was heated to 80° C. and stirred for 2 hours. The reaction solution was cooled to room temperature and filtered under reduced pressure. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography to obtain compound 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (6.2 mg, 17%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.76-11.91 (m, 1H), 8.68-8.73 (m, 2H), 8.40-8.44 (m, 1H), 8.02-7.95 (m, 2H), 7.76 (s, 1H), 7.65 (s, 1H), 6.41-6.44 (m, 1H), 3.69-3.76 (m, 2H), 3.19-3.13 (m, 2H), 2.77-2.85 (m, 3H), 2.66-2.74 (m, 2H), 2.51-2.59 (m, 4H), 1.18 (t, J = 7.4 Hz, 3H); MS m / z (ESI): 404.2 [M+H] + .

[0324] Example 2 5-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperidin-4-yl)-N-methylpicolinamide

[0325] [ka]

[0326] Step 1: Preparation of tert-butyl 4-(6-(methylcarbamoyl)pyridin-3-yl)piperidine-1-carboxylate

[0327] [ka]

[0328] Under nitrogen atmosphere, Pd / C (50 mg) was added to a solution of tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (400 mg, 1.3 mmol) in methanol (8 mL). The reaction solution was purged with hydrogen three times and stirred at room temperature for 16 h. The reaction solution was filtered and concentrated under reduced pressure to remove the organic solvent to give the crude product tert-butyl 4-(6-(methylcarbamoyl)pyridin-3-yl)piperidine-1-carboxylate (280 mg), which was used directly in the next step without further purification. MS m / z(ESI):320.2 [M+H] + .

[0329] Step 2: Preparation of N-methyl-5-(piperidin-4-yl)picolinamide

[0330] [ka]

[0331] In an ice bath, hydrochloric acid in dioxane (2 mL) was added to a solution of tert-butyl 4-(6-(methylcarbamoyl)pyridin-3-yl)piperidine-1-carboxylate (280 mg, 0.88 mmol) in dichloromethane (5 mL) and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to remove the organic solvent to give the crude product N-methyl-5-(piperidin-4-yl)picolinamide (230 mg), which was used directly in the next step without further purification. MS m / z(ESI):220.2 [M+H] + .

[0332] Step 3: Preparation of 5-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperidin-4-yl)-N-methylpicolinamide

[0333] [ka]

[0334] DIPEA (58 mg, 0.45 mmol) and potassium iodide (3 mg, 0.02 mmol) were added to a solution of 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (20 mg, 0.09 mmol) and N-methyl-5-(piperidin-4-yl)picolinamide (52 mg, 0.24 mmol) in acetonitrile (3 mL). The reaction solution was heated to 80° C. and stirred for 2 hours. The reaction solution was cooled to room temperature and filtered under reduced pressure. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography to obtain compound 5-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperidin-4-yl)-N-methylpicolinamide (6.5 mg, 18%). 1 H NMR (400 MHz, DMSO-d 6) δ 11.79-11.87 (m, 1H), 8.66-8.72 (m, 1H), 8.53 (s, 1H), 8.38-8.42 (m, 1H), 7.92-7.97 (m, 1H), 7.84-7.88 (m, 1H), 7.75 (s, 1H), 7.61 (s, 1H), 3.58-3.65 (m, 2H), 2.91-2.97 (m, 2H), 2.77-2.84 (m, 3H), 2.63-2.72 (m, 1H), 2.51-2.58 (m, 2H), 2.08-2.17 (m, 2H), 1.67-1.84 (m, 4H), 1.18 (t, J = 7.4 Hz, 3H); MS m / z (ESI): 406.2 [M+H] + .

[0335] Example 3 3-Ethyl-7-((4-(8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0336] [ka]

[0337] Preparation of 3-ethyl-7-((4-(8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 1.

[0338] It can also be synthesized by the following steps.

[0339] Step 1: Preparation of tert-butyl 4-(8-chloro-1,7-naphthyridin-3-yl)piperazine-1-carboxylate

[0340] [ka]

[0341] 3-Bromo-8-chloro-1,7-naphthyridine (1 g, 4.10 mmol), tert-butyl piperazine-1-carboxylate (918 mg, 4.93 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (146 mg, 0.20 mmol) and potassium carbonate (1.61 g, 11.65 mmol) were mixed in DMF (10 mL), heated to 100°C and reacted for 12 hours. The reaction solution was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the target compound tert-butyl 4-(8-chloro-1,7-naphthyridin-3-yl)piperazine-1-carboxylate (510 mg, 35.7%). MS m / z(ESI):349.1 [M+H] + .

[0342] Step 2: Preparation of tert-butyl 4-(8-(methylamino)-1,7-naphthyridin-3-yl)piperazine-1-carboxylate

[0343] [ka]

[0344] A solution of methylamine in alcohol (30 wt%, 2.0 g, 19.5 mmol) was added to a solution of tert-butyl 4-(8-chloro-1,7-naphthyridin-3-yl)piperazine-1-carboxylate (510 mg, 1.46 mmol) in methanol (8 mL), warmed to 80° C., and stirred for 12 h. The reaction solution was concentrated under reduced pressure and partitioned between DCM and water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to give the crude target compound tert-butyl 4-(8-(methylamino)-1,7-naphthyridin-3-yl)piperazine-1-carboxylate (500 mg), which was used directly in the next step. MS m / z(ESI):344.2 [M+H] + .

[0345] Step 3: Preparation of N-methyl-3-(piperazin-1-yl)-1,7-naphthyridin-8-amine

[0346] [ka]

[0347] In an ice bath, trifluoroacetic acid (1 mL) was added to a solution of tert-butyl 4-(8-(methylamino)-1,7-naphthyridin-3-yl)piperazine-1-carboxylate (200 mg, 0.58 mmol) in dichloromethane (5 mL) and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to give the crude target compound N-methyl-3-(piperazin-1-yl)-1,7-naphthyridin-8-amine (140 mg), which was used directly in the next step. MS m / z(ESI):244.2 [M+H] + .

[0348] Step 4: Preparation of 3-ethyl-7-((4-(8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0349] [ka]

[0350] DIPEA (52 mg, 0.41 mmol) and potassium iodide (3 mg, 0.02 mmol) were added to a solution of 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (30 mg, 0.13 mmol) and N-methyl-3-(piperazin-1-yl)-1,7-naphthyridin-8-amine (49 mg, 0.20 mmol) in acetonitrile (3 mL). The reaction solution was heated to 80° C. and reacted for 3 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography to obtain the target compound 3-ethyl-7-((4-(8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one (12 mg, 21.5%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.76 (s, 1H), 8.33 (s, 1H), 7.65-7.70 (s, 2H), 7.55 (s, 1H), 7.52-7.76 (m, 1H), 6.64-6.73 (m, 2H), 3.57 (s, 2H), 3.32-3.35 (m, 4H), 2.68 (d, J = 4.4 Hz, 3H), 2.47-2.51 (m, 6H), 1.11 (t, J = 7.4 Hz, 3H); MS m / z (ESI): 430.2 [M+H] + .

[0351] Example 4 3-Ethyl-7-((4-(2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0352] [ka]

[0353] Preparation of 3-ethyl-7-((4-(2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):430.2 [M+H] + .

[0354] Example 5 3-Ethyl-7-((4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0355] [ka]

[0356] Preparation of 3-ethyl-7-((4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):432.2 [M+H] + .

[0357] Example 6 3-Ethyl-7-((4-(2-methyl-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0358] [ka]

[0359] Preparation of 3-ethyl-7-((4-(2-methyl-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):418.2 [M+H] + .

[0360] Example 7 3-Ethyl-7-((4-(2-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0361] [ka]

[0362] Preparation of 3-ethyl-7-((4-(2-methyl-1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):431.2 [M+H] + .

[0363] Example 8 3-Ethyl-7-((4-(8-(methylamino)quinolin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0364] [ka]

[0365] Preparation of 3-ethyl-7-((4-(8-(methylamino)quinolin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. 1 H NMR (400 MHz, DMSO-d 6) δ 11.86 (s, 1H), 8.64 (d, J = 2.7 Hz, 1H), 8.43 (d, J = 1.5 Hz, 1H), 7.76 (s, 1H), 7.65 (s, 1H), 7.40 (d, J = 2.7 Hz, 1H), 7.23-7.27 (m, 1H), 6.88 (d, J = 7.8 Hz, 1H), 6.35-6.40 (m, 2H), 3.64-3.68 (m, 2H), 3.28-3.31 (m, 4H), 2.87 (d, J = 5.1 Hz, 3H), 2.58-2.62 (m, 4H), 2.53-2.59 (m, 2H), 1.19 (t, J = 7.4 Hz, 3H); MS m / z (ESI): 429.2 [M+H] + .

[0366] Example 9 3-Ethyl-7-((4-(8-(methylamino)-1,5-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0367] [ka]

[0368] Preparation of 3-ethyl-7-((4-(8-(methylamino)-1,5-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):430.2 [M+H] + .

[0369] Example 10 3-Ethyl-7-((4-(8-(methylamino)-1,6-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0370] [ka]

[0371] Preparation of 3-ethyl-7-((4-(8-(methylamino)-1,6-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):430.2 [M+H] + .

[0372] Example 11 3-Ethyl-7-((4-(4-(methylamino)pyrido[3,2-d]pyrimidin-7-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0373] [ka]

[0374] Preparation of 3-ethyl-7-((4-(4-(methylamino)pyrido[3,2-d]pyrimidin-7-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):431.2 [M+H] + .

[0375] Example 12 3-Ethyl-7-((4-(4-(methylamino)pyrido[3,2-c]pyridazin-7-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0376] [ka]

[0377] Preparation of 3-ethyl-7-((4-(4-(methylamino)pyrido[3,2-c]pyridazin-7-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):431.2 [M+H]+ .

[0378] Example 13 3-Ethyl-7-((4-(8-(methylamino)pyrido[2,3-d]pyridazin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0379] [ka]

[0380] Preparation of 3-ethyl-7-((4-(8-(methylamino)pyrido[2,3-d]pyridazin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):431.2 [M+H] + .

[0381] Example 14 3-Ethyl-7-((4-(3-(methylamino)isothiazolo[4,5-b]pyridin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0382] [ka]

[0383] Preparation of 3-ethyl-7-((4-(3-(methylamino)isothiazolo[4,5-b]pyridin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):436.2 [M+H] + .

[0384] Example 15 3-Ethyl-7-((4-(2-fluoro-3-(methylamino)thieno[3,2-b]pyridin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0385] [ka]

[0386] Preparation of 3-ethyl-7-((4-(2-fluoro-3-(methylamino)thieno[3,2-b]pyridin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):453.2 [M+H] + .

[0387] Example 16 1'-((3-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0388] [ka]

[0389] The method for preparing 1'-((3-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):407.2 [M+H] + .

[0390] (Example 17) 3-Ethyl-7-((4-(1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0391] [ka]

[0392] Preparation of 3-ethyl-7-((4-(1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):404.2 [M+H] + .

[0393] (Example 18) 3-Ethyl-7-((4-(1-oxo-1,2-dihydroisoquinolin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0394] [ka]

[0395] Preparation of 3-ethyl-7-((4-(1-oxo-1,2-dihydroisoquinolin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):416.2 [M+H] + .

[0396] (Example 19) 3-Ethyl-7-((4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0397] [ka]

[0398] Preparation of 3-ethyl-7-((4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):418.2 [M+H] + .

[0399] (Example 20) 3-Ethyl-7-((4-(1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0400] [ka]

[0401] Preparation of 3-ethyl-7-((4-(1-oxo-1,2-dihydrophthalazin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):417.2 [M+H] + .

[0402] Example 21 3-Ethyl-7-((4-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0403] [ka]

[0404] Preparation of 3-ethyl-7-((4-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):405.2 [M+H] + .

[0405] Example 22 3-Ethyl-7-((4-(2-oxoindolin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0406] [ka]

[0407] Preparation of 3-ethyl-7-((4-(2-oxoindolin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):404.2 [M+H] + .

[0408] Example 23 7-((4-(1H-pyrrolo[2,3-b]pyridin-5-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one

[0409] [ka]

[0410] Preparation of 7-((4-(1H-pyrrolo[2,3-b]pyridin-5-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):389.2 [M+H] + .

[0411] (Example 24) 3-Ethyl-7-((4-(2-methyl-1H-benzo[d]imidazol-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0412] [ka]

[0413] Preparation of 3-ethyl-7-((4-(2-methyl-1H-benzo[d]imidazol-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. 1 H NMR (400 MHz, DMSO-d 6) δ 11.83-11.90 (br s, 2H), 8.41 (s, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 6.89 (s, 1H), 6.83 (d, J = 8.0 Hz, 1H), 3.65 (s, 2H), 3.06-3.10 (m, 4H), 2.50-2.59 (m, 6H), 2.42 (s, 3H), 1.18 (t, J = 8.0 Hz, 3H); MS m / z (ESI): 403.2 [M+H] + .

[0414] (Example 25) 3-Ethyl-7-((4-(3-(methylamino)pyrazolo[1,5-a]pyrimidin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0415] [ka]

[0416] Preparation of 3-ethyl-7-((4-(3-(methylamino)pyrazolo[1,5-a]pyrimidin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):419.2 [M+H] + .

[0417] (Example 26) 3-Ethyl-7-((4-(8-(methylamino)pyrrolo[1,2-a]pyrimidin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0418] [ka]

[0419] Preparation of 3-ethyl-7-((4-(8-(methylamino)pyrrolo[1,2-a]pyrimidin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):418.2 [M+H] + .

[0420] Example 27 3-Ethyl-7-((4-(8-(methylamino)imidazo[1,5-a]pyrimidin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0421] [ka]

[0422] Preparation of 3-ethyl-7-((4-(8-(methylamino)imidazo[1,5-a]pyrimidin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):419.2 [M+H] + .

[0423] (Example 28) 3-Ethyl-7-((4-(7-(methylamino)imidazo[1,5-b]pyridazin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0424] [ka]

[0425] Preparation of 3-ethyl-7-((4-(7-(methylamino)imidazo[1,5-b]pyridazin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):419.2 [M+H] + .

