Piperazine fused ring system-containing derivatives, pharma-ceutically acceptable salts thereof, and methods for their preparation and use - Patents.com

Abstract

Provided are piperazine fused ring system derivatives of formula (I), pharma- ceutically acceptable salts thereof, processes for their preparation and pharmaceutical compositions comprising said compounds, and uses of said compounds as polyadenosine diphosphate ribose (ADP-ribose) polymerase (PARP) inhibitors in the treatment of related diseases such as cancer, inflammation, metabolic diseases, cardiovascular diseases, immune diseases and psychiatric diseases. [Formula 1] JPEG2025503798000246.jpg20169

Description

Detailed Description of the Invention

[0001] This application claims the priority of Chinese patent application No. 2022100392290, filed on January 13, 2022, the priority of Chinese patent application No. 2022106405877, filed on June 7, 2022, and the priority of Chinese patent application No. 2022117424814, filed on December 30, 2022. This application cites the above Chinese patent applications in full. [Technical field] The present invention is in the field of drug synthesis, particularly to piperazine fused ring system-containing derivatives, their pharma- ceutically acceptable salts and preparation methods thereof, and their use as PARP inhibitors in the preparation of cancer therapeutics. [Background technology] In the process of life, DNA in living cells is affected by various internal factors and external environments every day, which causes DNA damage. Under normal circumstances, these damages are repaired through various DNA repair pathways in cells, thereby maintaining normal cell proliferation and apoptosis. The intracellular DNA damage response (DDR) pathway is a complex protein network system and an important method for maintaining genome integrity. An important characteristic of tumor cells is genomic instability, which mainly manifests as changes in chromosome number and / or structure, and microsatellite instability (MSI), so DDR has become an important approach in tumor drug development.

[0002] In mammalian cells, the PARP enzyme family contains at least 17 members, among which PARP1 and PARP2 are the main members involved in cellular DNA damage repair. PARP is an important DNA break molecular sensor in the DDR pathway, and is activated after DNA damage. PARP senses DNA single-strand damage gaps and binds to the DNA break site, and when bound to the PARP enzyme, its catalytic activity increases by more than 500-fold. PARP catalyzes the decomposition of nicotinamide adenine dinucleotide (NAD+) into nicotinamide and ADP-ribose through its own glycosylation, and then the receptor protein and PARP1 itself are "PARylated" using ADP-ribose as a substrate to form PARP-ADP-ribose branched chains [poly(ADP-ribose) polymer, pADPr]. This can prevent DNA molecules around the damaged site from combining with the damaged DNA, and at the same time, it attracts DNA repair proteins, histone H1, and a series of transcription factors to bind to the DNA damage site. On the other hand, it reduces the affinity of PARP1 to DNA, dissociating PARP1 from DNA breaks, after which DNA repair proteins bind to the DNA gaps to repair the damaged sites. However, the "PARylation" of PARP1 is removed by other enzymes, restoring the activity of PARP1.

[0003] For tumor cells with BRCA mutations or defects in other DNA damage repair pathways, PARP inhibition or BRCA deletion alone is not lethal, but the two together lead to cell death. This synthetic lethality effect has provided a new direction for the development of tumor therapeutics, and currently, several PARP1 / 2 inhibitors have been approved for tumor treatment with good clinical results. Currently, one of the main side effects of PARP1 / 2 inhibitors is anemia, which increases patient pain, causes patients to discontinue treatment, and limits the possibility of combination with other drugs. 85-95% of PARP activity in cells is provided by PARP1. PARP2 is involved in regulating red blood cell differentiation, and inhibition of PARP2 function leads to a shortened red blood cell lifespan and a decrease in hematocrit and hemoglobin levels. Studies have confirmed that PARP2-deficient mice develop chronic anemia. Therefore, the development of selective PARP1 inhibitors would be beneficial in maintaining antitumor efficacy while reducing hematological side effects such as anemia.

[0004] The present invention has discovered a series of novel PARP1 inhibitor compounds that selectively inhibit PARP1 and may be used in tumor therapy. Summary of the Invention The object of the present invention is to provide a compound represented by general formula (I), its stereoisomer, or a pharma- ceutically acceptable salt thereof, wherein the structure represented by general formula (I) is as shown below.

[0005] [ka]

[0006] however, Ring A is a 3- to 18-membered heterocyclyl or a 5- to 18-membered heteroaryl, and the 3- to 18-membered heterocyclyl and the 5- to 18-membered heteroaryl may be further optionally substituted; Ring B is C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl,3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 The aryl and 5- to 14-membered heteroaryl may be further optionally substituted; Ring C is C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 The aryl and 5- to 14-membered heteroaryl may be further optionally substituted; R1 is independently hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy, C 3-12 Cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclyl-C 1-6 Alkyl, C 6-14 Aryl-C 1-6 Alkyl or 5-14 membered heteroaryl-C 1-6 alkyl, and the amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 Aryloxy and 5- to 14-membered heteroaryloxy can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 optionally substituted by one or more substituents selected from the group consisting of aryloxy and 5- to 14-membered heteroaryloxy; Alternatively, any two R1 together with the atoms on which they are located are C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C6-14 optionally substituted by one or more substituents selected from the group consisting of aryloxy and 5- to 14-membered heteroaryloxy; R2 is independently hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy, C 3-12 Cycloalkyl-C 1-6 Alkyl, 3-12 membered heterocyclyl-C 1-6 Alkyl, C 6-14 Aryl-C 1-6 Alkyl or 5-14 membered heteroaryl-C 1-6 alkyl, and the amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 Aryloxy and 5- to 14-membered heteroaryloxy can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 optionally substituted by one or more substituents selected from the group consisting of aryloxy and 5- to 14-membered heteroaryloxy; R3 is independently hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy, -(CH2) n1 R a , -(CH2) n1 OR a , -(CH2) n1 S.R. a , -(CH2) n1 NR b R a , -(CH2) n1 C(O)R a , -(CH2) n1 C(O)NR b R a , -(CH2) n1 NR b C(O)R a , -(CH2) n1 S(O)m1 R a , -(CH2) n1 S(O) m1 NR b R a , -(CH2) n1 S(O)(=NR b )R a , -(CH2) n1 N=S(=O)R a R b or -(CH2) n1 NR b S(O) m1 R a wherein the amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 Aryloxy and 5- to 14-membered heteroaryloxy can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 optionally substituted by one or more substituents selected from the group consisting of aryloxy and 5- to 14-membered heteroaryloxy; Alternatively, any two R3 may be joined together with the atoms on which they are located to form C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 optionally substituted by one or more substituents selected from the group consisting of aryloxy and 5- to 14-membered heteroaryloxy; R a and R b are each independently hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 aryloxy or 5-14 membered heteroaryloxy, 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 Aryloxy and 5- to 14-membered heteroaryloxy can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 optionally substituted by one or more substituents selected from the group consisting of aryloxy and 5- to 14-membered heteroaryloxy; L is -(CR4R5) n2 -, -C(O)-, -C(O)NR4- or -(CR4R5)2O; R4 and R5 each independently represent hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 aryloxy or 5-14 membered heteroaryloxy, 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 Aryloxy and 5-14 membered heteroaryloxy can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 optionally substituted by one or more substituents selected from the group consisting of aryloxy and 5- to 14-membered heteroaryloxy; Alternatively, R4 and R5 together with the atoms on which they are located form C 3-12 cycloalkyl or 3- to 12-membered heterocyclyl, 3-12Cycloalkyl and 3- to 12-membered heterocyclyl may further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 optionally substituted by one or more substituents selected from the group consisting of aryloxy and 5- to 14-membered heteroaryloxy; x, y, and z each independently represent an integer of 0 to 10; n1 is an integer from 0 to 10, n2 is 0, 1, 2 or 3, and m1 is 0, 1 or 2.

[0007] In a preferred embodiment of the present invention, the ring A is a 5- to 6-membered monocyclic heteroaryl, a 6- to 10-membered bicyclic fused ring heterocyclyl, an 8- to 10-membered bicyclic fused ring heteroaryl, an 8- to 14-membered tricyclic fused ring heterocyclyl, or a 10- to 14-membered tricyclic fused ring heteroaryl; The ring A may further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 It is optionally substituted with one or more substituents selected from aryloxy and 5-14 membered heteroaryloxy.

[0008] In a further preferred embodiment of the present invention, the ring A is

[0009] [ka]

[0010] JPEG2025503798000004.jpg25169

[0011] It is.

[0012] The present invention further provides a preferred embodiment, the compound represented, its stereoisomer or its pharma- ceutically acceptable salt, the specific structure of which is as represented by general formula (II).

[0013] [ka]

[0014] however, X1 is O, S, N, NR6, CR6 or CR6R7; X2 is O, S, N, C(O), NR8, CR8 or CR8R9; X3 is N or CR 10 and X4 is N or CR 11 and R6, R7, R8, R9, R 10 and R 11 are each independently hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy or -(CH2) n3 R c wherein the amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 Aryloxy and 5- to 14-membered heteroaryloxy can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 optionally substituted by one or more substituents selected from the group consisting of aryloxy and 5- to 14-membered heteroaryloxy; Or R6, R7, R8, R9, R 10 and R11 Any two of the following are linked together with the atom on which they are located: C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 optionally substituted by one or more substituents selected from the group consisting of aryloxy and 5- to 14-membered heteroaryloxy; R c is hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 aryloxy or 5-14 membered heteroaryloxy, 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 Aryloxy and 5- to 14-membered heteroaryloxy can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 Optionally substituted by one or more substituents selected from aryloxy and 5- to 14-membered heteroaryloxy; and n3 is 0, 1, 2, 3 or 4; Ring B, ring C, R2, R3, R4, R5, y and z are as defined in general formula (I).

[0015] In a preferred embodiment of the present invention, the ring B is 3-6 cycloalkyl or 3- to 6-membered heterocyclyl; The ring B may further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 It is optionally substituted with one or more substituents selected from aryloxy and 5-14 membered heteroaryloxy.

[0016] The present invention further provides a preferred embodiment, a compound represented by the formula (III), its stereoisomer or a pharma- ceutically acceptable salt thereof, the specific structure of which is as represented by the formula (III).

[0017] [ka]

[0018] however, n is 1, 2, 3, 4, 5 or 6; X2 is N or CR8; R6 and R8 are each independently hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy or -(CH2) n3 R c wherein the amino, C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 Aryloxy and 5- to 14-membered heteroaryloxy can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 optionally substituted by one or more substituents selected from the group consisting of aryloxy and 5- to 14-membered heteroaryloxy; Alternatively, R6 and R8 together with the atoms on which they are located form C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyloxy, 3-12 membered heterocyclyloxy, C 6-14 optionally substituted by one or more substituents selected from the group consisting of aryloxy and 5- to 14-membered heteroaryloxy; X2, X3, X4, ring C, R1, R2, R3, y and z are as defined in general formula (I).

[0019] In a further preferred embodiment of the present invention, the compound represented by the general formula (I) is

[0020] [ka]

[0021] isn't it.

[0022] In a further preferred embodiment of the present invention, the ring B is C 4-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, 4-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 The aryl and 5- to 14-membered heteroaryl may be further optionally substituted.

[0023] In a further preferred embodiment of the present invention, ring C is

[0024] [ka]

[0025] It is.

[0026] The present invention further provides a preferred embodiment, the compound represented, its stereoisomer or its pharma- ceutically acceptable salt, the specific structure of which is as represented by general formula (IIIA) and general formula (IIIB).

[0027] [ka]

[0028] however, X2, X3, X4, ring C, R1, R2, R3, R6, n, y and z are as defined in general formula (I).

[0029] The present invention further provides a preferred embodiment, the compound represented, its stereoisomer or its pharma- ceutically acceptable salt, the specific structure of which is as represented by general formula (IIIA) and general formula (IIIB).

[0030] [ka]

[0031] however, X2, X3, X4, ring C, R1, R2, R3, R6, n, y and z are as defined in general formula (I).

[0032] The present invention further provides a preferred embodiment, the compound represented, its stereoisomer or its pharma- ceutically acceptable salt, the specific structure of which is as represented by general formula (IV).

[0033] [ka]

[0034] however, X2, X3, X4, ring C, R1, R2, R3, R6, y and z are as defined in general formula (I).

[0035] The present invention further provides a preferred embodiment, the compound represented, its stereoisomer or its pharma- ceutically acceptable salt, the specific structure of which is as represented by general formula (IVA) and general formula (IVB).

[0036] [ka]

[0037] however, X2, X3, X4, ring C, R1, R2, R3, R6, y and z are as defined in general formula (I).

[0038] The present invention further provides preferred embodiments, the compounds represented, their stereoisomers or pharma- ceutically acceptable salts thereof, the specific structures of which are as represented by general formula (IVC) and general formula (IVD).

[0039] [ka]

[0040] however, X2, X3, X4, ring C, R1, R2, R3, R6, y and z are as defined in general formula (I).

[0041] The present invention further provides a preferred embodiment, the compound represented, its stereoisomer or its pharma- ceutically acceptable salt, the specific structure of which is as represented by general formula (V).

[0042] [ka]

[0043] however, X2, X3, X4, ring C, R1, R2, R3, R6, y and z are as defined in general formula (I).

[0044] The present invention further provides a preferred embodiment, the compound represented, its stereoisomer or its pharma- ceutically acceptable salt, the specific structure of which is as represented by general formula (VI).

[0045] [ka]

[0046] however, X2, X3, X4, ring B, R1, R2, R3, R6, y and z are as defined in general formula (I).

[0047] The present invention further provides a preferred embodiment, the compound represented, its stereoisomer or its pharma- ceutically acceptable salt, the specific structure of which is as represented by general formula (VII).

[0048] [ka]

[0049] X3, X4, ring C, ring B, R1, R2, R3, R4, R5, R6, y and z are as defined in general formula (I).

[0050] The present invention further provides a preferred embodiment, the compound represented, its stereoisomer or its pharma- ceutically acceptable salt, the specific structure of which is as represented by general formula (VIII).

[0051] [ka]

[0052] X3, X4, ring B, ring C, R1, R2, R3, R4, R5, y and z are as defined in general formula (I).

[0053] The present invention further provides a preferred embodiment, the compound represented, its stereoisomer or its pharma- ceutically acceptable salt, the specific structure of which is as represented by general formula (IX):

[0054] [ka]

[0055] X2, ring C, R1, R2, R3, R4, R5, R6, y and z are as defined in general formula (I).

[0056] In a preferred embodiment of the present invention, ring C is

[0057] [ka]

[0058] and however, M1, M2, M3, M4 and M5 are each independently N or CR3; M6 is independently N, NR3 or CR3R3; M7 is independently N or C; R3 is as defined in general formula (I).

[0059] In a further preferred embodiment of the invention, Ring C is phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, pyridopyrazolyl, pyridooxazolyl, pyridoisoxazolyl, pyridothiazolyl, pyridoisothiazolyl or pyridopyrrolyl.

[0060] In a further preferred embodiment of the invention, Ring C is phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, pyridopyrazolyl, pyridooxazolyl, pyridoisoxazolyl, pyridothiazolyl, pyridoisothiazolyl or pyridopyrrolyl.

[0061] In a further preferred embodiment of the present invention, the ring C is

[0062] [ka]

[0063] M1, M2, M3, M4 and M5 are each independently N or CR3; M6 is independently N, NR3 or CR3R3; M7 is independently N or C; R3 is as defined in general formula (I).

[0064] In a further preferred embodiment of the present invention, the ring C is

[0065] [ka]

[0066] and however, M1, M2, M3, M4 and M5 are each independently N or CR3; M6 is independently N, NR3 or CR3R3; M7 is independently N or C; R3 is as defined in general formula (I).

[0067] In a preferred embodiment of the present invention, R3 is independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OR a , -SR a , -NR b R a , -C(O)R a , -C(O)NR b R a , -NR b C(O)R a , -S(O)R a , -S(O)2R a , -S(O)NR b R a , -S(O)(=NR b )R a , -N=S(=O)R a R b or -NR b S(O)2R a wherein the amino, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated alkyl, C1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclyloxy, C 6-10 optionally substituted by one or more substituents selected from the group consisting of aryloxy and 5-10 membered heteroaryloxy; Alternatively, any two R3 together with the atoms on which they are located are C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclyloxy, C 6-10 optionally substituted by one or more substituents selected from the group consisting of aryloxy and 5-10 membered heteroaryloxy; R a and R b are each independently hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated alkyl, C 1-3Alkoxy, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclyloxy, C 6-10 It is optionally substituted with one or more substituents selected from aryloxy and 5-10 membered heteroaryloxy.

[0068] In a further preferred embodiment of the present invention, ring A is

[0069] [ka]

[0070] and Ring B is C 4-6 cycloalkyl or 5- to 6-membered heterocyclyl, the heteroatom of the 5- to 6-membered heterocyclyl is N, O or S, and the number of the heteroatom is 1; Ring C is pyridinyl or pyridoisoxazolyl; R1 is independently hydrogen, deuterium, halogen, or C 1-6 Alkyl, C substituted with one or more halogens 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 is an alkoxy; Alternatively, any two R1 together with the atoms on which they are located are C 3-6 forming a cycloalkyl or a 3- to 6-membered heterocyclyl, the heteroatom of the 3- to 6-membered heterocyclyl being N or O, and the number of the heteroatom being 1; R2 is independently hydrogen or deuterium; R3 is independently hydrogen, deuterium, halogen, or C 1-6 Alkyl, 5-6 membered heteroaryl, -(CH2) n1 C(O)NR b R a or -(CH2) n1 NR b R a wherein the 5- to 6-membered heteroaryl is optionally 1-6 substituted by alkyl, the heteroatom of the 5- to 6-membered heterocyclyl is N and / or O, the number of heteroatoms is 1 or 2, R a and R b are each independently hydrogen, C 1-6 Alkyl or C 3-6 is cycloalkyl, L is -(CR4R5) n2 - and R4 and R5 are each independently hydrogen or deuterium; x, y, and z each independently represent an integer of 0 to 3; n1 is an integer from 0 to 3, n2 is 1, and m1 is 0, 1 or 2.

[0071] In a further preferred embodiment of the present invention, ring B is C 4-6 It is cycloalkyl or 5- to 6-membered heterocyclyl, the heteroatom of the 5- to 6-membered heterocyclyl is N, O or S, and the number of the heteroatom is 1.

[0072] In a further preferred embodiment of the invention, Ring C is phenyl, pyridinyl or pyridoisoxazolyl.

[0073] In a further preferred embodiment of the present invention, R1 is independently selected from halogen, C 1-6 Alkyl, C substituted with one or more halogens 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 is an alkoxy; Alternatively, any two R1 together with the atoms on which they are located are C 3-6 It forms a cycloalkyl or a 3- to 6-membered heterocyclyl, the heteroatom of which is N or O, and the number of the heteroatom is 1.

[0074] In a further preferred embodiment of the present invention, R1 is independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C substituted with one or more halogens 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 It is an alkoxy, Alternatively, any two R1 together with the atoms on which they are located form a C5 cycloalkyl or a 6-membered heterocyclyl, the heteroatom of said 6-membered heterocyclyl is O and the number of heteroatoms is one.

[0075] In a further preferred embodiment of the present invention, R1 is independently selected from halogen, C 1-6 Alkyl, C substituted with one or more halogens 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 is an alkoxy; Alternatively, any two R1 together with the atoms on which they are located form a C5 cycloalkyl or a 6-membered heterocyclyl, the heteroatom of said 6-membered heterocyclyl is O and the number of heteroatoms is one.

[0076] In a further preferred embodiment of the present invention, R1 is independently C 1-6 Alkyl or C 3-6 is cycloalkyl, Alternatively, any two R1 together with the atoms on which they are located form a C5 cycloalkyl or a 6-membered heterocyclyl, the heteroatom of said 6-membered heterocyclyl is O and the number of heteroatoms is one.

[0077] In a further preferred embodiment of the present invention, R1 is independently C 1-6 alkyl or trifluoromethyl, or any two R1 together with the atoms on which they are located form a C5 cycloalkyl.

[0078] In a further preferred embodiment of the invention, R2 is independently hydrogen or deuterium.

[0079] In a further preferred embodiment of the present invention, R3 is independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, 5-6 membered heteroaryl, -(CH2) n1 C(O)NR b R a or -(CH2) n1 NR b R a wherein the 5- to 6-membered heteroaryl is optionally 1-6 The 5- to 6-membered heterocyclyl is substituted by alkyl, and the heteroatom of the 5- to 6-membered heterocyclyl is N and / or O, and the number of the heteroatoms is 1 or 2.

[0080] In a further preferred embodiment of the present invention, R3 is independently hydrogen, halogen or (CH2) n1 C(O)NR b R a It is.

[0081] In a further preferred embodiment of the present invention, R3 is independently hydrogen or (CH2) n1 C(O)NR b R a It is.

[0082] In a further preferred embodiment of the present invention, R a and R b are each independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl, R a and R b are each independently preferably hydrogen or C 1-6 It is alkyl, for example hydrogen or methyl.

[0083] In a further preferred embodiment of the present invention, x, y and z are each independently an integer of 0-3.

[0084] In a preferred embodiment of the invention, ring B is cyclopropyl, cyclobutyl, cyclopentyl or tetrahydrofuranyl, and when X2 is CH, X3 is N, and X4 is CH, ring B is not cyclopropyl.

[0085] In a preferred embodiment of the present invention, said n is 1, 2, 3, 4, 5 or 6, and when X2 is CH, X3 is N, and X4 is CH, n is not 1.

[0086] In a further preferred embodiment of the present invention, R1 is independently ethyl, methoxy, trifluoromethyl, difluoromethyl, cyclopropyl, fluorine or methyl, or any two R1 together with the atom on which they are located form a cyclopentyl or a 6-membered heterocyclyl, the heteroatom of which is N or O, and the number of heteroatoms is 1.

[0087] In a further preferred embodiment of the invention, R3 is independently hydrogen,

[0088] [ka]

[0089] Fluorine, methyl,

[0090] [ka]

[0091] It is.

[0092] In a further preferred embodiment of the present invention, x is an integer of 0-3.

[0093] In a further preferred embodiment of the present invention, L-(CR4R5) n2 - and n2 is 2.

[0094] In a further preferred embodiment of the present invention, L-(CR4R5) n2 - and n2 is 1.

[0095] In a further preferred embodiment of the present invention,

[0096] [ka]

[0097] teeth,

[0098] [ka]

[0099] and preferably

[0100] [ka]

[0101] For example,

[0102] [ka]

[0103] It is.

[0104] In a further preferred embodiment of the invention, y is 0.

[0105] In a further preferred embodiment of the present invention, ring C is

[0106] [ka]

[0107] It is.

[0108] In a further preferred embodiment of the present invention, ring C is

[0109] [ka]

[0110] It is.

[0111] In a further preferred embodiment of the invention, z is 1 or 2.

[0112] In a further preferred embodiment of the present invention, n1 is 0.

[0113] In a further preferred embodiment of the present invention,

[0114] [ka]

[0115] teeth,

[0116] [ka]

[0117] and preferably

[0118] [ka]

[0119] and more preferably

[0120] [ka]

[0121] or

[0122] [ka]

[0123] For example,

[0124] [ka]

[0125] It is.

[0126] In a further preferred embodiment of the present invention,

[0127] [ka]

[0128] teeth,

[0129] [ka]

[0130] and preferably

[0131] [ka]

[0132] or

[0133] [ka]

[0134] For example,

[0135] [ka]

[0136] It is.

[0137] In a preferred embodiment, the general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (V), general formula (VI), general formula (VII), general formula (VIII) or / and general formula (IX) according to the present invention are in a cis or trans configuration.

[0138] In a further preferred embodiment, the general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (V), general formula (VI), general formula (VII), general formula (VIII) or / and general formula (IX) according to the present invention are in a cis configuration.

[0139] The present invention further provides preferred embodiments of the compounds of each of the above-mentioned general formulas, their stereoisomers or pharma- ceutically acceptable salts thereof, specifically selected from the following compounds:

[0140] [Table 1]

[0141] JPEG2025503798000043.jpg239169

[0142] JPEG2025503798000044.jpg249169

[0143] JPEG2025503798000045.jpg249169

[0144] JPEG2025503798000046.jpg241169

[0145] JPEG2025503798000047.jpg255169

[0146] JPEG2025503798000048.jpg249169

[0147] JPEG2025503798000049.jpg239169

[0148] JPEG2025503798000050.jpg249169

[0149] JPEG2025503798000051.jpg156169

[0150] The present invention further relates to a process for preparing a compound represented by general formula (I), a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, comprising the steps of:

[0151] [ka]

[0152] obtaining a compound represented by general formula (Ia) and (Ib) through one or multiple nucleophilic substitution reactions, coupling reactions or other reactions, directly or further by deprotection reaction, a compound represented by general formula (Ic), a prodrug thereof, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof; Formula (Ic) and Formula (Id) can be prepared by one or multiple steps of nucleophilic substitution, coupling or other reactions to obtain a compound represented by general formula (I), a prodrug thereof, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, and optionally further chiral separation of the compound represented by general formula (I) to obtain a single configuration compound, a prodrug thereof, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof; however, X is selected from halogens, preferably X is fluorine, chlorine, bromine or iodine; X0 is selected from halogens, preferably X0 is fluorine, chlorine, bromine or iodine; R is hydrogen or an amino protecting group, including but not limited to tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and the like; when R is hydrogen, reacting formula (Ia) with formula (Ib) to directly obtain a compound represented by general formula (Ic), a prodrug thereof, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof; When R is an amino-protecting group, reacting formula (Ia) with formula (Ib) and then carrying out a deprotection reaction to obtain a compound represented by general formula (Ic), a prodrug thereof, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof; Ring A, ring B, ring C, L, R1, R2, R3, x, y and z are as described in general formula (I).

[0153] The present invention further relates to a method for preparing a compound represented by general formula (IV), a prodrug thereof, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, comprising the steps of:

[0154] [ka]

[0155] Formula (Ia) and formula (IVa) are reacted in one or multiple steps with nucleophilic substitution to obtain a compound represented by general formula (IVb), a prodrug thereof, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof; formula (IVb) and formula (IVc) are subjected to a nucleophilic substitution reaction to obtain a compound represented by general formula (IV), a prodrug thereof, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, and optionally the compound represented by general formula (IV) is further subjected to chiral separation to obtain a single configuration compound, a prodrug thereof, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof; however, X is selected from halogens, preferably X is fluorine, chlorine, bromine or iodine; X0 is selected from halogen or hydroxyl, preferably X0 is fluorine, chlorine, bromine or hydroxyl; R is hydrogen or an amino protecting group, including, but not limited to, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and the like; when R is hydrogen, reacting formula (Ia) with formula (Ib) to directly obtain a compound represented by general formula (Ic), a prodrug thereof, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof; When R is an amino-protecting group, reacting the compound represented by formula (Ia) with the compound represented by formula (Ib) and then carrying out a deprotection reaction to obtain a compound represented by general formula (Ic), a prodrug thereof, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof; Ring C, X2, X3, X4, R1, R2, R3, R6, y and z are as defined in general formula (IV).

[0156] The present invention further relates to a compound represented by formula (IC), a stereoisomer thereof or a salt thereof.

[0157] [ka]

[0158] Ring B, Ring C, R2, R3, y and z are as described in any embodiment of the present invention.

[0159] The present invention further covers compounds having any one of the following structures:

[0160] [ka]

[0161] JPEG2025503798000056.jpg33169

[0162] The present invention further relates to a pharmaceutical composition comprising a disease-treating effective amount of each of the compounds of the above general formulas, their prodrugs, stereoisomers or pharma- ceutically acceptable salts, and one or more pharma- ceutically acceptable carriers or excipients.

[0163] The present invention further relates to the use of a compound represented by general formula (I), its stereoisomer or a pharma- ceutically acceptable salt thereof, and said pharmaceutical composition in the manufacture of a medicament for treating a disease mediated by polyadenosine diphosphate ribose (ADP-ribose) polymerase (PARP).

[0164] The present invention further relates to the use of the compound represented by general formula (I), its stereoisomer or a pharma- ceutically acceptable salt thereof, and the above pharmaceutical composition in the manufacture of a medicament for treating a PARP1 inhibitor-associated disease.

[0165] The present invention further relates to the use of a compound of formula (I), a prodrug, a stereoisomer or a pharma- ceutically acceptable salt thereof, and the above pharmaceutical composition in the manufacture of a medicament for treating abnormal cell proliferation.

[0166] The present invention further relates to the use of the compound represented by general formula (I), its prodrug, stereoisomer or pharma- ceutically acceptable salt, and said pharmaceutical composition in the manufacture of a medicament for treating cancer, inflammation, metabolic disease, cardiovascular disease, immune disease, and related diseases such as psychiatric disorders.

[0167] Meanwhile, the present invention further relates to the use of the compound represented by general formula (I), its stereoisomer or its pharma- ceutically acceptable salt, and its pharmaceutical composition in the treatment of diseases mediated by polyadenosine diphosphate ribose (ADP-ribose) polymerase (PARP).

[0168] The present invention further relates to the use of the compound represented by general formula (I), its stereoisomer or a pharma- ceutically acceptable salt thereof, and the above pharmaceutical composition in the manufacture of a medicament for treating a PARP1 inhibitor-associated disease.

[0169] Meanwhile, the present invention further relates to the use of the compounds represented by general formula (I), their stereoisomers or pharma- ceutically acceptable salts, and pharmaceutical compositions thereof, in the treatment of abnormal cell proliferation.

[0170] Meanwhile, the present invention further relates to the use of the compound represented by general formula (I), its stereoisomer or its pharma- ceutically acceptable salt, and pharmaceutical composition thereof in the treatment of cancer, inflammation, metabolic disease, cardiovascular disease, immune disease, psychiatric disease, and other related diseases.

[0171] On the other hand, the present invention further relates to the use of the compound represented by general formula (I), its stereoisomer or its pharma- ceutically acceptable salt, and pharmaceutical composition thereof in the treatment of diseases mediated by polyadenosine diphosphate ribose (ADP-ribose) polymerase (PARP).

[0172] On the other hand, the present invention further relates to the use of a compound represented by general formula (I), its stereoisomer or a pharma- ceutically acceptable salt thereof, and a pharmaceutical composition thereof in the treatment of PARP1 inhibitor-associated diseases.

[0173] On the other hand, the present invention further relates to the use of the compounds represented by general formula (I), their stereoisomers or pharma- ceutically acceptable salts, and pharmaceutical compositions thereof in the treatment of abnormal cell proliferation.

[0174] Meanwhile, the present invention further relates to the use of the compound represented by general formula (I), its stereoisomer or its pharma- ceutically acceptable salt, and pharmaceutical composition thereof in the treatment of cancer, inflammation, metabolic disease, cardiovascular disease, immune disease, psychiatric disease, and other related diseases. Detailed Description of the Invention Unless otherwise specified to the contrary, the technical terms used in the present specification and claims have the following meanings.