[0426] (Example 29) N-Cyclopropyl-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0427] [ka]

[0428] Preparation of N-cyclopropyl-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.77 (s, 1H), 8.60 (d, J = 4.2 Hz, 2H), 8.30-8.43 (m, 1H), 7.85-8.01 (m, 2H), 7.69 (s, 1H), 7.58 (s, 1H), 6.34 (s, 1H), 3.65 (s, 2H), 3.09 (d, J = 3.5 Hz, 2H), 2.83 (q, J = 6.4, 5.2 Hz, 1H), 2.63 (t, J = 5.5 Hz, 2H), 2.48 (t, J = 7.2 Hz, 4H), 1.13 (q, J = 9.3, 7.4 Hz, 3H), 0.54-0.72 (m, 4H); MS m / z (ESI): 430.2 [M+H] + .

[0429] (Example 30) 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methoxy-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0430] [ka]

[0431] The method for preparing 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methoxy-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.92 (s, 1H), 11.78 (s, 1H), 8.61 (d, J = 2.2 Hz, 1H), 8.35 (d, J = 1.9 Hz, 1H), 7.94 (dd, J = 8.4, 2.3 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.69 (s, 1H), 7.58 (s, 1H), 6.36 (s, 1H), 3.64 (d, J = 13.4 Hz, 5H), 3.09 (d, J = 3.4 Hz, 2H), 2.64 (t, J = 5.6 Hz, 2H), 2.48 (d, J = 7.5 Hz, 4H), 1.12 (t, J = 7.4 Hz, 3H); MS m / z (ESI): 420.2 [M+H] + .

[0432] (Example 31) (S)-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-(tetrahydrofuran-3-yl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0433] [ka]

[0434] The method for preparing (S)-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-(tetrahydrofuran-3-yl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):460.2 [M+H] + .

[0435] Example 32 (R)-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-(tetrahydrofuran-3-yl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0436] [ka]

[0437] The preparation method of (R)-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-(tetrahydrofuran-3-yl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):460.2 [M+H] + .

[0438] (Example 33) 4-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluoro-N-methylbenzamide

[0439] [ka]

[0440] The method for preparing 4-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluoro-N-methylbenzamide with reference to Example 1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.80-11.89 (m, 1H), 8.38-8.45 (m, 1H), 8.13-8.21 (m, 1H), 7.75 (s, 1H), 7.57-7.67 (m, 2H), 7.31-7.38 (m, 2H), 6.33-6.39 (m, 1H), 3.71 (s, 2H), 3.10-3.17 (m, 2H), 2.74-2.81 (m, 3H), 2.65-2.71 (m, 2H), 2.50-2.60 (m, 4H), 1.18 (t, J = 7.4 Hz, 3H); MS m / z (ESI): 421.2 [M+H] + .

[0441] (Example 34) 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methoxy-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0442] [ka]

[0443] The method for preparing 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methoxy-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):434.2 [M+H] + .

[0444] Example 35 2-Cyano-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0445] [ka]

[0446] The method for preparing 2-cyano-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.78 (s, 1H), 8.74 (q, J = 4.8 Hz, 1H), 8.36 (d, J = 1.8 Hz, 1H), 8.04-8.21 (m, 2H), 7.69 (s, 1H), 7.59 (d, J = 1.9 Hz, 1H), 6.17 (d, J = 4.1 Hz, 1H), 3.68 (s, 2H), 3.12 (d, J = 3.3 Hz, 2H), 2.76 (d, J = 4.8 Hz, 3H), 2.66 (t, J = 5.5 Hz, 2H), 2.48 (d, J = 7.0 Hz, 4H), 1.12 (t, J = 7.4 Hz, 3H); MS m / z (ESI): 429.2 [M+H] + .

[0447] (Example 36) 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0448] [ka]

[0449] The method for preparing 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.78 (s, 1H), 8.57 (d, J = 5.0 Hz, 1H), 8.35 (d, J = 1.8 Hz, 1H), 8.02 (dd, J = 9.9, 7.7 Hz, 1H), 7.81-7.90 (m, 1H), 7.69 (s, 1H), 7.58 (s, 1H), 6.19 (s, 1H), 3.65 (s, 2H), 3.10 (s, 2H), 2.72 (d, J = 4.8 Hz, 3H), 2.62 (t, J = 5.6 Hz, 2H), 2.48 (dd, J = 10.3, 4.7 Hz, 4H), 1.12 (t, J = 7.4 Hz, 3H); MS m / z (ESI): 422.2 [M+H] + .

[0450] (Example 37) N-Methyl-1'-((2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinoline]-7'-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0451] [ka]

[0452] A method for preparing N-methyl-1'-((2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-quinoline]-7'-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):403.2 [M+H] + .

[0453] (Example 38) N-Methyl-1'-((2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-[1,5]naphthyridin]-7'-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0454] [ka]

[0455] A method for preparing N-methyl-1'-((2'-oxo-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-[1,5]naphthyridin]-7'-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):404.2 [M+H] + .

[0456] (Example 39) (R)-N-Methyl-1'-((3-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0457] [ka]

[0458] The preparation method of (R)-N-methyl-1'-((3-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):378.2 [M+H] + .

[0459] (Example 40) (S)-N-Methyl-1'-((3-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0460] [ka]

[0461] The method for preparing (S)-N-methyl-1'-((3-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide is shown in Example 1. MS m / z(ESI):378.2 [M+H] + .

[0462] (Example 41) 2-Cyclopropyl-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0463] [ka]

[0464] The method for preparing 2-cyclopropyl-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):444.2 [M+H] + .

[0465] (Example 42) 1'-((5-cyano-3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0466] [ka]

[0467] The method for preparing 1'-((5-cyano-3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.10 (s, 1H), 8.66-8.70 (m, 2H), 7.96-8.04 (m, 2H), 7.76 (s, 1H), 7.68 (s, 1H), 7.62 (m, 1H), 6.43 (s, 1H), 3.72 (s, 2H), 3.16 (s, 2H), 2.78-2.82 (m, 3H), 2.66-2.74 (m, 2H), 2.55-2.62 (m, 4H), 1.19 (t, J = 7.6 Hz, 3H); MS m / z (ESI): 428.2 [M+H] + .

[0468] (Example 43) 1'-((3-ethyl-5-fluoro-2-oxo-1,2-dihydroquinolin-7-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0469] [ka]

[0470] The method for preparing 1'-((3-ethyl-5-fluoro-2-oxo-1,2-dihydroquinolin-7-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):421.2 [M+H] + .

[0471] (Example 44) 1'-((3-ethyl-2-oxo-5-(trifluoromethyl)-1,2-dihydroquinolin-7-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0472] [ka]

[0473] The method for preparing 1'-((3-ethyl-2-oxo-5-(trifluoromethyl)-1,2-dihydroquinolin-7-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):471.2 [M+H] + .

[0474] (Example 45) 1'-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0475] [ka]

[0476] The method for preparing 1'-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.83-11.91 (m, 1H), 8.67-8.73 (m, 2H), 8.38-8.41 (m, 1H), 7.95-8.02 (m, 2H), 7.60-7.64 (m, 1H), 7.42 (s, 1H), 6.39-6.45 (m, 1H), 3.71 (s, 2H), 3.12-3.19 (m, 2H), 2.78-2.86 (m, 3H), 2.68-2.74 (m, 2H), 2.53-2.59 (m, 2H), 2.10-2.19 (m, 1H), 0.94-1.00 (m, 2H), 0.80-0.85 (m, 2H); MS m / z (ESI): 416.2 [M+H] + .

[0477] (Example 46) 5-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-methylthiazole-2-carboxamide

[0478] [ka]

[0479] The method for preparing 5-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-methylthiazole-2-carboxamide with reference to Example 1. MS m / z(ESI):410.2 [M+H] + .

[0480] (Example 47) 1'-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0481] [ka]

[0482] The method for preparing 1'-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-7-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):421.2 [M+H] + .

[0483] (Example 48) 1'-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0484] [ka]

[0485] The method for preparing 1'-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):420.2 [M+H] + .

[0486] (Example 49) 1'-((7-ethynyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0487] [ka]

[0488] The method for preparing 1'-((7-ethynyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):400.2 [M+H] + .

[0489] (Example 50) 3-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-methoxy-N,1-dimethyl-1H-pyrazole-5-carboxamide

[0490] [ka]

[0491] The method for preparing 3-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-methoxy-N,1-dimethyl-1H-pyrazole-5-carboxamide with reference to Example 1. MS m / z(ESI):437.2 [M+H] + .

[0492] (Example 51) 4-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N,1-dimethyl-1H-imidazole-2-carboxamide

[0493] [ka]

[0494] The method for preparing 4-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N,1-dimethyl-1H-imidazole-2-carboxamide with reference to Example 1. MS m / z(ESI):407.2 [M+H] + .

[0495] (Example 52) 3-Ethyl-7-((4-(8-(methylamino)imidazo[1,2-a]pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0496] [ka]

[0497] Preparation of 3-ethyl-7-((4-(8-(methylamino)imidazo[1,2-a]pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 1. MS m / z(ESI):416.2 [M+H] + .

[0498] (Example 53) 7-((4-(1,5-dimethyl-1H-imidazol-2-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one

[0499] [ka]

[0500] Preparation of 7-((4-(1,5-dimethyl-1H-imidazol-2-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one with reference to Example 1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.84 (s, 1H), 8.41 (s, 1H), 7.75 (s, 1H), 7.65 (s, 1H), 6.62 (t, J = 0.9 Hz, 1H), 5.93 (s, 1H), 3.70 (d, J = 2.7 Hz, 2H), 3.50 (s, 3H), 3.13 (t, J = 3.3 Hz, 2H), 2.62 (t, J = 5.5 Hz, 2H), 2.53-2.58 (m, 2H), 2.51-2.52 (m, 2H), 2.15 (s, 3H), 1.18 (t, J = 7.4Hz, 3H); MS m / z (ESI): 364.2 [M+H] + .

[0501] (Example 54) 3-Ethyl-7-((4-(4-methyl-4H-1,2,4-triazol-3-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0502] [ka]

[0503] Preparation of 3-ethyl-7-((4-(4-methyl-4H-1,2,4-triazol-3-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.75 (s, 1H), 8.48 (s, 2H), 7.75 (s, 1H), 7.60 (s, 1H), 6.25 (s, 1H), 3.75 (s, 2H), 3.57 (s, 3H), 3.10-3.25 (m, 2H), 2.61-2.74 (m, 2H), 2.51-2.60 (m, 4H), 1.20 (t, J = 7.4 Hz, 3H); MS m / z (ESI): 351.2 [M+H] + .

[0504] (Example 55) 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N,2-dimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0505] [ka]

[0506] The method for preparing 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N,2-dimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):418.2 [M+H] + .

[0507] (Example 56) 2-Chloro-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0508] [ka]

[0509] The method for preparing 2-chloro-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.80 (s, 1H), 8.82 (d, J = 2.8 Hz, 1H), 8.70 (s,1H), 7.98 (d, J = 1.8 Hz, 1H), 7.90 (d, J = 1.8 Hz, 1H), 7.75 (s, 1H), 7.60 (s, 1H), 6.80 (s, 1H), 3.76 (s, 2H), 3.114-3.24 (m, 2H), 2.85 (d, J = 4.8 Hz, 3H), 2.65-2.70 (m, 2H), 2.43-2.61 (m, 4H), 1.20 (t, J = 7.2Hz, 3H); MS m / z (ESI): 438.2 [M+H] + .

[0510] (Example 57) N-Cyano-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0511] [ka]

[0512] The method for preparing N-cyano-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):415.2 [M+H] + .

[0513] (Example 58) N-(cyanomethyl)-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0514] [ka]

[0515] The method for preparing N-(cyanomethyl)-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. 1 H NMR (400 MHz, DMSO-d 6) δ 11.85 (s, 1H), 9.41-9.48 (m, 1H), 8.75 (s, 1H), 8.40 (s, 1H), 8.01-8.10 (m, 2H), 7.74 (s, 1H), 7.67 (s, 1H), 5.97 (s, 1H), 4.28-4.35 (m, 2H), 3.74 (s, 2H), 3.12-3.21 (m, 2H), 2.70-2.78 (m, 2H), 2.49-2.60 (m, 4H), 1.21 (t, J = 7.4 Hz, 3H); MS m / z (ESI): 429.2 [M+H] + .

[0516] (Example 59) N-(1-cyanocyclopropyl)-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0517] [ka]

[0518] The method for preparing N-(1-cyanocyclopropyl)-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. 1 H NMR (400 MHz, DMSO-d 6) δ 11.84 (s, 1H), 9.67 (s, 1H), 8.71 (s, 1H), 8.41 (s, 1H), 8.00-8.04 (m, 2H), 7.76 (s, 1H), 7.65 (d, J = 5.6 Hz, 1H), 6.46 (s, 1H), 3.73 (s, 2H), 3.16 (d, J = 7.2 Hz, 2H), 2.70-2.73 (m, 2H), 2.53-2.57 (m, 4H), 1.51-1.54 (m, 2H), 1.38-1.40 (m, 2H), 1.22 (t, J = 7.2 Hz, 3H); MS m / z (ESI): 455.2 [M+H] + .

[0519] (Example 60) 1'-(1-(7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)cyclopropyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0520] [ka]

[0521] The method for preparing 1'-(1-(7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)cyclopropyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):430.2 [M+H] + .

[0522] (Example 61) 1'-(2-(7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)propan-2-yl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0523] [ka]

[0524] The method for preparing 1'-(2-(7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)propan-2-yl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):432.2 [M+H] + .

[0525] (Example 62) 1'-((6-ethyl-7-oxo-7,8-dihydro-1,8-naphthyridin-2-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0526] [ka]

[0527] The method for preparing 1'-((6-ethyl-7-oxo-7,8-dihydro-1,8-naphthyridin-2-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):404.2 [M+H] + .

[0528] (Example 63) N-Cyclopropyl-1'-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0529] [ka]

[0530] The method for preparing N-cyclopropyl-1'-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):442.2 [M+H] + .

[0531] (Example 64) N-Methyl-1'-((6-oxo-7-(prop-1-yn-1-yl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0532] [ka]

[0533] The method for preparing N-methyl-1'-((6-oxo-7-(prop-1-yn-1-yl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):414.2 [M+H] + .

[0534] (Example 65) 3-Chloro-4-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluoro-N-methylbenzamide

[0535] [ka]

[0536] The method for preparing 3-chloro-4-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluoro-N-methylbenzamide with reference to Example 1. MS m / z(ESI):455.2 [M+H] + .