[0175] The term "alkyl" refers to a hydrocarbon group that is a saturated aliphatic chain hydrocarbon of a straight or branched chain group containing 1 to 20 carbon atoms minus one hydrogen, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 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 dimethylhexyl 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, it is a lower alkyl containing 1 to 6 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, and the like. The alkyl may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, said substituents being preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carbamate groups, and which are preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl in the present invention.

[0176] The term "alkylene" refers to a group in which one hydrogen of an alkyl is further substituted, i.e., a hydrocarbon group lacking two hydrogens from a saturated aliphatic chain hydrocarbon that is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkylene containing 1 to 8 carbon atoms, more preferably an alkylene containing 1 to 6 carbon atoms, and most preferably an alkylene containing 1 to 3 carbon atoms. Non-limiting examples include "methylene" (-CH2-), "ethylene" (-(CH2)2-), "n-propylene" (-(CH2)3-), "isopropylene" (-(CH)(CH3)(CH2)-), "n-butylene" (-(CH2)4-), and the like.

[0177] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing at least two carbon atoms and at least one carbon-carbon double bond, which may be straight or branched chain containing 2 to 20 carbon atoms, preferably an alkenyl containing 2 to 8 carbon atoms, more preferably an alkenyl containing 2 to 6 carbon atoms, and most preferably an alkenyl containing 2 to 4 carbon atoms. For example, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. Alkenyl may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0178] The term "alkynyl" refers to an unsaturated aliphatic alkynyl group containing at least two carbon atoms and at least one carbon-carbon triple bond, which may be straight or branched chain containing 2 to 20 carbon atoms, preferably alkynyl containing 2 to 8 carbon atoms, more preferably alkynyl containing 2 to 6 carbon atoms, and most preferably alkynyl containing 2 to 4 carbon atoms. For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, etc. The alkynyl may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0179] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic non-aromatic cyclic hydrocarbon substituent, where the cycloalkyl ring atoms contain 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, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl, and polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls, and the like.

[0180] The term "spirocycloalkyl" refers to a polycyclic group containing 5-20 carbon atoms and sharing one carbon atom (referred to as a spiro atom) between the monocyclic rings, which may contain one or more double bonds and which, as a whole, does not have aromatic character (i.e., cannot form a conjugated π-electron system as a whole), although one or more of the rings may have a conjugated π-electron system. Spirocycloalkyls preferably contain 6-14 carbon atoms, more preferably 7-10 carbon atoms. Based on the number of shared spiro atoms between the rings, spirocycloalkyls can be classified as monospirocycloalkyls, bisspirocycloalkyls or polyspirocycloalkyls, preferably monospirocycloalkyls and bisspirocycloalkyls. More preferably, they are 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospirocycloalkyls. Non-limiting examples of spirocycloalkyls are:

[0181] [ka]

[0182] And so on. The term "fused cycloalkyl" refers to an all-carbon polycyclic group containing 5-20 carbon atoms, in which each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, where one or more rings may contain one or more double bonds and are not aromatic in their entirety (i.e., cannot form a conjugated π-electron system in their entirety), but may have one or more rings that do have a conjugated π-electron system. Fused cycloalkyls preferably contain 6-14 carbon atoms, more preferably 7-10 carbon atoms. Depending on the number of rings that they comprise, they can be classified as bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyls, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicycloalkyls. Non-limiting examples of fused cycloalkyls are:

[0183] [ka]

[0184] And so on.

[0185] The term "bridged cycloalkyl" refers to an all-carbon polycyclic group containing 5-20 carbon atoms, any two rings sharing two carbon atoms that are not directly connected, which may contain one or more double bonds, and which does not have aromaticity as a whole (i.e., cannot form a conjugated π-electron system as a whole), but may have one or more rings with a conjugated π-electron system. Bridged cycloalkyls preferably contain 6-14 carbon atoms, more preferably 7-10 carbon atoms. Depending on the number of rings that they constitute, they can be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyls are:

[0186] [ka]

[0187] And so on.

[0188] Said cycloalkyl ring can be fused to a cycloalkyl or aryl ring, where the ring connected to the core structure can be a cycloalkyl or aryl ring, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl can be optionally substituted or unsubstituted, and if substituted, the substituents are preferably selected from one or more of the following groups: independently alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carbamate.

[0189] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic non-aromatic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, in which one or more of the ring atoms is nitrogen, oxygen, phosphorus, boron, or S(O). m(where m is an integer of 0 to 2), but does not include the -OO-, -OS-, or -SS- ring moieties, with the remaining ring atoms being carbon. The heterocyclyl preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, 3 to 10 ring atoms; and most preferably, 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyls include oxetane, tetrahydropyranyl, azepanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, pyridonyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, preferably oxetane, tetrahydrofuranyl, tetrahydropyranyl, azepanyl, piperidinyl, pyridonyl, and piperazinyl. Polycyclic heterocyclyls include spirocyclic, fused and bridged heterocyclyls, and the like, where the associated spirocyclic, fused and bridged heterocyclyls are optionally linked to other groups through single bonds or further tandemly linked to other cycloalkyls, heterocyclyls, aryls and heteroaryls through any two or more atoms on the ring.

[0190] The term "spiroheterocyclyl" refers to a polycyclic heterocyclyl containing 5 to 20 ring atoms and sharing one atom (called a spiro atom) between the monocyclic rings, where one or more of the ring atoms is nitrogen, oxygen, phosphorus, boron, or S(O). m(where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, and may not have aromaticity as a whole (i.e., may not form a conjugated π-electron system as a whole), but may have one or more rings with conjugated π-electron systems. The spiroheterocyclyl ring atoms are preferably 6-14 membered, more preferably 7-10 membered. Based on the number of spiro atoms shared between the rings, spiroheterocyclyls can be classified as monospiroheterocyclyls, bisspiroheterocyclyls, or polyspiroheterocyclyls, and are preferably monospiroheterocyclyls and bisspiroheterocyclyls. More preferably, spiroheterocyclyls are 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyls. Non-limiting examples of spiroheterocyclyls are:

[0191] [ka]

[0192] And so on.

[0193] The term "fused heterocyclyl" refers to a polycyclic heterocyclyl containing from 5 to 20 ring atoms, in which each ring in the system shares an adjacent pair of atoms with each other ring in the system, where one or more of the ring atoms is nitrogen, oxygen, phosphorus, boron, or S(O). m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. One or more of the rings may contain one or more double bonds, and the ring as a whole is not aromatic (i.e., the whole cannot form a conjugated π-electron system), but may have one or more rings that have a conjugated π-electron system. The fused heterocyclyl ring atoms are preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings, the fused heterocyclyl may be classified as bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclo-fused heterocyclyl. Non-limiting examples of fused heterocyclyls are:

[0194] [ka]

[0195] And so on.

[0196] The term "bridged heterocyclyl" refers to a polycyclic heterocyclyl containing 5 to 20 ring atoms, in which any two rings share two atoms that are not directly connected, and in which one or more of the ring atoms is nitrogen, oxygen, phosphorus, boron, or S(O). m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds and may not have aromaticity as a whole (i.e., it cannot form a conjugated π-electron system as a whole), but may have one or more rings with conjugated π-electron systems. The bridged heterocyclyl ring atoms are preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings that constitute them, they can be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyls, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyls are:

[0197] [ka]

[0198] And so on.

[0199] The heterocyclyl ring can be fused to a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring, where the ring connected to the core structure is a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring, non-limiting examples of which are:

[0200] [ka]

[0201] And so on.

[0202] The heterocyclyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, independently selected from oxo (=O), thiox (=S), alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carbamate.

[0203] The term "aryl" refers to 6-20 membered all-carbon monocyclic and fused polycyclic rings (i.e., rings which share adjacent pairs of carbon atoms) having a conjugated π electron system, the aryl ring atoms preferably having 6-14 members, more preferably 6-10 members, such as phenyl and naphthyl, and more preferably phenyl.

[0204] Aryl can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carbamate.

[0205] The term "heteroaryl" refers to a heteroaromatic system containing 1-4 heteroatoms and 5-20 ring atoms, where the heteroatoms are selected from oxygen, sulfur, nitrogen, etc. Heteroaryl is divided into monocyclic heteroaryl and polycyclic heteroaryl, the heteroaryl ring atoms are preferably 5-14 members, more preferably 5-10 members, and the monocyclic heteroaryl ring atoms are preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, pyridazinyl, oxadiazolyl, etc., preferably pyridyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, thiadiazolyl, and oxadiazolyl. Polycyclic heteroaryl refers to a polycyclic fused heteroaryl formed by fusion of a heteroaryl ring to an aryl or heteroaryl, where the ring connected to the parent structure can be an aryl or heteroaryl ring, and the polycyclic fused heteroaryl is preferably a bicyclic fused heteroaryl, and non-limiting examples of bicyclic fused heteroaryl are:

[0206] [ka]

[0207] And so on.

[0208] Heteroaryl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carbamate.

[0209] The term "haloalkyl" refers to a group in which the hydrogen of an alkyl is replaced by one or more halogens, where alkyl is as defined above. Non-limiting examples of haloalkyl include: monofluoromethyl, difluoromethyl, trifluoromethyl, monochloromethyl, dichloromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, etc., where haloalkyl can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of the following groups: independently alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carbamate.

[0210] "Hydroxyalkyl" refers to a group in which the hydrogen of an alkyl is replaced by one or more hydroxy, where the alkyl is as defined above. Non-limiting examples of hydroxyalkyl include: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 1-hydroxypropyl, 1-hydroxybutyl, etc., where hydroxyalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carbamate.

[0211] The term "alkoxy" refers to -O-(alkyl), where alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, or butoxy, where alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carbamate.

[0212] The term "alkylthio" refers to -S-(alkyl), where alkyl is as defined above. Non-limiting examples of alkylthio include: methylthio, ethylthio, propylthio, butylthio, where alkylthio may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carbamate.

[0213] "Hydroxy" refers to --OH.

[0214] "Halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0215] "Amino" refers to -NH2.

[0216] "Cyano" refers to -CN.

[0217] "Nitro" refers to -NO2.

[0218] "Carboxyl" refers to --C(O)OH.

[0219] "THF" refers to tetrahydrofuran.

[0220] "PE" refers to petroleum ether.

[0221] "EA" refers to ethyl acetate;

[0222] "IPA" stands for isopropyl alcohol.

[0223] "MeOH" refers to methanol.

[0224] "DMF" refers to N,N-dimethylformamide;

[0225] "TFA" refers to trifluoroacetic acid.

[0226] "ACN" refers to acetonitrile

[0227] "DMA" refers to N,N-dimethylacetamide

[0228] "Et2O" refers to ethyl ether.

[0229] "DCM" refers to dichloromethane;

[0230] "DCE" refers to 1,2-dichloroethane.

[0231] "DIPEA" refers to N,N-diisopropylethylamine.

[0232] "NBS" refers to N-bromosuccinimide.

[0233] "NIS" refers to N-iodosuccinimide.

[0234] "Cbz-Cl" refers to benzyl chloroformate;

[0235] "Pd2(dba)3" refers to tris(dibenzylideneacetone)dipalladium.

[0236] "Dppf" refers to 1,1'-bis(diphenylphosphino)ferrocene.

[0237] "HATU" refers to O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0238] "KHMDS" refers to potassium bis(trimethylsilyl)amide.

[0239] "LiHMDS" refers to lithium bis(trimethylsilyl)amide.

[0240] "MeLi" stands for methyllithium.

[0241] "n-BuLi" refers to n-butyllithium.

[0242] "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0243] Different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", "X is A, B, and C" all mean the same thing, i.e., X can represent any one or more of A, B, and C.

[0244] Any hydrogen atom described in the present invention may be replaced by its isotope, deuterium, and any hydrogen atom in the example compounds according to the present invention may be replaced by deuterium.

[0245] "Optional" or "optionally" means that the following item or circumstance may, but does not necessarily, occur, and the description includes instances where the described item or circumstance occurs as well as instances where the item or circumstance does not occur. For example, "heterocyclyl optionally substituted with alkyl" means that alkyl may, but does not necessarily have to be present, and the description includes situations where the heterocyclyl is substituted with alkyl and situations where the heterocyclyl is not substituted with alkyl.

[0246] "Substituted" refers to one or more hydrogens of a group, preferably 5, more preferably 1 to 3 hydrogens, being independently replaced by the corresponding number of substituents. Needless to say, the substituents are only in their possible chemical positions, and a person skilled in the art can determine possible or impossible substitutions (through experiment and theory) without much effort. For example, when an amino or hydroxyl containing free hydrogen is bonded to a carbon atom having an unsaturated (e.g., olefinic) bond, it may be unstable.

[0247] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein or physiologically / pharmacologically acceptable salts or prodrugs thereof and other chemical components, as well as other components such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a "pharmaceutical composition" is to facilitate administration to a living body and favor the absorption of the active ingredient, thereby exerting biological activity.

[0248] "Pharmaceutically acceptable salt" refers to salts of compounds of the present invention which are safe and effective when used in mammals and which possess the desired biological activity. [Mode for carrying out the invention] Chemical synthesis method: The compounds described herein can be synthesized by various methods acquired by those skilled in the art of organic synthesis using starting materials that are commercially available or can be prepared by known experimental methods. The compounds of the present invention can be synthesized by the methods described below, or by combining synthetic methods known in the art of organic synthetic chemistry with modifications of methods acquired by those skilled in the art. Preferred synthetic methods include, but are not limited to, those described below. For detailed descriptions of the individual reaction steps, see the "Examples" section below.

[0249] Unless otherwise specified, the starting materials in the synthetic steps can be synthesized by methods known in the art or can be purchased from companies such as Sigma-Aldrich Co. Ltd, Bide Pharmatech Ltd., and Accela ChemBio Co. Ltd.

[0250] Unless otherwise stated, all reactions of the present invention are carried out under a continuous magnetic stirrer, under an atmosphere of dry nitrogen or argon gas, the solvents are dry solvents, and the reaction temperatures are in °C.

[0251] Analytical methods and equipment: The LCMS data used to characterize the examples was acquired on an Agilent 1260-6120 / 6125 MSD system equipped with a DAD detector. The test methods are as follows:

[0252] LCMS method A: Column: HALO C18 4.6 x 30 mm, 2.7 μm Column temperature: 45℃ Mobile phase: Solvent A is 0.025% trifluoroacetic acid + 99.975% water, solvent B is 0.025% trifluoroacetic acid + 99.975% acetonitrile.

[0253] Flow rate: 1.8mL / min Gradient: within 0.8 min, solvent B was increased linearly from 5% to 95%, then held at 95% for 0.8 min, and finally solvent B was held at 5% for 2.0 min.

[0254] LCMS method B: Column: HALO C18 4.6 x 30 mm, 2.7 μm Column temperature: 45℃ Mobile phase: Solvent A is 0.1% formic acid + 99.9% water, solvent B is 0.1% formic acid + 99.9% acetonitrile.

[0255] Flow rate: 1.8mL / min Gradient: within 0.8 min, solvent B was increased linearly from 5% to 95%, then held at 95% for 0.8 min, and finally solvent B was held at 5% for 2.0 min.

[0256] LCMS method C: Column: Xbrigde® C18 4.6×50 mm, 2.5 μm Column temperature: 40℃ Mobile phase: Solvent A is 0.05% aqueous ammonia + 99.5% water, and solvent B is 100% acetonitrile.

[0257] Flow rate: 1.8mL / min Gradient: Solvent B increased linearly from 5% to 95% over 1 min within 2.5 min, then maintained at 95% for 2 min, and finally solvent B was maintained at 5% from 2.05 min to 2.5 min.

[0258] NMR data used for characterization of the examples was obtained using a Bruker Fourier transform spectrometer ( 1 H NMR: 400 MHz. Data are given as chemical shifts (multiplicity, number of hydrogen atoms). Chemical shifts are measured using the internal standard tetramethylsilane (δ テトラメチルシラン =0 ppm) and / or a reference solvent peak, the reference solvent peak being 1In the H NMR spectrum, deuterated dimethyl sulfoxide (DMSO-d6) was at 2.49 ppm, deuterated methanol (CD3OD) was at 3.30 ppm, deuterated acetonitrile (CD3CN) was at 1.94 ppm, and deuterated chloroform (CDCl3) was at 7.24 ppm.

[0259] Purification method: Purification of the examples and intermediates was carried out by silica gel chromatography, reversed-phase silica gel chromatography and / or supercritical fluid chromatography (SFC). Silica gel chromatography is generally carried on silica gel or prepacked silica gel columns, and uses a reaction system such as petroleum ether / ethyl acetate or dichloromethane / methanol as an eluent; reversed-phase silica gel chromatography is generally carried on C18 silica gel columns, and is detected by UV detector (214 nm and 254 nm) and preparative LCMS, and the mobile phase includes reaction systems such as acetonitrile / water (0.1% formic acid), acetonitrile / water (0.1% trifluoroacetic acid) and acetonitrile / water (0.1% aqueous ammonia). Supercritical fluid chromatography (SFC) is generally carried on different types of columns, and uses a reaction system such as CO2 / methanol (7M ammonia methanol solution) with 0.2% NH3 as a mobile phase.

[0260] Intermediate a: cis-diazabicyclo[4.2.0]octane

[0261] [ka]

[0262] Synthesis Steps:

[0263] [ka]

[0264] Step 1: Synthesis of methyl 2-((1-((3-((formyl(formyloxy))methyl)phenyl)amino)cyclopropyl)formamido)acetate (a.2) Under nitrogen gas atmosphere, N-(3-dimethylaminopropyl)-N-ethylformimide hydrochloride (99 g, 0.64 mol), 1-hydroxybenzotriazole (86 g, 0.64 mol) and N,N-diisopropylethylamine (165 g, 1.28 mol) were added successively to a solution of methyl 1-(benzyloxycarbonyl)cyclopropanecarboxylate (100 g, 0.425 mol) in N,N-dimethylformamide (500 mL). Then, a solution of glycine methyl ester hydrochloride (80 g, 0.64 mol) in N,N-dimethylformamide (80 mL) was added dropwise to the above mixture. After the addition was completed, the mixture was stirred at room temperature for 24 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the resulting residue was diluted with water (2 L) and extracted with ethyl acetate (1 L x 3). The combined organic phase was dried over anhydrous sodium sulfate and filtered to remove solids. The filtrate was concentrated under reduced pressure to give the crude title compound a.2 (120 g), which was used directly in the next reaction. LC-MS (ESI), m / z: [M+H] + = 307.0 Step 2: Synthesis of methyl 2-((1-aminocyclopropyl)formamido)acetate (a.3) To a solution of compound a.2 (120 g, 0.392 mol) in ethanol (1200 mL) was added Pd / C (12 g). The reaction was purged with hydrogen gas three times, and then the reaction mixture was stirred at room temperature under an atmosphere of hydrogen gas for 5 hours. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated in vacuo to give the crude product of title compound a.3 (65 g), which was used directly in the next reaction. LC-MS (ESI), m / z [M+H] + = 173.1 Step 3: Synthesis of 4,7-diazaspiro[2.5]octane-5,8-dione (a.4) Compound a.3 (65 g, 0.38 mol) was stirred at 150° C. for 30 min, and the resulting reaction mixture was slurried with ethyl acetate to give the title compound a.4 (28 g, yield: 67%).

[0265] 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.03 (s, 1H), 3.85 (d, J = 2.0 Hz, 2H), 1.14 (q, J = 4.3 Hz, 2H), 0.91 (q, J = 4.4 Hz, 2H). Step 4: Synthesis of tert-butyl (7-(tert-butyl-3-oxo)-5,8-dicarbonyl-4,7-diazaspiro[2.5]octan-4-yl)carboxylate (a.5) To a solution of compound a.4 (30 g, 0.21 mol) in dichloromethane (500 mL), di-tert-butyl dicarbonate (141 g, 0.647 mol), triethylamine (65 g, 0.64 mol) and 4-dimethylaminopyridine (7.84 g, 0.0643 mol) were added sequentially. The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was diluted by adding water (300 mL) and the resulting mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered to remove solids and concentrated under reduced pressure. The resulting residue was slurried (EA / PE=10 / 1, 200 mL) and purified to give the title compound a.5 (52 g, yield: 73%). LC-MS (ESI), m / z [2M + Na] + = 702.8 Step 5: Synthesis of tert-butyl (7-(tert-butyl-3-oxo)-5,8-dihydroxy-4,7-diazaspiro[2.5]octan-4-yl)carboxylate (a.6) Under nitrogen gas atmosphere, a solution of compound a.5 (44 g, 0.13 mol) in tetrahydrofuran (1000 mL) was cooled to -78 °C, and a solution of diisobutylaluminum hydride in tetrahydrofuran (1.0 mol / L, 643 mL, 0.64 mol) was slowly added dropwise to the reaction. After the addition was completed, the reaction mixture was stirred at -78 °C for 2 hours. After the reaction was completed, ethyl acetate (2 L) was added to the reaction mixture and stirred at room temperature for 1 hour. The reaction was quenched by adding potassium sodium tartrate solution (2 L), the quenched mixture was filtered, and the filtrate was extracted with ethyl acetate (500 mL x 3). The combined organic phase was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under reduced pressure. The resulting residue was slurried (ethyl acetate, 100 mL) and purified to give the title compound a.6 (20 g, yield: 42%).

[0266] LC-MS (ESI), m / z [2M + Na] + = 711.2 Step 6: Synthesis of tert-butyl cis-(5-(tert-butyl-3-oxo)-2,5-diazabicyclo[4.2.0]octan-2-yl)carboxylate (a.7) In a nitrogen gas atmosphere, a dichloromethane solution (250 mL) of compound a.6 (25 g, 0.073 mol) was cooled to -78 °C, and triethylsilane (21 g, 0.18 mol) and boron trifluoride ethyl ether solution (217 mL, 0.217 mol) were slowly added to the reaction system. The reaction mixture was stirred at -78 °C for 2 hours. After the reaction was completed, water (200 mL) was added to the reaction system, and the resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered to remove solids, and then concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (PE / EA = 100 / 1 to 5 / 1) to give the title compound a.7 (12 g, yield: 55%). LC-MS (ESI), m / z [M-Boc] + =213.0 Step 7: cis-2,5-diazabicyclo[4.2.0]octane (intermediate a) To a solution of compound a.7 (24 g, 0.077 mol) in dichloromethane (250 mL) was added trifluoroacetic acid (60 mL), and the reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (400 mL), and methanol (80 mL) was added to the mixture with stirring. The solid precipitate was collected by filtration, and the resulting solid was subjected to reduced pressure to remove the solvent, after which the crude product of intermediate a (20 g) was obtained. LC-MS (ESI), m / z [M + 1] + =113.2 1 H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 4H), 4.01 - 3.96 (m, 2H), 3.41 - 3.31 (m, 2H), 3.24 - 3.14 (m, 2H), 2.33 - 2.22 (m, 2H), 2.21 - 2.12 (m, 2H). Intermediate b: cis-Octahydrofuro[3,4-b]pyrazine

[0267] [ka]

[0268] Synthesis scheme:

[0269] [ka]

[0270] Step 1: cis-Tetrahydrofuro[3,4-b]pyrazine-2,3(1H,4H)-dione (b-3) At room temperature, cis-tetrahydrofuran-3,4-diamine (1.0 g, 9.8 mmol) and dimethyl oxalate (1.2 g, 9.8 mmol) were dissolved in methanol (100 mL), and the reaction system was heated to 60° C. and stirred for 16 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure to give 1.6 g of a pale pink solid. The crude product was used directly in the next step. LC-MS (ESI), m / z: [M+H] + = 157.1. 1 HNMR (400 MHz, DMSO-d6) δ 8.58 (s, 2H), 4.13 - 4.06 (m, 2H), 3.88 - 3.82 (m, 2H), 3.66 (dd, J = 8.9, 4.2, 2H). Step 2: cis-Octahydrofuro[3,4-b]pyrazine (intermediate b) Compound b-3 (1.6 g, 10.3 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) at room temperature, and lithium aluminum hydride (2.1 g, 51.5 mmol) was added in batches at 0° C. under nitrogen gas protection. After the addition was completed, the reaction was stirred at 65° C. under nitrogen gas protection for 10 hours. It was cooled to room temperature, and anhydrous sodium sulfate (10 g) and ethyl acetate (50 mL) were added, and water (1 mL) was added dropwise at 0° C., and the mixture was stirred at room temperature for 30 minutes, then filtered and spin-dried to obtain the crude product of intermediate b (1.5 g), which was used directly in the next step. LC-MS (ESI), m / z: [M+H] + = 129.2. Intermediate A: 3-(hydroxymethyl)-5,7,8,9-tetrahydro-6H-cyclopenta[c][1,5]phthalazin-6-one

[0271] [ka]

[0272] Synthesis scheme:

[0273] [ka]

[0274] Step 1: Ethyl 2-(((trifluoromethyl)sulfonyl)oxo)cyclopent-1-ene-1-carboxylate (A-2) Sodium hydride (6.40 g, 0.16 mol, 60%) was added in batches to a solution of ethyl 2-carbonylcyclopentane-1-carboxylate (20.0 g, 0.13 mol) in ethyl ether (200 mL) at 0°C and under the protection of nitrogen gas. After the addition was completed, the mixture was stirred at 0°C for 0.5 h, and then trifluoromethanesulfonic anhydride (47.0 g, 0.17 mol) was slowly added at 0°C, and after the addition was completed, the mixture was warmed to 25°C and stirred for 3 h. The reaction was cooled to 0°C and quenched by adding ice water (700 mL), and the mixture was extracted with EA (300 mL x 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was separated and purified by silica gel chromatography (PE:EA = 9:1) to give the title compound A-2 (16.3 g, yield: 44%). LC-MS (ESI), m / z: [M+H] + = 288.9.

[0275] Step 2: Ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-1-ene-1-carboxylate (A-3) Compound A-2 (16.3 g, 0.056 mol) was dissolved in 1,4-dioxane (163 mL) at room temperature. Under the protection of nitrogen gas, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di(1,3,2-dioxaborolane) (17.1 g, 0.067 mol), bis(triphenylphosphine)palladium(II) dichloride (1.97 g, 2.8 mmol) and potassium carbonate (15.5 g, 0.11 mol) were added. The reaction mixture was stirred at 80° C. under the protection of nitrogen gas for 16 hours. It was cooled to room temperature, filtered and concentrated. The obtained residue was separated and purified by silica gel chromatography (PE:EA=5:1) to obtain the crude product of the title compound A-3 (15.4 g). LC-MS (ESI), m / z: [M+H] + = 267.0.

[0276] Step 3: Ethyl 6-(2-(ethyl(ethoxycarbonyl))cyclopent-1-en-1-yl)-5-nitronicotinate (A-5) At room temperature, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.34g, 0.47mmol) and cesium carbonate (6.13g, 18.8mmol) were added to a solution of compound A-3 (8.90g, 9.40mmol) and compound A-4 (2.16g, 9.40mmol) in 1,4-dioxane (25mL). The reaction mixture was stirred at 100°C under nitrogen gas protection for 16 hours. It was cooled to room temperature, filtered and concentrated. The resulting residue was separated and purified by silica gel chromatography (PE:EA=4:1) to obtain the crude product of the title compound A-5 (1.90g).

[0277] LC-MS (ESI), m / z: [M+H] + = 335.1.

[0278] Step 4: 6-Carbonyl-6,6a,7,8,9,9a-hexahydro-5H-cyclopenta[c][1,5]phthalazine-3-carboxylate ethyl (A-6) Compound A-5 (1.90 g, 5.69 mmol) was dissolved in glacial acetic acid (19 mL) solution at room temperature, iron powder (2.55 g, 45.5 mmol) was added, and the reaction system was stirred at 30° C. for 16 hours. After completion of the reaction, the mixture was filtered and concentrated, and the concentrate was slurried in a mixed solvent of dichloromethane and methanol, and filtered to obtain the crude product of title compound A-6 (0.90 g). LC-MS (ESI), m / z: [M+H] + = 259.0.

[0279] Step 5: 3-(hydroxymethyl)-5,7,8,9-tetrahydro-6H-cyclopenta[c][1,5]phthalazin-6-one (A-7) At 0°C and under the protection of nitrogen gas, lithium aluminum hydride (0.27g, 6.98mmol) was added in batches to a solution of compound A-6 (0.90g, 3.49mmol) in tetrahydrofuran (22.5mL). After the addition was completed, the mixture was stirred at 0°C for 2 hours. Then, water (0.27mL) was slowly added dropwise at 0°C, stirred for 10 minutes, and 15% sodium hydroxide solution (0.27mL) was further added dropwise and stirred for 10 minutes. Finally, water (0.80mL) was added dropwise and stirred for 10 minutes. After that, a small amount of anhydrous magnesium sulfate powder was added, filtered and concentrated. The resulting crude product of title compound A-7 (0.70g) was directly used in the next reaction. LC-MS (ESI), m / z: [M+H] + = 217.2. Step 6: 3-(Chloromethyl)-5,7,8,9-tetrahydro-6H-cyclopenta[c][1,5]phthalazin-6-one (Intermediate A) Compound A-7 (0.70 g, 3.24 mmol) was suspended in dichloromethane (20 mL) at room temperature, thionyl chloride (7.71 g, 64.8 mmol) was added, and the mixture was reacted at room temperature for 5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was added to a mixed solvent of dichloromethane and petroleum ether (35 mL), and a solid was precipitated. The mixture was filtered to obtain the crude product of the title compound intermediate A (0.40 g). LC-MS (ESI), m / z: [M+H] + = 235.0.

[0280] Intermediate B: 3-(hydroxymethyl)-9,10-dihydro-5H-pyran[2,3-c][1,5]naphthyridin-6(8H)-one 3-(chloromethyl)-9,10-dihydro-6H-pyran[22,3-c],1,5]

[0281] [ka]

[0282] Synthesis scheme:

[0283] [ka]

[0284] Step 1: Synthesis of methyl 5-nitro-6-(trimethylstannyl)nicotinate (B-2) Under nitrogen gas atmosphere, hexamethyldistannane (2.13 g, 6.50 mmol) and bis(triphenylphosphine)palladium(II) dichloride (110 mg, 0.150 mmol) were added to a solution of compound B-1 (1.08 g, 4.99 mmol) in toluene (15 mL). After the addition was completed, the reaction mixture was stirred at 120° C. for 1 h under microwave conditions. After the reaction was completed, n-hexane (150 mL) was added to the reaction system and the mixture was stirred at room temperature for 3 min. The mixture was filtered and the filtrate was concentrated to obtain the crude product of title compound B-2 (1.40 g). LC-MS (ESI), m / z: [M+H] + = 346.9.

[0285] Step 2: Synthesis of methyl 6-(6-(methoxycarbonyl)-3,4-dihydro-2H-pyran-5-yl)-5-nitronicotinate (B-3) At room temperature, 5-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydro-2H-pyran-6-methyl carboxylate (580 mg, 2.00 mmol), tetrakis(triphenylphosphine)palladium (230 mg, 0.200 mmol) and cuprous iodide (19.0 mg, 0.100 mmol) were added to a solution of compound B-2 (1.50 g, 2.00 mmol) in toluene (20 mL). After the addition was completed, the reaction mixture was stirred at 140 °C for 0.5 h under microwave conditions. After the reaction was completed, the reaction system was diluted with water (50 mL) and the resulting mixture was extracted with ethyl acetate (30 mL × 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was separated and purified by silica gel chromatography (PE:EA = 5:1) to give the title compound B-3 (70.0 mg, yield: 11%). LC-MS (ESI), m / z: [M+H] + = 323.0.