[0537] (Example 66) 4-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluoro-N,3-dimethylbenzamide

[0538] [ka]

[0539] The method for preparing 4-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluoro-N,3-dimethylbenzamide with reference to Example 1. MS m / z(ESI):435.2 [M+H] + .

[0540] (Example 67) 4-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-2,3-difluoro-N-methylbenzamide

[0541] [ka]

[0542] The method for preparing 4-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-2,3-difluoro-N-methylbenzamide with reference to Example 1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.84 (s, 1H), 8.41(s, 1H), 8.34 (s, 1H), 7.76 (s, 1H), 7.65 (s, 1H), 7.35-7.39 (m, 1H), 7.22-7.26 (m, 1H), 6.13 (s, 1H), 3.72 (s, 2H), 3.14 (s, 2H), 2.74-2.81 (m, 3H), 2.64-2.71 (m, 2H), 2.50-2.62 (m, 3H), 2.33 (s, 1H), 1.18 (t, J = 7.4 Hz, 3H); MS m / z (ESI): 439.2 [M+H] + .

[0543] (Example 68) 3-Ethyl-7-((4-(2-methyl-8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0544] [ka]

[0545] Preparation of 3-ethyl-7-((4-(2-methyl-8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):444.2 [M+H] + .

[0546] (Example 69) 3-Ethyl-7-((4-(2-(methyl-d3)-8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0547] [ka]

[0548] Preparation of 3-ethyl-7-((4-(2-(methyl-d3)-8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):447.2 [M+H] + .

[0549] (Example 70) 3-Ethyl-7-((4-(2-fluoro-8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0550] [ka]

[0551] Preparation of 3-ethyl-7-((4-(2-fluoro-8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):448.2 [M+H] + .

[0552] (Example 71) 7-((4-(2-chloro-8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one

[0553] [ka]

[0554] Preparation of 7-((4-(2-chloro-8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):464.2 [M+H] + .

[0555] (Example 72) 3-Ethyl-7-((4-(6-methyl-8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0556] [ka]

[0557] Preparation of 3-ethyl-7-((4-(6-methyl-8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):444.2 [M+H] + .

[0558] (Example 73) 3-Ethyl-7-((4-(6-(methyl-d3)-8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0559] [ka]

[0560] Preparation of 3-ethyl-7-((4-(6-(methyl-d3)-8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):447.2 [M+H] + .

[0561] (Example 74) 3-Ethyl-7-((4-(6-fluoro-8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0562] [ka]

[0563] Preparation of 3-ethyl-7-((4-(6-fluoro-8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):448.2 [M+H] + .

[0564] (Example 75) 7-((4-(6-chloro-8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one

[0565] [ka]

[0566] Preparation of 7-((4-(6-chloro-8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):464.2 [M+H] + .

[0567] (Example 76) 3-Ethyl-7-((4-(8-(methylamino)-1,7-naphthyridin-3-yl-6-d)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0568] [ka]

[0569] Preparation of 3-ethyl-7-((4-(8-(methylamino)-1,7-naphthyridin-3-yl-6-d)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):431.2 [M+H] + .

[0570] (Example 77) 3-Ethyl-7-((4-(8-(methylamino)-1,7-naphthyridin-3-yl-4-d)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0571] [ka]

[0572] Preparation of 3-ethyl-7-((4-(8-(methylamino)-1,7-naphthyridin-3-yl-4-d)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):431.2 [M+H] + .

[0573] (Example 78) 3-Ethyl-7-((4-(8-(methylamino)-5H-pyrido[2,3-d][1,2]oxazin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0574] [ka]

[0575] Preparation of 3-ethyl-7-((4-(8-(methylamino)-5H-pyrido[2,3-d][1,2]oxazin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. MS m / z(ESI):434.2 [M+H] + .

[0576] (Example 79) 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-methylisoindoline-1,3-dione

[0577] [ka]

[0578] Preparation of 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-2-methylisoindoline-1,3-dione with reference to Example 3. MS m / z(ESI):432.2 [M+H] + .

[0579] (Example 80) 6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylimidazo[1,5-a]pyridine-1-carboxamide

[0580] [ka]

[0581] Preparation of 6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylimidazo[1,5-a]pyridine-1-carboxamide with reference to Example 3. MS m / z(ESI):446.2 [M+H] + .

[0582] (Example 81) 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-5'-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0583] [ka]

[0584] The method for preparing 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-5'-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):422.2 [M+H] + .

[0585] (Example 82) 5-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-methylthiazole-2-carboxamide

[0586] [ka]

[0587] The method for preparing 5-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-methylthiazole-2-carboxamide with reference to Example 1. MS m / z(ESI):410.2 [M+H] + .

[0588] (Example 83) 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-(2,2,2-trifluoroethyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0589] [ka]

[0590] The method for preparing 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-(2,2,2-trifluoroethyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):472.2 [M+H] + .

[0591] (Example 84) N-Methyl-1'-((6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0592] [ka]

[0593] The method for preparing N-methyl-1'-((6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):444.2 [M+H] + .

[0594] (Example 85) 2-Chloro-1'-((3-ethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0595] [ka]

[0596] The method for preparing 2-chloro-1'-((3-ethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):442.2 [M+H] +

[0597] (Example 86) 1'-((3-ethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)methyl)-N,2-dimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0598] [ka]

[0599] The method for preparing 1'-((3-ethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)methyl)-N,2-dimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):422.2 [M+H] + .

[0600] (Example 87) 2-Chloro-1'-((2-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0601] [ka]

[0602] The method for preparing 2-chloro-1'-((2-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.62 (s, 1H), 8.61 (d, J = 2.8 Hz, 1H), 7.96 (d, J = 2.8 Hz, 1H), 7.89 (d, J = 2.8 Hz, 1H), 6.86-6.93 (m, 3H), 5.84 (s, 1H), 3.48 (m, 1H), 3.48-3.51 (m, 2H), 3.03-3.06 (m, 2H), 2.81 (d, J = 4.9, 3H), 2.63 (t, J = 8.0 Hz, 2H), 2.37-2.42 (m, 2H), 1.74-1.82 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); MS m / z (ESI): 441.2 [M+H]+ .

[0603] (Example 88) 1'-((2-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)-N,2-dimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0604] [ka]

[0605] The method for preparing 1'-((2-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)-N,2-dimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):421.2 [M+H] + .

[0606] (Example 89) 2-Chloro-1'-((3-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0607] [ka]

[0608] The method for preparing 2-chloro-1'-((3-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. 1 H NMR (400 MHz, DMSO-d 6) δ 11.20 (s, 1H), 8.6 (d, J = 3.0 Hz, 1H), 7.90 (d, J = 2.8 Hz, 1H), 7.75-7.80 (m, 2H), 7.20 (s, 1H), 5.82 (s,1H), 3.64 (s, 2H), 3.02-3.15 (m, 2H), 2.75 (d, J = 4.8 Hz, 3H), 2.52-2.69 (m, 3H), 2.32-2.41 (m, 2H), 0.82-0.98 (m, 2H), 0.58-0.70 (m, 2H); MS m / z (ESI): 466.2 [M+H] + .

[0609] (Example 90) 1'-((3-ethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0610] [ka]

[0611] The method for preparing 1'-((3-ethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):426.2 [M+H] + .

[0612] (Example 91) 1'-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0613] [ka]

[0614] The method for preparing 1'-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.42 (s, 1H), 8.71 (s, 1H), 8.03-8.15 (m, 1H), 7.82-7.98 (m, 2H), 7.20-7.30 (m, 2H), 6.28 (s,1H), 3.84-3.95 (m, 2H), 3.65 (s, 2H), 3.13-3.22 (m, 2H), 2.75 (d, J = 4.8 Hz, 3H), 2.50-2.72 (m, 4H), 1.18 (t, J = 7.4 Hz, 3H); MS m / z (ESI): 438.2 [M+H] + .

[0615] (Example 92) 1'-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-N,2-dimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0616] [ka]

[0617] The method for preparing 1'-((3-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)-N,2-dimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. 1 H NMR (400 MHz, DMSO-d6 ) δ 11.38 (s, 1H), 8.50 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 1.8 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.10-7.21 (m, 2H), 5.60 (s, 1H), 3.79-3.92 (m, 2H), 3.60 (s, 2H), 3.11-3.15 (m, 2H), 2.75 (d, J = 5.0 Hz, 3H), 2.62-2.71 (m, 2H), 2.48 (s, 3H), 2.25-2.40 (m, 2H), 1.12 (t, J = 7.2 Hz, 3H); MS m / z (ESI): 434.2 [M+H] + .

[0618] (Example 93) 1'-(1-(7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)ethyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0619] [ka]

[0620] The method for preparing 1'-(1-(7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)ethyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. 1 H NMR (400 MHz, DMSO-d 6) δ 11.82 (s, 1H), 8.67-8.73 (m, 2H), 8.46 (s, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.76 (s, 1H), 7.64 (s, 1H), 6.43 (s, 1H), 3.72 (q, J = 6.8 Hz, 1H), 3.09-3.11 (m, 2H), 2.81 (d, J = 4.7 Hz, 3H), 2.64 (t, J = 10.0 Hz, 3H), 2.52-2.58 (m, 3H), 1.40 (d, J = 6.5 Hz, 3H), 1.18 (t, J = 7.4 Hz, 3H); MS m / z (ESI): 418.2 [M+H] + .

[0621] (Example 94) 3-Ethyl-7-((4-(5-fluoro-8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0622] [ka]

[0623] Preparation of 3-ethyl-7-((4-(5-fluoro-8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. 1 H NMR (400 MHz, DMSO-d 6) δ 11.85 (s, 1H), 8.71 (d, J = 2.7 Hz, 1H), 8.40 (d, J = 1.6 Hz, 1H), 7.78 (d, J = 2.2 Hz, 1H), 7.74 (s, 1H), 7.62 (s, 1H), 7.22-7.25 (m, 2H), 3.62-3.65 (m, 2H), 3.39-3.43 (m, 4H), 2.93 (d, J = 4.8 Hz, 3H), 2.54-2.58 (m, 4H), 2.49-2.52 (m, 2H), 1.17 (t, J = 7.4 Hz, 3H); MS m / z (ESI): 448.2 [M+H] + .

[0624] (Example 95) 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N,5'-dimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0625] [ka]

[0626] The method for preparing 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N,5'-dimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):418.2 [M+H] + .

[0627] (Example 96) 5'-Chloro-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0628] [ka]

[0629] The method for preparing 5'-chloro-1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):438.2 [M+H] + .

[0630] (Example 97) 3-Ethyl-7-((4-(8-(methylamino)-1,7-naphthyridin-3-yl-5-d)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0631] [ka]

[0632] Preparation of 3-ethyl-7-((4-(8-(methylamino)-1,7-naphthyridin-3-yl-5-d)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.86 (s, 1H), 8.64 (d, J = 2.8 Hz, 1H), 8.42 (d, J = 1.7 Hz, 1H), 7.77 (d, J = 4.9 Hz, 2H), 7.64 (s, 1H), 7.29-7.32 (m, 2H), 3.64-3.67 (m, 2H), 2.95 (d, J = 4.9 Hz, 3H), 2.58-2.61 (m, 4H), 2.55 (d, J = 7.4 Hz, 2H), 2.51-2.53 (m, 4H), 1.19 (t, J = 7.4 Hz, 3H); MS m / z (ESI): 431.2 [M+H] + .

[0633] (Example 98) 3-Ethyl-7-((4-(8-((methyl-d3)amino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0634] [ka]

[0635] Preparation of 3-ethyl-7-((4-(8-((methyl-d3)amino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.79 (s, 1H), 8.57 (d, J = 2.7 Hz, 1H), 8.35 (s, 1H), 7.70 (d, J = 5.7 Hz, 2H), 7.57 (s, 1H), 7.23 (d, J = 2.6 Hz, 2H), 6.62 (d, J = 5.9 Hz, 1H), 3.55-3.60 (m, 2H), 3.25-3.31 (m, 4H), 2.47-2.53 (m, 4H), 2.48 (d, J = 7.4 Hz, 2H), 1.12 (t, J = 7.4 Hz, 3H); MS m / z (ESI): 433.3 [M+H] + .

[0636] (Example 99) 3-Ethyl-7-((4-(4-isopropyl-8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0637] [ka]

[0638] Preparation of 3-ethyl-7-((4-(4-isopropyl-8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.86 (s, 1H), 8.62 (s, 1H), 8.41 (s, 1H), 7.82 (d, J = 6.1 Hz, 1H), 7.74 (s, 1H), 7.61 (s, 1H), 7.48-7.54 (m, 1H), 7.05 (d, J = 6.1 Hz, 1H), 3.78-4.03 (m, 2H), 3.62-3.66 (m, 2H), 2.89-3.07 (m, 8H), 2.55-2.62 (m, 4H), 1.40 (d, J = 7.0 Hz, 6H), 1.16 (t, J = 7.3Hz, 3H); MS m / z (ESI): 472.2 [M+H] + .

[0639] (Example 100) 3-Ethyl-7-((4-(2-isopropyl-8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0640] [ka]

[0641] Preparation of 3-ethyl-7-((4-(2-isopropyl-8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. 1 H NMR (400 MHz, DMSO-d 6) δ 11.87 (s, 1H), 8.42 (s, 1H), 7.80 (d, J = 5.7 Hz, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.60 (s, 1H), 7.21-7.24 (m, 1H), 6.74 (d, J = 5.8 Hz, 1H), 3.64-3.69 (m, 2H), 3.46-3.66 (m, 2H), 2.87-3.04 (m, 8H), 2.52-2.69 (m, 4H), 1.27 (d, J = 6.6 Hz, 6H), 1.18 (t, J = 7.4Hz, 3H); MS m / z (ESI): 472.2 [M+H] + .

[0642] (Example 101) 3-Ethyl-7-((4-(5-methyl-8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0643] [ka]

[0644] Preparation of 3-ethyl-7-((4-(5-methyl-8-(methylamino)-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 3. 1 H NMR (400 MHz, DMSO-d 6) δ 11.86 (s, 1H), 8.65 (d, J = 2.6 Hz, 1H), 8.42 (d, J = 1.6 Hz, 1H), 7.76 (s, 1H), 7.63-7.64 (m, 2H), 7.21 (d, J = 2.6 Hz, 1H), 7.15 (s, 1H), 3.64-3.68 (m, 2H), 3.39-3.42 (m, 4H), 2.93 (d, J = 4.8 Hz, 3H), 2.57-2.61 (m, 4H), 2.52-2.58 (m, 2H), 2.27 (s, 3H), 1.19 (t, J = 7.4 Hz, 3H); MS m / z (ESI): 444.2 [M+H] + .