[0286] Step 3: Synthesis of methyl 6-oxo-6,8,9,10-tetrahydro-5H-pyran[2,3-c][1,5]naphthyridine-3-carboxylate (B-4) At room temperature, iron powder (805 mg, 14.9 mmol) was added to a solution of compound B-3 (480 mg, 1.49 mmol) in acetic acid (20 mL), and the reaction mixture was stirred for 16 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, and the resulting residue was diluted with dichloromethane (100 mL) and methanol (10 mL). The resulting mixture was filtered and concentrated, and the residue was separated and purified by silica gel chromatography (DCM:MeOH=20:1) to obtain the title compound B-4 (250 mg, yield: 65%). LC-MS (ESI), m / z: [M+H] + = 261.1. Step 4: Synthesis of 3-(hydroxymethyl)-9,10-dihydro-5H-pyran[2,3-c][1,5]naphthyridin-6(8H)-one (B-5) In a nitrogen gas atmosphere, a solution of compound B-4 (150 mg, 0.577 mmol) in tetrahydrofuran (5 mL) was cooled to 0°C, and a solution of lithium aluminum hydride in tetrahydrofuran (1.0 mol / L, 1.15 mL, 1.15 mmol) was added, and the reaction mixture was stirred at 0°C for 2 hours. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (20 mL) and quenched by adding water (40 mg). After the quenching, solid silica gel was added to the reaction system, which was concentrated to remove the solvent, and the product was separated and purified by silica gel chromatography (DCM:MeOH=10:1) to obtain the title compound B-5 (70.0 mg, yield: 52%). LC-MS (ESI), m / z: [M+H] + = 233.0.

[0287] Step 5: Synthesis of 3-(hydroxymethyl)-9,10-dihydro-5H-pyran[2,3-c][1,5]naphthyridin-6(8H)-one 3-(chloromethyl)-9,10-dihydro-6H-pyran[22,3-c],1,5] (Intermediate B) Compound B-5 (35.0 mg, 0.150 mmol) was dissolved in thionyl chloride (1.00 mL), and the resulting reaction mixture was stirred at 80° C. for 2 hours. After completion of the reaction, the reaction mixture was concentrated, and the resulting residue was the crude product of the title compound intermediate B (40.0 mg), which was used directly in the next reaction. LC-MS (ESI), m / z: [M+H] + = 251.0.

[0288] Intermediate C: 7-(chloromethyl)-3-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one:

[0289] [ka]

[0290] Synthesis scheme:

[0291] [ka]

[0292] Step 1: Synthesis of ethyl 2-bromo-2-(diethoxyphosphoryl)acetate (C-2) Sodium hydride (428 mg, 17.8 mmol) was added to a solution of compound C-1 (4.00 g, 17.8 mmol) in tetrahydrofuran (50 mL) under nitrogen gas atmosphere. After the addition was completed, the reaction mixture was stirred at 0°C for 0.5 h, 1,2-dibromo-1,1,2,2-tetrachloroethane (6.97 g, 21.4 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, water (50 mL) was added to the reaction system, and the resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered to remove solids, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (PE / EA=5 / 1) to give the title compound C-2 (2.59 g, yield: 43%). LC-MS (ESI), m / z: [M+H] + = 303.0, 305.0 Step 2: Synthesis of ethyl 6-(2-bromo-3-ethoxy-3-oxopropionate)-5-nitronicotinate (C-3) Sodium hydride (307 mg, 12.8 mmol) was added to a solution of compound C-2 (2.59 g, 8.54 mmol) in tetrahydrofuran (40 mL) under nitrogen gas atmosphere. After the addition was completed, the reaction mixture was stirred at 0°C for 0.5 h, ethyl 6-formyl-5-nitro-pyridine-3-carboxylate (1.9 g, 8.5 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, water (40 mL) was added to the reaction system, and the resulting mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered to remove solids, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (PE / EA=10 / 1) to give the title compound C-3 (2.28 g, yield: 72%). LC-MS (ESI), m / z: [M+H] + = 373.0, 375.0 Step 3: Synthesis of ethyl 6-(2-(ethoxycarbonyl)-3,3,3-trifluoroprop-1-en-1-yl)-5-nitronicotinate (C-4) To a solution of compound C-3 (1.47 g, 3.93 mmol) in N,N-dimethylformamide (30 mL), 2,2-difluoro-2-(fluorosulfonyl)methyl acetate (1.51 g, 7.88 mmol) and cuprous iodide (1.50 g, 7.88 mmol) were added. After the addition was completed, the reaction mixture was stirred at 100 °C for 4 hours. After the reaction was completed, water (30 mL) was added to the reaction system, and the resulting mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered to remove solids, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (PE / EA = 8 / 1) to give the title compound C-4 (1.02 g, yield: 64%). LC-MS (ESI), m / z: [M+H] + = 363.1 Step 4: Synthesis of ethyl 6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridine-3-carboxylate (C-5) Iron powder (627 mg, 11.2 mmol) was added to a solution of compound C-4 (1.02 g, 2.81 mmol) in acetic acid (10 mL), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with dichloromethane (100 mL) and methanol (100 mL), filtered to remove the solvent, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain the title compound C-5 (434 mg, yield: 48%). LC-MS (ESI), m / z: [M+H] + = 287.1 Step 5: Synthesis of 7-(hydroxymethyl)-3-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (C-6) In a nitrogen gas atmosphere, a solution of compound C-5 (434 mg, 1.51 mmol) in tetrahydrofuran (5 mL) was cooled to 0°C, a solution of lithium aluminum hydride in tetrahydrofuran (1.0 mol / L, 1.81 mL, 1.81 mmol) was added, and the mixture was stirred at 0°C for 2 hours. After the reaction was completed, ethyl acetate (20 mL) and water (40 mg) were added to the reaction system, and the mixture was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (DCM / MeOH=10 / 1) to obtain the title compound C-6 (239 mg, yield: 58%). LC-MS (ESI), m / z: [M+H] + = 245.1 Step 6: Synthesis of 7-(chloromethyl)-3-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Intermediate C) A solution of compound C-6 (100 mg, 0.408 mmol) in thionyl chloride (5 mL) was stirred at 80° C. for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was the crude product of the title compound intermediate C (93 mg). It was used directly in the next reaction. LC-MS (ESI), m / z: [M+H] + = 263.0 Intermediate D: 3-(chloromethyl)-7-ethylpyridine[3,2-c]pyridazin-6(5H)-one

[0293] [ka]

[0294] Synthesis scheme:

[0295] [ka]

[0296] Step 1: Synthesis of methyl 6-chloro-4-((4-methoxybenzyl)amino)pyridazine-3-carboxylate (D-2) 4-Methoxybenzylamine (19.1mL, 146mmol) and triethylamine (37.0mL, 266mmol) were added to a solution of compound D-1 (27.5g, 133mmol) in dimethylsulfoxide (200mL), and the mixture was stirred at room temperature overnight. After completion of the reaction, water (800mL) was added to the reaction system, the precipitated solid was collected by filtration, and the cake was washed with water. The obtained solid was dissolved (dichloromethane / methanol=95 / 5, 200mL), dried over anhydrous sodium sulfate, filtered to remove the solid, and concentrated under reduced pressure to obtain the title compound D-2 (36.9g, yield: 90%). LC-MS (ESI), m / z: [M+H] + = 308.1 Step 2: Synthesis of 6-chloro-4-((4-methoxybenzyl)amino)pyridazine-3-carbaldehyde (D-3) A solution of compound D-2 (36.9 g, 120 mol) in dry tetrahydrofuran (500 mL) was cooled to -78 ° C under nitrogen gas atmosphere, and a solution of DIBAL-H in n-hexane (1.0 mol / L, 180 mL, 180 mmol) was added to the solution. After the dropwise addition was completed, the mixture was continued to stir at -78 ° C for 2 hours. After the reaction was completed, the reaction mixture was quenched with isopropanol (10 mL), a saturated aqueous solution of sodium potassium tartrate (300 mL) and ethyl acetate (300 mL) were added, and the mixture was stirred at room temperature for 2 hours. The resulting mixture was extracted with ethyl acetate (150 mL × 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (dichloromethane / methanol = 95 / 5) to obtain the title compound D-3 (26.6 g, yield: 80%). LC-MS (ESI), m / z: [M+H] + = 278.3 Step 3: Synthesis of (Z)-ethyl 2-((6-chloro-4-((4-methoxybenzyl)amino)pyridazin-3-yl)methylene)butyrate (D-3) Under nitrogen gas atmosphere, sodium hydride (60% wt, 3.3 g, 83 mmol) in tetrahydrofuran (300 mL) was cooled to 0° C., and triethyl 2-phosphonobutyrate (21 g, 82 mmol) was added to the suspension. The reaction mixture was stirred at room temperature for 1 hour. Compound D-3 (19.3 g, 69.4 mmol) in tetrahydrofuran (300 mL) was added dropwise to the reaction at −78° C., and the mixture was stirred for 1 hour. After completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride solution (500 mL), and the resulting mixture was quenched with ethyl acetate (150 mL×3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under reduced pressure. The resulting residue was separated and purified by reverse phase chromatography (water (0.05% trifluoroacetic acid) / acetonitrile = 20 / 80 to 5 / 95) to obtain the title compound D-4 (19 g, yield: 73%). LC-MS (ESI), m / z: [M+H] + = 376.2 Step 4: Synthesis of ethyl 2-((6-chloro-4-((4-methoxybenzyl)amino)pyridazin-3-yl)methyl)butyrate (D-5) Compound D-4 (19 g, 51 mmol) was dissolved in ethanol / tetrahydrofuran (1 / 1, 600 mL), and Raney nickel (0.7 g) was added to the solution. The mixture was stirred overnight at room temperature under an atmosphere of hydrogen gas. After the reaction was completed, the mixture was filtered to remove solids, and the filtrate was concentrated under reduced pressure to obtain the title compound D-5 (19.1 g, yield: 100%). LC-MS (ESI), m / z: [M+H] + = 378.2 Step 5: Synthesis of 2-((4-amino-6-chloropyridazin-3-yl)methyl)butyric acid ethyl ester (D-6) Compound D-5 (19 g, 51 mmol) was dissolved in trifluoroacetic acid (100 mL) and the mixture was heated to reflux for 24 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product of the title compound D-6 (10.6 g). LC-MS (ESI), m / z: [M+H] + = 258.1 Step 6: Synthesis of 3-chloro-7-ethyl-7,8-dihydropyridine[3,2-c]pyridazin-6(5H)-one (D-7) Potassium carbonate (14.0 g, 101 mmol) was added to a solution of compound D-6 (12.9 g, 50.1 mmol) in methanol (300 mL), and the mixture was stirred at 50° C. for 3 hours. After completion of the reaction, dichloromethane (300 mL) and water (300 mL) were added to the reaction system, and the resulting mixture was extracted with dichloromethane (300 mL x 3). The combined organic phase was washed with saturated saline (100 mL), dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 95 / 5) to obtain the title compound D-7 (8.7 g, yield: 81%). LC-MS (ESI), m / z: [M+H] + = 212.1 Step 7: Synthesis of butyl 7-ethyl-6-oxo-5,6,7,8-tetrahydropyridine[3,2-c]pyridazine-3-carboxylate (D-8) In an argon gas atmosphere, a mixture of compound D-7 (0.45 g, 2.1 mmol), 1,1'-bis(diphenylphosphino)ferrocene (153 mg, 0.210 mmol), potassium acetate (0.31 g, 3.2 mmol) and diisopropylethylamine (557 mL, 3.20 mmol) was added with n-butanol (5 mL), and the mixture was stirred at 130 °C for 1 hour in a carbon monoxide atmosphere. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The obtained residue was separated and purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 95 / 5) to obtain the title compound D-8 (0.50 g, yield: 86%). LC-MS (ESI), m / z: [M+H] + = 278.2 Step 8: Synthesis of butyl 7-ethyl-6-oxo-5,6-dihydropyridine[3,2-c]pyridazine-3-carboxylate (D-9) Dichlorodicyanobenzoquinone (409 mg, 1.80 mmol) was added to a solution of compound D-8 (0.50 g, 1.80 mmol) in 1,2-dichloroethane (10 mL), and the reaction mixture was stirred at 70° C. for 2 hours. After completion of the reaction, saturated aqueous sodium bicarbonate was added to the reaction mixture, and it was extracted with dichloromethane (20 mL×4). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under reduced pressure. The obtained residue was the title compound D-9 (0.38 g, yield: 77%). LC-MS (ESI), m / z: [M+H] + = 276.2 Step 9: Synthesis of 7-ethyl-3-(hydroxylmethyl)pyridine[3,2-c]pyridazin-6(5H)-one (D-10) A solution of compound D-9 (0.38 g, 1.4 mmol) in tetrahydrofuran (5 mL) was cooled to 0° C., and lithium aluminum hydride (2.5 mol / L in tetrahydrofuran, 607 mL, 1.52 mmol) was added to the solution. The reaction mixture was stirred at 0° C. until the completion of the reaction was indicated by liquid chromatography. After the reaction was completed, sodium sulfate decahydrate (0.2 g) was added to the reaction system. The solvent was removed by concentration under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (dichloromethane / methanol=95 / 5) to obtain the title compound D-10 (0.24 g, yield: 85%). LC-MS (ESI), m / z: [M+H] + = 206.1 Step 10: Synthesis of 3-(chloromethyl)-7-ethylpyridine[3,2-c]pyridazin-6(5H)-one (Intermediate D) To a suspension of compound D-9 (327 mg, 1.60 mmol) in dichloromethane (4 mL), tetrahydrofuran (4 mL) and acetonitrile (4 mL) were added, and the mixture was cooled to 0° C. To the above mixture, thionyl chloride (0.58 mL, 8.0 mmol) and N,N-dimethylformamide (5 mL) were added, and the mixture was stirred at 0° C. for 10 minutes, and then at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was the crude product of intermediate D (357 mg). It was used directly in the next reaction. LC-MS (ESI), m / z: [M+H] + = 224.1 Intermediate E: 3-Ethyl-7-hydroxymethylpyrido[2,3-b]pyrazin-2(1H)one

[0297] [ka]

[0298] Synthesis scheme:

[0299] [ka]

[0300] Step 1: Synthesis of methyl 2-((5-bromo-3-nitropyridin-2-yl)amino)butyrate (E-2) Under nitrogen gas atmosphere, 2-aminobutyric acid methyl ester (14.2 g, 92.4 mmol) and diisopropylethylamine (32.5 g, 25.2 mmol) were added to a solution of compound E-1 (20.0 g, 84.0 mmol) in N,N-dimethylformamide (200 mL). After the addition was completed, the reaction mixture was stirred at 45° C. for 1 hour. After the reaction was completed, water (600 mL) was added to the reaction system, and the resulting mixture was extracted with ethyl acetate (300 mL×3). The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (PE / EA=10 / 1) to obtain the title compound E-2 (15.7 g, yield: 59%). LC-MS (ESI), m / z: [M+H] + = 317.8, 319.8 Step 2: Synthesis of 7-bromo-3-ethyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)one (E-3) In a nitrogen gas atmosphere, reduced iron powder (22.2 g, 396 mmol) was added to a solution of compound E-2 (15.7 g, 49.5 mmol) in glacial acetic acid (300 mL). After the addition was completed, the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (500 mL) and methanol (50 mL), filtered to remove solids, and the filtrate was further concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain the crude product of title compound E-3 (11.5 g). It was used directly in the next reaction. LC-MS (ESI), m / z: [M+H] + = 255.9, 257.9 Step 3: Synthesis of 7-bromo-3-ethylpyrido[2,3-b]pyrazin-2(1H)one (E-4) Under nitrogen gas atmosphere, manganese dioxide (118 g, 1.35 mol) was added to a solution of compound E-3 (11.5 g, 45.1 mmol) in tetrahydrofuran (230 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with dichloromethane (500 mL) and methanol (50 mL), and filtered to remove solids. The resulting filtrate was concentrated, and the resulting residue was the crude product of title compound E-4 (7.0 g), which was used directly in the next reaction. LC-MS (ESI), m / z: [M+H] + = 254.0, 256.0 Step 4: Synthesis of 3-ethyl-7-hydroxymethylpyrido[2,3-b]pyrazin-2(1H)one (Intermediate E) In a nitrogen gas atmosphere, (tributylstannyl)methanol (3.82 mg, 11.9 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloride (311 mg, 0.395 mmol) were added to a solution of compound E-4 (2.01 g, 7.91 mmol) in dioxane (40 mL). After the addition was completed, the reaction mixture was stirred at 80°C for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (DCM / MeOH=30 / 1) to obtain intermediate E (570 mg, yield: 35%). LC-MS (ESI), m / z: [M+H] + = 206.1 Intermediate F: 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one

[0301] [ka]

[0302] Synthesis scheme:

[0303] [ka]

[0304] Synthesis Steps: Step 1: Ethyl 2-cyclopropylacetate (F-2): 2-Cyclopropylacetic acid (21.5 g, 0.21 mol) was dissolved in DCM (150 mL) and cooled to 0° C. A solution of oxalyl chloride (32.7 g, 0.26 mol) in DCM (50 mL) was added to the above mixture at 0° C., and the mixture was stirred at room temperature for 4 hours. The resulting mixture was concentrated under reduced pressure. The resulting solution was slowly diluted with 200 mL of ethanol at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give the title compound F-2 (18.5 g, yield: 67%).

[0305] 1 H NMR (400 MHz, DMSO-d6) δ 4.05 (q, J = 7.2 Hz, 2H), 2.20 (d, J = 7.2 Hz, 2H), 1.18 (t, J = 7.2 Hz, 3H), 0.96 - 0.92 (m, 1H), 0.48 - 0.44 (m, 2H), 0.14 - 0.10 (m, 2H).

[0306] Step 2: Ethyl 2-bromo-2-cyclopropylacetate (F-3): Under the protection of nitrogen gas, ethyl 2-cyclopropylacetate (15.0 g, 0.12 mol) was dissolved in dry THF (150 mL) and cooled to -78 °C. LDA (0.15 mmol, 2.0 M in THF, 76.1 mL) was slowly added dropwise to the reaction mixture. After 1 h, TMSCl (12.7 g, 0.12 mmol) was added. The mixture was stirred at room temperature for 3 h, then cooled to -78 °C, N-bromosuccinimide (25.0 g, 0.14 mmol) was added and stirred at room temperature for 2 h. The mixture was quenched with saturated NH4Cl solution and extracted with n-hexane (200 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound F-3 (22.0 g, yield: 90%).

[0307] 1H NMR (400 MHz, CDCl3) δ 4.24 (q, J = 7.1 Hz, 2H), 3.57 (d, J = 10.4 Hz, 1H), 1.62 - 1.51 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H), 0.90 - 0.78 (m, 2H), 0.56 - 0.51 (m, 1H), 0.45 - 0.39 (m, 1H).

[0308] Step 3: Ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate (F-5): Ethyl 2-bromo-2-cyclopropyl acetate (3.0 g, 14.5 mmol) was dissolved in triethyl phosphite (3.61 g, 21.7 mmol) and the mixture was stirred at 130° C. for 12 hours. The reaction was cooled to room temperature and the reaction mixture was concentrated under reduced pressure to give the title compound F-5 (3.50 g, yield: 90%).

[0309] 1 H NMR (400 MHz, CDCl3) δ 4.22 - 4.14 (m, 6H), 2.24 - 2.15 (m, 1H), 1.31 - 1.26 (m, 10H), 0.76 - 0.68 (m, 1 Hz), 0.65 - 0.54 (m, 1H), 0.48 - 0.37 (m, 1H), 0.28 - 0.19 (m, 1H).

[0310] Step 4: Ethyl 6-((1Z)-2-cyclopropyl-3-ethoxy-3-oxopropyl-1-en-1-yl)-5-nitropyridine-3-carboxylate (F-7): A solution of NaH (0.20 g, 8.40 mmol) in THF (25.0 mL) was cooled to 0° C. To the above mixture was added ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate (1.40 g, 5.30 mmol) at 0° C. The mixture was stirred at room temperature for 30 min and then cooled to 0° C. To the above mixture was added ethyl 6-formyl-5-nitropyridine-3-carboxylate (1.78 g, 7.90 mmol) at 0° C. The resulting mixture was stirred at room temperature for 30 min under the protection of argon gas. To the above reaction mixture was added NH4Cl (aq., 20 mL) dropwise slowly at 0° C. The resulting mixture was diluted with water (50 mL) and extracted with EA (50 mL×2). The combined organic phase was washed with saturated brine (20 mL×2) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (PE:EA=4:1) to give the title compound F-7 (0.85 g, yield: 47%). LC-MS (ESI), m / z: [M+H] + = 335.1.

[0311] Step 5: Ethyl 7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate (F-8): A mixture of 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxopropyl-1-en-1-yl]-5-nitropyridine-3-carboxylate (0.85 g, 2.54 mmol), Fe (0.71 g, 12.7 mmol) and AcOH (2.0 mL) was stirred at room temperature for 1 h. After filtration, the filtrate was concentrated under reduced pressure. At room temperature, the mixture was diluted with hydrogen chloride in 1-4-dioxane (2.0 M) and stirred at 80° C. for 12 h. The mixture was cooled to room temperature and concentrated under reduced pressure to give the title compound F-8 (0.40 g, yield: 60%) as a yellow solid. LC-MS (ESI), m / z: [M+H] + = 259.1.

[0312] Step 6: 3-Cyclopropyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (F-9) A solution of LiAlH4 (162.6 mg, 4.07 mmol) in THF (5.0 mL) was cooled to 0° C. At 0° C., ethyl 7-cyclopropyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (0.35 g, 1.36 mol) was added dropwise to the above mixture. After the addition was completed, the reaction mixture was stirred at 0° C. for 4 h. At 0° C., sodium sulfate decahydrate (0.20 g) was slowly added to the reaction mixture. The resulting mixture was diluted with EA (10.0 mL). Filtered and the cake was rinsed with EA (10 mL). The filtrate was combined and dried over anhydrous magnesium sulfate. The filtrate was dried by filtration and concentrated to give the title compound F-9 (0.29 g, yield: 91%). LC-MS (ESI), m / z: [M+H] + = 217.1.

[0313] Step 7: 7-(Bromomethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one (Intermediate F): 3-Cyclopropyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (0.10 g, 0.46 mmol) was dissolved in THF (1.50 mL) and cooled to 0°C. PBr3 (187.8 mg, 0.70 mmol) was slowly added dropwise to the above mixture at 0°C. The mixture was stirred at 0°C for 2 h. Saturated sodium bicarbonate solution (5.0 mL) was added dropwise to the reaction mixture at 0°C. The resulting mixture was diluted with water (5.0 mL) and extracted with EA (10 mL x 2). The combined organic phase was washed with saturated brine (10 mL x 2) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (PE:EA = 4:1) to give the title compound intermediate F (45.0 mg, yield: 33%). LC-MS (ESI), m / z: [M+H] + = 278.9.

[0314] Intermediate G: 7-(hydroxymethyl)-3-methoxy-1,5-phthalazin-2(1H)-one

[0315] [ka]

[0316] Synthesis scheme:

[0317] [ka]

[0318] Step 1: Ethyl 2-(diethoxyphosphonyl)-2-hydroxylacetate (G-3): Ethyl 2-carbonylacetate (15.0 g, 0.15 mol), diethyl phosphonate (22.0 g, 0.16 mol) and 4-methylbenzenesulfonic acid (0.25 g, 1.40 mmol) were added to 150 mL of toluene, and the resulting mixture was stirred at 110° C. for 16 h. After the reaction was cooled to room temperature, 100 mL of water was added to the reaction mixture, which was then extracted with EA (100 mL×2). The combined organic phase was washed with saturated brine (150 mL×2) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (using EA / PE, EA: 0%~80% EA) to obtain the title compound G-3 (15.0 g, yield: 43%).

[0319] 1 H NMR (400 MHz, DMSO-d6) δ 4.59 (d, J = 11.2 Hz, 1H), 4.17 (q, J = 7.2 Hz, 1H), 4.09 - 4.00 (m, 5H), 3.32 (s, 1H), 1.27 - 1.21 (m, 9H).

[0320] Step 2: Ethyl 2-(diethoxyphosphonyl)-2-methoxyacetate (G-4): Ethyl 2-(diethoxyphosphonyl)-2-hydroxylacetate (2.0 g, 8.30 mmol), silver oxide (2.89 g, 12.4 mmol) and methyl iodide (11.8 g, 0.083 mol) were added to dichloromethane (20 mL) and the mixture was stirred from 0 °C to room temperature for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (15 mL × 2). The extracted organic phases were combined, washed with saturated brine (15 mL × 2) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (gradient elution of EA from 0% to 50% in a mixed solvent with petroleum ether) to obtain the title compound G-4 (1.60 g, yield: 72%).

[0321] 1 H NMR (400 MHz, DMSO-d6) δ 4.52 (d, J = 18.8 Hz, 1H), 4.23 - 4.15 (m, 2H), 4.11 - 4.04 (m, 4H), 3.37 (s, 3H), 1.25 - 1.21 (m, 9H).

[0322] Step 3: (E)-6-(3-ethoxy-2-methoxy-3-carbonylprop-1-en-1-yl)-5-nitronicotinic acid ethyl ester (G-6): A suspension of sodium hydride (0.12 g, 5.0 mmol) in tetrahydrofuran (10 mL) was cooled to 0° C., and 2-(diethoxyphosphonyl)-2-methoxyethyl acetate (1.0 g, 3.9 mmol) was slowly added dropwise while maintaining the temperature at 0° C., and the mixture was stirred at 0° C. for 30 min., and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (1.50 g, 0.012 mol) and ethyl 6-formyl-5-nitronicotinate (1.05 g, 4.60 mol) were slowly added dropwise, and the reaction system was slowly warmed to room temperature and stirred for 4 h. After completion of the reaction, the mixture was quenched with saturated aqueous ammonium chloride solution (10 mL), diluted with water (20 mL), and extracted with EA (15 mL×2). The extracted organic phases were combined, washed with saturated brine (15 mL×2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient elution of EA from 0% to 80% in a mixture of petroleum ether) to obtain the title compound G-6 (0.29 g, yield: 23%). LC-MS (ESI), m / z: [M+H] + = 325.1.

[0323] Step 4: Ethyl 7-methoxy-6-carbonyl-5,6-dihydro-1,5-phthalazine-3-carboxylate (G-7): (E)-6-(3-ethoxy-2-methoxy-3-carbonylprop-1-en-1-yl)-5-nitronicotinic acid ethyl ester (2.50 g, 7.7 mmol) and iron powder (3.44 g, 0.062 mol) were added to acetic acid (30 mL) and stirred at room temperature for 2 hours under argon gas protection. After completion of the reaction, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound G-7 (2.0 g), which was used directly in the next step. LC-MS (ESI), m / z: [M+H] + = 249.0.

[0324] Step 5: 7-(hydroxymethyl)-3-methoxy-1,5-phthalazin-2(1H)-one (G-8): A suspension of lithium aluminum hydride (1.46 g, 38.5 mmol) in tetrahydrofuran (50 mL) was cooled to 0°C. A solution of ethyl 7-methoxy-6-carbonyl-5,6-dihydro-1,5-phthalazine-3-carboxylate (1.90 g, 7.7 mmol) in tetrahydrofuran was slowly added dropwise to the above suspension at 0°C. The mixture was warmed to room temperature and stirred for 1 h. After the reaction was completed, sodium sulfate decahydrate (1.30 g) was added to the reaction system to quench the reaction. The solid was collected by filtration, then dissolved in water (100 mL), adjusted to pH 6-7 with dilute hydrochloric acid, and extracted with EA (150 mL x 2). The extracts were then combined to obtain a suspended aqueous layer, and the solid was collected by filtration. The residue was purified by silica gel chromatography (dichloromethane mixed solvent, MeOH gradient elution from 0% to 12.5% ​​specific gravity) to obtain the title compound G-8 (0.25 g, yield: 16%). LC-MS (ESI), m / z: [M+H] + = 207.1.

[0325] Step 6: 7-(Bromomethyl)-3-methoxy-1,5-phthalazin-2(1H)-one (Intermediate G): A solution of 7-(hydroxymethyl)-3-methoxy-1,5-phthalazin-2(1H)-one (50.0 mg, 0.24 mmol) in tetrahydrofuran (1.0 mL) was cooled to 0° C., and then phosphorus tribromide (98.5 mg, 0.36 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to give the crude product of the title compound intermediate G (30.0 mg), which was used directly in the next step. LC-MS (ESI), m / z: [M+H] + = 269.0.

[0326] Intermediate H: 7-(hydroxymethyl)-6-fluoro-1,2,3,5-tetrahydro-1,2,3,5-tetrahydro-4H-cyclopentane[c]quinolin-4-one

[0327] [ka]

[0328] Synthesis scheme:

[0329] [ka]

[0330] Step 1: Synthesis of methyl 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro-2-nitrophenyl)cyclopent-1-ene-1-carboxylate (H-3) Under nitrogen gas atmosphere, ethyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopentyl-1-ene-1-carboxylate (600 mg, 2.08 mmol), tetrakis(triphenylphosphine)palladium (241 mg, 0.210 mmol) and sodium carbonate (662 mg, 6.24 mmol) were added to a solution of compound H-1 (1.28 g, 3.12 mmol) in dioxane (10 mL). After the addition was completed, the reaction mixture was stirred at 100 °C for 12 hours. After the reaction was completed, ethyl acetate (20 mL) and water (15 mL) were added to the reaction system. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and filtered to remove solids, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (PE / EA = 20 / 1) to obtain the title compound H-3 (350 mg, yield: 26%). LC-MS (ESI), m / z: [M+H] + = 424.0 Step 2: 7-((((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-1,2,3,5-tetrahydro-4H-cyclopentane[c]quinolin-4-one (H-4) Palladium on carbon (60 mg) was added to a solution of compound H-3 (300 mg, 0.709 mmol) in methanol (10 mL), and the reaction mixture was stirred at room temperature for 16 hours under a hydrogen gas atmosphere. After completion of the reaction, the reaction mixture was filtered to remove solids, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (PE / EA=5 / 1) to obtain the title compound H-4 (220 mg, yield: 89%). LC-MS (ESI), m / z: [M+H]+ = 348.1 Step 3: 7-(hydroxymethyl)-6-fluoro-1,2,3,5-tetrahydro-1,2,3,5-tetrahydro-4H-cyclopentane[c]quinolin-4-one (H-5) To a solution of compound H-4 (200 mg, 0.576 mmol) in dichloromethane (5 mL), aqueous hydrobromic acid (40%, 2 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give H-5 (120 mg, yield: 89%). LC-MS (ESI), m / z: [M+H] + = 234.0 Step 4: 7-Bromo-6-fluoro-1,2,3,5-tetrahydro-4H-cyclopentane[c]quinolin-4-one (Intermediate H) At room temperature, hydrobromic acid (40% aqueous solution, 5.00 mL) was added to compound H-5 (120 mg, 0.513 mmol), and the reaction mixture was stirred at 80° C. for 2 hours. After completion of the reaction, ethyl acetate (10.0 mL) was added to dilute, and the organic phase was washed with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated. The title compound intermediate H (140 mg, yield: 93%) was obtained. LC-MS (ESI), m / z: [M+H] + = 295.9, 297.9 Intermediate I: 7-(hydroxymethyl)-6-methyl-1,2,3,5-tetrahydro-4H-cyclopentadiene[c]quinolin-4-one

[0331] [ka]

[0332] Synthesis scheme:

[0333] [ka]

[0334] Step 1: Synthesis of methyl 2-methyl-3-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzoate (I-2) Under nitrogen gas atmosphere, bis(pinacolato)diboron (2.23 g, 8.80 mmol), tris(dibenzylideneacetone)dipalladium (0.400 g, 0.440 mmol), tricyclohexylphosphine (0.250 g, 0.880 mmol) and potassium acetate (1.30 g, 13.2 mmol) were added to a solution of compound I-1 (1.00 g, 4.40 mmol) in 1,4-dioxane (20 mL). After the addition was complete, the mixture was stirred at 90° C. for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature and used directly in the next reaction.