[0645] (Example 102) 3-Ethyl-7-((4-(8-(methylamino)-1,7-naphthyridin-3-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0646] [ka]

[0647] Preparation of 3-ethyl-7-((4-(8-(methylamino)-1,7-naphthyridin-3-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1,5-naphthyridin-2(1H)-one with reference to Example 1. 1 H NMR (400 MHz, DMSO-d 6) δ 11.84 (s, 1H), 8.92 (d, J = 2.2 Hz, 1H), 8.43 (d, J = 1.7 Hz, 1H), 8.06 (d, J = 2.2 Hz, 1H), 7.90 (d, J = 5.8 Hz, 1H), 7.76 (s, 1H), 7.66 (s, 1H), 7.57 (q, J = 4.7 Hz, 1H), 6.84 (d, J = 5.8 Hz, 1H), 6.53 (s, 1H), 3.70-3.74 (m, 2H), 3.19 (d, J = 2.6 Hz, 2H), 2.99 (d, J = 4.9 Hz, 3H), 2.72-2.75 (m, 2H), 2.58-2.62 (m, 2H), 2.51-2.57 (m, 2H), 1.19 (t, J = 7.4 Hz, 3H); MS m / z (ESI): 427.2 [M+H] + .

[0648] (Example 103) 1'-(7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0649] [ka]

[0650] The method for preparing 1'-(7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide with reference to Example 1. MS m / z(ESI):418.2 [M+H] + .

[0651] Biological Assays and Evaluation The present invention is further illustrated in conjunction with the following test examples, which are not intended to limit the scope of the invention.

[0652] Test Example 1: Determination of the inhibitory activity of the compounds of the present invention against the PARP1 enzyme 1. Experimental Objective: The experimental objective of this test example is to determine the inhibitory activity of compounds against the PARP1 enzyme.

[0653] 2. Experimental equipment: Centrifuge (Eppendorf 5810R) Microplate reader (BioTek Synergy H1 or PerkinElmer Envision) Pipette (Eppendorf or Rainin)

[0654] 3. Experimental Reagents: PARP1 chemiluminescence assay kit, purchased from BPS bioscience, product number 80569 20×PBST, purchased from Thermo, product number 28352 PBS, purchased from Gibco, product number 10010023

[0655] 4. Experimental Method: The inhibitory activity of the compounds against the PARP1 enzyme was determined by chemiluminescence in the experiment. The experiment was performed in a 384-well plate. Coating histones in 384-well plates: 5x histone solution was diluted 5-fold with PBS and added to a 384-well ELISA plate (25 μL per well) and incubated overnight at 4°C. The coated ELISA plate was rinsed with 1x PBST buffer, blocked with blocking buffer (blocking buffer 3 in the kit, 100 μL per well) for 30-120 min, and rinsed 3-6 times with 1x PBST buffer. A mixture of PARP reaction biotin-labeled substrate, activated DNA, 10x PARP buffer and water was added (12.5 μL per well). Compound solutions with different concentrations were formulated using the experiment buffer (10% DMSO aqueous solution containing 1.25 mM DTT). The final detection concentration was started from 100 nM with 3-fold dilutions and 8 concentrations. The compound solution was added to the reaction wells of a 384-well plate (2.5 μL per well). 2.5 μL of 10% DMSO aqueous solution containing 1.25 mM DTT was added to the positive control wells and blank wells (2.5 μL per well). 10 μL of PARP1 enzyme solution formulated in 1×PARP buffer was added to start the reaction. The plate was centrifuged at 1000 rpm for 1 min and reacted at room temperature for 60 min. After completion of the reaction, the reaction solution was discarded and the plate was rinsed with 1×PBST buffer. Streptavidin-HRP solution diluted 50-fold with blocking buffer 3 was added (25 μL per well) and the plate was incubated at room temperature for 30 min. The reaction solution was discarded and the plate was rinsed 3 to 6 times with 1×PBST buffer. For the reaction, the luminescence reaction solution obtained by mixing ECL substrate A and ELISA ECL substrate B (1:1) was added (50 μL per well). Chemiluminescence values ​​were immediately measured using a BioTek Synergy H1 or Envision instrument.

[0656] 5. Experimental data processing method: Chemiluminescence values ​​were measured using a BioTek Synergy H1 or Envision instrument. Percentage inhibition was calculated, and concentrations and percent inhibition were fitted to a nonlinear regression curve using Graphpad Prism software to obtain IC values. 50 Got the value.

[0657] The inhibitory activity of some compounds according to the present invention examples against the PARP1 enzyme is shown in the table below.

[0658] [Table 1A]

[0659] [Table 1B]

[0660] 6. Experimental Conclusion: The compounds of the present invention show excellent biological activity in PARP1 enzyme inhibition experiments.

[0661] Test Example 2: Determination of the inhibitory activity of the compounds of the present invention against the PARP2 enzyme 1. Experimental Objective: The experimental objective of this test example is to determine the inhibitory activity of compounds against the PARP2 enzyme.

[0662] 2. Experimental equipment: Centrifuge (Eppendorf 5810R) Microplate reader (BioTek Synergy H1 or PerkinElmer Envision) Pipette (Eppendorf or Rainin)

[0663] 3. Experimental Reagents: PARP2 chemiluminescence assay kit, purchased from BPS bioscience, product number 80552 20×PBST, purchased from Thermo, product number 28352 PBS, purchased from Gibco, product number 10010023

[0664] 4. Experimental Method: The inhibitory activity of the compounds against PARP2 enzyme was determined by chemiluminescence method in the experiment. The experiment was performed in 96-well plate. Coating histones in 96-well plate: 5x histone solution was diluted 5-fold with PBS and added to 96-well ELISA plate (50 μL per well) and incubated at 4°C overnight. The coated ELISA plate was rinsed with 1x PBST buffer, blocked with blocking buffer (blocking buffer 3 in the kit, 200 μL per well) for 30-120 min, and rinsed 3-6 times with 1x PBST buffer. PARP reaction A mixture of biotin-labeled substrate, activated DNA, 10x PARP buffer and water was added (25 μL per well). Compound solutions with different concentrations were formulated using the experiment buffer (10% DMSO aqueous solution containing 1.25 mM DTT). The final detection concentration was started from 10 μM, with 3-fold dilutions and 8 concentrations. Compound solutions were added to the reaction wells of 96-well plate (5 μL per well). 5 μL of 10% DMSO aqueous solution containing 1.25 mM DTT was added to the positive control wells and blank wells (5 μL per well). 20 μL of PARP2 enzyme solution formulated in 1×PARP buffer was added to start the reaction. The plate was centrifuged at 1000 rpm for 1 min and reacted at room temperature for 60 min. After completion of the reaction, the reaction solution was discarded and the plate was rinsed with 1×PBST buffer. Streptavidin-HRP solution diluted 50-fold with blocking buffer 3 was added (50 μL per well) and the plate was incubated at room temperature for 30 min. The reaction solution was discarded and the plate was rinsed 3-6 times with 1×PBST buffer. For the reaction, luminescence reaction solution obtained by mixing ECL substrate A and ELISA ECL substrate B (1:1) was added (100 μL per well). Chemiluminescence values ​​were immediately measured using a BioTek Synergy H1 or Envision instrument.

[0665] 5. Experimental data processing method: Chemiluminescence values ​​were measured using a BioTek Synergy H1 or Envision instrument. Percentage inhibition was calculated, and concentrations and percent inhibition were fitted to a nonlinear regression curve using Graphpad Prism software to obtain IC values. 50 Got the value.

[0666] 6. Experimental Conclusion: The compounds of the present invention show high selectivity for PARP2 in PARP2 enzyme inhibitory activity experiments.

[0667] Test Example 3: Determination of the inhibitory effect of the compounds of the present invention on the proliferation activity of BRCA2 knockout DLD-1 cells 1. Experimental Objective: The experimental objective of this test example is to determine the inhibitory effect of compounds on the proliferation activity of BRCA2 knockout DLD-1 cells.

[0668] 2. Experimental equipment: Centrifuge (Eppendorf 5810R) Microplate reader (BioTek Synergy H1 or PerkinElmer Envision) Pipette (Eppendorf or Rainin)

[0669] 3. Experimental Reagents: BRCA2 knockout DLD-1 cells, purchased from Creative Biogene Cell Titer-Glo, purchased from Promega, product number G7573 RPMI 1640, purchased from Gibco, product number 22400089 FBS, purchased from Gibco, product number 10091148 PBS, purchased from Gibco, product number 10010023 Trypsin, purchased from Gibco, product number 25200056 Cell culture plates, purchased from Corning, product number 3610

[0670] 4. Experimental Method: BRCA2 knockout DLD-1 cells were cultured to an appropriate cell density using RPMI1640 culture medium containing 10% FBS. The cells were harvested and adjusted to an appropriate cell concentration using complete culture medium. The cell suspension was spread onto a 96-well plate (90 μL per well) and incubated at 37°C, 5% CO 2 The cells were then placed in an incubator at 37° C. overnight. Compound solutions at different concentrations were formulated using DMSO and culture medium to provide a vehicle control. Compound solutions were added to a 96-well plate (10 μL per well) and the plate was incubated at 37° C., 5% CO 2 The plates were incubated in a 37°C incubator for approximately 144 hours. CellTiter-Glo solution was added, the plates were shaken to mix evenly, and incubated in the dark for 10-30 minutes. Values ​​were measured using a Synergy H1 or Envision microplate reader.

[0671] 5. Experimental data processing method: The luminescence signal values ​​were used to calculate the percent inhibition. The concentrations and percent inhibition were fitted to a nonlinear regression curve using Graphpad Prism software to obtain the IC 50 Got the value.

[0672] The inhibitory effects of some compounds according to the examples of the present invention on the proliferation activity of BRCA2 knockout DLD-1 cells are shown in the table below.

[0673] [Table 2]

[0674] 6. Experimental Conclusion: The compounds of the present invention show excellent biological activity in a proliferation activity inhibition experiment of BRCA2 knockout DLD-1 cells.

[0675] Test Example 4: Bidirectional permeability test of compounds through Caco-2 cell model 1. Purpose of the experiment: The purpose of this experiment is to determine the bidirectional permeability of compounds through the Caco-2 cell model.

[0676] 2. Experimental equipment and materials: Liquid chromatography mass spectrometer, centrifuge, vortexer, pipette, 24-well test plate, acetonitrile solution containing internal standards, Caco-2 cells (ATCC), Hank's balanced salt solution (HBSS), dimethyl sulfoxide (DMSO)

[0677] 3. Experimental Method: 1) Cultivation of Caco-2 monolayer cells: Caco-2 cells in good condition were spread on plates and cultured for 21-28 days (the culture medium was changed every 2-3 days) to form a dense cell monolayer for permeability testing.

[0678] 2) Evaluation of permeability of test compounds: a. 100 μL of transport buffer (HBSS containing 10 μM test compound, 0.5% BSA and 0.5% DMSO) was added from A to B at the administration end. b. 300 μL of transport buffer (HBSS containing 0.5% BSA) was added to the receiving end from A to B. c. 300 μL of transport buffer (HBSS containing 10 μM test compound, 0.5% BSA and 0.5% DMSO) was added to the B to A dosing end. d. 100 μL of transport buffer (HBSS containing 0.5% BSA) was added to the B to A receiving end. e. 2 hour incubation d. Samples were collected, processed, and detected by mass spectrometry.

[0679] 4. Chromatographic conditions: Instrumentation: Liquid chromatography; Chromatographic column: Waters XSelect HSS T3 C18 (2.1 × 50 mm, 2.5 μm); Mobile phase: Phase A: water containing 0.1% formic acid; Phase B: acetonitrile containing 0.1% formic acid.

[0680] 5.Mass spectrometry conditions: Instrumentation: API4000 liquid chromatography mass spectrometer; Ion source: electrospray ionization source (ESI); Detection method: cation detection; Scanning mode: multiple reaction monitoring (MRM) mode.

[0681] 6. Experimental results: The bidirectional permeability of compounds of the examples of the present invention through the Caco-2 cell model is shown in the table below.

[0682] [Table 3]

[0683] 7.Conclusion of the experiment: From the experimental results in the above table, it can be seen that the compounds of the examples of the present invention have high permeability.

[0684] Test Example 5. Pharmacokinetic assay in Balb / C mice 1. Purpose of the experiment: Balb / C mice were used as test animals. The pharmacokinetic behavior of the compounds of the examples was studied in the mouse body (plasma) by oral administration at a dose of 1 mg / kg.

[0685] 2. Experimental Protocol 2.1 Test Compounds: Compounds of the examples of the present invention prepared by the applicant.

[0686] 2.2 Test animals: Male Balb / C mice (6 mice per example) were purchased from Shanghai Jiesijie Laboratory Animal Co., LTD, with approval number SCXK(Shanghai)2013-0006 No.311620400001794.

[0687] 2.3 Compound Formulation: 5 g of hydroxyethyl cellulose (HEC, CMC-Na, viscosity: 800-1200 Cps) was weighed and dissolved in 1000 mL of purified water, followed by the addition of 10 g of Tween 80. The mixture was mixed thoroughly to obtain a clear solution.

[0688] 2.05 mg of compound was weighed and dissolved in the solution. The mixture was shaken thoroughly, crushed in a cell crusher for 1 min, and sonicated for 15 min to obtain a suspension with a concentration of 0.1 mg / mL.

[0689] 2.4 Administration: After an overnight fast, male Balb / C mice were administered test compounds po at a dose of 1 mg / kg in a volume of 10 mL / kg.

[0690] 2.5 Sample Collection: At 0, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration, 0.04 mL of blood was collected from the orbit of each mouse. 2 The tubes were stored and centrifuged at 6000 rpm for 6 minutes at 4° C. to separate the plasma. Plasma samples were stored at −80° C. Mice were fed for 4 hours after dosing.

[0691] 2.6 Sample Processing: 1) For precipitation, 160 μL of acetonitrile was added to 40 μL of plasma sample, and then the mixture was centrifuged at 3500 × g for 5 to 20 min. 2) After the above steps, 100 μL of the supernatant was collected and analyzed for the concentration of the test compound by LC / MS / MS.