[0335] LC-MS (ESI), m / z: [M+HCOO] - = 284.1 Step 2: Synthesis of methyl 4-(2-(methoxycarbonyl)cyclopent-1-en-1-yl)-2-methyl-3-nitrobenzoate (I-3) Under nitrogen gas atmosphere, ethyl 2-(((trifluoromethyl)sulfonyl)oxo)cyclopent-1-ene-1-carboxylate (880 mg, 3.20 mmol), tetrakis(triphenylphosphine)palladium (180 mg, 0.160 mmol) and sodium carbonate (510 mg, 4.80 mmol) were added to the reaction mixture of the above step, and the reaction mixture was stirred at 100° C. for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was the crude product of the title compound I-3 (2.50 g). LC-MS (ESI), m / z: [M + 35 Cl - H] - = 354.0 Step 3: Synthesis of methyl 6-methyl-4-oxo-2,3,4,5-tetrahydro-1H-cyclopentadiene[c]quinoline-7-carboxylate (I-4) Palladium carbon (40 mg) was added to a methanol solution (10 mL) of compound I-3 (200 mg, 0.626 mmol), and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (PE / EA=1 / 1) to obtain the title compound I-4 (100 mg, yield: 62%). LC-MS (ESI), m / z: [M+H] + = 258.0 Step 4: Synthesis of 7-(hydroxymethyl)-6-methyl-1,2,3,5-tetrahydro-4H-cyclopentadiene[c]quinolin-4-one (I-5) A solution of compound I-4 (100 mg, 0.388 mmol) in tetrahydrofuran (3 mL) was cooled to 0°C, and a solution of lithium aluminum hydride in tetrahydrofuran (1.0 mol / L, 0.77 mL, 0.77 mmol) was added to the reaction system, and the reaction mixture was stirred for 1 hour. After completion of the reaction, water (0.1 mL) was added to the reaction system, and the resulting mixture was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (DCM / MeOH=10 / 1) to obtain I-5 (50 mg, yield: 50%). LC-MS (ESI), m / z: [M+H] + = 229.3 Step 5: 7-Chloromethyl-6-methyl-1,2,3,5-tetrahydro-4H-cyclopentoquinolin-4-one (Intermediate I) Compound I-5 (50.0 mg, 0.218 mmol) in aqueous hydrobromic acid (30.0%) (2.00 mL) was heated to 80° C., and the reaction mixture was stirred at 80° C. for 2 h. After completion of the reaction, the solvent was concentrated under reduced pressure to give the crude product of intermediate I (50.0 mg), which was used directly in the next step. LC-MS (ESI), m / z: [M+H]+ = 292.0, 294.0.

[0336] Intermediate J: 7-Fluoro-8-(hydroxymethyl)-2,3-dihydro-1H-pyrano[2,3-c]quinolin-5(6H)-one

[0337] [ka]

[0338] Synthesis scheme:

[0339] [ka]

[0340] Step 1: Synthesis of (4-amino-2-fluoro-3-nitrophenyl)methanol (J-2) Under nitrogen gas atmosphere, (tributylstannyl)methanol (10.2 g, 31.9 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloride (0.840 g, 1.06 mmol) were added to a solution of 4-bromo-3-fluoro-2-nitroaniline (5.00 g, 21.3 mmol) in 1,4-dioxane (50 mL). After the addition was completed, the reaction mixture was stirred at 80° C. for 16 hours. After the reaction was completed, saturated aqueous potassium fluoride solution (150 mL) was added to the reaction system and stirred at room temperature for 3 minutes. The solid was removed by filtration and the filtrate was extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove solids, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (PE / EA=5 / 1) to obtain the title compound J-2 (3.00 g, yield: 76%). LC-MS (ESI), m / z: [MH] - = 185.1 Step 2: Synthesis of (4-bromo-2-fluoro-3-nitrophenyl)methanol (J-3) Copper bromide (4.34 g, 19.4 mmol) was added to a solution of isoamyl nitrite (2.28 g, 19.4 mmol) in acetonitrile (50 mL), and the reaction mixture was stirred at 25° C. for 1 hour. Compound J-2 (3.00 g, 16.1 mmol) was added to the reaction system, and stirring was continued for 0.5 hours. The temperature of the reaction system was raised to 70° C., and the mixture was stirred for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the obtained residue was diluted with water (50 mL) and extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered to remove solids, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (PE / EA=5 / 1) to obtain the title compound J-3 (2.00 g, yield: 50%).

[0341] 1 H (400 MHz, DMSO-d6) δ 7.76 (dd, J = 8.4, 1.2 Hz, 1H), 7.69 (t, J = 7.9 Hz, 1H), 5.63 (s, 1H), 4.60 (s, 2H). Step 3: Synthesis of ((4-bromo-2-fluoro-3-nitrobenzyl)oxy)(tert-butyl)dimethylsilane (J-4) Imidazole (1.09 g, 16.0 mmol) and tert-butyldimethylsilyl chloride (2.41 g, 16.0 mmol) were added to a solution of compound J-3 (2.00 g, 8.00 mmol) in N,N-dimethylformamide (20 mL), and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction system was diluted with water (100 mL), and the mixture was extracted with ethyl acetate (50.0 mL x 3). The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered to remove solids, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (PE / EA = 20 / 1) to obtain the title compound J-4 (2.30 g, yield: 79%).

[0342] Step 4: Synthesis of tert-butyl((2-fluoro-3-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)dimethylsilane (J-5) Under nitrogen gas atmosphere, bis(pinacolato)diboron (2.79 g, 11.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.402 g, 0.549 mmol) and potassium acetate (1.61 g, 16.5 mmol) were added to a solution of compound J-4 (2.00 g, 5.49 mmol) in 1,4-dioxane (30 mL). After the addition was completed, the reaction mixture was stirred at 100° C. for 16 hours. After the reaction was completed, a mixture solution containing the title compound J-5 was obtained and used directly in the next reaction. LC-MS (ESI), m / z: [M + HCOO] - = 374.1. Step 5: Synthesis of methyl 5-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro-2-nitrophenyl)-3,4-dihydro-2H-pyran-6-carboxylate (J-6) In a nitrogen gas atmosphere, 5-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydro-2H-pyran-6-methyl carboxylate (565 mg, 1.95 mmol), tetrakis(triphenylphosphine)palladium (112 mg, 0.0972 mmol) and sodium carbonate (309 mg, 2.92 mmol) were added to the mixture containing compound J-5, and the reaction mixture was stirred at 100° C. for 10 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was the crude product of the title compound J-6 (1.20 g). LC-MS (ESI), m / z: [M ‐ TBS + 35 Cl] - = 346.0 Step 6: Synthesis of 8-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-2,3-dihydro-1H-pyrano[2,3-c]quinolin-5(6H)-one (J-7) Palladium carbon (50 mg) was added to a methanol solution (10 mL) of compound J-6 (300 mg, 0.706 mmol), and the reaction mixture was stirred at 25° C. for 16 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel chromatography (PE / EA=1 / 1) to obtain the title compound J-7 (200 mg, yield: 78%). LC-MS (ESI), m / z: [M+H] + = 364.2 Step 7: Synthesis of 7-fluoro-8-(hydroxymethyl)-2,3-dihydro-1H-pyrano[2,3-c]quinolin-5(6H)-one (J-8) Compound J-7 (200 mg, 0.550 mmol) was dissolved in aqueous hydrobromic acid (30%, 5 mL), and the reaction mixture was stirred at room temperature for 0.5 h. After completion of the reaction, a mixture solution containing the title compound J-8 was obtained and used directly in the next reaction. LC-MS (ESI), m / z: [M+H] + = 250.0 Step 8: Synthesis of 8-(bromomethyl)7-fluoro-2,3-dihydro-1H-pyrano[2,3-c]quinolin-5(6H)-one (Intermediate J) The mixture solution containing the reacted title compound J-8 from the above step was heated to 80° C. and stirred at that temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, diluted with water (20 mL), slurried, purified, and filtered. The solid was collected and washed with ethyl acetate (20 mL). The obtained solid was subjected to removal of the solvent under reduced pressure to obtain the title compound intermediate J (60.0 mg, yield: 48%). LC-MS (ESI), m / z: [M+H] + = 311.9, 313.9 Intermediate K: 8-(bromomethyl)-7-methyl-1H,2H,3H,6H-pyrano[2,3-c]quinolin-5-one

[0343] [ka]

[0344] Synthesis scheme:

[0345] [ka]

[0346] Step 1: Synthesis of methyl 2-methyl-3-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzoate (K-2) Under nitrogen gas atmosphere, bis(pinacolato)diboron (1.11 g, 4.35 mmol), bis(dibenzylideneacetone)palladium (125 mg, 0.218 mmol), tricyclohexylphosphine (122 mg, 0.435 mmol) and potassium acetate (320 mg, 3.26 mmol) were added to a solution of compound K-1 (500 mg, 2.18 mmol) in 1,4-dioxane (2 mL), and the reaction mixture was stirred at 90° C. for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product of title compound K-2 (1.40 g). It was used directly in the next reaction.

[0347] LC-MS (ESI), m / z: [M + 35 Cl] + = 274.1 Step 2: Synthesis of methyl 3-[4-(methoxycarbonyl)-3-methyl-2-nitrophenyl]-5,6-dihydro-4H-pyran-2-carboxylate (K-3) Under nitrogen gas atmosphere, 5-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydro-2H-pyran-6-methyl carboxylate (904 mg, 3.11 mmol), tetrakis(triphenylphosphine)palladium (180 mg, 0.156 mmol) and sodium carbonate (330 mg, 3.11 mmol) were added to a solution of compound K-2 (500 mg, 1.56 mmol) in 1,4-dioxane (10 mL), and the reaction mixture was stirred at 100° C. for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product of title compound K-3 (2.0 g). It was used directly in the next reaction. LC-MS (ESI), m / z: [M+H] + = 336.1 Step 3: Synthesis of methyl 7-methyl-5-oxo-1H,2H,3H,6H-pyrano[2,3-c]quinoline-8-carboxylate (K-4) Palladium carbon (100 mg) was added to a solution of compound K-3 (500 mg, 1.49 mmol) in methanol (10 mL) under nitrogen gas atmosphere, and the reaction mixture was stirred at room temperature under hydrogen gas atmosphere for 16 hours. After the reaction was completed, the reaction mixture was filtered to remove solids, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (DCM / MeOH=100 / 1) to obtain the title compound K-4 (590 mg, yield: 94%). LC-MS (ESI), m / z: [M+H] + = 274.1 Step 4: Synthesis of 8-(hydroxymethyl)-7-methyl-1H,2H,3H,6H-pyrano[2,3-c]quinolin-5-one (K-5) In a nitrogen gas atmosphere, a solution of compound K-4 (540 mg, 2.00 mmol) in tetrahydrofuran (10 mL) was cooled to 0°C, and a solution of lithium aluminum hydride in tetrahydrofuran (1.0 mol / L, 6.0 mL, 6.0 mmol) was added, and the reaction mixture was stirred for 2 hours. After the reaction was completed, ethyl acetate (20 mL) and water (240 mg) were added to the reaction system. The resulting mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (DCM / MeOH=10 / 1) to obtain the title compound K-5 (174 mg, yield: 32%). LC-MS (ESI), m / z: [M+H] + = 246.1 Step 5: Synthesis of 8-(bromomethyl)-7-methyl-1H,2H,3H,6H-pyrano[2,3-c]quinolin-5-one (Intermediate K) Compound K-5 (30.0 mg, 0.122 mmol) in aqueous hydrogen bromide (2 mL) was stirred at 80° C. for 2 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (20 mL). The organic phase was concentrated under reduced pressure, and the resulting residue was the crude product of intermediate K (32 mg). LC-MS (ESI), m / z: [M+H] + = 308.0, 310.0 Intermediate L: 3-Ethyl-7-(hydroxymethyl)quinoxalin-2(1H)-one

[0348] [ka]

[0349] Synthesis scheme:

[0350] [ka]

[0351] Step 1: Synthesis of methyl 2-(4-bromo-2-nitrophenyl)amino)butyrate (L-2) Under nitrogen gas atmosphere, methyl 2-aminobutyrate (8.0 g, 68 mmol) and diisopropylethylamine (17.6 g, 136 mmol) were added to a solution of compound L-1 (10.0 g, 45.5 mmol) in N,N-dimethylformamide (40 mL). After the addition was completed, the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (300 mL) was added to the reaction system, and the resulting mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (DCM / MeOH=20 / 1) to give the title compound L-2 (14.4 g, yield: 90%). LC-MS (ESI), m / z: [M+H] + = 317.0 Step 2: Synthesis of 7-bromo-3-ethyl-3,4-dihydroquinoxalin-2(1H)-one (L-3) Reduced iron powder (20.3 g, 363 mmol) was added to a solution of compound L-2 (14.4 g, 45.4 mmol) in glacial acetic acid (250 mL) under nitrogen gas atmosphere. After the addition was completed, the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, diluted with water (200 mL), and the resulting mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (DCM / MeOH=30 / 1) to give the title compound L-3 (13.2 g, yield: 96%). LC-MS (ESI), m / z: [M+H] + = 255.1 Step 3: Synthesis of 7-bromo-3-ethylquinoxalin-2(1H)-one (L-4) In a nitrogen atmosphere, manganese dioxide (6.78 g, 78.0 mmol) was added to a solution of compound L-3 (2.0 g, 7.8 mmol) in tetrahydrofuran (100 mL), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with dichloromethane (100 mL) and methanol (10 mL), and filtered to remove solids. The resulting filtrate was concentrated, and the resulting residue was the title compound L-4 (1.50 g, yield: 68%).

[0352] LC-MS (ESI), m / z: [M+H] + = 253.0 Step 4: 3-Ethyl-7-(hydroxymethyl)quinoxalin-2(1H)-one (Intermediate L) In a nitrogen gas atmosphere, (tributylstannyl)methanol (913 mg, 2.84 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloride (186 mg, 0.237 mmol) were added to a solution of compound L-4 (600 mg, 2.37 mmol) in dioxane (10 mL). After the addition was completed, the reaction mixture was stirred at 80°C for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain intermediate L (360 mg, yield: 67%). LC-MS (ESI), m / z: [M+H] + = 205.1 Intermediate M: 3-methyl-4-fluoro-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one

[0353] [ka]

[0354] Synthesis scheme:

[0355] [ka]

[0356] Step 1: Synthesis of methyl 1-2-[(4-bromo-2-fluoro-6-nitrophenyl)amino]butyrate (M-2) Under nitrogen gas atmosphere, methyl 2-aminobutyrate (2.70 g, 22.6 mmol) and potassium carbonate (7.84 g, 56.7 mmol) were added to a solution of compound M-1 (10.0 g, 45.5 mmol) in acetonitrile (50 mL). After the addition was completed, the reaction mixture was stirred at 80° C. for 12 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (100 mL), washed with saturated saline (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (PE / EA=5 / 1) to obtain the title compound M-2 (4.10 g, yield: 58%). LC-MS (ESI), m / z: [M+H] + = 334.9 Step 2: Synthesis of 7-bromo-3-ethyl-5-fluoro-3,4-dihydro-1H-quinoxalin-2-one (M-3) Reduced iron powder (3.31 g, 59.5 mmol) was added to a solution of compound M-2 (4.01 g, 11.9 mmol) in glacial acetic acid (20 mL) under nitrogen gas atmosphere. After the addition was complete, the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, it was filtered to remove solids and concentrated under reduced pressure. The resulting residue was the crude product of title compound M-3 (2.80 g), which was used directly in the next reaction. LC-MS (ESI), m / z: [M+H] + = 273.0 Step 3: Synthesis of 7-bromo-3-ethyl-5-fluoro-1H-quinoxalin-2-one (M-4) Under nitrogen gas atmosphere, manganese dioxide (8.60 g, 9.90 mmol) was added to a solution of compound M-3 (2.70 g, 9.90 mmol) in tetrahydrofuran (15 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, it was filtered to remove solids and concentrated under reduced pressure. The resulting residue was the crude product of title compound M-4 (2.30 g) and was used directly in the next reaction. LC-MS (ESI), m / z: [M+H] + = 270.9 Step 4: Synthesis of 3-ethyl-5-fluoro-7-(hydroxymethyl)-1H-quinoxalin-2-one (Intermediate M) In a nitrogen gas atmosphere, (tributylstannyl)methanol (888, 2.80 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloride (145 mg, 0.200 mmol) were added to a solution of compound M-4 (500 mg, 1.80 mmol) in dioxane (10 mL). After the addition was completed, the reaction mixture was stirred at 80°C for 12 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (PE / EA=1 / 1) to obtain intermediate M (230 mg, yield: 52%). LC-MS (ESI), m / z: [M+H] + = 223.1 Intermediate N: 3-Ethyl-4-fluoro-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one

[0357] [ka]

[0358] Synthesis scheme:

[0359] [ka]

[0360] Step 1: Synthesis of N-(5-bromo-2-cyanopyridin-3-yl)butanamide (N-2) In a nitrogen gas atmosphere, dry pyridine (4.79 g, 60.6 mmol) and butyryl chloride (6.46 g, 60.6 mmol) were added to a solution of compound N-1 (10.0 g, 50.5 mmol) in dichloromethane (100 mL). After the addition was completed, the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (100 mL) was added to the reaction system, and the resulting mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (PE / EA = 10 / 1) to give the title compound N-2 (12.5 g, yield: 92%). LC-MS (ESI), m / z: [M+H] + = 268.0, 269.9 Step 2: Synthesis of 4-amino-7-bromo-3-ethyl-1,5-naphthyridin-2(1H)-one (N-3) Under nitrogen gas atmosphere, a solution of compound J-2 (10.0 g, 37.3 mmol) in tetrahydrofuran (100 mL) was cooled to -78 ° C., and lithium bis(trimethylsilyl)amide (1.0 mmol / L, 41.0 mL, 41.0 mmol) was added dropwise to the solution. After the addition was completed, the reaction mixture was stirred at -78 ° C. for 2 hours. Then, lithium bis(trimethylsilyl)amide (1.0 mmol / L, 41.0 mL, 41.0 mmol) was further added to the reaction system. After the addition was completed, the reaction mixture was allowed to warm to room temperature naturally and continued to stir for 16 hours. After the reaction was completed, the reaction mixture was quenched by adding saturated aqueous ammonium chloride solution (200 mL), and the resulting mixture was extracted with ethyl acetate (150 mL × 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH=20 / 1) to give the title compound N-3 (2.5 g, yield: 25%). LC-MS (ESI), m / z: [M+H] + = 268.0, 270.0 Step 3: Synthesis of 7-bromo-3-ethyl-4-fluoro-1,5-naphthyridin-2(1H)-one (N-4) Hydrogen fluoride pyridine solution (65-70%, 27 mL) was cooled to -40°C, and compound N-3 (2.70 g, 10.1 mmol) and isoamyl nitrite (2.37 g, 20.2 mmol) were added. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for 16 hours. After the reaction was complete, the reaction system was diluted with water (100 mL), and the resulting mixture was extracted with ethyl acetate (70 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under reduced pressure. The resulting residue was slurried (EA / MeOH=2 / 1), separated, and purified to give the title compound N-4 (270 mg, yield: 10%). LC-MS (ESI), m / z: [M+H] + = 271.0, 273.0 Step 4: Synthesis of 3-ethyl-4-fluoro-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one (Intermediate N) Under nitrogen gas atmosphere, (tributylstannyl)methanol (313 mg, 0.974 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloride (34.8 mg, 0.0443 mmol) were added to a solution of compound N-4 (240 mg, 0.885 mmol) in 1,4-dioxane (5 mL). After the addition was completed, the reaction mixture was stirred at 80°C for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was slurried (EA / MeOH=2 / 1), separated and purified to obtain intermediate N (120 mg, yield: 61%). LC-MS (ESI), m / z: [M+H] + = 223.1 Intermediate O: 3-Methyl-4-fluoro-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one

[0361] [ka]

[0362] Synthesis scheme:

[0363] [ka]

[0364] Step 1: Synthesis of N-(5-bromo-2-cyanopyridin-3-yl)propionamide (O-2) In a nitrogen gas atmosphere, dry pyridine (4.79 g, 60.6 mmol) and propionyl chloride (5.61 g, 60.6 mmol) were added to a solution of compound O-1 (10.0 g, 50.5 mmol) in anhydrous dichloromethane (100 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (100 mL) was added to the reaction system, and the resulting mixture was extracted with dichloromethane (100 mL x 2). The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain the title compound O-2 (12.0 g, yield: 84%). LC-MS (ESI), m / z: [M+H] + = 254.0, 256.0 Step 2: Synthesis of 4-amino-7-bromo-3-methyl-1,5-naphthyridin-2(1H)-one (O-3) Under nitrogen gas atmosphere, a solution of compound O-2 (1.00 g, 3.90 mmol) in tetrahydrofuran (10 mL) was cooled to -78 °C, and lithium bis(trimethylsilyl)amide (1.0 mmol / L, 9.0 mL, 9.0 mmol) was added dropwise to the solution. After the addition was completed, the reaction mixture was allowed to warm to room temperature naturally and stirred for 16 hours. After the reaction was completed, the reaction mixture was quenched by adding saturated aqueous ammonium chloride solution (20 mL), and the resulting mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain the title compound O-3 (420 mg, yield: 38%). LC-MS (ESI), m / z: [M+H] + = 253.9, 255.9 Step 3: Synthesis of 7-bromo-3-methyl-4-fluoro-1,5-naphthyridin-2(1H)-one (O-4) A hydrogen fluoride pyridine solution (HF-pyridine) (65-70%, 7.0 mL) was cooled to -40°C, and compound O-3 (500 mg, 1.97 mmol) and isoamyl nitrite (575 g, 4.92 mmol) were added. After the addition was completed, the reaction mixture was slowly warmed to room temperature and stirred for 16 hours. After the reaction was completed, the reaction system was diluted with water (15 mL), and the resulting mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give the title compound O-4 (90 mg, yield: 18%). LC-MS (ESI), m / z: [M+H] + = 257.0, 259.0 Step 4: Synthesis of 3-methyl-4-fluoro-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one (Intermediate O) Under nitrogen gas atmosphere, (tributylstannyl)methanol (375 mg, 1.17 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloride (30.6 mg, 0.00389 mmol) were added to a solution of compound O-4 (200 mg, 0.778 mmol) in 1,4-dioxane (5 mL). After the addition was completed, the reaction mixture was stirred at 80°C for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was slurried (EA / MeOH=2 / 1), separated and purified to obtain intermediate O (90 mg, yield: 52%). LC-MS (ESI), m / z: [M+H] + = 209.1 Intermediate P: 3-(1,1-difluoroethyl)-7-(hydroxymethyl)quinoxalin-2(1H)-one

[0365] [ka]

[0366] Synthesis scheme:

[0367] [ka]

[0368] Step 1: Synthesis of methyl 2-((4-bromo-2-nitrophenyl)amino)-3-hydroxylbutyrate (P-2) To a solution of compound P-1 (2.00 g, 11.8 mmol) in N,N-dimethylformamide (30 mL), diisopropylethylamine (4.58 g, 35.5 mmol) and 2-fluoro-5-bromonitrobenzene (2.60 g, 11.8 mmol) were added, and the reaction mixture was stirred at 50° C. for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain the title compound P-2 (2.80 g, yield: 76%). LC-MS (ESI), m / z: [M+H] + = 333.0, 335.0 Step 2: Synthesis of 7-bromo-3-(1-hydroxyethyl)-3,4-dihydroquinoxalin-2(1H)-one (P-3) In a nitrogen gas atmosphere, reduced iron powder (3.58 g, 64.0 mmol) was added to a solution of compound P-2 (2.80 g, 8.41 mmol) in glacial acetic acid (250 mL). After the addition was completed, the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with dichloromethane (500 mL) and methanol (100 mL), filtered to remove solids, and further concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain the title compound P-3 (2.00 g, yield: 88%). LC-MS (ESI), m / z: [M+H] + = 271.0, 273.0 Step 3: Synthesis of 7-bromo-3-(1-hydroxyethyl)quinoxalin-2(1H)-one (P-4) Under nitrogen gas atmosphere, manganese dioxide (870 mg, 10.0 mmol) was added to a solution of compound P-3 (271 mg, 1.00 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was filtered to remove solids, and the filtrate was concentrated under reduced pressure. The resulting residue was the crude product of title compound P-4 (200 mg), which was used directly in the next reaction. LC-MS (ESI), m / z: [M+H] + = 269.0, 271.0 Step 4: Synthesis of 3-acetyl-7-bromoquinoxalin-2(1H)-one (P-5) In a nitrogen gas atmosphere, a solution of compound P-4 (200 mg, 0.743 mmol) in dichloromethane (5 mL) was cooled to 0°C, Dess-Martin oxidant (424 mg, 1.00 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by liquid chromatography (mobile phase: acetonitrile / 0.1% formic acid water; gradient: 10-100%) to obtain the title compound P-5 (130 mg, yield: 66%). LC-MS (ESI), m / z: [M+H] + = 267.0, 269.0 Step 5: Synthesis of 7-bromo-3-(1,1-difluoroethyl)quinoxalin-2(1H)-one (P-6) In a nitrogen gas atmosphere, a solution of compound P-5 (130 mg, 0.487 mmol) in dichloromethane (5 mL) was cooled to 0°C, N,N-diethylaminosulfur trifluoride (DAST) (391 mg, 2.43 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by liquid chromatography (mobile phase: acetonitrile / 0.1% formic acid water; gradient: 10-100%) to obtain the title compound P-6 (30 mg, yield: 21%). LC-MS (ESI), m / z: [M+H] + = 289.0, 291.0 Step 6: Synthesis of 3-(1,1-difluoroethyl)-7-(hydroxymethyl)quinoxalin-2(1H)-one (Intermediate P) In a nitrogen gas atmosphere, (tributylstannyl)methanol (35.0 mg, 0.110 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloride (8.0 mg, 0.10 mmol) were added to a solution of compound P-6 (28.9 mg, 0.100 mmol) in 1,4-dioxane (2 mL). After the addition was completed, the reaction mixture was stirred at 80°C for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (DCM / MeOH=10 / 1) to obtain intermediate P (20 mg, yield: 83%). LC-MS (ESI), m / z: [M+H] + = 241.1 Intermediate Q: 3-(chloromethyl)-4-methyl-5,7,8,9-tetrahydro-6H-cyclopent[c][1,5]naphthyridin-6-one

[0369] [ka]

[0370] Synthesis scheme:

[0371] [ka]

[0372] Step 1: Synthesis of ethyl 2-(5-bromo-4-methyl-3-nitropyridin-2-yl)cyclopent-1-ene-1-carboxylate (Q-3) In a nitrogen gas atmosphere, compound Q-2 (155 mg, 0.583 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (42.7 mg, 0.0583 mmol) and cesium carbonate (380 mg, 1.17 mmol) were added to a solution of compound Q-1 (200 mg, 0.583 mmol) in toluene (2 mL), and the reaction mixture was stirred at 110°C for 1.5 hours under microwave conditions. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel chromatography (PE / EA=5 / 1) to obtain the title compound Q-3 (60 mg, yield: 29%). LC-MS (ESI), m / z: [M+H] + = 355.0, 357.0 Step 2: Synthesis of 3-bromo-4-methyl-5,7,8,9-tetrahydro-6H-cyclopento[c][1,5]naphthyridin-6-one (Q-4) Reduced iron powder (378 mg, 6.76 mmol) was added to a solution of compound Q-3 (300 mg, 0.844 mmol) in glacial acetic acid (5 mL) under nitrogen gas atmosphere. After the addition was completed, the reaction mixture was stirred at 40° C. for 16 hours. After the reaction was completed, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain the title compound Q-4 (80 mg, yield: 34%). LC-MS (ESI), m / z: [M+H] + = 279.0, 281.1 Step 3: Synthesis of 3-(hydroxymethyl)-4-methyl-5,7,8,9-tetrahydro-6H-cyclopento[c][1,5]naphthyridin-6-one (Q-5) In a nitrogen gas atmosphere, (tributylstannyl)methanol (184 mg, 0.573 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloride (22.6 mg, 0.0290 mmol) were added to a solution of compound Q-4 (80.0 mg, 0.286 mmol) in 1,4-dioxane (3 mL). After the addition was completed, the reaction mixture was stirred at 80°C for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel chromatography (DCM / MeOH=10 / 1) to obtain the title compound Q-5 (50 mg, yield: 76%). LC-MS (ESI), m / z: [M+H] + = 231.1 Step 4: Synthesis of 3-(chloromethyl)-4-methyl-5,7,8,9-tetrahydro-6H-cyclopento[c][1,5]naphthyridin-6-one (Intermediate Q) A solution of compound Q-5 (50.0 mg, 0.217 mmol) in thionyl chloride (2 mL) was cooled to 0° C., N,N-dimethylformamide (1.6 mg, 0.022 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was the crude product of the title compound intermediate Q, which was used directly in the next reaction. LC-MS (ESI), m / z: [M+H] + = 249.1 Intermediate R: 3-chloromethyl-4-methyl-9,10-dihydropyrano[2,3-c][1,5]naphthyridin-6(8H)one

[0373] [ka]

[0374] Synthesis scheme:

[0375] [ka]

[0376] Step 1: Methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3,4-dihydro-2H-pyran-6-carboxylate (R-2) Under nitrogen gas atmosphere, bis(pinacolato)diboron (2.10 g, 8.28 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (500 mg, 0.690 mmol) and potassium acetate (1.40 g, 13.8 mmol) were added to a solution of methyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydro-2H-pyran-6-carboxylate (2.00 g, 6.90 mmol) in 1,4-dioxane (40 mL), and the reaction mixture was stirred at 80° C. for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with water (50 mL), and the resulting mixture was extracted with ethyl acetate (50 mL×2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=5 / 1) to give the title compound R-2 (1.00 g, yield: 52%). LC-MS (ESI), m / z: [M+H] + = 269.2 Step 2: Synthesis of methyl 5-(5-bromo-4-methyl-3-nitropyridin-2-yl)-3,4-dihydropyran-6-carboxylate (R-4) In a nitrogen atmosphere, 5-bromo-2-iodo-4-methyl-3-nitropyridine (300 mg, 0.875 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (60 mg, 0.088 mmol) and cesium carbonate (570 mg, 1.75 mmol) were added to a mixture of compound R-2 (234 mg, 0.875 mmol) in 1,4-dioxane (10 mL) and water (1 mL), and the reaction mixture was stirred at 110°C for 4 hours. After completion of the reaction, water (10 mL) was added to the reaction system, and the resulting mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (PE / EA=5 / 1) to obtain the title compound R-4 (90 mg, yield: 28%). LC-MS (ESI), m / z: [M+H] + = 357.0, 359.0 Step 3: Synthesis of 3-bromo-4-methyl-9,10-dihydro-5H-pyran[2,3-c][1,5]naphthyridin-6(8H)one (R-5) Reduced iron powder (141 mg, 2.25 mmol) was added to a solution of compound R-4 (90.0 mg, 0.252 mmol) in glacial acetic acid (4 mL) under nitrogen gas atmosphere. After the addition was completed, the reaction mixture was stirred at 40° C. for 16 hours. After the reaction was completed, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain the title compound R-5 (40 mg, yield: 54%). LC-MS (ESI), m / z: [M+H] + = 295.0, 297.0 Step 4: Synthesis of 3-hydroxymethyl-4-methyl-9,10-dihydropyran[2,3-c][1,5]naphthyridin-6(8H)one (R-6) In a nitrogen gas atmosphere, (tributylstannyl)methanol (56.5 mg, 0.176 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloride (12.0 mg, 0.0140 mmol) were added to a solution of compound R-5 (40.0 mg, 0.136 mmol) in 1,4-dioxane (3 mL). After the addition was completed, the reaction mixture was stirred at 90°C for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (DCM / MeOH=10 / 1) to obtain the title compound R-6 (20 mg, yield: 59%). LC-MS (ESI), m / z: [M+H] + = 247.1 Step 5: Synthesis of 3-chloromethyl-4-methyl-9,10-dihydropyrano[2,3-c][1,5]naphthyridin-6(8H)one (Intermediate R): A solution of compound R-6 (20.0 mg, 0.0813 mmol) in dichloromethane (2 mL) was cooled to 0° C., and thionyl chloride (0.5 mL) and N,N-dimethylformamide (0.59 mg, 0.0081 mmol) were added dropwise to the reaction system. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was the crude product of intermediate R (20 mg), which was used directly in the next reaction. LC-MS (ESI), m / z: [M+H] + = 265.1, 267.1 Intermediate S: 3-Ethyl-7-(hydroxymethyl)-1H-quinolin-2-one

[0377] [ka]

[0378] Synthesis scheme:

[0379] [ka]

[0380] Step 1: Synthesis of ethyl 2-((4-bromo-2-nitrophenyl)methylene)butyrate (S-2) Under nitrogen gas atmosphere, a suspension of sodium hydride (0.250 g, 0.0103 mmol) in tetrahydrofuran (20 mL) was cooled to 0° C., ethyl 2-(diethoxyphosphoryl)butyrate (2.60 g, 10.3 mmol) was added to the suspension, and the reaction mixture was stirred for 0.5 hours. The reaction system was cooled to −78° C., compound 4-bromo-2-nitrobenzaldehyde (1.00 g, 4.30 mmol) was added, and the reaction mixture was stirred at −78° C. for 2 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (200 mL) was added to the reaction system and stirred at room temperature for 3 minutes. After the reaction was completed, the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (PE / EA=20 / 1) to obtain the title compound S-2 (1.35 g, yield: 86%). LC-MS (ESI), m / z: [M+H] + = 327.9, 330.0 Step 2: Synthesis of 7-bromo-3-ethyl-1H-quinolin-2-one (S-3) In a nitrogen gas atmosphere, reduced iron powder (1.83 g, 32.8 mmol) was added to a solution of compound S-2 (1.35 g, 4.10 mmol) in glacial acetic acid (40 mL). After the addition was completed, the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with dichloromethane (100 mL) and methanol (10 mL), filtered to remove solids, and further concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain the title compound S-3 (0.287 g, yield: 24%). LC-MS (ESI), m / z: [M+H] + = 252.0, 254.0 Step 3: Synthesis of 3-ethyl-7-(hydroxymethyl)-1H-quinolin-2-one (Intermediate S) In a nitrogen gas atmosphere, (tributylstannyl)methanol (153 mg, 0.476 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloride (32.0 mg, 0.0397 mmol) were added to a solution of compound S-3 (100 mg, 0.397 mmol) in 1,4-dioxane (10 mL). After the addition was completed, the reaction mixture was stirred at 80°C for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (DCM / MeOH=10 / 1) to obtain intermediate S (54.0 mg, yield: 60%). LC-MS (ESI), m / z: [M+H] + = 204.1 Intermediate T: 8-(hydroxymethyl)-2,3-dihydro-1H-pyran[2,3-c]quinolin-5(6H)-one

[0381] [ka]

[0382] Synthesis scheme:

[0383] [ka]

[0384] Step 1: Synthesis of methyl 3-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzoate (T-2) In a nitrogen gas atmosphere, bis(pinacolato)diboron (7.31 g, 28.8 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride dichloromethane (1.57 g, 1.92 mmol) and potassium acetate (5.65 g, 57.6 mmol) were added to a solution of compound T-1 (5.00 g, 19.2 mmol) in 1,4-dioxane (50 mL), and the reaction mixture was stirred at 80°C for 16 hours. The reaction system was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate (100 mL), washed with saturated saline, dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (PE / EA=1 / 1) to obtain the title compound T-2 (3.6 g, yield: 61%).

[0385] Step 2: Synthesis of 5-(4-methoxycarbonyl)-2-nitrophenyl-3,4-dihydropyran-6-carboxylic acid methyl ester (T-3) In a nitrogen gas atmosphere, 5-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydro-2H-pyran-6-methyl carboxylate (283 mg, 0.977 mmol), tetrakis(triphenylphosphine para)radium (113 mg, 0.0980 mmol) and sodium carbonate (207 mg, 0.954 mmol) were added to a solution of compound T-2 (300 mg, 0.977 mmol) in 1,4-dioxane (10 mL), and the reaction mixture was stirred at 110° C. for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate (100 mL), washed with saturated saline, dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (PE / EA=10 / 1) to obtain the title compound T-3 (200 mg, yield: 64%). LC-MS (ESI), m / z: [M+Na] + = 344.1 Step 3: Synthesis of methyl 5-oxo-2,3,5,6-tetrahydropyrano[2,3-c]quinoline-8-carboxylate (T-4) Under hydrogen gas atmosphere, palladium on carbon (100 mg) was added to a solution of compound T-3 (200 mg, 0.623 mmol) in methanol (20 mL), and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered to remove solids, and the filtrate was concentrated under reduced pressure to obtain a residue, which was the crude product of title compound T-4 (130 mg), which was used directly in the next reaction. LC-MS (ESI), m / z: [M+H] + = 260.1 Step 4: Synthesis of 8-(hydroxymethyl)-2,3-dihydro-1H-pyran[2,3-c]quinolin-5(6H)-one (Intermediate T) In a nitrogen gas atmosphere, a solution of compound T-4 (130 mg, 0.502 mmol) in tetrahydrofuran (3 mL) was cooled to 0°C, and a solution of lithium aluminum hydride in tetrahydrofuran (2.5 mol / L, 1.0 mL, 2.5 mmol) was added, and the reaction mixture was stirred for 2 hours. After the reaction was completed, ethyl acetate (10 mL) and water (100 mg) were added to the reaction system. The resulting mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (DCM / MeOH=10 / 1) to obtain intermediate T (60 mg, yield: 52%). LC-MS (ESI), m / z: [M+H] + = 232.1 Intermediate U: 7-(bromomethyl)-3-ethyl-8-fluoroquinolin-2(1H)-one

[0386] [ka]

[0387] Synthesis Steps:

[0388] [ka]

[0389] Step 1: Synthesis of 6-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluoroaniline (U-2) To a solution of compound U-1 (500 mg, 1.37 mmol) in ethanol (10 mL) and water (2 mL), iron powder (383 mg, 6.86 mmol) and ammonium chloride (734 mg, 13.7 mmol) were added, and the reaction mixture was stirred at 80° C. for 16 hours. After completion of the reaction, the reaction mixture was filtered to remove solids, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (PE / EA=5 / 1) to obtain the title compound U-2 (300 mg, yield: 66%). LC-MS (ESI), m / z: [M+H] + = 334.1, 336.1 Step 2: Synthesis of 7-(((tert-butyldimethylsilyl)oxy)methyl)-3-ethyl-8-fluoroquinolin-2(1H)-one (U-3) Under nitrogen gas atmosphere, ethyl 2-ethylacrylate (500 mg, 1.37 mmol), triethylamine (417 mg, 4.12 mmol), tris(o-methylbenzene)phosphine (83.6 mg, 0.275 mmol) and palladium acetate (22.9 mg, 0.137 mmol) were added to a solution of compound U-2 (352 mg, 2.75 mmol) in N,N-dimethylformamide (5 mL), and the reaction mixture was stirred at 105° C. for 12 hours. After the reaction was completed, the reaction mixture was filtered to remove solids, and the filtrate was diluted with ethyl acetate (10 mL), washed with saturated saline, dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under reduced pressure. The obtained residue was purified by silica gel plate preparative thin layer chromatography (PE / EA=10 / 1, R f =0.1) to obtain the title compound U-3 (23 mg, yield: 2%). LC-MS (ESI), m / z: [M+H] + = 336.0 Step 3: Synthesis of 3-ethyl-8-fluoro-7-(hydroxymethyl)quinolin-2(1H)-one (U-4) To a solution of compound U-3 (30 mg, 0.089 mmol) in dichloromethane (5 mL) was added aqueous hydrobromic acid (40%, 2.0 mL), and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (5 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under reduced pressure. The resulting residue was the crude product of title compound U-4 (15 mg), which was used directly in the next reaction. LC-MS (ESI), m / z: [M+H] + = 222.2 Step 4: Synthesis of 7-(bromomethyl)-3-ethyl-8-fluoroquinolin-2(1H)-one (Intermediate U) Compound U-4 (15 mg, 0.068 mmol) in aqueous hydrobromic acid (40%, 5.0 mL) was stirred at 80° C. for 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under reduced pressure. The resulting residue was intermediate U (15 mg, yield: 78%). LC-MS (ESI), m / z: [M+H] + = 284.0, 286.0 Intermediate V: 7-(bromomethyl)-3-ethyl-8-methylquinolin-2(1H)-one

[0390] [ka]

[0391] Synthesis Steps:

[0392] [ka]

[0393] Step 1: 1-(2-isopropylphenyl)-1H-pyrazol-3-ol (V-2) At 25°C, N-iodosuccinimide (14.0 g, 62.3 mmol) was added in batches to a solution of compound V-1 (10.0 g, 60.5 mmol) in acetic acid (100 mL). The reaction mixture was stirred at room temperature for 0.5 h. The reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was separated and purified by silica gel chromatography (PE:EA = 8:1) to give the title compound V-2 (0.600 g, yield: 3%). LC-MS (ESI), m / z: [M+H] + = 292.0. Step 2: Methyl 3-ethyl-8-methyl-2-oxo-1,2-dihydroquinoline-7-carboxylate (V-3) At 25°C under nitrogen gas protection, ethyl 2-ethylacrylate (660mg, 5.15mmol), palladium acetate (38.6mg, 0.170mmol), tris(o-methylphenyl)phosphine (52.3mg, 0.170mmol), and triethylamine (348mg, 3.44mmol) were added to a solution of compound V-2 (500mg, 1.72mmol) in N,N-dimethylformamide (5.00mL). After the addition was completed, the reaction system was heated to 100°C under nitrogen gas protection and stirred for 10 hours. The reaction system was cooled to 25°C, and the reaction solution was diluted with water (100mL), extracted with ethyl acetate (100mL x 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was separated and purified by silica gel chromatography (PE:EA=3:1) to give the title compound V-3 (0.300 g, yield: 64%). LC-MS (ESI), m / z: [M+H] + = 246.1. Step 3: 3-Ethyl-7-(hydroxymethyl)-8-methylquinolin-2(1H)-one (V-4) A solution of lithium aluminum hydride in tetrahydrofuran (1M, 2.40mL) was added dropwise to a solution of compound V-3 (300mg, 1.22mol) in tetrahydrofuran (5.00mL) at 0℃ under nitrogen gas protection. After the addition was completed, the reaction mixture was stirred at 0℃ for 2 hours under nitrogen gas protection. The reaction system was diluted with ice water (50.0mL) and the mixture was extracted with ethyl acetate (30.0mL×3). The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was separated and purified by silica gel chromatography (PE:EA=1:1) to give the title compound V-4 (160mg, yield: 54%). LC-MS (ESI), m / z: [M+H] + = 218.0. Step 4: 7-(Bromomethyl)-3-ethyl-8-methylquinolin-2(1H)-one (Intermediate V) Compound V-4 (160 mg, 0.740 mmol) was dissolved in hydrobromic acid (5.00 mL) solution at room temperature, and the reaction mixture was stirred at 80 °C for 2 hours. The reaction solution was diluted with water (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was separated and purified by silica gel chromatography (PE:EA = 4:1) to obtain intermediate V (120 mg, yield: 52%). LC-MS (ESI), m / z: [M+H] + = 280.1 / 282.1. Intermediate W: 5-(2,5-diazabicyclo[4.1.0]heptan-2-yl)-N-methylpyridine-2-carboxamide

[0394] [ka]

[0395] Synthesis scheme:

[0396] [ka]

[0397] Step 1: Synthesis of tert-butyl 5-(6-(methoxycarbonyl)pyridin-3-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate: Potassium carbonate (535 mg, 3.87 mmol) was added to a solution of methyl 5-fluoropyridine-2-carboxylate (300 mg, 1.93 mmol) and tert-butyl 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (767 mg, 3.87 mmol) in dimethyl sulfoxide (10 mL) at room temperature. The reaction solution was stirred at 120°C for 2 hours. The reaction solution was cooled to room temperature, and ethyl acetate (100 mL) and water (10 mL) were added to the reaction solution, followed by separation and extraction. The organic phase obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was separated and purified by silica gel chromatography (EA:PE=0:1-3:2) to obtain the title compound W-2 (210 mg, yield: 29%). LC-MS (ESI), m / z: [M+H] + = 334.1. Step 2: Synthesis of tert-butyl 5-(6-(methylcarbamoyl)pyridin-3-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate: At room temperature, tert-butyl 5-(6-(methoxycarbonyl)pyridin-3-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (210 mg, 0.63 mmol) was dissolved in a methanol solution of methylamine (15 mL). The reaction solution was reacted in a sealed tube at 60°C for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel chromatography (PE:EA=1:1) to obtain the title compound W-3 ​​(140 mg, yield: 60%). LC-MS (ESI), m / z: [M+H] + = 333.0. Step 3: Synthesis of 5-(2,5-diazabicyclo[4.1.0]heptan-2-yl)-N-methylpyridine-2-carboxamide: At room temperature, 5-(6-(methylcarbamoyl)pyridin-3-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate tert-butyl (140 mg, 0.42 mmol) was dissolved in a mixture (15 mL) of dichloromethane / trifluoroacetic acid (10:1). The reaction system was stirred at 25°C for 12 hours. The reaction solution was concentrated, and the resulting crude product was dissolved in dichloromethane (100 mL), and saturated sodium bicarbonate (50 mL) was added and stirred for 10 minutes, and the organic phase was separated, washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was separated and purified by silica gel chromatography (EA:PE=0:1-4:1) to obtain the title compound intermediate W (80 mg, yield: 74%).

[0398] LC-MS (ESI), m / z: [M+H] + = 233.1. Example 1: 5-(5-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-phthalazin-3-yl)methyl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)-N-methylpicolinamide

[0399] [ka]

[0400] Synthesis scheme:

[0401] [ka]

[0402] Step 1: Synthesis of tert-butyl 5-(6-(methoxycarbonyl)pyridin-3-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (1.2): Potassium carbonate (535 mg, 3.87 mmol) was added to a solution of methyl 5-fluoropyridine-2-carboxylate (300 mg, 1.93 mmol) and tert-butyl 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (767 mg, 3.87 mmol) in dimethyl sulfoxide (10 mL) at room temperature. The reaction solution was stirred at 120 ° C for 2 hours. The reaction solution was cooled to room temperature, and ethyl acetate (100 mL) and water (10 mL) were added to the reaction solution, followed by separation and extraction. The organic phase obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was separated and purified by silica gel chromatography (EA:PE = 0:1 to 3:2) to obtain the title compound 1.2 (210 mg, yield: 29%).

[0403] LC-MS (ESI), m / z: [M+H] + = 334.1. Step 2: Synthesis of tert-butyl 5-(6-(methylcarbamoyl)pyridin-3-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (1.3): At room temperature, tert-butyl 5-(6-(methoxycarbonyl)pyridin-3-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (210 mg, 0.63 mmol) was dissolved in a methanol solution of methylamine (15 mL). The reaction solution was reacted in a sealed tube at 60°C for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel chromatography (PE:EA=1:1) to obtain the title compound 1.3 (140 mg, yield: 60%).

[0404] LC-MS (ESI), m / z: [M+H] + = 333.0. Step 3: Synthesis of 5-(2,5-diazabicyclo[4.1.0]heptan-2-yl)-N-methylpyridine-2-carboxamide (1.4): At room temperature, 5-(6-(methylcarbamoyl)pyridin-3-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate tert-butyl (140 mg, 0.42 mmol) was dissolved in a mixture (15 mL) of dichloromethane / trifluoroacetic acid (10:1). The reaction system was stirred at 25°C for 12 hours. The reaction solution was concentrated, and the obtained crude product was dissolved in dichloromethane (100 mL), saturated sodium bicarbonate (50 mL) was added, stirred for 10 minutes, the organic phase was separated, and the organic phase was washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was separated and purified by silica gel chromatography (EA:PE=0:1-4:1) to obtain the title compound 1.4 (80 mg, yield: 74%).

[0405] LC-MS (ESI), m / z: [M+H] + = 233.1. Step 4: Synthesis of 5-5-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-phthalazin-3-yl)methyl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)-N-methylpyridine-2-carboxamide (Example 1): To a solution of 5-(2,5-diazabicyclo[4.1.0]heptan-2-yl)-N-methylpyridine-2-carboxamide (80 mg, 0.34 mmol) and 7-(chloromethyl)-3-ethyl-1,5-phthalazin-2(1H)-one (77 mg, 0.34 mmol) in acetonitrile (10 mL) was added diisopropylethylamine (134 mg, 1.04 mmol) and potassium iodide (11 mg, 0.07 mmol) at room temperature and purged with nitrogen gas three times. The reaction was stirred at 80° C. under a nitrogen atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was separated and purified by preparative high performance liquid chromatography (chromatography column model: Gemini-C18 150×21.2 mm, 5 μm, mobile phase: acetonitrile / water (0.1% formic acid), gradient: 12-18%, flow rate: 20 mL / min) to obtain the title compound Example 1 (80 mg, yield: 55%).

[0406] LC-MS (ESI), m / z: [M+H] + = 419.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.45 (s, 1H), 8.37 (d, J = 4.8 Hz, 1H), 8.19 (d, J = 2.8 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.69 (s, 1H), 7.28 (dd, J = 8.8 Hz, 2.4, 1H), 3.94 (br, 2H), 3.66 - 3.33 (m, 3H), 3.27 - 3.15 (m, 1H), 2.77 (d, J = 4.8 Hz, 3H), 2.90 - 2.70 (m, 1H), 2.66 - 2.52 (m, 3H), 1.18 (t, J = 7.2 Hz, 3H), 0.88 - 0.75 (m, 1H), 0.50 - 0.37 (m, 1H). Example 1-1 and Example 1-2: 5-((1S,6R)-5-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-phthalazin-3-yl)methyl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)-N-methylpicolinamide and 5-((1R,6S)-5-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-phthalazin-3-yl)methyl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)-N-methylpicolinamide

[0407] [ka]

[0408] Synthesis scheme:

[0409] [ka]

[0410] Example 1 (76 mg, 0.18 mmol) was prepared by supercritical fluid chromatography (SFC) (chromatography column model: chiralpak-OD 250 mm x 20 mm, 5 μm, mobile phase: 50% EtOH (0.2% aqueous ammonia), flow rate: 14 mL / min) and separated to obtain the following compounds.

[0411] Example 1-1 (t R = 10.53 min, 4.2 mg, yield: 5.5%) LC-MS (ESI), m / z: [M+H] + = 419.1. 11H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.45 (s, 1H), 8.37 (d, J = 4.8 Hz, 1H), 8.19 (d, J = 2.8 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.69 (s, 1H), 7.28 (dd, J = 8.8 Hz, 2.4, 1H), 3.94 (br, 2H), 3.66 ‐ 3.33 (m, 3H), 3.27 ‐ 3.15 (m, 1H), 2.77 (d, J = 4.8 Hz, 3H), 2.90 ‐ 2.70 (m, 1H), 2.66 ‐ 2.52 (m, 3H), 1.18 (t, J = 7.2 Hz, 3H), 0.88 ‐ 0.75 (m, 1H), 0.50 ‐ 0.37 (m, 1H). Example 1-2(t R = 12.21 min, 3.5 mg, Yield: 4.6%) LC-MS (ESI), m / z: [M+H] + = 419.2. 1 1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.45 (s, 1H), 8.37 (d, J = 4.8 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.69 (s, 1H), 7.28 (dd, J = 8.8, 2.4 Hz, 1H), 3.93 (br, 2H), 3.66 ‐ 3.33 (m, 3H), 3.27 ‐ 3.15 (m, 1H), 2.78 (d, J = 4.8 Hz, 3H), 2.90 ‐ 2.70 (m, 1H), 2.61 ‐ 2.53 (m, 3H), 1.18 (t, J = 7.2 Hz, 3H), 0.90 ‐ 0.68 (m, 1H), 0.50 ‐ 0.33 (s, 1H). Example 2: 5-(5-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-phthalazin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-N-methylpyridine-2-carboxamide

[0412] [ka]

[0413] Synthesis scheme:

[0414] [ka]

[0415] Step 1: Synthesis of 5-(2,5-diazabicyclo[4.2.0]octan-2-yl)-N-methylpyridine-2-carboxamide (2.1): At room temperature, 5-bromo-N-methylpyridine-2-carboxamide (766 mg, 3.56 mmol), sodium tert-butoxide (685 mg, 7.13 mmol), tris(dibenzylideneacetone)dipalladium (163 mg, 0.18 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (222 mg, 0.36 mmol) and triethylamine (1 mL) were added in sequence to a solution of 2,5-diazabicyclo[4.2.0]octane (200 mg, 1.78 mmol) in toluene (3 mL). The reaction system was purged with nitrogen gas three times, then heated to 110°C and stirred for 6 hours. After completion of the reaction, water (20 mL) was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL), then dried over anhydrous sodium sulfate, filtered, concentrated in vacuum, and the crude product was separated and purified by flash silica gel column chromatography (dichloromethane:methanol=1:99-3:97) to give the title compound 2.2 (200 mg, yield: 41%).

[0416] LCMS (ESI), m / z: [M+H] + =247.1 Step 2: Synthesis of 5-(5-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-phthalazin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-N-methylpyridine-2-carboxamide (Example 2): At room temperature, 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (90 mg, 0.41 mmol) in acetonitrile (5 mL) was successively added with N,N-diisopropylethylamine (156 mg, 1.21 mmol), potassium iodide (7 mg, 0.04 mmol) and 5-(2,5-diazabicyclo[4.2.0]octan-2-yl)-N-methylpyridine-2-carboxamide (100 mg, 0.40 mmol), and the reaction mixture was heated to 80° C. and stirred for 2 hours. After completion of the reaction, water (20.0 mL) was added to dilute the mixture, and the aqueous phase was extracted with ethyl acetate (20.0 mL×3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated in vacuum, and the crude product was purified by preparative high performance liquid chromatography (chromatography column model: gemini-C18 150×21.2 mm, 5 μm, mobile phase: acetonitrile / water (0.1% formic acid), gradient: 2%-25%, flow rate: 20 mL / min) 0.1% FA) to obtain the title compound Example 2 (15.3 mg, yield: 8.7%).

[0417] LC-MS (ESI), m / z: [M+H] + = 433.1. 1H NMR (400 MHz, MeOD) δ 8.49 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 2.8 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.82 (s, 1H), 7.81 (s, 1H), 7.19 (dd, J = 8.8, 2.8 Hz, 1H), 4.38 - 4.28 (m, 1H), 3.98 (d, J = 14.2 Hz, 1H), 3.51 - 3.36 (m, 3H), 3.36 - 3.28 (m, 1H), 2.91 (s, 3H), 2.94 - 2.84 (m, 1H), 2.70 - 2.60 (m, 2H), 2.42 - 2.14 (m, 3H), 1.99 - 1.88 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H). Example 2-1 and Example 2-2: 5-((1S,6R)-5-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-phthalazin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-N-methylpyridine-2-carboxamide and 5-((1R,6S)-5-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-phthalazin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-N-methylpyridine-2-carboxamide;

[0418] [ka]

[0419] Synthesis scheme:

[0420] [ka]

[0421] Example 2 (15.3 mg, 0.04 mmol) Supercritical fluid (SFC) manufactured by CHIRALPAK OJ-H 250 mm × 20 mm, 5 μm, 40% EtOH (NH4OH) 0.2%) to isolate and purify the して2つの compound.

[0422] Example 2-1(t R =6.24min, 5.80mg, yield: 38%) LC-MS (ESI), m / z: [M+H] + = 433.1. 1 H NMR (400 MHz, MeOD) δ 8.49 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 2.8 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.82 (s, 1H), 7.81 (s, 1H), 7.19 (dd, J = 8.8, 2.8 Hz, 1H), 4.38 - 4.28 (m, 1H), 3.98 (d, J = 14.2 Hz, 1H), 3.51 - 3.36 (m, 3H), 3.36 - 3.28 (m, 1H), 2.91 (s, 3H), 2.94 ‐ 2.84 (m, 1H), 2.70 ‐ 2.60 (m, 2H), 2.42 - 2.14 (m, 3H), 1.99 - 1.88 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H). Example 2-2(t R =12.10min, 6.8mg, yield: 44%) LC-MS (ESI), m / z: [M+H] + = 433.1. 1H NMR (400 MHz, MeOD) δ 8.49 (d, J = 1.6 Hz, 1H), 8.12 (d, J = 2.8 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.82 (s, 1H),7.81 (s, 1H), 7.19 (dd, J = 8.8, 2.8 Hz, 1H), 4.38 - 4.28 (m, 1H), 3.98 (d, J = 14.2 Hz, 1H), 3.51 - 3.36 (m, 3H), 3.36 - 3.28 (m, 1H), 2.91 (s, 3H), 2.94 - 2.84 (m, 1H), 2.70 - 2.60 (m, 2H), 2.42 - 2.14 (m, 3H), 1.99 - 1.88 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H). Example 2: cis-5-(5-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-phthalazin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-N-methylpyridine-2-carboxamide

[0423] [ka]

[0424] By replacing 2,5-diazabicyclo[4.2.0]octane with trans-2,5-diazabicyclo[4.2.0]octane, Example 2'' was obtained by referring to the synthesis method of Example 2. LC-MS (ESI), m / z: [M+H] + = 433.1 Examples 2-1 and 2-2 can also be obtained by the following method.

[0425] [ka]

[0426] Example 2'' (15.3 mg, 0.04 mmol) was prepared by supercritical fluid chromatography (SFC) (column: CHIRALPAK OJ-H 250 mm x 20 mm, 5 μm, 40% EtOH (NH4OH 0.2%)) and separated and purified to obtain Example 2-1 (t R = 6.24 min, 5.80 mg) and Example 2-2 (t R =12.10 min, 6.8 mg, yield: 44%).

[0427] Example 2': trans-5-(5-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-phthalazin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-N-methylpyridine-2-carboxamide

[0428] [ka]

[0429] By replacing 2,5-diazabicyclo[4.2.0]octane with trans-2,5-diazabicyclo[4.2.0]octane, Example 2' was obtained by referring to the synthesis method of Example 2.

[0430] LC-MS (ESI), m / z: [M+H] + = 433.1 Example 2-3 and Example 2-4: 5-((1R,6R)-5-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-phthalazin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-N-methylpyridine-2-carboxamide and 5-((1S,6S)-5-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-phthalazin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-N-methylpyridine-2-carboxamide

[0431] [ka]

[0432] Synthesis scheme:

[0433] [ka]

[0434] Example 2' was separated by chiral column chromatography (chromatography column model: CHIRALPAK AD-H 250 mm x 20 mm, 5 μm; mobile phase: 40% isopropanol (0.2% aqueous ammonia); flow rate: 40 g / min) to obtain Example 2-3 (t R = 9.36 min, 20.5 mg, yield: 41%) and Example 2-4 (t R = 11.08 min, 19.6 mg, yield: 39%).

[0435] Example 2-3: LC-MS (ESI), m / z: [M+H] + = 433.2 1 H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.46 - 8.39 (m, 1H), 8.11 (m, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 7.27 (dd, J = 8.7, 2.5 Hz, 1H), 3.85 (d, J = 12.1 Hz, 1H), 3.59 - 3.51 (m, 2H), 3.02 (d, J = 11.3 Hz, 1H), 2.89 - 2.80 (m, 2H), 2.77 (d, J = 4.8 Hz, 3H), 2.57 - 2.53 (m, 1H), 2.38 - 2.28 (m, 4H), 2.03 - 1.97 (m, 1H), 1.75 - 1.68 (m, 1H), 1.45 - 1.35 (m, 1H), 1.18 (t, J = 7.4 Hz, 3H). Example 2-4: LC-MS (ESI), m / z: [M+H] + = 433.2 1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.46 - 8.38 (m, 1H), 8.14 - 8.09 (m, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 7.27 (dd, J = 8.7, 2.5 Hz, 1H), 3.85 (d, J = 12.1 Hz, 1H), 3.59 - 3.51 (m, 2H), 3.02 (d, J = 11.3 Hz, 1H), 2.89 - 2.77 (m, 2H), 2.76 (d, J = 4.8 Hz, 3H), 2.57 - 2.54 (m, 1H), 2.40 - 2.24 (m, 4H), 2.04 - 1.95 (m, 1H), 1.75 - 1.68 (m, 1H), 1.44 - 1.34 (m, 1H), 1.18 (t, J = 7.4 Hz, 3H). Example 3: cis-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-phthalazin-3-yl)methyl)hexahydrofuro[3,4-b]pyrazine-1(2H)-yl)-N-methylpyridine-2-carboxamide

[0436] [ka]

[0437] Synthesis scheme:

[0438] [ka]

[0439] Step 1: Synthesis of cis-methyl 5-(hexahydrofuro[3,4-b]pyrazine-1(2H)-yl)pyridine-2-carboxylate (3.2): Potassium carbonate (535 mg, 3.88 mmol) was added to a solution of methyl 5-fluoropyridine-2-carboxylate (300 mg, 1.93 mmol) and cis-decahydrofuro[3,4-b]pyrazine (intermediate b, 1.2 g, 9.4 mmol) in dimethyl sulfoxide (10 mL) at room temperature. The reaction was stirred at 120° C. for 2 hours. It was cooled to room temperature, filtered and concentrated. The resulting residue was separated and purified by silica gel chromatography (PE:EA=5:1) to give the title compound 3.2 (275 mg, yield: 55%).