[0692] 2.7 Liquid Chromatography Analysis Liquid chromatography conditions: Shimadzu LC-20AD pump ·Mass spectrometry conditions: AB Sciex API4000 mass spectrometer Chromatography column: phenomenex Gemiu 5μm C18 50×4.6mm Mobile phase: Eluent A was 0.1% formic acid in water and Eluent B was acetonitrile. ·Flow rate: 0.8mL / min Elution time: 0-4.0 min., eluent:

[0693] [Table 4]

[0694] 3. Experimental results and analysis: The main pharmacokinetic parameters were calculated by WinNonlin 8.2. The results of the pharmacokinetic study in mice are shown in the table below.

[0695] [Table 5]

[0696] 4. Experimental conclusion: From the results of the pharmacokinetic study in mice shown in the table, the compounds in the examples of the present invention showed good absorption and metabolic properties, and the exposure AUC and maximum plasma concentration C max It can be seen that both are good.

[0697] Test Example 6. PK / PD test of compounds in a human breast cancer cell line MDA-MB-436 subcutaneous xenograft tumor model in nude mice 1. Purpose of the experiment: To evaluate the distribution of the compound in plasma and tumor, and the inhibitory effect on PAR in tumor tissue after a single oral administration in a human breast cancer cell line MDA-MB-436 subcutaneous xenograft tumor model in nude mice.

[0698] 2. Laboratory equipment and reagents: 2.1 Equipment Refrigerator (BCD-268TN, Haier) Biological safety cabinet (BSC-1300II A2, medical equipment factory of Shanghai Boxun Industrial Co., Ltd.) Ultra-clean workbench (CJ-2F, Suzhou Fengshi Laboratory Equipment Co., Ltd.) Electronic pipette aid (Easypet 3, Eppendorf) Constant temperature water bath (HWS-12, Shanghai Yiheng Scientific Instruments Co., Ltd.) CO 2 Incubator (Thermo-311, Thermo) Centrifuge (Centrifuge 5720R, Eppendorf) Automatic cell counter (Countess II, Life Technologies) Caliper (CD-6''AX, Mitutoyo, Japan) Cell culture flasks (T25 / T75 / T225, Corning) Electronic balance (CPA2202S, Sartorius) Electronic balance (BSA2202S-CW, Sartorius) Ultrasonic cleaner (115F0032, Shanghai Kudos Ultrasonic Instrument Co., Ltd.) Pure water meter (Pacific TII, Thermo) Magnetic stirrer (08-2G, Chijiu) Centrifuge (Centrifuge 5418R, Eppendorf) Small protein vertical electrophoresis and transfer system (PowerPac Universal Power Supply, Bio-Rad) Microplate reader (H1MFD, Biotek) Molecular imaging system (ChemiDoc™ MP, Bio-Rad) Semi-dry film transfer device (690BR027087, Bio-Rad) Tissue grinder (TISS-48, Shanghai Jingxin Experimental Equipment Co., Ltd.) Pipette (METTLER TOLEDO / Eppendorf) Dry thermostat (MK200-2, Hangzhou Aokangsheng Instrument Co., Ltd.)

[0699] 2.2 Reagents DMEM culture medium (31600-034, Gibco) Fetal bovine serum (FBS) (10099-141C, Gibco) Insulin-transferrin-selenium (ITS-G) (41400-045, Gibco) Phosphate buffered saline (PBS) (10010-023, Gibco) Tween 80 (30189828, Sinopharm Chemical Reagent Co., Ltd.) Sodium carboxymethylcellulose (30036365, Sinopharm Chemical Reagent Co., Ltd.) Matrigel Matrix (356234, Corning) Trans-Blot Turbo Transfer Pack (1704157, Bio-Rad) 4-15% Criterion™ TGX™ Gel (5671085, Bio-Rad) GAPDH(D4C6R) mice (97166S, CST) IRDye® 800CW Goat Anti-Mouse IgG (H+L) (P / N 926-32210, LI-COR) IRDye® 680RD Goat Anti-Rabbit IgG (H+L) (P / N 926-68071, LI-COR) Poly / mono-ADP-ribose (E6F6A) rabbit mAb (83732S, CST) Pierce BCA Protein Assay Kit (23227, Thermo Fisher) QuickBlock Western Blocking Buffer (P0252-500ml, Beyotime) NuPAGE® Sample Reducing Agent (10x) (NP0009, Thermo Fisher) NuPAGE™ LDS Sample Buffer (4x) (NP0007, Thermo Fisher) Pierce 20x TBS with Tween-20 (28360, Thermo Fisher)

[0700] 3. Experimental Method 3.1 Animals BALB / c nude mice, 6-8 weeks old, female, purchased from the Laboratory Animal Care Department of Shanghai Institute of Family Planning Co., Ltd.

[0701] 3.2 Cell culture and preparation of cell suspension A line of MDA-MB-436 cells was obtained from a cell bank and restored in DMEM culture medium (DMEM + 10% FBS + 1% ITS-G). The restored cells were seeded into cell culture flasks (labeled on the flask wall with the cell type, date, and name of the experimenter) and incubated with CO. 2 The culture was performed in an incubator (temperature was 37°C, CO 2 The concentration was 5%. b. Cells were passaged every 3 days. After passage, cells were incubated at 4°C for 3 h at 4°C for 1 h. 2 The cells were then allowed to continue to grow in the incubator. This process was repeated until the number of cells was sufficient for in vivo efficacy testing. c. The cultured cells were harvested and counted using an automated cell counter. Depending on the counting results, the cells were resuspended in PBS and mixed with Matrigel matrix at a 1:1 ratio of 5 × 10 7 The resulting suspension was placed in an ice chest for later use.

[0702] 3.3 Cell inoculation a. Prior to inoculation, nude mice were tagged with disposable common ear tags for rats and mice. b. During inoculation, the cell suspension was mixed thoroughly. 0.1-1 mL of cell suspension was aspirated into a 1 mL syringe, air bubbles were removed, and then the syringe was placed on an ice pack for later use. c. The nude mouse was restrained with the left hand. The right side of the back near the right shoulder (the inoculation site) of the nude mouse was disinfected with 75% alcohol. Inoculation was started after 30 seconds. d. Test nude mice were inoculated subsequently (each mouse was inoculated with 0.1 mL of the cell suspension).

[0703] 3.4 PK / PD Studies a. Grouping: According to tumor growth, tumors 300-500 mm 3 When the tumors grew to a volume of 100 μg / kg, the tumor-bearing mice were selected according to the experimental design and randomly divided into groups (3 mice per time point) to initiate the PK / PD study. b. Fasting: All tumor-bearing mice were fasted overnight (with free access to water) prior to dosing (>8 hours fasting). c. Administration: Except for the blank control group, a single oral administration was performed with a dosing volume of 10 mL / kg according to the time of the experimental design. d. Sample collection: Mice were incubated with CO according to the experimental design. 2 Animals were euthanized by asphyxiation and samples were collected. One plasma sample and three tumor tissue samples were collected from each animal.

[0704] Mice were incubated with CO according to the experimental design. 2 Animals were euthanized by asphyxiation and samples were collected.

[0705] Plasma collection: After euthanasia of the mice, blood was collected from the heart. The collected blood was diluted with EDTA-K 2 The tubes were manually inverted 3-4 times, placed on ice, and centrifuged at 8000 rpm for 5 min at 4°C. 100 μL of centrifuged plasma was transferred to a new, labeled centrifuge tube. One aliquot of plasma was quickly frozen on dry ice and stored in a refrigerator at -80 ± 10°C for PK studies.

[0706] Tumor tissue collection: Following blood collection, tumor tissue was collected. The collected tumor tissue was divided into 3 aliquots (approximately 0.1 g each) and placed into labeled 2 mL centrifuge tubes and stored in a refrigerator at -80±10°C for PK or PD studies.

[0707] The remaining tumor-bearing mice were used to collect blank plasma and blank tumor tissue.

[0708] 3.5 PK studies a. Sample processing: 1) 4 parts of 20% methanol in water was added to 1 part of tumor tissue sample and homogenized at 40 Hz for 400 s. 100 μL of acetonitrile was added to 20 μL of the resulting homogenate for precipitation, and the mixture was then centrifuged at 3500 × g for 5–20 min.

[0709] 2) After the above steps, 100 μL of the supernatant was collected and analyzed for the concentration of the test compound by LC / MS / MS.

[0710] b. Liquid Chromatography Analysis Liquid chromatography conditions: Shimadzu LC-20AD pump ·Mass spectrometry conditions: AB Sciex API4000 mass spectrometer Chromatography column: phenomenex Gemiu 5μm C18 50×4.6mm Mobile phase: Eluent A was 0.1% formic acid in water and Eluent B was acetonitrile. ·Flow rate: 0.8mL / min Elution time: 0-4.0 min., eluent:

[0711] [Table 6]

[0712] 3.6 PD Test Lysis of tumor tissue samples 1 mL of tumor lysis solution was added to each tube of tumor tissue samples, followed by the addition of steel beads. For tissue homogenization, the samples were placed in a tissue grinder, lysed on ice for 20 min, and centrifuged at 10,000 g for 5 min at 4°C. The protein supernatant was collected.

[0713] b. Protein sample preparation Protein quantification was performed by BCA protein quantification kit. Depending on the concentration, protein supernatant samples, 10x sample reducing agent, 4x LDS sample buffer and lysate were formulated into a protein loading solution of a fixed concentration. The protein loading solution was placed in a pre-heated dry thermostat and incubated at 100°C for 10 minutes to denature the proteins.

[0714] c. Western blot experiment of protein samples 1) Electrophoresis: Protein samples were loaded onto 4-15% Criterion™ TGX™ Gel protein gels (15 μL for each protein sample). The gels were placed in an electrophoresis tank filled with electrophoresis solution, and protein gel electrophoresis was performed at 150 V for 60 min.

[0715] 2) Transfer: Using the Trans-Blot Turbo Transfer Pack kit, the multi-layer filter paper, the PVDF membrane, the protein gel and the thick filter paper were placed in order and placed in the transfer machine. The transfer was performed by the program MIXED MW (2.5A-25V-7min).

[0716] 3) Antibody blocking and incubation: The PVDF membrane was removed from the transfer machine and placed in QuickBlock Western blocking buffer and shaken on a shaker at room temperature for more than 1 hour to block the proteins. The PVDF membrane was added to PAR (1:500) or GAPDH (1:5000) primary antibody dilutions diluted in QuickBlock Western blocking buffer and incubated overnight at 4°C. The primary antibody dilutions were removed and the membrane was rinsed six times with 1xTBST. Goat anti-rabbit (1:3000) and goat anti-mouse (1:5000) fluorescent secondary antibody solutions diluted in QuickBlock Western blocking buffer were added and incubated at room temperature in the dark for 1 hour. The antibody dilutions were removed and the membrane was rinsed six times with 1xTBST.

[0717] 4) Imaging: For imaging, the washed PVDF membrane was placed in a Biorad ChemiDoc™ MP imager. PAR was subjected to fluorescent imaging and Gapdh internal control was subjected to fluorescent imaging using the IRDye 800 CW channel.

[0718] 4. Experimental Results

[0719] [Table 7]

[0720] 5. Conclusion of the Experiment In MDA-MB-436 (breast cancer, BRCA1 mutation) model, the plasma concentration within 24 hours after single administration of the compound of Example 1 is higher than that of AZD5305, and the inhibition of PAR in tumor is comparable. A single administration of the compound of Example 1 can inhibit PAR in tumor for 72 hours, which is superior to AZD5305.

[0721] Test Example 7: Human colorectal cancer cell line DLD-1 BRCA2 in nude mice - / - In vivo pharmacodynamic testing of compounds in subcutaneous xenograft tumor models 1. Purpose of the experiment: Human colorectal cancer cell line DLD-1 BRCA2 in nude mice - / - To evaluate the in vivo efficacy of compounds in subcutaneous xenograft tumor models.

[0722] 2. Laboratory equipment and reagents: 2.1 Equipment Refrigerator (BCD-268TN, Haier) Biological safety cabinet (BSC-1300II A2, medical equipment factory of Shanghai Boxun Industrial Co., Ltd.) Ultra-clean workbench (CJ-2F, Suzhou Fengshi Laboratory Equipment Co., Ltd.) Electronic pipette aid (Easypet 3, Eppendorf) Constant temperature water bath (HWS-12, Shanghai Yiheng Scientific Instruments Co., Ltd.) CO 2 Incubator (Thermo-311, Thermo) Centrifuge (Centrifuge 5720R, Eppendorf) Automatic cell counter (Countess II, Life Technologies) Caliper (CD-6''AX, Mitutoyo, Japan) Cell culture flasks (T25 / T75 / T225, Corning) Electronic balance (CPA2202S, Sartorius) Electronic balance (BSA2202S-CW, Sartorius) Ultrasonic cleaner (115F0032, Shanghai Kudos Ultrasonic Instrument Co., Ltd.) Pure water meter (Pacific TII, Thermo) Magnetic stirrer (08-2G, Chijiu)

[0723] 2.2 Reagents RPMI-1640 culture medium (22400-089, Gibco) Fetal bovine serum (FBS) (10099-141C, Gibco) Phosphate buffered saline (PBS) (10010-023, Gibco) Tween 80 (30189828, Sinopharm Chemical Reagent Co., Ltd.) Sodium carboxymethylcellulose (30036365, Sinopharm Chemical Reagent Co., Ltd.)

[0724] 3. Experimental methods and data processing 3.1 Animals BALB / c nude mice, 6-8 weeks old, female, purchased from the Laboratory Animal Care Department of Shanghai Institute of Family Planning Co., Ltd.

[0725] 3.2 Cell culture and preparation of cell suspension a. DLD-1 BRCA2 - / - Cell lines were harvested from cell banks and recovered in RPMI-1640 culture medium (RPMI-1640 + 10% FBS). The recovered cells were seeded into cell culture flasks (labeled on the flask wall with cell type, date, and experimenter name) and incubated in CO 2 The culture was performed in an incubator (temperature was 37°C, CO 2 The concentration was 5%.

[0726] b. Cells were passaged every 3 days. After passage, cells were incubated at 4°C for 3 h at 4°C for 1 h. 2 The cells were then allowed to continue to grow in the incubator. This process was repeated until the number of cells was sufficient for in vivo efficacy testing.

[0727] c. The cultured cells were collected and counted using an automatic cell counter. Depending on the counting results, the cells were resuspended in PBS to obtain a cell suspension (density: 5 × 10 7 / mL) was obtained and placed in an icebox for later use.

[0728] 3.3 Cell inoculation a. Prior to inoculation, nude mice were tagged with disposable common ear tags for rats and mice.

[0729] b. During inoculation, the cell suspension was mixed thoroughly. 0.1-1 mL of cell suspension was aspirated into a 1 mL syringe, air bubbles were removed, and then the syringe was placed on an ice pack for later use.

[0730] c. The nude mouse was restrained with the left hand. The right side of the back near the right shoulder (the inoculation site) of the nude mouse was disinfected with 75% alcohol. Inoculation was started after 30 seconds.

[0731] d. Test nude mice were inoculated subsequently (each mouse was inoculated with 0.1 mL of the cell suspension).

[0732] 3.4 Tumor Measurement, Grouping, and Dosing of Tumor-Bearing Mice a. Tumors were measured 10-18 days after inoculation and tumor size was calculated according to tumor growth.

[0733] Tumor volume calculation: Tumor volume (mm 3 ) = length (mm) x width (mm) x width (mm) / 2

[0734] b. Tumor-bearing mice were randomly divided into groups according to their body weight and tumor size.

[0735] c. The test compound was administered according to the grouping results (administration route: oral administration, administration volume: 10 mL / kg, administration frequency: once a day, administration cycle: 21 days, vehicle: 0.5% CMC-Na / 1% Tween 80).

[0736] d. After test compound dosing was initiated, tumors were measured and mice were weighed twice weekly.

[0737] e. Animals were euthanized at the end of the experiment.

[0738] f. Data was processed by using software such as Excel. Calculation of tumor growth inhibition rate TGI(%) of compound: If tumor does not regress, TGI(%)=[1-(mean tumor volume of treatment group at end of administration-mean tumor volume of treatment group at start of administration) / (mean tumor volume of vehicle control group at end of administration-mean tumor volume of vehicle control group at start of treatment)]×100%. If tumor regresses, TGI(%)=[1-(mean tumor volume of treatment group at end of administration-mean tumor volume of treatment group at start of administration) / mean tumor volume of treatment group at start of administration]×100%.

[0739] 1.4 Experimental results and conclusions: The compounds of Examples 1, 3, 29, 35 and 46 of the present invention showed excellent tumor inhibition effects in this model experiment, and their tumor growth inhibition rates TGI(%) were >90%, and the tumor growth inhibition rates of the preferred compounds were TGI(%)>150%, and the animal body weight was not significantly reduced.

Claims

1. Formula (I) 【Chemistry 1】 wherein Ring A, Ring B, Ring C, and Ring D are each independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 1 is hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R 11 , -(CH 2 ) n OR 11 , -(CH 2 ) n C(O)R 11 , -(CH 2 ) n C(O)OR 11 , -(CH 2 ) n S(O) m R 11 , -(CH 2 ) n NR 22 R 33 , -(CH 2 ) n NR 22 C(O)OR 33 , -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , -(CH 2 ) n NR 22 C(O)NR 22 R 33 , -(CH 2 ) n C(O)NR 22 (CH 2 ) n1 R 33 , -OC(R 11 R 22 ) n (CH 2 ) n1 R 33 and -(CH 2 ) n NR 22 S(O) m R 33 wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted; R 11 , R 22 and R 33 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkyl substituted with cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally further substituted; L 1 , L 2 and L 3 represents a bond, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -(CH 2 ) n -, -(CH 2 ) n C(O)(CR aa R bb ) n1 -, -(CH 2 ) n C(O)NR aa (CH 2 ) n1 -, -(CH 2 ) n (CR aa R bb ) n2 -, -(CR aa R bb ) n O(CH 2 ) n1 -, -(CH 2 ) n O(CR aa R bb ) n1 -, -(CR aa R bb ) n3 S(CH 2 ) n4 -, -(CH 2 ) n S(CR aa R bb ) n3 -, -(CR aa R bb ) n3 (CH 2 ) n NR cc -, -(CH 2 ) n NR aa (CR bb R cc ) n -, -(CH 2 ) n NR aa C(O)-, -(CH 2 ) n P(O) p R aa -, -(CH 2 ) n S(O) m -, -(CH 2 ) n S(O) m NR aa - and -(CH 2 ) n NR aa S(O) m - each independently selected from the group consisting of R aa , R bb and R cc are each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally further substituted; Each R a is hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R a1 , -(CH 2 ) n OR a1 , -(CH 2 ) n C(O)R a1 , -(CH 2 ) n C(O)OR a1 , -(CH 2 ) n S(O) m R a1 , -(CH 2 ) n NR a2 R a3 , -(CH 2 ) n NR a2 C(O)OR a3 , -(CH 2 ) n NR a2 C(O)(CH 2 ) n1 R a3 , -(CH 2 ) n NR a2 C(O)NR a2 R a3 , -(CH 2 ) n C(O)NR a2 (CH 2 ) n1 R a3 , -OC(R a1 R a2 ) n (CH 2 ) n1 R a3 and -(CH 2 ) n NR a2 S(O) m R a3 wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted; R a1 , R a2 and R a3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally further substituted; Each R b is hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R b1 , -(CH 2 ) n OR b1 , -(CH 2 ) n C(O)R b1 , -(CH 2 ) n C(O)OR b1 , -(CH 2 ) n S(O) m R b1 , -(CH 2 ) n NR b2 R b3 , -(CH 2 ) n NR b2 C(O)OR b3 , -(CH 2 ) n NR b2 C(O)(CH 2 ) n1 R b3 , -(CH 2 ) n NR b2 C(O)NR b2 R b3 , -(CH 2 ) n C(O)NR b2 (CH 2 ) n1 R b3 , -OC(R b1 R b2 ) n (CH 2 ) n1 R b3 and -(CH 2 ) n NR b2 S(O) m R b3 wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted; R b1 , R b2 and R b3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally further substituted; Each R c is hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R c1 , -(CH 2 ) n OR c1 , -(CH 2 ) n C(O)R c1 , -(CH 2 ) n C(O)OR c1 , -(CH 2 ) n S(O) m R c1 , -(CH 2 ) n NR c2 R c3 , -(CH 2 ) n NR c2 C(O)OR c3 , -(CH 2 ) n NR c2 C(O)(CH 2 ) n1 R c3 , -(CH 2 ) n NR c2 C(O)NR c2 R c3 , -(CH 2 ) n C(O)NR c2 (CH 2 ) n1 R c3 , -OC(R c1 R c2 ) n (CH 2 ) n1 R c3 and -(CH 2 ) n NR c2 S(O) m R c3 wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted; R c1 , R c2 and R c3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally further substituted; Each R d is hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R d1 , -(CH 2 ) n OR d1 , -(CH 2 ) n C(O)R d1 , -(CH 2 ) n C(O)OR d1 , -(CH 2 ) n S(O) m R d1 , -(CH 2 ) n NR d2 R d3 , -(CH 2 ) n NR d2 C(O)OR d3 , -(CH 2 ) n NR d2 C(O)(CH 2 ) n1 R d3 , -(CH 2 ) n NR d2 C(O)NR d2 R d3 , -(CH 2 ) n C(O)NR d2 (CH 2 ) n1 R d3 , -OC(R d1 R d2 ) n (CH 2 ) n1 R d3 and -(CH 2 ) n NR d2 S(O) m R d3 wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted; R d1 , R d2 and R d3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally further substituted; w, x, y and z are each independently 1, 2, 3 or 4; each m is independently 0, 1, or 2; each n is independently 0, 1, 2, 3, or 4; each p is independently 0 or 1; n1, n2, n3 and n4 are each independently 0, 1, 2, 3 or 4. or a stereoisomer or a pharma- ceutically acceptable salt thereof.

2. Formula (III) 【Chemistry 2】 (In the formula, 【Chemistry 3】 is a single bond or a double bond, L 1 is a bond, -(CH 2 ) n C(O)(CR aa R bb ) n1 -, -(CH 2 ) n (CR aa R bb ) n2 -or- aa R bb ) n O(CH 2 ) n1 - and L 2 is a bond or -(CH 2 ) n (CR aa R bb ) n2 - and L 3 is a bond, -(CH 2 ) n C(O)(CR aa R bb ) n1 -, -(CH 2 ) n C(O)NR aa (CH 2 ) n1 -, -(CH 2 ) n (CR aa R bb ) n2 -, -(CR aa R bb ) n O(CH 2 ) n1 - and -(CH 2 ) n NR aa (CR bb R cc ) n - selected from the group consisting of R aa , R bb and R cc are each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, and alkynyl; Or R aa , R bb and R cc any two of the following may be joined to form a cycloalkyl: M 1 is N, C or CR 2 and M 2 is N or CR 3 and M 5 HA-CR 6 R 7 -, -CR 6 R 7 -CR 8 R 9 -, -CR 6 =CR 8 -, -CR 6 R 7 -NR 8 -, -NR 8 -C(=O)-, -CR 6 R 7 -O- or -CR 6 =N-, M 6 is N or CR 10 and R 1 is hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R 11 , -(CH 2 ) n OR 11 , -(CH 2 ) n C(O)R 11 , -(CH 2 ) n C(O)OR 11 , -(CH 2 ) n S(O) m R 11 , -(CH 2 ) n NR 22 R 33 , -(CH 2 ) n NR 22 C(O)OR 33 , -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , -(CH 2 ) n NR 22 C(O)NR 22 R 33 , -(CH 2 ) n C(O)NR 22 (CH 2 ) n1 R 33 , -OC(R 11 R 22 ) n (CH 2 ) n1 R 33 and -(CH 2 ) n NR 22 S(O) m R 33 wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted; R 11 , R 22 and R 33 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkyl substituted with cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally further substituted; R 2 and R 3 are the same or different and each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, optionally substituted with alkyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, preferably R 2 and R 3 are each independently hydrogen, deuterium, halogen, alkyl, or cycloalkyl; R 6 , R 7 , R 8 , R 9 and R 10 are the same or different and each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, optionally substituted with alkyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, preferably R 6 , R 7 , R 8 and R 9 are each independently hydrogen, deuterium, halogen, cyano, alkyl, alkynyl, or cycloalkyl; Or R 6 , R 7 are joined together with adjacent carbon atoms to form a cycloalkyl, which is optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, and amino; Or R 6 , R 8 are joined together with adjacent carbon atoms to form a cycloalkyl, which is optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, and amino; Each R b is hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R b1 , -(CH 2 ) n OR b1 , -(CH 2 ) n C(O)R b1 , -(CH 2 ) n C(O)OR b1 , -(CH 2 ) n S(O) m R b1 , -(CH 2 ) n NR b2 R b3 , -(CH 2 ) n NR b2 C(O)OR b3 , -(CH 2 ) n NR b2 C(O)(CH 2 ) n1 R b3 , -(CH 2 ) n NR b2 C(O)NR b2 R b3 , -(CH 2 ) n C(O)NR b2 (CH 2 ) n1 R b3 , -OC(R b1 R b2 ) n (CH 2 ) n1 R b3 and -(CH 2 ) n NR b2 S(O) m R b3 wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted; R b1 , R b2 and R b3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally further substituted; Each R c is hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R c1 , -(CH 2 ) n OR c1 , -(CH 2 ) n C(O)R c1 , -(CH 2 ) n C(O)OR c1 , -(CH 2 ) n S(O) m R c1 , -(CH 2 ) n NR c2 R c3 , -(CH 2 ) n NR c2 C(O)OR c3 , -(CH 2 ) n NR c2 C(O)(CH 2 ) n1 R c3 , -(CH 2 ) n NR c2 C(O)NR c2 R c3 , -(CH 2 ) n C(O)NR c2 (CH 2 ) n1 R c3 , -OC(R c1 R c2 ) n (CH 2 ) n1 R c3 and -(CH 2 ) n NR c2 S(O) m R c3 wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted; R c1 , R c2 and R c3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally further substituted; Each R d is hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R d1 , -(CH 2 ) n OR d1 , -(CH 2 ) n C(O)R d1 , -(CH 2 ) n C(O)OR d1 , -(CH 2 ) n S(O) m R d1 , -(CH 2 ) n NR d2 R d3 , -(CH 2 ) n NR d2 C(O)OR d3 , -(CH 2 ) n NR d2 C(O)(CH 2 ) n1 R d3 , -(CH 2 ) n NR d2 C(O)NR d2 R d3 , -(CH 2 ) n C(O)NR d2 (CH 2 ) n1 R d3 , -OC(R d1 R d2 ) n (CH 2 ) n1 R d3 and -(CH 2 ) n NR d2 S(O) m R d3 wherein amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted; R d1 , R d2 and R d3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally further substituted; w, y and z are each independently 1, 2, 3 or 4; each m is independently 0, 1, or 2; each n is independently 0, 1, 2, 3, or 4; n1 and n2 each independently represent 0, 1, 2, 3, or 4; n5 and n6 each independently represent 0, 1, or 2; M 1 is N and M 2 is N, then ring D is not a monocyclic ring, and ring D is 【Chemistry 4】 If R 1 is not hydrogen, M 2 is N and M 1 is CH and ring D is 【Chemistry 5】 If R 1 is not hydrogen, M 1 is N and M 2 is CH and ring D is 【Chemistry 6】 If R 1 is not hydrogen, 【Chemistry 7】 is a double bond, and M 1 is C and M 2 is N and ring D is phenyl, R 1 is not hydrogen) 2. The compound according to claim 1, its stereoisomer or a pharma- ceutically acceptable salt thereof, further characterized in that it is as shown in

3. Formula (II) 【Chemistry 8】 2. The compound according to claim 1, its stereoisomer or a pharma- ceutically acceptable salt thereof, further characterized in that it is as shown in

4. Formula (IV) 【Chemistry 9】 (In the formula, M 1 is N or CR a is) 2. The compound according to claim 1, its stereoisomer or a pharma- ceutically acceptable salt thereof, further characterized in that it is as shown in