[0440] LC-MS (ESI), m / z: [M+H] + = 264.0. Step 2: Synthesis of cis-5-(hexahydrofuro[3,4-b]pyrazin-1(2H)-yl)-N-methylpyridine-2-carboxamide (3.3): Cis-5-(hexahydrofuro[3,4-b]pyrazine-1(2H)-yl)pyridine-2-carboxylate methyl ester (100 mg, 0.38 mmol) was dissolved in a methanol solution of methylamine (10 mL) at room temperature. The reaction solution was reacted in a sealed tube at 60° C. for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to give the title compound 3.3 (80 mg, yield: 80%).

[0441] LC-MS (ESI), m / z: [M+H] + = 263.0. Step 3: Synthesis of cis-5-4-((7-ethyl-6-oxo-5,6-dihydro-1,5-phthalazin-3-yl)methyl)hexahydrofuro[3,4-b]pyrazine-1(2H)-yl)-N-methylpyridine-2-carboxamide (Example 3): Diisopropylethylamine (120 mg, 0.93 mmol) and potassium iodide (10 mg, 0.06 mmol) were added to a solution of cis-5-(hexahydrofuro[3,4-b]pyrazine-1(2H)-yl)-N-methylpyridine-2-carboxamide (80 mg, 0.31 mmol) and 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (68 mg, 0.31 mmol) in acetonitrile (10 mL) at room temperature, and the atmosphere was purged with nitrogen gas three times. The reaction was stirred at 80° C. under a nitrogen atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was separated and purified by preparative high performance liquid chromatography (chromatography column model: gemini-C18 150×21.2 mm, 5 μm, mobile phase: acetonitrile / water (0.1% formic acid), gradient: 2-30%, flow rate: 20 mL / min) to obtain the title compound Example 3 (30 mg, yield: 22%).

[0442] LC-MS (ESI), m / z: [M+H] + = 448.9. 1 H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.41 (d, J = 1.6 Hz, 1H), 8.41 - 8.36 (m, 1H), 8.26 (d, J = 2.8, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.66 (s, 1H), 7.40 (dd, J = 8.8, 2.8 Hz, 1H), 4.77 - 4.67 (m, 1H), 4.18 - 4.07 (m, 2H), 3.94 - 3.87 (m, 2H), 3.70 - 3.58 (m, 2H), 3.34 - 3.27 (m, 1H), 3.08 - 2.95 (m, 2H), 2.77 (d, J = 4.8 Hz, 3H), 2.59 - 2.50 (m, 2H), 2.32 - 2.22 (m, 1H), 2.04 - 1.93 (m, 1H), 1.19 (t, J = 6.8 Hz, 3H). Example 3-1 and Example 3-2: 5-((4aS,7aR)-4-((7-ethyl-6-oxo-5,6-dihydro-1,5-phthalazin-3-yl)methyl)hexahydrofuro[3,4-b]pyrazine-1(2H)-yl)-N-methylpyridine-2-carboxamide and 5-((4aR,7aS)-4-((7-ethyl-6-oxo-5,6-dihydro-1,5-phthalazin-3-yl)methyl)hexahydrofuro[3,4-b]pyrazine-1(2H)-yl)-N-methylpyridine-2-carboxamide

[0443] [ka]

[0444] Synthesis scheme:

[0445] [ka]

[0446] Example 3 (26 mg, 0.06 mmol) was prepared by supercritical fluid chromatography (SFC) (chromatography column model: CHIRALPAK AD-H 250×20 mm, 5 μm, mobile phase: 30% MeOH (0.2% aqueous ammonia), flow rate: 40 g / min) and separated to obtain the following compounds.

[0447] Example 3-1 (t R = 18.40 min, 4.2 mg, yield: 14%) LC-MS (ESI), m / z: [M+H] + = 448.9. 1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.41 (d, J = 1.6 Hz, 1H), 8.41 - 8.36 (m, 1H), 8.26 (d, J = 2.8, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.66 (s, 1H), 7.40 (dd, J = 8.8, 2.8 Hz, 1H), 4.77 ‐ 4.67 (m, 1H), 4.18 ‐ 4.07 (m, 2H), 3.94 ‐ 3.87 (m, 2H), 3.70 ‐ 3.58 (m, 2H), 3.34 ‐ 3.27 (m, 1H), 3.08 ‐ 2.95 (m, 2H), 2.77 (d, J = 4.8 Hz, 3H), 2.59 ‐ 2.50 (m, 2H), 2.32 ‐ 2.22 (m, 1H), 2.04 ‐ 1.93 (m, 1H), 1.19 (t, J = 6.8 Hz, 3H). Example 3-2(t R =26.40min, 3.5mg, yield: 12%) LC-MS (ESI), m / z: [M+H] + = 449.0. 1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.41 (d, J = 1.6 Hz, 1H), 8.41 - 8.36 (m, 1H), 8.26 (d, J = 2.8, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.66 (s, 1H), 7.40 (dd, J = 8.8, 2.8 Hz, 1H), 4.77 - 4.67 (m, 1H), 4.18 - 4.07 (m, 2H), 3.94 - 3.87 (m, 2H), 3.70 - 3.58 (m, 2H), 3.34 - 3.27 (m, 1H), 3.08 - 2.95 (m, 2H), 2.77 (d, J = 4.8 Hz, 3H), 2.59 - 2.50 (m, 2H), 2.32 - 2.22 (m, 1H), 2.04 - 1.93 (m, 1H), 1.19 (t, J = 6.8 Hz, 3H). Example 4: cis-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)octahydro-1H-cyclopentyl[b]pyrazin-1-yl)-N-methyl-pyridine-2-carboxamide

[0448] [ka]

[0449] Example 4 was obtained by referring to the synthesis method of Example 1. LC-MS (ESI), m / z: [M+H] + = 446.9 1H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 8.40 (d, J = 1.8 Hz, 1H), 8.33 (d, J = 4.9 Hz, 1H), 8.20 (d, J = 2.8 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.75 (s, 1H), 7.66 (s, 1H), 7.33 (dd, J = 8.9, 2.9 Hz, 1H), 4.38 - 4.28 (m, 1H), 4.12 (d, J = 14.5 Hz, 1H), 3.57 (d, J = 12.0 Hz, 1H), 3.22 (d, J = 14.5 Hz, 1H), 3.01 - 2.91 (m, 1H), 2.77 (d, J = 4.7 Hz, 3H), 2.74 - 2.69 (m, 2H), 2.57 - 2.52 (m, 1H), 2.25 - 2.17 (m, 1H), 2.07 - 1.95 (m, 1H), 1.93 - 1.76 (m, 2H), 1.75 - 1.57 (m, 2H), 1.18 (t, J = 7.4 Hz, 3H). Example 4-1 and Example 4-2: 5-((4aS,7aR)-4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)octahydro-1H-cyclopentyl[b]pyrazin-1-yl)-N-methyl-pyridine-2-carboxamide and 5-((4aR,7aS)-4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)octahydro-1H-cyclopentyl[b]pyrazin-1-yl)-N-methyl-pyridine-2-carboxamide

[0450] [ka]

[0451] Synthesis scheme:

[0452] [ka]

[0453] Example 4 (26 mg, 0.06 mmol) was prepared by supercritical fluid chromatography (SFC) (chromatography column model: CHIRALPAK OJ-H 250 mm x 4.6 mm, 5 μm, mobile phase: 40% EtOH (0.2% ammonia water), flow rate: 2.5 mL / min) and divided to obtain Example 4-1 (tR = 5.68 min) and Example 4-2 (tR = 11.04 min).

[0454] Example 4-1: LC-MS (ESI), m / z: [M+H] + = 446.9 1 H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.40 (d, J = 1.8 Hz, 1H), 8.35 (d, J = 4.9 Hz, 1H), 8.20 (d, J = 2.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.75 (s, 1H), 7.66 (s, 1H), 7.33 (dd, J = 8.9, 2.9 Hz, 1H), 4.38 - 4.28 (m, 1H), 4.12 (d, J = 14.5 Hz, 1H), 3.57 (d, J = 12.0 Hz, 1H), 3.22 (d, J = 14.5 Hz, 1H), 3.01 - 2.91 (m, 1H), 2.77 (d, J = 4.7 Hz, 3H), 2.74 - 2.69 (m, 2H), 2.57 - 2.52 (m, 1H), 2.25 - 2.17 (m, 1H), 2.07 - 1.95 (m, 1H), 1.93 - 1.76 (m, 2H), 1.75 - 1.57 (m, 2H), 1.18 (t, J = 7.4 Hz, 3H). Example 4-2: LC-MS (ESI), m / z: [M+H] + = 446.9 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.40 (d, J = 1.8 Hz, 1H), 8.35 (d, J = 4.9 Hz, 1H), 8.20 (d, J = 2.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.75 (s, 1H), 7.66 (s, 1H), 7.33 (dd, J = 8.9, 2.9 Hz, 1H), 4.38 - 4.28 (m, 1H), 4.12 (d, J = 14.5 Hz, 1H), 3.57 (d, J = 12.0 Hz, 1H), 3.22 (d, J = 14.5 Hz, 1H), 3.01 - 2.91 (m, 1H), 2.77 (d, J = 4.7 Hz, 3H), 2.74 - 2.69 (m, 2H), 2.57 - 2.52 (m, 1H), 2.25 - 2.17 (m, 1H), 2.07 - 1.95 (m, 1H), 1.93 - 1.76 (m, 2H), 1.75 - 1.57 (m, 2H), 1.18 (t, J = 7.4 Hz, 3H). Example 5: cis-5-(5-((7-ethyl-6-oxo-5,6-dihydro-pyridine[3,2-c]pyridazine-2,5-diazabicyclo[4.1.0]octan-2-yl)-N-methylpicolinamide

[0455] [ka]

[0456] Example 5 (50 mg, yield: 46%) was obtained by following the synthesis method of Example 1.

[0457] LC-MS (ESI), m / z: [M+H] + = 420.2 1H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 8.40 (d, J = 4.8 Hz, 1H), 8.21 (d, J = 2.6 Hz, 1H), 8.07 (s, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.53 (s, 1H), 7.33 (dd, J = 8.8, 2.8 Hz, 1H), 4.54 (m, 2H), 3.72 - 3.66 (m, 1H), 3.35 - 3.27 (m, 1H), 3.23 - 3.16 (m, 1H), 3.02 - 2.88 (m, 3H), 2.79 (d, J = 4.7 Hz, 3H), 2.60 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.4 Hz, 3H), 1.03 (q, J = 6.3 Hz, 1H), 0.82 (s, 1H). Example 5-1 and Example 5-2: 5-((1S,6R)-5-((7-ethyl-6-oxo-5,6-dihydro-pyridine[3,2-c]pyridazine-2,5-diazabicyclo[4.1.0]octan-2-yl)-N-methylpicolinamide and 5-((1R,6S)-5-((7-ethyl-6-oxo-5,6-dihydro-pyridine[3,2-c]pyridazine-2,5-diazabicyclo[4.1.0]octan-2-yl)-N-methylpicolinamide:

[0458] [ka]

[0459] Synthesis method:

[0460] [ka]

[0461] Example 5 (48 mg) was separated and purified by chiral column chromatography (chromatography column model: XBridge peptide BEH C18 19 mm × 250 mm, 10 μm, 130 angstroms; mobile phase: acetonitrile (0.05% TFA) / water (0.05% TFA): 5 to 35%; flow rate: 25 mL / min) to obtain Example 5-1 (t R = 28.5 min, 8.4 mg, yield: 18%) and Example 5-2 (t R = 36.5 min, 10.0 mg, yield: 21%).

[0462] Example 5-1: LC-MS (ESI), m / z: [M+H] + = 420.2 1 H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 8.40 (d, J = 4.8 Hz, 1H), 8.21 (d, J = 2.6 Hz, 1H), 8.07 (s, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.53 (s, 1H), 7.33 (dd, J = 8.8, 2.8 Hz, 1H), 4.54 (m, 2H), 3.72 - 3.66 (m, 1H), 3.35 - 3.27 (m, 1H), 3.23 - 3.16 (m, 1H), 3.02 - 2.88 (m, 3H), 2.79 (d, J = 4.7 Hz, 3H), 2.60 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.4 Hz, 3H), 1.03 (q, J = 6.3 Hz, 1H), 0.82 (s, 1H). Example 5-2: LC-MS (ESI), m / z: [M+H] + = 420.2 1H NMR (400 MHz, DMSO-d6) 12.01 (s, 1H), 8.35 (d, J = 4.8 Hz, 1H), 8.19 (d, J = 2.5 Hz, 1H), 8.02 (s, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.47 (s, 1H), 7.28 (dd, J = 8.8, 2.7 Hz, 1H), 4.35 ‐ 4.05 (q, J = 15.8 Hz, 2H), 3.55 ‐ 3.44 (m, 1H), 3.31 (s, 1H), 3.28 ‐ 3.20 (m, 1H), 2.89 ‐ 2.81 (m, 1H). Example 6:

[0463]

change

[0464] The synthesis method of Example 1 can be obtained by referring to the method of Example 6. LC-MS (ESI), m / z: [M+H] + = 419.9 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 1.8 Hz, 1H), 8.35 (d, J = 4.9 Hz, 1H), 8.19 (d, J = 2.6 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 1.9 Hz, 1H), 7.27 (dd, J = 8.8, 2.8 Hz, 1H), 3.55 ‐ 3.47 (m, 1H), 3.26 ‐ 3.18 (m, 1H), 2.84 (q, J = 7.4 Hz, 2H), 2.78 (d, J = 4.9 Hz, 2H), 2.75 ‐ 2.69 (m, 1H), 2.58 ‐ 2.52 (m, 3H), 1.23 (t, J = 7.3 Hz, 2H), 0.80 ‐ 0.74 (m, 2H), 0.41 ‐ 0.35 (m, 1H). Example 6-1 and Example 6-2:

[0465] [ka]

[0466] Example 6 was separated by chiral preparative separation (CHIRALPAK IC 0.46 cm ID x 15 cm; mobile phase: mobile phase A = n-hexane, mobile phase B = methanol (0.1% diethylamine), A / B = 0 / 100; flow rate: 0.7 ml / min) to obtain Example 6-1 (t R =4.02) and Example 6-2 (t R = 5.02).

[0467] Example 6-1: LC-MS (ESI), m / z: [M+H] + = 420.1 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 1.5 Hz, 1H), 8.36 (q, J = 4.8 Hz, 1H), 8.19 (d, J = 2.6 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.27 (dd, J = 8.8, 2.7 Hz, 1H), 3.92 (q, J = 13.9 Hz, 2H), 3.55 - 3.48 (m, 1H), 3.26 - 3.18 (m, 1H), 2.84 (q, J = 7.3 Hz, 2H), 2.78 (d, J = 4.8 Hz, 3H), 2.75 - 2.69 (m, 1H), 2.59 - 2.53 (m, 2H), 1.24 (t, J = 7.3 Hz, 3H), 0.89 - 0.82 (m, 1H), 0.81 - 0.74 (m, 1H), 0.38 (q, J = 4.9 Hz, 1H). Example 6-2: LC-MS (ESI), m / z: [M+H] + = 420.1 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 1.5 Hz, 1H), 8.35 (q, J = 4.8 Hz, 1H), 8.19 (d, J = 2.6 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.27 (dd, J = 8.8, 2.7 Hz, 1H), 3.91 (q, J = 13.9 Hz, 2H), 3.55 - 3.48 (m, 1H), 3.26 - 3.18 (m, 1H), 2.84 (q, J = 7.3 Hz, 2H), 2.78 (d, J = 4.8 Hz, 3H), 2.75 - 2.69 (m, 1H), 2.59 - 2.53 (m, 2H), 1.24 (t, J = 7.3 Hz, 3H), 0.89 - 0.82 (m, 1H), 0.81 - 0.74 (m, 1H), 0.38 (q, J = 4.9 Hz, 1H). Example 7: cis-N-methyl-5-(5-((6-oxo-6,7,8,9-tetrahydro-5H-cyclopentane[c][1,5]naphthyridin-3-yl)methyl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)picolinamide

[0468] [ka]

[0469] Example 7 was obtained by referring to the synthesis method of Example 1. LC-MS (ESI), m / z: [M+H] + = 431.2 1H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 8.45 (d, J = 1.6 Hz, 1H), 8.35 (d, J = 4.8 Hz, 1H), 8.19 (d, J = 2.7 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.70 (s, 1H), 7.27 (dd, J = 8.8, 2.9 Hz, 1H), 3.95 - 3.83 (m, 2H), 3.54 - 3.46 (m, 1H), 3.24 - 3.20 (m, 1H), 3.17 (t, J = 7.2Hz, 3H), 2.83-2.79 (m, 2H), 2.78 (d, J = 4.8 Hz, 3H), 2.75 - 2.69 (m, 1H), 2.58 - 2.52 (m, 2H), 2.11 (p, J = 7.3 Hz, 2H), 0.77 (q, J = 6.3 Hz, 1H), 0.38 (q, J = 5.0 Hz, 1H). Example 10: cis-5-(5-((7-ethyl-6-oxo-5,6-dihydro-pyridine[3,2-c]pyridazine-2,5-diazabicyclo[4.2.0]octan-2-yl)-N-methylpicolinamide

[0470] [ka]

[0471] Example 10 (51 mg, yield: 44%) was obtained by following the synthesis method of Example 1.

[0472] LC-MS (ESI), m / z: [M+H] + = 434.2 Example 10-1 and Example 10-2: 5-((1S,6R)-(5-((7-ethyl-6-oxo-5,6-dihydro-pyridine[3,2-c]pyridazine-2,5-diazabicyclo[4.2.0]octan-2-yl)-N-methylpicolinamide and 5-((1R,6S)-(5-((7-ethyl-6-oxo-5,6-dihydro-pyridine[3,2-c]pyridazine-2,5-diazabicyclo[4.2.0]octan-2-yl)-N-methylpicolinamide

[0473] [ka]

[0474] Example 10 (48 mg) was separated by a chiral SCF prepared chromatography column (instrument model: SFC-80 (Thar, Waters); chromatography column model: CHIRALCEL OD (30×250 mm 5 μm); mobile phase: mobile phase A=carbon dioxide, mobile phase B=methanol (0.2% ammonia (7 mol / L ammonia-methanol solution)); total flow rate: 45 ml / min) to obtain Example 10-1 (t R = 14.0 min, 10.2 mg, yield: 22%) and Example 10-2 (t R = 21.5 min, 12.0 mg, yield: 25%).

[0475] [ka]

[0476] Example 10-1: LC-MS (ESI), m / z: [M+H] + = 434.2 11H NMR (400 MHz, DMSO-d6) δ 11.86 (br, 1H), 8.37 (d, J = 4.0 Hz, 1H), 8.11 (s, 1H), 8.03 (s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.54 (s, 1H), 7.24 (dd, J = 8.9, 2.8 Hz, 1H), 4.33 (q, J = 6.5 Hz, 1H), 4.11 (d, J = 14.4 Hz, 1H), 3.77 (d, J = 14.4 Hz, 1H), 3.53 ‐ 3.38 (m, 2H), 3.26 ‐ 3.13 (m, 2H), 2.88 ‐ 2.80 (m, 1H), 2.77 (m, 3H), 2.62 ‐ 2.55 (m, 2H), 2.40 (t, J = 10.2 Hz, 1H), 2.29 ‐ 2.21 (m, 1H), 2.13 ‐ 2.00 (m, 1H), 1.82 (m, 2H), 1.21 (t, J = 7.2 Hz, 3H). Example 10-2: LC-MS (ESI), m / z: [M+H] + = 434.2 1H NMR (400 MHz, DMSO-d6) δ 11.74 (br, 1H), 8.36 (d, J = 4.0 Hz, 1H), 8.11 (s, 1H), 8.03 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.54 (s, 1H), 7.23 (dd, J = 8.9, 2.8 Hz, 1H), 4.33 (q, J = 6.9 Hz, 1H), 4.10 (d, J = 14.5 Hz, 1H), 3.76 (d, J = 14.4 Hz, 1H), 3.51 - 3.45 (m, 1H), 3.43 - 3.38 (m, 1H), 3.27 - 3.17 (m, 2H), 2.86 - 2.80 (m, 1H), 2.77 (d, J = 4.4 Hz, 3H), 2.62 - 2.56 (m, 2H), 2.39 (t, J = 9.9 Hz, 1H), 2.29 - 2.21 (m, 1H), 2.13 - 2.00 (m, 1H), 1.83 (m, 2H), 1.21 (t, J = 7.4 Hz, 3H). Example 11: cis-5-(5-((3-ethyl-2-oxo-1,2-dihydropyrido[2,3-b]pyrazin-7-yl)methyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-N-methylpicolinamide

[0477] [ka]

[0478] [ka]

[0479] At 25°C, N,N-diisopropylethylamine (210mg, 1.62mmol), intermediate E (16.7mg, 0.810mmol), and (cyanomethyl)trimethylammonium phosphonium iodide (78.9mg, 0.325mmol) were added to a nitrile solution (2.00mL) of compound 11.1 (20.0mg, 0.810mmol), and the reaction mixture was stirred at 80°C under nitrogen gas protection for 2 hours. The reaction system was concentrated, and the residue obtained by concentration was separated and purified by preparative liquid chromatography (chromatography column model: Gemini-C18 150×21.2mm, 5.00μm, mobile phase: acetonitrile / 0.100% formic acid water, gradient: 2.00%~21.0%) to obtain Example 11 (10.0mg, yield: 27.0%). LC-MS (ESI), m / z: [M+H] + = 433.9 Example 11-1 and Example 11-2: 5-(((1S,6R)-5-((3-ethyl-2-oxo-1,2-dihydropyrido[2,3-b]pyrazin-7-yl)methyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-N-methylpicolinamide and 5-((1R,6S)-5-((3-ethyl-2-oxo-1,2-dihydropyrido[2,3-b]pyrazin-7-yl)methyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)-N-methylpicolinamide

[0480] [ka]

[0481] [ka]

[0482] Example 11 was separated by chiral preparative separation (CHIRALPAK OJ-H 250 mm×4.6 mm, 5 μm; mobile phase: mobile phase A=carbon dioxide, mobile phase B=methanol (0.2% aqueous ammonia), A / B=60 / 40; flow rate: 40 g / min) to obtain Example 11-1 (t R =10.9) and Example 11-2 (tR = 19.8 was obtained.

[0483] Example 11-1: LC-MS (ESI), m / z: [M+H] + = 433.9 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.37 (q, J = 4.9 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.64 (s, 1H), 7.23 (dd, J = 8.9, 2.6 Hz, 1H), 4.32 (q, J = 7.0 Hz, 1H), 3.90 (d, J = 14.1 Hz, 1H), 3.52 ‐ 3.40 (m, 3H), 3.26 ‐ 3.17 (m, 1H), 2.85 (q, J = 7.3 Hz, 2H), 2.77 (d, J = 4.8 Hz, 3H), 2.35 ‐ 2.20 (m, 2H), 2.13 ‐ 1.94 (m, 2H), 1.87 ‐ 1.77 (m, 2H), 1.24 (t, J = 7.3 Hz, 3H). Example 11-2: LC-MS (ESI), m / z: [M+H] + = 433.9 1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.37 (q, J = 4.9 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.70 (s, 1H), 7.23 (dd, J = 8.9, 2.6 Hz, 1H), 4.32 (q, J = 7.0 Hz, 1H), 3.92 (d, J = 14.1 Hz, 1H), 3.52 - 3.40 (m, 3H), 3.26 - 3.17 (m, 1H), 2.85 (q, J = 7.3 Hz, 2H), 2.77 (d, J = 4.8 Hz, 3H), 2.35 - 2.20 (m, 2H), 2.13 - 1.94 (m, 2H), 1.87 - 1.77 (m, 2H), 1.24 (t, J = 7.3 Hz, 3H). Example 12: cis-N-methyl-5-(5-((6-oxo-6,7,8,9-tetrahydro-5H-cyclopentane[c][1,5]naphthyridin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)picolinamide

[0484] [ka]

[0485] Synthesis scheme:

[0486] [ka]

[0487] Step 1: Synthesis of cis-methyl 5-(2,5-diazabicyclo[4.2.0]octyl-2-yl)pyridine-2-carboxylate (12.2) Under nitrogen gas atmosphere, 2,5-diazabicyclo[4.2.0]octane bistrifluoroacetate (355 mg, 1.04 mmol) and triethylamine (489 mg, 4.80 mmol) were added to a solution of compound 12.1 (150 mg, 0.970 mmol) in dimethyl sulfoxide (2 mL). After the addition was completed, the reaction mixture was stirred at 120° C. for 5 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by column chromatography (DCM / MeOH=20 / 3) to give the title compound 12.2 (316 mg, yield: 93%). LC-MS (ESI), m / z: [M+H] + = 248.2.

[0488] Step 2: Synthesis of cis-5-(2,5-diazabicyclo[4.2.0]oct-2-yl)-N-methylpyridine-2-carboxamide (12.3) At room temperature, methylamine solution (10 mL) was added to a solution of compound 12.2 (316 mg, 1.30 mmol) in methanol (10 mL). After the addition was completed, the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by column chromatography (DCM / MeOH=10 / 1) to give title compound 12.3 (219 mg, yield: 63%). LC-MS (ESI), m / z: [M+H] + = 247.1 Step 3: Synthesis of cis-N-methyl-5-(5-((6-oxo-6,7,8,9-tetrahydro-5H-cyclopentane[c][1,5]naphthyridin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)picolinamide (Example 12) Under nitrogen gas atmosphere, intermediate A (22.0 mg, 0.0900 mmol), ethyldiisopropylamine (42.0 mg, 0.300 mmol) and potassium iodide (3.00 mg, 0.0200 mmol) were added to a solution of compound 12.3 (19.8 mg, 0.0800 mmol) in acetonitrile (1 mL). After the addition was completed, the reaction mixture was stirred at 80° C. for 16 hours. After the reaction was completed, the reaction system was concentrated under reduced pressure, and the resulting residue was separated and purified by preparative liquid chromatography (chromatography column model: Gemini-C18 150×21.2 mm, 5 μm; mobile phase: acetonitrile / 0.1% formic acid water; gradient: 20-40%) to obtain the title compound Example 12 (40.0 mg, yield: 70%). LC-MS (ESI), m / z: [M+H] + = 445.3 Examples 12-1 and 12-2: N-methyl-5-[(1S,6R)-5-((6-oxo-5H,7H,8H,9H-cyclopentane[c]1,5-naphthyridin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]oct-2-yl]pyridine-2-carboxamide and N-methyl-5-[(1R,6S)-5-((6-oxo-5H,7H,8H,9H-cyclopentane[c]1,5-naphthyridin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]oct-2-yl]pyridine-2-carboxamide

[0489] [ka]

[0490] Synthesis scheme:

[0491] [ka]

[0492] Example 12 was separated by chiral column chromatography (chromatography column model: CHIRALPAK AD-H 250 mm x 20 mm, 5 μm; mobile phase: 40% isopropanol (0.2% aqueous ammonia); flow rate: 40 g / min) to obtain Example 12-1 (t R = 12.01 min, 12.0 mg, yield: 33%) and Example 12-2 (t R =14.06 min, 13.8 mg, yield: 37%).

[0493] Example 12-1: LC-MS (ESI), m / z: [M+H] + = 445.1 1 H NMR (400 MHz, MeOH-d4) δ 8.55 (d, J = 1.8 Hz, 1H), 8.16 (d, J = 2.8 Hz, 1H), 7.92 - 7.87 (m, 2H), 7.23 (dd, J = 8.9, 2.9 Hz, 1H), 4.37 (dd, J = 14.7, 6.9 Hz, 1H), 4.03 (d, J = 14.2 Hz, 1H), 3.54 - 3.41 (m, 4H), 3.02 - 2.89 (m, 6H), 2.46 - 2.22 (m, 6H), 2.01 - 1.95 (m, 2H). Example 12-2: LC-MS (ESI), m / z: [M+H] + = 445.2 1 H NMR (400 MHz, MeOH-d4) δ 8.55 (d, J = 1.7 Hz, 1H), 8.16 (d, J = 2.7 Hz, 1H), 7.92 - 7.87 (m, 2H), 7.23 (dd, J = 8.9, 2.9 Hz, 1H), 4.37 (dd, J = 14.7, 6.9 Hz, 1H), 4.03 (d, J = 14.2 Hz, 1H), 3.54 - 3.41 (m, 4H), 3.02 - 2.89 (m, 6H), 2.46 - 2.22 (m, 6H), 2.01 - 1.95 (m, 2H). Example 16:

[0494] [ka]

[0495] Example 16 was obtained by referring to the synthesis method of Example 29. LC-MS (ESI), m / z: [M+H] + = 445.1 Example 16-1 and Example 16-2:

[0496] [ka]

[0497] Example 16 was separated by chiral preparative separation (CHIRALPAK OJ-H 250 mm×20 mm, 5 μm; mobile phase: mobile phase A=carbon dioxide, mobile phase B=ethanol (0.2% aqueous ammonia), A / B=60 / 40; flow rate: 40 g / min) to obtain Example 16-1 (t R =9.67) and Example 16-2 (t R = 13.25).