5. Ring C is a 3- to 10-membered heterocyclyl, more preferably Ring C is a 4- to 8-membered heterocyclyl, in which the heteroatoms in the 3- to 10-membered heterocyclyl and the 4- to 8-membered heterocyclyl are each independently selected from the group consisting of nitrogen, oxygen and sulfur, and the number of heteroatoms is independently 1, 2 or 3, preferably the rings of the 3- to 10-membered heterocyclyl and the 4- to 8-membered heterocyclyl are each independently monocyclic, bridged, spiro or fused; Ring C is more preferably 【Chemistry 10】 The compound according to claim 1, its stereoisomer or a pharma- ceutically acceptable salt thereof, characterized in that it is selected from the group consisting of:

6. Ring D is 6- to 10-membered heterocyclyl, C 6～10 aryl or 5-10 membered heteroaryl, preferably ring D is a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a benzene ring, a 5-membered heteroaromatic ring fused with a 6-membered heteroaromatic ring, a 6-membered heteroaromatic ring fused with a 6-membered heteroaromatic ring, a 6-membered heteroaromatic ring fused with a 6-membered heterocyclic ring, a 6-membered heteroaromatic ring fused with a 5-membered heterocyclic ring, a benzene ring fused with a 5-membered heterocyclic ring, a benzene ring fused with a 6-membered heteroaromatic ring, a benzene ring fused with a 6-membered heterocyclic ring, and the heteroatoms in the 3-14 membered heterocyclyl, the 6-10 membered heterocyclyl, the 5-10 membered heteroaryl and the 5-14 membered heteroaryl are each independently selected from the group consisting of nitrogen, oxygen and sulfur, and the number of heteroatoms is independently 1, 2 or 3; Ring D is more preferably 【Chemistry 11】 The compound according to claim 1, its stereoisomer or a pharma- ceutically acceptable salt thereof, characterized in that it is selected from the group consisting of:

7. R 1 are hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 Aryl, 5- to 12-membered heteroaryl, -(CH 2 ) n R 11 , -(CH 2 ) n OR 11 , -(CH 2 ) n C(O)R 11 , -(CH 2 ) n C(O)OR 11 , -(CH 2 ) n S(O) m R 11 , -(CH 2 ) n NR 22 R 33 , -(CH 2 ) n NR 22 C(O)OR 33 , -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , -(CH 2 ) n NR 22 C(O)NR 22 R 33 , -(CH 2 ) n C(O)NR 22 (CH 2 ) n1 R 33 , -OC(R 11 R 22 ) n (CH 2 ) n1 R 33 and -(CH 2 ) n NR 22 S(O) m R 33 Amino, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 Aryl and 5-12 membered heteroaryl are each optionally selected from hydroxy, halogen, nitro, hydroxy, thiol, cyano, amino, oxo, C 1～6 Alkyl, C 1～6 Alkoxy, C 6～12 may be further substituted by one or more substituents selected from the group consisting of aryl, 5- to 12-membered heteroaryl, and 3- to 12-membered heterocyclyl; Preferably, R 1 are hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 Aryl, 5- to 12-membered heteroaryl, -(CH 2 ) n R 11 , -(CH 2 ) n OR 11 , -(CH 2 ) n C(O)R 11 , -(CH 2 ) n C(O)OR 11 , -(CH 2 ) n S(O) m R 11 , -(CH 2 ) n NR 22 R 33 , -(CH 2 ) n NR 22 C(O)OR 33 , -(CH 2 ) n NR 22 C(O)(CH 2 ) n1 R 33 , -(CH 2 ) n NR 22 C(O)NR 22 R 33 , -(CH 2 ) n C(O)NR 22 (CH 2 ) n1 R 33 , -OC(R 11 R 22 ) n (CH 2 ) n1 R 33 and -(CH 2 ) n NR 22 S(O) m R 33 Amino, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 Aryl and 5-12 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1～6 may be further substituted by one or more substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; R 11 , R 22 and R 33 Each of these may be deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl and C 3～12 cycloalkyl, substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 Aryl, 5-12 membered heteroaryl, -O(CH 2 ) n1 R 66 , -OC(R 44 R 55 ) m1 (CH 2 ) n1 R 66 , -NR 44 (CH 2 ) n1 R 66 , -(CH 2 ) n1 -, -(CH 2 ) n1 R 66 , -(CH 2 ) n1 OR 66 , -(CH 2 ) n1 S.R. 66 , -(CH 2 ) n1 C(O)R 66 , -(CH 2 ) n1 C(O)OR 66 , -(CH 2 ) n1 S(O) m1 R 66 , -(CH 2 ) n1 NR 44 R 55 , -(CH 2 ) n1 C(O)NR 44 R 55 , -(CH 2 ) n1 NR 44 C(O)R 66 and -(CH 2 ) n1 NR 44 S(O) m1 R 66 each independently selected from the group consisting of R 44 , R 55 and R 66 Each of these may be deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl and C 3～12 cycloalkyl, substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, cyano substituted C 1～6 Alkyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 each independently selected from the group consisting of aryl and 5-12 membered heteroaryl; More preferably, R 1 Each of these may optionally be hydroxy, halogen, amino, C 1～6 may be further substituted by one or more substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 selected from the group consisting of aryl and 5-12 membered heteroaryl; More preferably, R 1 Each of them may optionally be hydroxy, halogen, amino, C 1～3 may be further substituted by one or more substituents selected from the group consisting of alkyl and 3- to 6-membered heterocyclyl; 1～3 Deuterated alkyl, C 1～3 Alkyl, C 1～3 Alkoxy, C 3～6 selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclyl; Even more preferably, R 1 is hydrogen, -CH 3 , -CD 3 , -CH 2 CN, ethyl, methoxy, cyano, cyclopropyl, 【Chemistry 12】 The compound according to claim 1, its stereoisomer or a pharma- ceutically acceptable salt thereof, characterized in that it is selected from the group consisting of:

8. Each R a are hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 Aryl, 5- to 12-membered heteroaryl, -(CH 2 ) n R a1 , -(CH 2 ) n OR a1 , -(CH 2 ) n C(O)R a1 , -(CH 2 ) n C(O)OR a1 , -(CH 2 ) n S(O) m R a1 , -(CH 2 ) n NR a2 R a3 , -(CH 2 ) n NR a2 C(O)OR a3 , -(CH 2 ) n NR a2 C(O)(CH 2 ) n1 R a3 , -(CH 2 ) n NR a2 C(O)NR a2 R a3 , -(CH 2 ) n C(O)NR a2 (CH 2 ) n1 R a3 , -OC(R a1 R a2 ) n (CH 2 ) n1 R a3 and -(CH 2 ) n NR a2 S(O) m R a3 Independently selected from the group consisting of amino, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 Aryl and 5-12 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1～6 may be further substituted by one or more substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Preferably, each R a are hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, C 1～3 Alkyl, C 1～3 Deuterated alkyl, C 1～3 Haloalkyl, C 1～3 Hydroxyalkyl, C 1～3 Alkoxy, C 2～3 Alkenyl, C 2～3 Alkynyl, C 3～6 Cycloalkyl, 3-6 membered heterocyclyl, C 6～10 Aryl, 5-10 membered heteroaryl, -(CH 2 ) n R a1 , -(CH 2 ) n OR a1 , -(CH 2 ) n C(O)R a1 , -(CH 2 ) n C(O)OR a1 , -(CH 2 ) n S(O) m R a1 , -(CH 2 ) n NR a2 R a3 , -(CH 2 ) n NR a2 C(O)OR a3 , -(CH 2 ) n NR a2 C(O)(CH 2 ) n1 R a3 , -(CH 2 ) n NR a2 C(O)NR a2 R a3 , -(CH 2 ) n C(O)NR a2 (CH 2 ) n1 R a3 , -OC(R a1 R a2 ) n (CH 2 ) n1 R a3 and -(CH 2 ) n NR a2 S(O) m R a3 Independently selected from the group consisting of amino, C 1～3 Alkyl, C 1～3 Deuterated alkyl, C 1～3 Haloalkyl, C 1～3 Hydroxyalkyl, C 1～3 Alkoxy, C 2～3 Alkenyl, C 2～3 Alkynyl, C 3～6 Cycloalkyl, 3-6 membered heterocyclyl, C 6～10 Aryl and 5-10 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1～3 may be further substituted by one or more substituents selected from the group consisting of alkyl and 3- to 6-membered heterocyclyl; R a1 , R a2 and R a3 are hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 aryl and 5- to 12-membered heteroaryl; 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 Aryl and 5-12 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1～6 may be further substituted by one or more substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; More preferably, each R a are hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, C 1～3 Alkyl and C 3～6 cycloalkyl; x is preferably 1, 2 or 3 2. The compound according to claim 1, its stereoisomer or a pharma- ceutically acceptable salt thereof.

9. Each R b are hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 Aryl, 5- to 12-membered heteroaryl, -(CH 2 ) n R b1 , -(CH 2 ) n OR b1 , -(CH 2 ) n C(O)R b1 , -(CH 2 ) n C(O)OR b1 , -(CH 2 ) n S(O) m R b1 , -(CH 2 ) n NR b2 R b3 , -(CH 2 ) n NR b2 C(O)OR b3 , -(CH 2 ) n NR b2 C(O)(CH 2 ) n1 R b3 , -(CH 2 ) n NR b2 C(O)NR b2 R b3 , -(CH 2 ) n C(O)NR b2 (CH 2 ) n1 R b3 , -OC(R b1 R b2 ) n (CH 2 ) n1 R b3 and -(CH 2 ) n NR b2 S(O) m R b3 Independently selected from the group consisting of amino, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 Aryl and 5-12 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1～6 may be further substituted by one or more substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Preferably, each R b are hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, C 1～3 Alkyl, C 1～3 Deuterated alkyl, C 1～3 Haloalkyl, C 1～3 Hydroxyalkyl, C 1～3 Alkoxy, C 2～3 Alkenyl, C 2～3 Alkynyl, C 3～6 Cycloalkyl, 3-6 membered heterocyclyl, C 6～10 Aryl, 5-10 membered heteroaryl, -(CH 2 ) n R b1 , -(CH 2 ) n OR b1 , -(CH 2 ) n C(O)R b1 , -(CH 2 ) n C(O)OR b1 , -(CH 2 ) n S(O) m R b1 , -(CH 2 ) n NR b2 R b3 , -(CH 2 ) n NR b2 C(O)OR b3 , -(CH 2 ) n NR b2 C(O)(CH 2 ) n1 R b3 , -(CH 2 ) n NR b2 C(O)NR b2 R b3 , -(CH 2 ) n C(O)NR b2 (CH 2 ) n1 R b3 , -OC(R b1 R b2 ) n (CH 2 ) n1 R b3 and -(CH 2 ) n NR b2 S(O) m R b3 Independently selected from the group consisting of amino, C 1～3 Alkyl, C 1～3 Deuterated alkyl, C 1～3 Haloalkyl, C 1～3 Hydroxyalkyl, C 1～3 Alkoxy, C 2～3 Alkenyl, C 2～3 Alkynyl, C 3～6 Cycloalkyl, 3-6 membered heterocyclyl, C 6～10 Aryl and 5-10 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1～3 may be further substituted by one or more substituents selected from the group consisting of alkyl and 3- to 6-membered heterocyclyl; R b1 , R b2 and R b3 are hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 aryl and 5- to 12-membered heteroaryl; 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 Aryl and 5-12 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1～6 may be further substituted by one or more substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; More preferably, each R b are hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, C 1～3 Alkyl, C 1～3 Haloalkyl and C 3～6 cycloalkyl; More preferably, each R b is hydrogen, F, -CF 3 independently selected from the group consisting of cyano, methyl and cyclopropyl; y is preferably 1 2. The compound according to claim 1, its stereoisomer or a pharma- ceutically acceptable salt thereof.

10. Each R c are hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 Aryl, 5- to 12-membered heteroaryl, -(CH 2 ) n R c1 , -(CH 2 ) n OR c1 , -(CH 2 ) n C(O)R c1 , -(CH 2 ) n C(O)OR c1 , -(CH 2 ) n S(O) m R c1 , -(CH 2 ) n NR c2 R c3 , -(CH 2 ) n NR c2 C(O)OR c3 , -(CH 2 ) n NR c2 C(O)(CH 2 ) n1 R c3 , -(CH 2 ) n NR c2 C(O)NR c2 R c3 , -(CH 2 ) n C(O)NR c2 (CH 2 ) n1 R c3 , -OC(R c1 R c2 ) n (CH 2 ) n1 R c3 and -(CH 2 ) n NR c2 S(O) m R c3 Independently selected from the group consisting of amino, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 Aryl and 5-12 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1～6 may be further substituted by one or more substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Preferably, each R c are hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, C 1～3 Alkyl, C 1～3 Deuterated alkyl, C 1～3 Haloalkyl, C 1～3 Hydroxyalkyl, C 1～3 Alkoxy, C 2～3 Alkenyl, C 2～3 Alkynyl, C 3～6 Cycloalkyl, 3-6 membered heterocyclyl, C 6～10 Aryl, 5-10 membered heteroaryl, -(CH 2 ) n R c1 , -(CH 2 ) n OR c1 , -(CH 2 ) n C(O)R c1 , -(CH 2 ) n C(O)OR c1 , -(CH 2 ) n S(O) m R c1 , -(CH 2 ) n NR c2 R c3 , -(CH 2 ) n NR c2 C(O)OR c3 , -(CH 2 ) n NR c2 C(O)(CH 2 ) n1 R c3 , -(CH 2 ) n NR c2 C(O)NR c2 R c3 , -(CH 2 ) n C(O)NR c2 (CH 2 ) n1 R c3 , -OC(R c1 R c2 ) n (CH 2 ) n1 R c3 and -(CH 2 ) n NR c2 S(O) m R c3 Independently selected from the group consisting of amino, C 1～3 Alkyl, C 1～3 Deuterated alkyl, C 1～3 Haloalkyl, C 1～3 Hydroxyalkyl, C 1～3 Alkoxy, C 2～3 Alkenyl, C 2～3 Alkynyl, C 3～6 Cycloalkyl, 3-6 membered heterocyclyl, C 6～10 Aryl and 5-10 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1～3 may be further substituted by one or more substituents selected from the group consisting of alkyl and 3- to 6-membered heterocyclyl; R c1 , R c2 and R c3 are hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 aryl and 5- to 12-membered heteroaryl; 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 Aryl and 5-12 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1～6 may be further substituted by one or more substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; More preferably, each R c are hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, C 1～3 Alkyl, C 1～3 Haloalkyl and C 3～6 cycloalkyl; More preferably, each R c is independently selected from the group consisting of hydrogen, deuterium, F, chlorine, hydroxy, methyl, methoxy, oxo, and cyano; z is preferably 1 or 2 2. The compound according to claim 1, its stereoisomer or a pharma- ceutically acceptable salt thereof.