[0498] Example 16-1: LC-MS (ESI), m / z: [M+H] + = 445.1 11H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.41 (d, J = 1.7 Hz, 1H), 8.36 (q, J = 4.9 Hz, 1H), 8.10 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.43 (s, 1H), 7.22 (dd, J = 8.9, 2.9 Hz, 1H), 4.31 (q, J = 6.9 Hz, 2H), 3.89 (d, J = 14.1 Hz, 1H), 3.48 ‐ 3.42 (m, 1H), 3.39 (d, J = 14.1 Hz, 1H), 3.25 ‐ 3.17 (m, 1H), 2.79 (m, 1H), 2.77 (d, J = 4.9 Hz, 3H), 2.67 (p, J = 1.9 Hz, 1H), 2.34 ‐ 2.20 (m, 2H), 2.17 ‐ 2.01 (m, 2H), 1.86 ‐ 1.79 (m, 2H), 1.00 ‐ 0.94 (m, 2H), 0.85 ‐ 0.78 (m, 2H). Example 16-2: LC-MS (ESI), m / z: [M+H] + = 445.1 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.41 (d, J = 1.7 Hz, 1H), 8.36 (q, J = 4.9 Hz, 1H), 8.10 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.43 (s, 1H), 7.22 (dd, J = 8.9, 2.9 Hz, 1H), 4.31 (q, J = 6.9 Hz, 2H), 3.89 (d, J = 14.1 Hz, 1H), 3.48 - 3.42 (m, 1H), 3.39 (d, J = 14.1 Hz, 1H), 3.25 - 3.17 (m, 1H), 2.79 (m, 1H), 2.77 (d, J = 4.9 Hz, 3H), 2.67 (p, J = 1.9 Hz, 1H), 2.34 - 2.20 (m, 2H), 2.17 - 2.01 (m, 2H), 1.86 - 1.79 (m, 2H), 1.00 - 0.94 (m, 2H), 0.85 - 0.78 (m, 2H). Example 29: cis-3-ethyl-7-((5-(6-(5-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)methyl)-1H-1,5-naphthyridin-2-one:

[0499] [ka]

[0500] Synthesis scheme:

[0501] [ka]

[0502] Step 1: Synthesis of cis-5-(2,5-diazabicyclo[4.2.0]octan-2-ylpyridine-2-carbonitrile (29.2) To a DMSO solution (15 mL) of intermediate a (250 mg, 0.735 mmol) and 5-fluoropyridine-2-carbonitrile (90 mg, 0.735 mmol) was added K2CO3 (508 mg, 3.675 mmol) at room temperature, and the mixture was stirred at 100 °C for 24 hours. After completion of the reaction, dry ice (10 g) was added to the reaction mixture (about 20 mL), and the mixture was stirred for 16 hours and then cooled to room temperature. The reaction mixture was used directly in the next reaction. LC-MS (ESI), m / z: [M+H] + = 215.1 Step 2: Synthesis of cis-5-(5-((7-ethyl-6-oxa-5H-1,5 naphthyridin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)pyridine-2-carbonitrile (29.4): A solution of compound 29.3 in DCM was added to the reaction mixture containing compound 29.2, and the resulting reaction was allowed to react at room temperature for 30 min, quenched with 30 mL of water, and extracted with EA (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by pre-TLC to give the title compound 29.4 (120 mg, 29%). LC-MS (ESI), m / z: [M+H] + = 401.2 Step 3: Synthesis of cis-3-ethyl-7-((5-(6-(5-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)methyl)-1H-1,5-naphthyridin-2-one (Example 29) Acetohydrazide (55 mg, 0.75 mmol) and K2CO3 (155 mg, 1.13 mmol) were added to a solution of compound 29.4 (30 mg, 0.075 mmol) in n-butanol (2.5 mL) at room temperature, and the resulting mixture was stirred at 150 ° C for 6 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (5 mL × 2), the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (chromatography column model: Gemini 5 μm C18 150 × 21.2 mm; mobile phase: 10-40% acetonitrile / water (0.1% formic acid); flow rate: 20 ml / min) to obtain the title compound Example 29 (15 mg, yield: 43%).

[0503] Example 29-1 and Example 29-2: 3-ethyl-7-((1R,6S)-(5-(6-(5-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)methyl)-1H-1,5-naphthyridin-2-one and 3-ethyl-7-((1S,6R)-(5-(6-(5-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-2,5-diazabicyclo[4.2.0]octan-2-yl)methyl)-1H-1,5-naphthyridin-2-one

[0504] [ka]

[0505] Example 29 (15 mg, 0.033 mmol) was separated and purified by chiral SFC chromatography (chromatography column model: CHIRALPAK AD-H 250 mm × 20 mm, 5 μm; mobile phase: 40% isopropanol (0.2% ethylenediamine); flow rate: 40 g / min) to obtain Example 29-1 (t R = 21.7 min, 2.5 mg, yield: 17%) and Example 29-2 (t R = 31.5 min, 1.7 mg, yield: 11%).

[0506] Example 29-1: LC-MS (ESI), m / z: [M+H] + = 457.2 1 H NMR (400 MHz, DMSO-d6) δ 13.89 (s, 1H), 11.84 (s, 1H), 8.44 (d, J = 1.7 Hz, 1H), 8.18 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.68 (s, 1H), 7.25 (s, 1H), 4.35 ‐ 4.25 (m, 1H), 3.90 (d, J = 14.0 Hz, 1H), 3.49 ‐ 3.37 (m, 3H), 3.26 ‐ 3.18 (m, 1H), 2.82 ‐ 2.76 (m, 1H), 2.58 ‐ 2.52 (m, 2H), 2.40 ‐ 2.30 (m, 2H), 2.30 ‐ 2.20 (m, 3H), 2.13 ‐ 2.03 (m, 1H), 1.88 ‐ 1.78 (m, 2H), 1.19 (t, J = 7.4 Hz, 3H). Example 29-2: LC-MS (ESI), m / z: [M+H] + = 457.2 1 H NMR (400 MHz, DMSO-d6) δ 13.89 (s, 1H), 11.84 (s, 1H), 8.44 (d, J = 1.7 Hz, 1H), 8.18 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.69 (s, 1H), 7.25 (s, 1H), 4.35 ‐ 4.25 (m, 1H), 3.90 (d, J = 14.0 Hz, 1H), 3.49 ‐ 3.37 (m, 3H), 3.27 ‐ 3.18 (m, 1H), 2.83 ‐ 2.76 (m, 1H), 2.59 ‐ 2.52 (m, 2H), 2.39 ‐ 2.30 (m, 2H), 2.30 ‐ 2.20 (m, 3H), 2.13 ‐ 2.03 (m, 1H), 1.88 ‐ 1.78 (m, 2H), 1.19 (t, J = 7.4 Hz, 3H). Example 30: cis-N-methyl-5-(5-((6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)picolinamide

[0507] [ka]

[0508] Synthesis scheme:

[0509] [ka]

[0510] Synthesis of cis-N-methyl-5-(5-((6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)picolinamide (Example 30): Diisopropylethylamine (137 mg, 1.06 mmol), compound 30.1 (87 mg, 0.35 mmol), and potassium iodide (5.8 mg, 0.035 mmol) were added to a solution of compound intermediate C (93 mg, 0.35 mmol) in acetonitrile (5 mL), and the reaction mixture was stirred at 80° C. for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by preparative liquid chromatography (chromatography column model: Gemini-C18 150×21.2 mm, 5 μm; mobile phase: acetonitrile / water (0.1% formic acid); gradient: 20-40%) to obtain the title compound Example 30 (42 mg, yield: 22%). LC-MS (ESI), m / z: [M+H] + = 473.1 Example 30-1 and Example 30-2: N-methyl-5-((1S,6R)-5-((6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)picolinamide and N-methyl-5-((1R,6S)-5-((6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)picolinamide

[0511] [ka]

[0512] Synthesis scheme:

[0513] [ka]

[0514] Example 30 (42 mg) was separated and purified by chiral column chromatography (chromatography column model: CHIRALPAK AD-H 250 mm × 20 mm, 5 μm; mobile phase: 40% isopropanol (0.2% ammonia water); flow rate: 40 g / min) to obtain Example 30-1 (t R = 5.02 min, 10.1 mg, yield: 24%) and Example 30-2 (t R = 11.02 min, 9.50 mg, yield: 23%).

[0515] Example 30-1: LC-MS (ESI), m / z: [M+H] + = 473.2 11H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.61 (s, 1H), 8.42 (s, 1H), 8.37 (d, J = 4.8 Hz, 1H), 8.11 (d, J = 2.5 Hz, 1H), 7.86 ‐ 7.78 (m, 2H), 7.23 (dd, J = 8.8, 2.6 Hz, 1H), 4.33 (q, J = 6.9 Hz, 1H), 3.96 (d, J = 14.7 Hz, 1H), 3.53 ‐ 3.45 (m, 2H), 3.23 (t, J = 9.5 Hz, 1H), 2.80 (m, 1H), 2.78 (d, J = 4.7 Hz, 3H), 2.33 (t, J = 9.9 Hz, 1H), 2.28 ‐ 2.22 (m, 1H), 2.09 (p, J = 9.0 Hz, 1H), 1.89 ‐ 1.77 (m, 1H). Example 30-2: LC-MS (ESI), m / z: [M+H] + = 473.2 1 1H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.61 (s, 1H), 8.42 (s, 1H), 8.37 (d, J = 4.8 Hz, 1H), 8.11 (d, J = 2.5 Hz, 1H), 7.84 ‐ 7.78 (m, 2H), 7.23 (dd, J = 8.8, 2.6 Hz, 1H), 4.33 (q, J = 6.9 Hz, 1H), 3.96 (d, J = 14.7 Hz, 1H), 3.53 ‐ 3.45 (m, 2H), 3.23 (t, J = 9.5 Hz, 1H), 2.80 (m, 1H), 2.78 (d, J = 4.7 Hz, 3H), 2.33 (t, J = 9.9 Hz, 1H), 2.28 ‐ 2.22 (m, 1H), 2.15 ‐ 2.05 (m, J = 9.0 Hz, 1H), 1.89 ‐ 1.77 (m, 1H) Example 31: cis-N-methyl-5-(5-((6-oxo-6,8,9,10-tetrahydro-5H-pyran[2,3-c][1,5]naphthyridin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)picolinamide

[0516] [ka]

[0517] Synthesis scheme:

[0518] [ka]

[0519] Step 1: cis-N-methyl-5-(5-((6-oxo-6,8,9,10-tetrahydro-5H-pyran[2,3-c][1,5]naphthyridin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)picolinamide (Example 31) At room temperature, N,N-diisopropylethylamine (90.0 mg, 0.700 mmol), intermediate B (35.0 mg, 0.140 mmol) and potassium iodide (3.00 mg, 0.0200 mmol) were added to a solution of compound 1.2 (34.0 mg, 0.140 mmol) in acetonitrile (2 mL), and the reaction mixture was stirred at 80° C. for 3 hours. After completion of the reaction, the reaction mixture was concentrated, and the resulting residue was separated and purified by preparative liquid chromatography (chromatography column model: Gemini-C18 150×21.2 mm, 5 μm; mobile phase: acetonitrile / 0.1% formic acid water; gradient: 20-40%) to obtain the title compound Example 31 (45 mg, yield: 70%). LC-MS (ESI), m / z: [M+H] + = 461.2. Example 31-1 and Example 31-2: N-methyl-5-((1S,6R)-5-(6-oxo-6,8,9,10-tetrahydro-5H-pyran[2,3-c][1,5]naphthyridin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)picolinamide and N-methyl-5-((1R,6S)-5-(6-oxo-6,8,9,10-tetrahydro-5H-pyran[2,3-c][1,5]naphthyridin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)picolinamide

[0520] [ka]

[0521] Synthesis scheme:

[0522] [ka]

[0523] Example 31 was separated by chiral column chromatography (chromatography column model: CHIRALPAK AD-H 250 mm x 20 mm, 5 μm; mobile phase: 40% isopropanol (0.2% aqueous ammonia); flow rate: 40 g / min) to obtain compound Example 31-1 (t R = 28.37 min, 17.5 mg, yield: 39%) and compound Example 31-2 (t R = 36.19 min, 17.0 mg, yield: 38%).

[0524] Example 31-1: LC-MS (ESI), m / z: [M+H] + = 461.1 1H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 8.43 (d, J = 1.7 Hz, 1H), 8.36 (d, J = 4.9 Hz, 1H), 8.10 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 1.5 Hz, 1H), 7.22 (dd, J = 8.9, 2.8 Hz, 1H), 4.93 (s, 2H), 4.30 (dd, J = 15.2, 7.1 Hz, 1H), 3.94 ‐ 3.87 (m, 3H), 3.49 ‐ 3.38 (m, 2H), 3.26 ‐ 3.19 (m, 1H), 2.80 ‐ 2.74 (m, 4H), 2.34 ‐ 2.19 (m, 3H), 2.11 ‐ 2.02 (m, 1H), 1.86 ‐ 1.79 (m, 2H). Example 31-2: LC-MS (ESI), m / z: [M+H] + = 461.1 1 H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 8.42 (d, J = 1.7 Hz, 1H), 8.36 (d, J = 4.9 Hz, 1H), 8.10 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 1.5 Hz, 1H), 7.22 (dd, J = 8.9, 2.8 Hz, 1H), 4.93 (s, 2H), 4.30 (dd, J = 15.2, 7.1 Hz, 1H), 3.94 ‐ 3.87 (m, 3H), 3.49 ‐ 3.38 (m, 2H), 3.26 ‐ 3.19 (m, 1H), 2.80 ‐ 2.74 (m, 4H), 2.34 ‐ 2.19 (m, 3H), 2.11 ‐ 2.02 (m, 1H), 1.86 ‐ 1.79 (m, 2H). Example 33:

[0525]

change

[0526] Example 33 was obtained by referring to the synthesis method of Example 29. LC-MS (ESI), m / z: [M+H] + = 435.2 Example 33-1 and Example 33-2:

[0527] [ka]

[0528] Example 33 was separated by chiral preparative separation (CHIRALPAK OJ-H 250 mm×20 mm, 5 μm; mobile phase: mobile phase A=carbon dioxide, mobile phase B=ethanol (0.2% aqueous ammonia), A / B=60 / 40; flow rate: 40 g / min) to give Example 33-1 (t R =13.46) and Example 33-2 (t R = 21.0).

[0529] Example 33-1: LC-MS (ESI), m / z: [M+H] + = 435.2 1 H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.40 (d, J = 1.7 Hz, 1H), 8.39 - 8.35 (m, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 1.6 Hz, 1H), 7.25 - 7.16 (m, 2H), 4.31 (q, J = 6.9 Hz, 1H), 3.91 - 3.84 (m, 4H), 3.49 - 3.42 (m, 1H), 3.38 (d, J = 14.2 Hz, 1H), 3.25 - 3.17 (m, 1H), 2.80 (m, 1H), 2.77 (d, J = 4.8 Hz, 3H), 2.34 - 2.20 (m, 2H), 2.10 - 2.01 (m, 1H), 1.87 - 1.79 (m, 2H). Example 33-2: LC-MS (ESI), m / z: [M+H] + = 435.2 1 H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.40 (d, J = 1.7 Hz, 1H), 8.39 - 8.35 (m, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.24 - 7.18 (m, 2H), 4.31 (q, J = 6.9 Hz, 1H), 3.92 - 3.84 (m, 4H), 3.49 - 3.42 (m, 1H), 3.38 (d, J = 14.2 Hz, 1H), 3.25 - 3.17 (m, 1H), 2.80 (m, 1H), 2.77 (d, J = 4.8 Hz, 3H), 2.34 - 2.20 (m, 2H), 2.10 - 2.01 (m, 1H), 1.87 - 1.79 (m, 2H). Example 34:

[0530] [ka]

[0531] Example 34 was obtained by referring to the synthesis method of Example 29. LC-MS (ESI), m / z: [M+H] + = 462.0 Example 34-1 and Example 34-2:

[0532] [ka]

[0533] Example 34 was separated by chiral preparative separation (CHIRALPAK OJ-H 250 mm×20 mm, 5 μm; mobile phase: mobile phase A=carbon dioxide, mobile phase B=methanol (0.2% aqueous ammonia), A / B=60 / 40; flow rate: 40 g / min) to give Example 34-1 (t R= 10.8) and Example 34-2 (t R = 18.96) was obtained.

[0534] Example 34-1: LC-MS (ESI), m / z: [M+H] + = 462.0 1 H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 8.35 (d, J = 5.1 Hz, 1H), 8.09 (d, J = 2.9 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.25 (t, J = 7.3 Hz, 1H), 7.20 (dd, J = 8.9, 2.9 Hz, 1H), 4.30 (q, J = 7.2 Hz, 1H), 3.85 (d, J = 13.6 Hz, 1H), 3.55 (d, J = 13.5 Hz, 1H), 3.50 ‐ 3.43 (m, 1H), 3.21 ‐ 3.13 (m, 1H), 3.10 (t, J = 7.6 Hz, 2H), 2.86 ‐ 2.80 (m, 2H), 2.77 (d, J = 4.6 Hz, 3H), 2.35 ‐ 2.17 (m, 2H), 2.16 ‐ 1.98 (m, 4H), 1.89 ‐ 1.77 (m, 2H). Example 34-2: LC-MS (ESI), m / z: [M+H] + = 462.0 1H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 8.35 (d, J = 5.1 Hz, 1H), 8.09 (d, J = 2.9 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.23 (t, J = 7.3 Hz, 1H), 7.20 (dd, J = 8.9, 2.9 Hz, 1H), 4.30 (q, J = 7.2 Hz, 1H), 3.85 (d, J = 13.6 Hz, 1H), 3.55 (d, J = 13.5 Hz, 1H), 3.50 - 3.47 (m, 1H), 3.20 - 3.13 (m, 1H), 3.10 (t, J = 7.6 Hz, 2H), 2.86 - 2.80 (m, 2H), 2.77 (d, J = 4.6 Hz, 3H), 2.35 - 2.17 (m, 2H), 2.16 - 1.98 (m, 4H), 1.89 - 1.75 (m, 2H). Example 35:

[0535] [ka]

[0536] Example 35 was obtained by referring to the synthesis method of Example 29. LC-MS (ESI), m / z: [M+H] + = 457.5 Example 35-1 and Example 35-2:

[0537] [ka]

[0538] Example 35 was separated by chiral preparative separation (CHIRALPAK OJ-H 250 mm×20 mm, 5 μm; mobile phase: mobile phase A=carbon dioxide, mobile phase B=methanol (0.2% aqueous ammonia), A / B=60 / 40; flow rate: 40 g / min) to give Example 35-1 (t R =6.09) and Example 35-2 (t R=11.55)を got た.

[0539] Example 35-1: LC-MS (ESI), m / z: [M+H] + = 457.5 1 H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.36 (q, J = 4.6 Hz, 1H), 8.08 (d, J = 2.7 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.20 (dd, J = 8.5, 3.0 Hz, 2H), 4.31 (q, J = 7.1 Hz, 1H), 3.91 (d, J = 13.1 Hz, 1H), 3.44 ‐ 3.39 (m, 1H), 3.31 ‐ 3.24 (m, 2H), 3.13 ‐ 3.06 (m, 3H), 2.78 (t, J = 7.4 Hz, 2H), 2.77 (d, J = 4.8 Hz, 3H), 2.73 ‐ 2.66 (m, 1H), 2.28 ‐ 2.17 (m, 2H), 2.16 ‐ 2.07 (m, 2H), 2.07 ‐ 1.99 (m, 1H), 1.87 - 1.78 (m, 2H). Example 35-2: LC-MS (ESI), m / z: [M+H] + = 457.5 1H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.36 (q, J = 4.6 Hz, 1H), 8.09 (d, J = 2.7 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.20 (dd, J = 8.5, 3.0 Hz, 2H), 4.33 (q, J = 7.1 Hz, 1H), 3.91 (d, J = 13.1 Hz, 1H), 3.44 - 3.39 (m, 1H), 3.31 - 3.24 (m, 2H), 3.13 - 3.06 (m, 3H), 2.78 (t, J = 7.4 Hz, 2H), 2.77 (d, J = 4.8 Hz, 3H), 2.73 - 2.66 (m, 1H), 2.28 - 2.17 (m, 2H), 2.16 - 2.07 (m, 2H), 2.07 - 1.99 (m, 1H), 1.87 - 1.79 (m, 2H). Example 36:

[0540] [ka]

[0541] Example 36 was obtained by referring to the synthesis method of Example 29. LC-MS (ESI), m / z: [M+H] + = 478.2 Example 36-1 and Example 36-2:

[0542] [ka]

[0543] Example 36 was separated by chiral preparative separation (CHIRALPAK OJ-H 250 mm×20 mm, 5 μm; mobile phase: mobile phase A=carbon dioxide, mobile phase B=ethanol (0.2% aqueous ammonia), A / B=60 / 40; flow rate: 40 g / min) to give Example 36-1 (t R =12.6) and Example 36-2 (t R=11.55)を got た.

[0544] Example 36-1: LC-MS (ESI), m / z: [M+H] + = 478.2 1 H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 8.35 (d, J = 5.0 Hz, 1H), 8.09 (d, J = 2.6 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.25 (d, J = 6.6 Hz, 1H), 7.20 (dd, J = 9.1, 2.9 Hz, 1H), 4.87 (s, 2H), 4.31 (q, J = 7.0 Hz, 1H), 3.89 (t, J = 5.5 Hz, 2H), 3.84 (d, J = 13.9 Hz, 1H), 3.55 (d, J = 13.6 Hz, 1H), 3.47 (d, J = 11.7 Hz, 1H), 3.30 ‐ 3.26 (m, 1H), 3.21 ‐ 3.12 (m, 1H), 2.82 (d, J = 12.0 Hz, 1H), 2.77 (d, J = 4.8 Hz, 3H), 2.34 ‐ 2.17 (m, 3H), 2.10 ‐ 1.98 (m, 2H), 1.86 ‐ 1.79 (m, 2H). Example 36-2: LC-MS (ESI), m / z: [M+H] + = 478.2 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.35 (d, J = 5.0 Hz, 1H), 8.12 (d, J = 2.6 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.25 (d, J = 6.6 Hz, 1H), 7.20 (dd, J = 9.1, 2.9 Hz, 1H), 4.86 (s, 2H), 4.31 (q, J = 7.0 Hz, 1H), 3.89 (t, J = 5.5 Hz, 2H), 3.84 (d, J = 13.9 Hz, 1H), 3.55 (d, J = 13.6 Hz, 1H), 3.47 (d, J = 11.7 Hz, 1H), 3.30 ‐ 3.26 (m, 1H), 3.21 ‐ 3.12 (m, 1H), 2.82 (d, J = 12.0 Hz, 1H), 2.78 (d, J = 4.8 Hz, 3H), 2.34 ‐ 2.17 (m, 3H), 2.11 ‐ 1.98 (m, 2H), 1.86 ‐ 1.80 (m, 2H). Example 37:

[0545]

change

[0546] The synthesis method of Example 11 can be obtained by referring to the method of Example 37. LC-MS (ESI), m / z: [M+H] + = 433.1 Example 37-1 and Example 37-2:

[0547]

change

[0548] Example 37 was separated by chiral preparative separation (CHIRALPAK OJ-H 250 mm×20 mm, 5 μm; mobile phase: mobile phase A=carbon dioxide, mobile phase B=ethanol (0.2% aqueous ammonia), A / B=60 / 40; flow rate: 40 g / min) to give Example 37-1 (t R =7.81) and Example 37-2 (t R = 18.4).

[0549] Example 37-1: LC-MS (ESI), m / z: [M+H] + = 433.1 1 H NMR (400 MHz, MeOH-d4) δ 8.16 (d, J = 2.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.43 - 7.38 (m, 2H), 7.23 (dd, J = 8.9, 2.9 Hz, 1H), 4.35 (q, J = 6.8 Hz, 1H), 3.98 (d, J = 13.9 Hz, 1H), 3.52 - 3.47 (m, 1H), 3.44 - 3.38 (m, 2H), 2.95 (s, 3H), 2.94 - 2.89 (m, 2H), 2.42 - 2.21 (m, 4H), 1.99 - 1.93 (m, 2H), 1.34 (t, J = 7.4 Hz, 3H). Example 37-2: LC-MS (ESI), m / z: [M+H] + = 433.1 1H NMR (400 MHz, MeOH-d4) δ 8.16 (d, J = 2.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.43 - 7.38 (m, 2H), 7.23 (dd, J = 8.9, 2.9 Hz, 1H), 4.35 (q, J = 6.8 Hz, 1H), 3.98 (d, J = 13.9 Hz, 1H), 3.52 - 3.47 (m, 1H), 3.44 - 3.38 (m, 2H), 2.95 (s, 3H), 2.94 - 2.89 (m, 2H), 2.42 - 2.21 (m, 4H), 1.99 - 1.93 (m, 2H), 1.34 (t, J = 7.4 Hz, 3H). Example 38:

[0550] [ka]

[0551] Example 38 was obtained by referring to the synthesis method of Example 11. LC-MS (ESI), m / z: [M+H] + = 451.2 Example 38-1 and Example 38-2:

[0552] [ka]

[0553] Example 38 was separated by chiral preparative separation (OJ-H 20×250 mm, 10 um; mobile phase: mobile phase A=n-hexane, mobile phase B=ethanol (0.2% aqueous ammonia), A / B=50 / 50; flow rate: 0.8 ml / min), A / B=60 / 40; flow rate: 40 g / min) to give Example 38-1 (t R =6.93) and Example 38-2 (t R =8.84).

[0554] Example 38-1: LC-MS (ESI), m / z: [M+H] += 451.2 1 H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 8.37 (s, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 7.2 Hz, 1H), 7.53 ‐ 7.15 (m, 3H), 4.19 (m, 1H), 3.79 (d, J = 12.6 Hz, 2), 3.49 ‐ 3.39 (m, 3H), 3.22 ‐ 3.13 (m, 1H), 2.86 ‐ 2.77 (m, 2H), 2.76 (d, J = 4.8 Hz, 3H), 2.44 ‐ 2.34 (m, 1H), 2.12 ‐ 2.01 (m, 1H), 1.99 - 1.90 (m, 1H), 1.89 - 1.79 (m, 1H), 1.77 - 1.68 (m, 1H), 1.22 (t, J = 7.4 Hz, 3H). Example 38-2: LC-MS (ESI), m / z: [M+H] + = 451.2 1 H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 8.36 (s, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.44 ‐ 7.26 (m, 3H), 4.19 (m, 1H), 3.79 (d, J = 12.6 Hz, 2), 3.49 ‐ 3.39 (m, 3H), 3.22 ‐ 3.13 (m, 1H), 2.86 ‐ 2.77 (m, 2H), 2.76 (d, J = 4.8 Hz, 3H), 2.44 ‐ 2.34 (m, 1H), 2.12 ‐ 2.01 (m, 1H), 1.99 ‐ 1.90 (m, 1H), 1.89 ‐ 1.79 (m, 1H), 1.77 ‐ 1.68 (m, 1H), 1.21 (t, J = 7.4 Hz, 3H). Example 39:

[0555]

change

[0556] Example 39 was obtained by referring to the synthesis method of Example 11. LC-MS (ESI), m / z: [M+H] + = 451.0 Example 39-1 and Example 39-2:

[0557] [ka]

[0558] Example 39 was separated by chiral preparative separation (CHIRALPAK OJ-H 250 mm×20 mm, 5 μm; mobile phase: mobile phase A=carbon dioxide, mobile phase B=ethanol (0.2% aqueous ammonia), A / B=60 / 40; flow rate: 40 g / min) to give Example 39-1 (t R =7.91) and Example 39-2 (t R = 14.8).

[0559] Example 39-1: LC-MS (ESI), m / z: [M+H] + = 451.0 1 H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 8.37 (q, J = 4.7 Hz, 1H), 8.11 (d, J = 2.6 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.23 (dd, J = 8.9, 2.7 Hz, 1H), 7.18 - 7.10 (m, 2H), 4.32 (q, J = 6.9 Hz, 1H), 3.86 (d, J = 14.3 Hz, 1H), 3.47 (d, J = 11.7 Hz, 1H), 3.35 (m, 2H), 3.28 - 3.19 (m, 1H), 2.85 - 2.76 (m, 5H), 2.34 - 2.20 (m, 2H), 2.10 (p, J = 9.2 Hz, 1H), 1.89 - 1.75 (m, 2H), 1.22 (t, J = 7.4 Hz, 3H). Example 39-2: LC-MS (ESI), m / z: [M+H] + = 451.0 1 H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 8.37 (q, J = 4.7 Hz, 1H), 8.11 (d, J = 2.6 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.23 (dd, J = 8.9, 2.7 Hz, 1H), 7.18 - 7.09 (m, 2H), 4.32 (q, J = 6.9 Hz, 1H), 3.86 (d, J = 14.3 Hz, 1H), 3.47 (d, J = 11.7 Hz, 1H), 3.35 (m, 2H), 3.28 - 3.19 (m, 1H), 2.85 - 2.74 (m, 5H), 2.34 - 2.20 (m, 2H), 2.10 (p, J = 9.2 Hz, 1H), 1.89 - 1.75 (m, 2H), 1.22 (t, J = 7.4 Hz, 3H). Example 40:

[0560] [ka]

[0561] Example 40 was obtained by referring to the synthesis method of Example 11. LC-MS (ESI), m / z: [M+H] + = 451.2 Example 40-1 and Example 40-2:

[0562] [ka]

[0563] Example 40 was separated by chiral preparative separation (CHIRALPAK OJ-H 250 mm×20 mm, 5 μm; mobile phase: mobile phase A=carbon dioxide, mobile phase B=isopropanol (0.2% aqueous ammonia), A / B=60 / 40; flow rate: 40 g / min) to give Example 40-1 (t R= 6.91) and Example 40-2 (t R = 18.6) were obtained.

[0564] Example 40-1: LC-MS (ESI), m / z: [M+H] + = 451.2 1 H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.37 (q, J = 4.7 Hz, 1H), 8.11 (d, J = 2.7 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.23 (dd, J = 8.9, 2.9 Hz, 1H), 4.32 (q, J = 6.9 Hz, 1H), 3.93 (d, J = 14.4 Hz, 1H), 3.49 ‐ 3.41 (m, 2H), 3.22 (td, J = 11.2, 3.2 Hz, 2H), 2.79 (m, 1H), 2.77 (d, J = 4.8 Hz, 4H), 2.59 (q, J = 7.7 Hz, 2H), 2.35 ‐ 2.21 (m, 2H), 2.08 (p, J = 9.0 Hz, 1H), 1.86 ‐ 1.79 (m, 2H), 1.12 (t, J = 7.5 Hz, 3H). Example 40-2: LC-MS (ESI), m / z: [M+H] + = 451.2 1H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.37 (q, J = 4.7 Hz, 1H), 8.11 (d, J = 2.7 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.23 (dd, J = 8.9, 2.9 Hz, 1H), 4.32 (q, J = 6.9 Hz, 1H), 3.93 (d, J = 14.4 Hz, 1H), 3.49 - 3.41 (m, 2H), 3.22 (td, J = 11.2, 3.2 Hz, 2H), 2.80 (m, 1H), 2.77 (d, J = 4.8 Hz, 4H), 2.59 (q, J = 7.7 Hz, 2H), 2.35 - 2.21 (m, 2H), 2.08 (p, J = 9.0 Hz, 1H), 1.86 - 1.79 (m, 2H), 1.12 (t, J = 7.5 Hz, 3H). Example 41:

[0565] [ka]

[0566] Example 41 was obtained by referring to the synthesis method of Example 11. LC-MS (ESI), m / z: [M+H] + = 437.2 Example 41-1 and Example 41-2:

[0567] [ka]

[0568] Example 41 was separated by chiral preparative separation (chromatographic column model: OD(AB50)-50 min.1 cm, mobile phase: 40% ethanol (0.2% aqueous ammonia), flow rate: 40 g / min) to obtain Example 41-1 (t R =11.9) and Example 41-2 (t R = 15.7).