11. Each R d are hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 Aryl, 5- to 12-membered heteroaryl, -(CH 2 ) n R d1 , -(CH 2 ) n OR d1 , -(CH 2 ) n C(O)R d1 , -(CH 2 ) n C(O)OR d1 , -(CH 2 ) n S(O) m R c1 , -(CH 2 ) n NR d2 R d3 , -(CH 2 ) n NR d2 C(O)OR d3 , -(CH 2 ) n NR d2 C(O)(CH 2 ) n1 R d3 , -(CH 2 ) n NR d2 C(O)NR d2 R d3 , -(CH 2 ) n C(O)NR d2 (CH 2 ) n1 R d3 , -OC(R d1 R d2 ) n (CH 2 ) n1 R d3 and -(CH 2 ) n NR d2 S(O) m R d3 Independently selected from the group consisting of amino, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 Aryl and 5-12 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1～6 may be further substituted by one or more substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; Preferably, each R d are hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, C 1～3 Alkyl, C 1～3 Deuterated alkyl, C 1～3 Haloalkyl, C 1～3 Hydroxyalkyl, C 1～3 Alkoxy, C 2～3 Alkenyl, C 2～3 Alkynyl, C 3～6 Cycloalkyl, 3-6 membered heterocyclyl, C 6～10 Aryl, 5-10 membered heteroaryl, -(CH 2 ) n R d1 , -(CH 2 ) n OR d1 , -(CH 2 ) n C(O)R d1 , -(CH 2 ) n C(O)OR d1 , -(CH 2 ) n S(O) m R c1 , -(CH 2 ) n NR d2 R d3 , -(CH 2 ) n NR d2 C(O)OR d3 , -(CH 2 ) n NR d2 C(O)(CH 2 ) n1 R d3 , -(CH 2 ) n NR d2 C(O)NR d2 R d3 , -(CH 2 ) n C(O)NR d2 (CH 2 ) n1 R d3 , -OC(R d1 R d2 ) n (CH 2 ) n1 R d3 and -(CH 2 ) n NR d2 S(O) m R d3 Independently selected from the group consisting of amino, C 1～3 Alkyl, C 1～3 Deuterated alkyl, C 1～3 Haloalkyl, C 1～3 Hydroxyalkyl, C 1～3 Alkoxy, C 2～3 Alkenyl, C 2～3 Alkynyl, C 3～6 Cycloalkyl, 3-6 membered heterocyclyl, C 6～10 Aryl and 5-10 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1～3 may be further substituted by one or more substituents selected from the group consisting of alkyl and 3- to 6-membered heterocyclyl; R d1 , R d2 and R d3 are hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 aryl and 5- to 12-membered heteroaryl; 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 Aryl and 5-12 membered heteroaryl are each optionally selected from hydroxy, halogen, amino, C 1～6 may be further substituted by one or more substituents selected from the group consisting of alkyl and 3- to 12-membered heterocyclyl; More preferably, each R d are hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, C 1～3 Alkyl, C 1～3 Alkoxy, C 1～3 Haloalkyl and C 3～6 cycloalkyl; More preferably, each R d are hydrogen, deuterium, cyclopropyl, isopropyl, cyano, F, Cl, methyl, -CD 3 , -NHCH 3 , -NHCD 3 , methoxy and oxo; w is preferably 1 or 2, and more preferably 1 2. The compound according to claim 1, its stereoisomer or a pharma- ceutically acceptable salt thereof.

12. Formula (VII) 【Chemistry 13】 (In the formula, L 2 is a bond or O, 【Chemistry 14】 is a single bond or a double bond, M 1 is C or CR 2 and M 2 is N or CR 3 and M 3 is N or CR 4 and M 4 is N or CR 5 and M 5 HA-CR 6 R 7 -, -CR 6 R 7 -CR 8 R 9 -, -CR 6 =CR 8 -, -CR 6 R 7 -NR 8 -, -NR 8 -C(=O)-, -CR 6 R 7 -O- or -CR 6 =N-, M 6 is N or CR 10 and R 1 is C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, -(CH 2 ) n R 11 , -(CH 2 ) n OR 11 , -(CH 2 ) n C(O)R 11 , -(CH 2 ) n C(O)OR 11 , -(CH 2 ) n NR 22 R 33 and -(CH 2 ) n NR 22 C(O)OR 33 is selected from the group consisting of R 11 , R 22 and R 33 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 each independently selected from the group consisting of aryl and 5-12 membered heteroaryl; R 2 , R 3 , R 4 and R 5 are the same or different, and optionally C 1～3 Alkyl, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, substituted with aryl and 5-12 membered heteroaryl, preferably R 2 , R 3 , R 4 and R 5 are each independently hydrogen, deuterium, halogen, C 1～3 Alkyl or C 3～6 is cycloalkyl, R b In some cases, C 1～3 Alkyl, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy and C 3～6 selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, substituted by cycloalkyl; R c In some cases, C 1～3 Alkyl, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy and C 3～6 selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, substituted by cycloalkyl; R d In some cases, C 1～3 Alkyl, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy and C 3～6 selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, substituted by cycloalkyl; R 6 , R 7 , R 8 , R 9 and R 10 are the same or different, and optionally C 1～3 Alkyl, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, substituted with aryl and 5-12 membered heteroaryl, preferably R 6 , R 7 , R 8 and R 9 are each independently hydrogen, deuterium, halogen, cyano, C 1～3 Alkyl or C 3～6 cycloalkyl, or Or R 6 , R 7 is bonded together with the adjacent carbon atom to form C 3～6 Forms a cycloalkyl, C 3～6 Cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, and amino; Or R 6 , R 8 is bonded together with the adjacent carbon atom to form C 3～6 Forms a cycloalkyl, C 3～6 cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, and amino; n5 and n6 each independently represent 0, 1, or 2; w is 1 or 2; y is 1 or 2; z is 1 or 2; n is 0, 1, 2 or 3.

2. The compound according to claim 1, its stereoisomer or a pharma- ceutically acceptable salt thereof, further characterized in that it is as shown in

13. Formula (VI) 【Chemistry 15】 (In the formula, L 2 is a bond or O, 【Chemistry 16】 is a single bond or a double bond, M 1 is C or CR 2 and M 2 is N or CR 3 and M 3 is N or CR 4 and M 4 is N or CR 5 and M 5 HA-CR 6 R 7 -, -CR 6 R 7 -CR 8 R 9 -, -CR 6 =CR 8 -, -CR 6 R 7 -NR 8 -, -NR 8 -C(=O)-, -CR 6 R 7 -O- or -CR 6 =N-, R 1 is C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, -(CH 2 ) n R 11 , -(CH 2 ) n OR 11 , -(CH 2 ) n C(O)R 11 , -(CH 2 ) n C(O)OR 11 , -(CH 2 ) n NR 22 R 33 and -(CH 2 ) n NR 22 C(O)OR 33 is selected from the group consisting of R 11 , R 22 and R 33 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 each independently selected from the group consisting of aryl and 5-12 membered heteroaryl; R 2 , R 3 , R 4 and R 5 are the same or different, and optionally C 1～3 Alkyl, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, substituted with aryl and 5-12 membered heteroaryl, preferably R 2 , R 3 , R 4 and R 5 are each independently hydrogen, deuterium, halogen, C 1～3 Alkyl or C 3～6 is cycloalkyl, R c In some cases, C 1～3 Alkyl, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy and C 3～6 selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, substituted by cycloalkyl; R d In some cases, C 1～3 Alkyl, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy and C 3～6 selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, substituted by cycloalkyl; R 6 , R 7 , R 8 and R 9 are the same or different, and optionally C 1～3 Alkyl, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, substituted with aryl and 5-12 membered heteroaryl, preferably R 6 , R 7 , R 8 and R 9 are each independently hydrogen, deuterium, halogen, C 1～3 Alkyl or C 3～6 cycloalkyl, or Or R 6 , R 7 is bonded together with the adjacent carbon atom to form C 3～6 Forms a cycloalkyl, C 3～6 Cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, and amino; Or R 6 , R 8 is bonded together with the adjacent carbon atom to form C 3～6 Forms a cycloalkyl, C 3～6 cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, and amino; n5 and n6 each independently represent 0, 1, or 2; w is 1 or 2; z is 1 or 2; n is 0, 1, 2 or 3.

2. The compound according to claim 1, its stereoisomer or a pharma- ceutically acceptable salt thereof, further characterized in that it is as shown in

14. Formula (V) 【Chemistry 17】 (In the formula, 【Chemistry 18】 is a single bond or a double bond, M 1 is C or CR 2 and M 2 is N or CR 3 and M 3 is N or CR 4 and M 4 is N or CR 5 and R 1 is C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, -(CH 2 ) n R 11 , -(CH 2 ) n OR 11 , -(CH 2 ) n C(O)R 11 , -(CH 2 ) n C(O)OR 11 , -(CH 2 ) n NR 22 R 33 and -(CH 2 ) n NR 22 C(O)OR 33 is selected from the group consisting of R 11 , R 22 and R 33 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy, C 1～6 Haloalkoxy, C 1～6 Hydroxyalkyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 each independently selected from the group consisting of aryl and 5-12 membered heteroaryl; R 2 , R 3 , R 4 and R 5 are the same or different and are hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 aryl and 5-12 membered heteroaryl, preferably R 2 , R 3 , R 4 and R 5 are each independently hydrogen, deuterium, halogen, C 1～3 Alkyl or C 3～6 is cycloalkyl, R c is hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, oxo, cyano, amino, C 1～6 Alkyl, C 1～6 Haloalkyl and C 3～6 cycloalkyl; z is 1 or 2; n is 0, 1, 2 or 3.

2. The compound according to claim 1, its stereoisomer or a pharma- ceutically acceptable salt thereof, further characterized in that it is as shown in

15. Formula (IX) 【Chemistry 19】 (Wherein, ring D is a 9- to 10-membered heterocyclyl; C 6～10 aryl or 9-10 membered heteroaryl, preferably a 6 membered heteroaromatic ring fused with a 6 membered heteroaromatic ring, a 6 membered heteroaromatic ring fused with a 6 membered heterocyclic ring, or a 6 membered heteroaromatic ring fused with a 5 membered heterocyclic ring, and more preferably 【Chemistry 20】 is) 3. The compound according to claim 2, its stereoisomer or a pharma- ceutically acceptable salt thereof, further characterized in that it is as shown in

16. Formula (VIII) 【Chemistry 21】 (In the formula, 【Chemical 22】 represents a single bond or a double bond, M 1 is N, C or CR 2 and M 2 is N or CR 3 and M 6 is N or CR 10 and M 7 is CR 12 or N, M 8 is CR 13 or O, preferably 【Chemistry 23】 teeth 【Chemistry 24】 and R 2 , R 3 , R 10 , R 12 and R 13 are the same or different, and optionally one or more C 1～3 Alkyl, C 1～6 Alkyl, C 1～6 Deuterated alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, C 3～12 Cycloalkyl, 3-12 membered heterocyclyl, C 6～12 Each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, substituted with aryl and 5-12 membered heteroaryl, preferably R 2 , R 3 , R 10 , R 12 and R 13 are the same or different, and optionally one or more C 1～3 Alkyl, C 1～3 Alkyl, C 1～3 Deuterated alkyl, C 1～3 Haloalkyl, C 1～3 Hydroxyalkyl and C 1～3 each independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, cyano, and amino substituted with alkoxy; Each R b may be one or more C 1～3 Alkyl, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy and C 3～6 Hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, and preferably optionally one or more C substituted with cycloalkyl. 1～3 Alkyl, C 1～3 Alkyl, C 1～3 Haloalkyl and C 1～3 independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, substituted by alkoxy; Each R c may be one or more C 1～3 Alkyl, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy and C 3～6 Hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, and preferably optionally one or more C substituted with cycloalkyl. 1～3 Alkyl, C 1～3 Alkyl, C 1～3 Haloalkyl and C 1～3 independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, substituted by alkoxy; Each R d may be one or more C 1～3 Alkyl, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy and C 3～6 Hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, and preferably optionally one or more C substituted with cycloalkyl. 1～3 Alkyl, C 1～3 Alkyl, C 1～3 Haloalkyl and C 1～3 independently selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxy, thiol, oxo, cyano, amino, substituted by alkoxy; w, y and z are each independently 1, 2, 3 or 4.

2. The compound according to claim 1, its stereoisomer or a pharma- ceutically acceptable salt thereof, further characterized in that it is as shown in

17. The specific structure is 【Chemical 25A】 【Chemistry 25B】 【Chemical 25C】 【Chemistry 25D】 2. The compound according to claim 1, its stereoisomer or its pharma- ceutically acceptable salt, characterized in that:

18. A method for preparing a compound of formula (III), its stereoisomer or its pharma- ceutically acceptable salt, comprising subjecting a compound of formula (III-1) and a compound of formula (III-2) to the following reaction to obtain a compound of formula (III): 【Chemistry 26】 wherein X is a halogen, and preferably fluorine, chlorine, bromine or iodine; Preferably, the reaction is carried out in the presence of a base and a catalyst, the base is preferably DIPEA and the catalyst is preferably potassium iodide; 【Chemical 27】 , M 1 , M 2 , M 4 , M 6 , R b , R c , R d , L 1 , L 2 , L 3 , R 1 , ring D, n5, n6, y, z and w are as defined in claim 2. A method comprising:

19. Formula (III-2) 【Chemistry 28】 (In the formula, 【Chemical 29】 , M 1 , M 2 , R c , R d , L 2 , L 3 , R 1 , ring D, n5, n6, z and w are as defined in claim 2. Compound.

20. 18. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 17, its stereoisomer or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers, diluents or excipients.

21. 21. The pharmaceutical composition according to claim 20 for use as a PARP inhibitor medicament, wherein the PARP is preferably PARP1.

22. 21. The pharmaceutical composition according to claim 20 for use in the treatment of cancer, an ischemic disease or a neurodegenerative disease, wherein the cancer is preferably selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematological cancer, gastric cancer, colorectal cancer, gastrointestinal cancer and lung cancer.

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