[0569] Example 41-1: LC-MS (ESI), m / z: [M+H] + = 437.2 1 H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.51 (d, J = 1.5 Hz, 1H), 8.37 (q, J = 4.8 Hz, 1H), 8.11 (d, J = 2.7 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.23 (dd, J = 8.9, 2.8 Hz, 1H), 4.32 (q, J = 6.9 Hz, 1H), 3.93 (d, J = 14.3 Hz, 1H), 3.49 ‐ 3.41 (m, 2H), 3.27 ‐ 3.18 (m, 1H), 2.80 (s, 1H), 2.77 (d, J = 4.8 Hz, 3H), 2.36 ‐ 2.22 (m, 2H), 2.12 ‐ 2.04 (m, 4H), 1.86 ‐ 1.81 (m, 2H). Example 41-2: LC-MS (ESI), m / z: [M+H] + = 437.2 1 H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.50 (d, J = 1.5 Hz, 1H), 8.37 (q, J = 4.8 Hz, 1H), 8.11 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.23 (dd, J = 8.9, 2.8 Hz, 1H), 4.32 (q, J = 7.0 Hz, 1H), 3.93 (d, J = 14.3 Hz, 1H), 3.49 ‐ 3.42 (m, 2H), 3.27 ‐ 3.18 (m, 1H), 2.80 (s, 1H), 2.77 (d, J = 4.8 Hz, 3H), 2.36 ‐ 2.22 (m, 2H), 2.11 ‐ 2.04 (m, 4H), 1.86 ‐ 1.81 (m, 2H). Example 42:

[0570] [ka]

[0571] Example 42 was obtained by referring to the synthesis method of Example 11. LC-MS (ESI), m / z: [M+H] + = 469.0 Example 42-1 and Example 42-2:

[0572] [ka]

[0573] Example 42 was separated by chiral preparative separation (CHIRALPAK OJ-H 250 mm×20 mm, 5 μm; mobile phase: mobile phase A=carbon dioxide, mobile phase B=ethanol (0.2% aqueous ammonia), A / B=60 / 40; flow rate: 40 g / min) to give Example 42-1 (t R =6.57) and Example 42-2 (t R = 18.3).

[0574] Example 42-1: LC-MS (ESI), m / z: [M+H] + = 469.0 1 H NMR (400 MHz, MeOH-d4) δ 8.12 (d, J = 2.8 Hz, 1H), 7.85 (t, J = 8.4 Hz, 2H), 7.45 - 7.42 (m, 2H), 7.19 (dd, J = 8.9, 2.9 Hz, 1H), 4.32 (q, J = 6.8 Hz, 1H), 3.97 (d, J = 14.3 Hz, 1H), 3.49 - 3.31 (m, 4H), 2.91 - 2.85 (m, 4H), 2.39 - 2.20 (m, 3H), 2.05 (t, J = 19.0 Hz, 3H), 1.95 - 1.88 (m, 2H). Example 42-2: LC-MS (ESI), m / z: [M+H] += 469.0 1 H NMR (400 MHz, MeOH-d4) δ 8.12 (d, J = 2.8 Hz, 1H), 7.85 (t, J = 8.4 Hz, 2H), 7.45 - 7.42 (m, 2H), 7.19 (dd, J = 8.9, 2.9 Hz, 1H), 4.32 (q, J = 6.8 Hz, 1H), 3.97 (d, J = 14.3 Hz, 1H), 3.48 - 3.31 (m, 4H), 2.91 - 2.85 (m, 4H), 2.39 - 2.20 (m, 3H), 2.05 (t, J = 19.0 Hz, 3H), 1.95 - 1.88 (m, 2H). Example 43:

[0575] [ka]

[0576] Example 43 was obtained by referring to the synthesis method of Example 11. LC-MS (ESI), m / z: [M+H] + = 432.3 Example 43-1 and Example 43-2:

[0577] [ka]

[0578] Example 43 was separated by chiral preparative separation (CHIRALPAK OJ-H 250 mm×20 mm, 5 μm; mobile phase: mobile phase A=carbon dioxide, mobile phase B=ethanol (0.2% aqueous ammonia), A / B=60 / 40; flow rate: 40 g / min) to give Example 43-1 (t R =3.86) and Example 43-2 (t R =7.58).

[0579] Example 43-1: LC-MS (ESI), m / z: [M+H] + = 432.3 11H NMR (400 MHz, MeOH-d4) δ 8.14 (d, J = 2.8 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.42 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.20 (dd, J = 8.9, 2.9 Hz, 1H), 4.32 (q, J = 6.9 Hz, 1H), 3.96 (d, J = 13.8 Hz, 1H), 3.50 ‐ 3.44 (m, 1H), 3.42 ‐ 3.33 (m, 3H), 2.93 (s, 3H), 2.90 (m, 1H), 2.62 (q, J = 7.5 Hz, 1H), 2.39 ‐ 2.18 (m, 3H), 1.97 ‐ 1.91 (m, 2H), 1.26 (t, J = 7.5 Hz, 1H). Example 43-2: LC-MS (ESI), m / z: [M+H] + = 432.3 1 1H NMR (400 MHz, MeOH-d4) δ 8.15 (d, J = 2.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.42 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.21 (dd, J = 8.9, 2.9 Hz, 1H), 4.33 (q, J = 6.9 Hz, 1H), 3.96 (d, J = 13.8 Hz, 1H), 3.50 ‐ 3.44 (m, 1H), 3.42 ‐ 3.33 (m, 3H), 2.93 (s, 3H), 2.90 (m, 1H), 2.62 (q, J = 7.5 Hz, 1H), 2.39 ‐ 2.18 (m, 3H), 1.98 ‐ 1.94 (m, 2H), 1.26 (t, J = 7.5 Hz, 1H). Example 44:

[0580]

Chemical Structure

[0581] Example 44 was obtained by referring to the synthesis method of Example 1. LC-MS (ESI), m / z: [M+H] + = 446.3 Example 44-1 and Example 44-2:

[0582] [ka]

[0583] Example 44 was separated by chiral preparative separation (CHIRALPAK OJ-H 250 mm×20 mm, 5 μm; mobile phase: mobile phase A=carbon dioxide, mobile phase B=methanol (0.2% aqueous ammonia), A / B=60 / 40; flow rate: 40 g / min) to give Example 44-1 (t R =5.7) and Example 44-2 (t R = 11.2).

[0584] Example 44-1: LC-MS (ESI), m / z: [M+H] + = 446.3 11H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.36 (q, J = 4.6 Hz, 1H), 8.08 (d, J = 2.7 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.70 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.20 (dd, J = 8.9, 2.8 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 4.31 (q, J = 6.9 Hz, 1H), 3.90 (d, J = 13.2 Hz, 1H), 3.42 (d, J = 11.7 Hz, 2H), 3.33 (d, J = 6.2 Hz, 1H), 3.30 ‐ 3.26 (m, 1H), 3.12 (td, J = 11.3, 3.2 Hz, 1H), 2.77 (d, J = 4.8 Hz, 3H), 2.74 ‐ 2.66 (m, 1H), 2.56 ‐ 2.52 (m, 2H), 2.47 (s, 3H), 2.26 ‐ 2.17 (m, 2H), 2.07 ‐ 1.99 (m, 1H), 1.88 ‐ 1.78 (m, 2H), 1.18 (t, J = 7.4 Hz, 3H). Example 44-2: LC-MS (ESI), m / z: [M+H] + = 446.3 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.36 (d, J = 4.6 Hz, 1H), 8.08 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.70 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.22 ‐ 7.14 (m, 2H), 4.31 (q, J = 6.9 Hz, 1H), 3.90 (d, J = 13.2 Hz, 1H), 3.42 (d, J = 11.7 Hz, 2H), 3.33 (d, J = 6.2 Hz, 1H), 3.30 ‐ 3.26 (m, 1H), 3.12 (td, J = 11.3, 3.2 Hz, 1H), 2.77 (d, J = 4.8 Hz, 3H), 2.74 ‐ 2.66 (m, 1H), 2.56 ‐ 2.52 (m, 2H), 2.47 (s, 3H), 2.26 ‐ 2.17 (m, 2H), 2.07 - 1.99 (m, 1H), 1.88 - 1.78 (m, 2H), 1.19 (t, J = 7.4 Hz, 3H). Example 45:

[0585]

change

[0586] The synthesis method of Example 2 can be obtained by referring to the method of Example 45. LC-MS (ESI), m / z: [M+H] + = 450.2 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 8.36 (q, J = 4.6 Hz, 1H), 8.09 (d, J = 2.7 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.26 - 7.17 (m, 2H), 4.31 (q, J = 6.7 Hz, 1H), 3.83 (d, J = 13.7 Hz, 1H), 3.53 (d, J = 13.4 Hz, 1H), 3.49 - 3.43 (m, 1H), 3.30 - 3.25 (m, 1H), 3.21 - 3.13 (m, 1H), 2.85 - 2.79 (m, 1H), 2.77 (d, J = 4.8 Hz, 3H), 2.55 - 2.52 (m, 2H), 2.33 - 2.19 (m, 2H), 2.09 - 1.99 (m, 1H), 1.86 - 1.79 (m, 2H), 1.17 (t, J = 7.4 Hz, 3H). Example 46: cis-N-cyclopropyl-5-(5-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)pyridine-2-carboxamide

[0587] [ka]

[0588] Synthesis scheme:

[0589] [ka]

[0590] Step 1: Synthesis of tert-butyl cis-5-(6-(methoxycarbonyl)pyridin-3-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylate (46.2) To a solution of methyl 5-bromopyridine-2-carboxylate (248 mg, 1.15 mmol) in NMP (20 mL), cis-2,5-diazabicyclo[4.2.0]octane dihydrochloride (425 mg, 2.30 mmol), cesium carbonate (3.0 g, 9.2 mmol), tris(dibenzylideneacetone)dipalladium (105 mg, 0.115 mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (144 mg, 0.230 mmol) were added, and the mixture was stirred at 85°C for 24 hours. After the reaction was completed, dry ice (10 g) was added to the reaction mixture (about 20 mL), and the mixture was stirred for 30 minutes, followed by the addition of tetrahydrofuran (20 mL), saturated aqueous sodium bicarbonate (20 mL) and di-tert-butyl dicarbonate (1 mL). The mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and extracted (petroleum ether / ethyl acetate=1 / 1, 100mL×2). The combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered to remove solids, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol=97 / 3) to give the crude product of title compound 46.2 (330mg). It was used directly in the next reaction. LC-MS (ESI), m / z: [M+H] + = 348.2 Step 2: Synthesis of tert-butyl cis-5-(6-(cyclopropylcarbamoyl)pyridin-3-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylate (46.3) A solution of cyclopropylamine (149 mg, 2.61 mmol) in tetrahydrofuran (2 mL) was cooled to 0° C., and DIBAL-H (1.0 mol / L, 2.3 mL, 2.3 mmol) was added to the solution. After stirring the mixture at room temperature for 1 hour, the reaction system was cooled to 0° C., compound 46.2 (165 mg, crude product, approximately 0.47 mmol) was added to the reaction system, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, sodium potassium tartrate aqueous solution (10 mL) and ethyl acetate (20 mL) were added to the reaction mixture, and the mixture was stirred for 2 hours. The resulting mixture was extracted with ethyl acetate (50 mL×2), washed with saturated saline, dried over anhydrous sodium sulfate, filtered to remove solids, and the filtrate was concentrated under reduced pressure, and the resulting residue was the crude product of title compound 46.3 (120 mg). It was used directly in the next reaction. LC-MS (ESI), m / z: [M+H] + = 373.3 Step 3: Synthesis of cis-5-(2,5-diazabicyclo[4.2.0]octan-2-yl)-N-cyclopropyl-2-picolinamide (46.4) Trifluoroacetic acid (2 mL) was added to a solution of compound 46.3 (165 mg, 0.345 mmol) in dichloromethane (2 mL) and stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 0 to 90 / 10) to give the title compound 46.4 (30 mg, yield: 32%). LC-MS (ESI), m / z: [M+H] + = 273.2 Step 4: Synthesis of cis-N-cyclopropyl-5-(5-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)pyridin-2-amide (Example 46) To a solution of compound 46.4 (30 mg, 0.11 mmol) in acetonitrile (2 mL), 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (35.0 mg, 0.171 mmol), potassium iodide (5.0 mg, 0.022 mmol) and diisopropylethylamine (94 mL, 0.55 mmol) were added, and the mixture was stirred at 70° C. for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (chromatography column type: XBridge peptide BEH C18 19 mm×250 mm, 10 μm, 130 Å; mobile phase: acetonitrile / water (0.05% trifluoroacetic acid); gradient: 5-65%, 20 min; flow rate: 25 mL / min) to obtain the title compound Example 46 (50 mg, yield: 99%). LC-MS (ESI), m / z: [M+H] + = 459.1 Examples 46-1 and 46-2: N-cyclopropyl-5-((1S,6R)-5-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)picolinamide and N-cyclopropyl-5-((1R,6S)-5-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)picolinamide

[0591] [ka]

[0592] Synthesis scheme:

[0593] [ka]

[0594] Example 46 (47 mg) was separated and purified by chiral preparative SCF (instrument model: SFC-150 (Waters); chromatography column model: OJ 20 × 250 mm, 10 um; mobile phase: mobile phase A = carbon dioxide, mobile phase B = methanol (0.2% ammonia (7 mol / L ammonia methanol solution)), A / B = 50 / 50; flow rate: 120 g / min) to obtain Example 46-1 (t R = 1.69 min, 13 mg, yield: 28%) and Example 46-2 (t R = 2.61 min, 13 mg, yield: 28%).

[0595] Example 46-1: LC-MS (ESI), m / z: [M+H] + = 459.3 1 H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.43 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 4.8 Hz, 1), 8.06 (d, J = 2.8 Hz,1H), 7.82 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.68 (s, 1H), 7.22 (dd, J = 2.8, 8.8 Hz, 1H), 4.30 (dd, J = 7.2, 14.4 Hz, 1H), 3.90 (d, J = 14.0 Hz, 1H), 3.46 - 3.40 (m, 2H), 3.35 - 3.28 (m, 1H), 3.25 - 3.16 (m, 1H), 2.88 - 2.74 (m, 2H), 2.55 (q, J = 7.2 Hz, 2H), 2.35 - 2.18 (m, 2H), 2.12 - 2.00 (m, 1H), 1.87 - 1.78 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H), 0.71 - 0.57 (m, 4H). Example 46-2: LC-MS (ESI), m / z: [M+H] + = 459.3 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.43 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 4.8 Hz, 1), 8.06 (d, J = 2.8 Hz,1H), 7.82 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.68 (s, 1H), 7.22 (dd, J = 2.8, 8.8 Hz, 1H), 4.30 (dd, J = 7.2, 14.4 Hz, 1H), 3.90 (d, J = 14.0 Hz, 1H), 3.46 - 3.40 (m, 2H), 3.35 - 3.28 (m, 1H), 3.23 - 3.18 (m, 1H), 2.85 - 2.74 (m, 2H), 2.55 (q, J = 7.2 Hz, 2H), 2.35 - 2.18 (m, 2H), 2.12 - 2.00 (m, 1H), 1.87 - 1.78 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H), 0.67 - 0.61 (m, 4H). Example 47: cis-N-cyclopropyl-5-(5-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-6-fluoropicolinamide

[0596] [ka]

[0597] Example 47 (12.0 mg) was obtained by referring to the synthesis method of Example 2. LC-MS (ESI), m / z: [M+H] + = 477.1 Example 47-1 and Example 47-2: N-cyclopropyl-5-((1R,6S)-5-(7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-6-fluoropicolinamide and N-cyclopropyl-5-((1S,6R)-5-(7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-6-fluoropicolinamide

[0598] [ka]

[0599] Example 47 (12.0 mg, 0.0251 mmol) was separated and purified by chiral SFC chromatography (chromatography column model: CHIRALPAK OJ-H 250 mm × 20 mm, 5 μm; mobile phase: 40% ethanol (0.2% aqueous ammonia); flow rate: 14 ml / min) to obtain Example 47-1 (t R = 7.59 min, 3.4 mg, yield: 27%) and Example 47-2 (t R = 9.01 min, 3.6 mg, yield: 30%).

[0600] Example 47-1: LC-MS (ESI), m / z: [M+H] + = 476.9 11H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.42 (d, J = 1.7 Hz, 11H), 8.31 (d, J = 4.8 Hz, 1H), 7.83 ‐ 7.78 (m, 1H), 7.76 (s, 1H), 7.65 (s, 1H), 7.39 (dd, J = 10.5, 8.3 Hz, 1H), 4.19 (q, J = 6.2 Hz, 1H), 3.81 (d, J = 14.1 Hz, 1H), 3.47 (d, J = 14.0 Hz, 1H), 3.44 ‐ 3.38 (m, 1H), 3.20 ‐ 3.14 (m, 1H), 2.87 ‐ 2.80 (m, 1H), 2.79 ‐ 2.71 (m, 1H), 2.58 ‐ 2.52 (m, 2H), 2.43 ‐ 2.36 (m, 1H), 2.10 ‐ 1.80 (m, 5H), 1.78 ‐ 1.69 (m, 1H), 1.18 (t, J = 7.4 Hz, 3H), 0.67 ‐ 0.65 (m, 1H), 0.65 ‐ 0.62 (m, 2H). Example 47-2: LC-MS (ESI), m / z: [M+H] + = 476.9 1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.42 (d, J = 1.7 Hz, 11H), 8.31 (d, J = 4.8 Hz, 1H), 7.83 - 7.78 (m, 1H), 7.76 (s, 1H), 7.65 (s, 1H), 7.39 (dd, J = 10.5, 8.3 Hz, 1H), 4.19 (q, J = 6.2 Hz, 1H), 3.81 (d, J = 14.1 Hz, 1H), 3.47 (d, J = 14.0 Hz, 1H), 3.44 - 3.38 (m, 1H), 3.20 - 3.14 (m, 1H), 2.87 - 2.80 (m, 1H), 2.78 - 2.71 (m, 1H), 2.58 - 2.52 (m, 2H), 2.43 - 2.36 (m, 1H), 2.11 - 1.81 (m, 5H), 1.78 - 1.69 (m, 1H), 1.18 (t, J = 7.4 Hz, 3H), 0.67 - 0.65 (m, 1H), 0.65 - 0.62 (m, 2H). Example 48: cis-N-cyclobutyl-5-(5-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)picolinamide

[0601] [ka]

[0602] Example 48 (13.6 mg) was obtained by following the synthesis method of Example 2.

[0603] LC-MS (ESI), m / z: [M+H] + = 473.3 Example 48-1 and Example 48-2: N-cyclobutyl-5-((1R,6S)-5-(7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)picolinamide and N-cyclobutyl-5-((1S,6R)-5-(7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)picolinamide

[0604] [ka]

[0605] Example 48 (13.6 mg, 0.288 mmol) was separated and purified by chiral SFC chromatography (chromatography column model: CHIRALPAK AD-H 250 mm × 20 mm, 5 μm; mobile phase: 40% isopropanol (0.2% aqueous ammonia); flow rate: 40 g / min) to obtain Example 48-1 (t R = 3.87 min, 3.2 mg, yield: 24%) and Example 48-2 (t R = 4.96 min, 3.6 mg, yield: 26%).

[0606] Example 48-1: LC-MS (ESI), m / z: [M+H] + = 473.3 11H NMR (400 MHz, MeOH-d4) δ 8.41 (d, J = 1.7 Hz, 1H), 8.05 (d, J = 2.7 Hz, 1H), 7.79 ‐ 7.73 (m, 2H), 7.11 (dd, J = 8.9, 2.8 Hz, 1H), 4.39 (dt, J = 16.2, 7.9 Hz, 1H), 4.25 (q, J = 6.9 Hz, 1H), 3.90 (d, J = 14.3 Hz, 1H), 3.43 ‐ 3.30 (m, 3H), 3.24 (m, 1H), 2.81 (dt, J = 11.9, 3.7 Hz, 1H), 2.57 (q, J = 7.0 Hz, 2H), 2.33 ‐ 2.20 (m, 3H), 2.19 ‐ 2.09 (m, 1H), 2.06 ‐ 1.95 (m, 2H), 1.91 ‐ 1.80 (m, 2H), 1.74 ‐ 1.63 (m, 2H), 1.19 (t, J = 7.4 Hz, 3H). Example 48-2: LC-MS (ESI), m / z: [M+H] + = 473.3 1 1H NMR (400 MHz, MeOH-d4) δ 8.42 (d, J = 1.7 Hz, 1H), 8.05 (d, J = 2.7 Hz, 1H), 7.79 ‐ 7.73 (m, 2H), 7.11 (dd, J = 8.9, 2.8 Hz, 1H), 4.39 (dt, J = 16.2, 7.9 Hz, 1H), 4.25 (q, J = 6.9 Hz, 1H), 3.90 (d, J = 14.3 Hz, 1H), 3.43 ‐ 3.30 (m, 3H), 3.24 (m, 1H), 2.81 (dt, J = 11.9, 3.7 Hz, 1H), 2.57 (q, J = 7.0 Hz, 2H), 2.33 ‐ 2.20 (m, 3H), 2.19 ‐ 2.09 (m, 1H), 2.06 ‐ 1.95 (m, 2H), 1.91 ‐ 1.80 (m, 2H), 1.74 ‐ 1.63 (m, 2H), 1.19 (t, J = 7.4 Hz, 3H). Example 49: cis-3-ethyl-7-((5-(3-(methylamino)isoxazolo[4,5-b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]oct-2-yl)methyl)-1,5-naphthyridin-2(1H)-one

[0607] [ka]

[0608] Synthesis scheme:

[0609] [ka]

[0610] Step 1: 6-Bromo-N-methylisoxazolo[4,5-b]pyridin-3-amine (49.2) Sodium methoxide (5.4M in MeOH) (2.20mL, 11.9mmol) and paraformaldehyde (1.48g, 23.8mmol) were added to a solution of compound 49.1 (510mg, 2.38mmol) in methanol (10.0mL) at 25°C, and after the addition was complete, the reaction mixture was stirred at 25°C for 16 hours. Sodium borohydride (271mg, 7.15mmol) was then added at 0°C, and the reaction was stirred at 25°C for 1 hour, and sodium borohydride (271mg, 7.15mmol) was added at 0°C, and the reaction was stirred at 25°C for 1 hour. After the reaction was complete, water (20.0mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (15.0mL x 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was separated and purified by silica gel chromatography (PE:EA=5:1) to give the title compound 49.2 (280 mg, yield: 52%). LC-MS (ESI), m / z: [M+H] + = 228.0 / 230.0.

[0611] Step 2: cis-6-(2,5-diazabicyclo[4.2.0]oct-2-yl)-N-methylisoxazolo[4,5-b]pyridin-3-amine (49.3) Compound intermediate a (487 mg, 1.58 mmol), cesium carbonate (1.29 g, 3.95 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (73.7 mg, 0.158 mmol) and chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (61.3 mg, 0.0790 mmol) were added to a solution of compound 49.2 (180 mg, 0.789 mmol) in 1,4-dioxane (5.00 mL) at 25° C. After addition was complete, the reaction mixture was stirred at 110° C. for 16 hours under the protection of nitrogen gas. After completion of the reaction, the solvent was evaporated under reduced pressure. The resulting residue was separated and purified by silica gel chromatography (DCM:MeOH=10:1) to give the title compound 49.3 (40.0 mg, yield: 19.5%). LC-MS (ESI), m / z: [M+H] + = 260.2.

[0612] Step 3: cis-3-ethyl-7-((5-(3-(methylamino)isoxazolo[4,5-b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]oct-2-yl)methyl)-1,5-naphthyridin-2(1H)-one (Example 49) At 25°C, N,N-diisopropylethylamine (59.8mg, 0.463mmol), compound 5 (68.7mg, 0.309mmol) and potassium iodide (5.12mg, 0.0309mmol) were added to a solution of compound 49.3 (40.0mg, 0.154mmol) in acetonitrile (2.00mL), and the reaction mixture was stirred at 80°C for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (DCM:MeOH=20:1) to obtain the title compound Example 49 (30.0mg, yield: 44%). LC-MS (ESI), m / z: [M+H] + = 446.2.

[0613] Example 49-1 and Example 49-2: 3-Ethyl-7-(((1R,6S)-5-(3-(methylamino)isoxazolo[4,5-b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]oct-2-yl)methyl)-1,5-naphthyridin-2(1H)-one and 3-Ethyl-7-(((1S,6R)-5-(3-(methylamino)isoxazolo[4,5-b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]oct-2-yl)methyl)-1,5-naphthyridin-2(1H)-one:

[0614] [ka]

[0615] Example 49 was separated by chiral preparative separation (chromatographic column model: CHIRALPAK OJ-H 250 mm x 20 mm, 5 μm, mobile phase: 40% ethanol (0.2% aqueous ammonia), flow rate: 40 g / min) to give Example 49-1 (3.00 mg, yield: 10%, t R =8.45 min) and Example 49-2 (4.70 mg, yield: 16%, t R =17.57min).

[0616] Example 49-1: LC-MS (ESI), m / z: [M+H] + = 446.2 1HNMR (400 MHz, ) δ 11.85 (s, 1H), 8.45 (s, 1H), 8.22 (s, 1H), 7.77 (s, 1H), 7.69 (s, 1H), 7.09 (s, 1H), 6.76 (d, J = 3.8 Hz, 1H), 4.34 (s, 1H), 3.91 (d, J = 10.8 Hz, 1H), 3.49 (d, J = 10.5 Hz, 3H), 3.24 (s, 1H), 2.80 (dd, J = 17.3, 5.1 Hz, 4H), 2.58 - 2.52 (m, 3H), 2.27 (s, 1H), 2.07 (s, 1H), 1.82 (s, 2H), 1.19 (t, J = 7.4 Hz, 3H). Example 49-2: LC-MS (ESI), m / z: [M+H] + = 446.2 1 HNMR (400 MHz, ) δ 11.80 (s, 1H), 8.40 (d, J = 1.8 Hz, 1H), 8.18 (d, J = 2.3 Hz, 1H), 7.72 (s, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.04 (d, J = 2.2 Hz, 1H), 6.71 (d, J = 5.0 Hz, 1H), 4.31 (dd, J = 14.4, 6.8 Hz, 1H), 3.87 (d, J = 14.0 Hz, 1H), 3.40 (dd, J = 22.0, 13.0 Hz, 3H), 3.19 (td, J = 11.3, 3.1 Hz, 1H), 2.80 - 2.72 (m, 4H), 2.54 - 2.48 (m, 3H), 2.24 (s, 1H), 2.06 - 1.98 (m, 1H), 1.78 (dd, J = 8.5, 4.2 Hz, 2H), 1.14 (d, J = 7.4Hz, 3H). <Biological evaluation> The present invention is further illustrated in conjunction with the following tests, which are not intended to limit the scope of the invention.

[0617] 1. Enzyme Activity Experiment (1) PARP1 and PARP2 enzyme activity test 1. Purpose of the experiment: The purpose is to test the enzyme inhibitory activity of the example compounds of the present invention against PARP1.

[0618] 2. Laboratory equipment and reagents: 2.1 Reagents: PARP1 (BPS, Cat. No. 80501); PARP2 (BPS, Cat. No. 80502); Histone (Active Motif, Cat. No. 81167); Activated DNA (Genscript, Cat. No. L05182-01&02&03); Secondary antibody (anti-rabbit IgG, HRP-linked Antibody, CST, Cat. No. 7074P2); Primary antibody (anti-Poly / Mono-ADP Ribose (E6F6A) Rabbit mAb, CST, Cat. No. 83732S); SuperSignal ELISA Femto Substrate (Thermo Pierce, Cat. No. 37074); Biotin-NAD+ (R&D, Cat. No. 6573); NAD+(TCI, Cat.No. D0919-5G); Strep-HRP (Thermo Pierce, Cat. No. 21127); QuantaRed Enhanced Chemiluminescent HRP Substrate Kit (Thermo Pierce, Cat. No. 15159).

[0619] 2.2 Equipment:

[0620] [Table 2]

[0621] 3. Experimental Method: 3.1 PARP1 enzyme activity experiment steps 1) A 50 ng / mL histone coating solution was prepared in 1x PBS, and 25 µL of the coating solution was transferred to a 384-well reaction plate and coated overnight at 4°C.

[0622] 2) After coating was completed, the coating solution was discarded and washed with PBST (1x PBS, 0.05% Tween-20) solution, the method was to transfer 50μL of PBST to the 384-well reaction plate, leave it for 5 minutes, discard the washing solution, refill, and wash repeatedly three times, and finally tap the reaction plate to dry and seal it.

[0623] 3) 50 μL of blocking solution (1×PBS, 0.05% Tween-20, 5% BSA) was transferred to a 384-well reaction plate and left to stand for 1 hour. Wash, discard the blocking solution, wash 3 times with PBST solution as described above, and finally tap the reaction plate dry.

[0624] 4) 1000x compound dilutions were prepared, and 1 μL of compound was transferred to 199 μL of reaction buffer (50 mM Tris-HCl (pH 7.5), 0.005% Tween-20, 0.01% BSA) in a 96-well plate, mixed evenly, and 5 μL of the mixed compound was transferred to a 384-well reaction plate.

[0625] 5) Prepare 25 / 10x PARP1-DNA solution in reaction buffer, transfer 10μL of PARP1-DNA solution to 384-well reaction plate, transfer 10μL of DNA solution to negative control wells, the final concentration of PARP1 was 0.02nM, and the final DNA concentration was 0.8nM.

[0626] 6) Prepare 25 / 10x NAD+ solution in reaction buffer, transfer 10μL of NAD+ solution to a 384-well reaction plate, the final concentration of NAD+ is 3.5μM, and incubate at room temperature for 60 minutes.

[0627] 7) After the reaction was completed, discard the reaction solution, wash with PBST solution three times according to step 2, and finally tap the reaction plate dry.

[0628] 8) The primary antibody was diluted 2000-fold with the blocking solution, 20 μL of the primary antibody was added, and the cells were incubated at room temperature for 1.5 hours.

[0629] 9) Discard the primary antibody, wash three times with PBST solution according to step 2, and finally tap the reaction plate dry.

[0630] 10) The secondary antibody was diluted 2000-fold with blocking solution, 20 μL of the secondary antibody was added, and the cells were incubated at room temperature for 1 hour.

[0631] 11) Discard the secondary antibody, wash three times with PBST solution according to step 2, and finally tap the reaction plate dry.

[0632] 12) Femto-ECL Substrate A and Femto-ECL Substrate B were mixed at a 1:1 ratio, and 25 μL was transferred to a 384-well reaction plate. The chemiluminescence RLU value was read using Envision.

[0633] 3.2 PARP2 enzyme activity experiment steps 1) A 100 ng / mL histone coating solution was prepared in 1x PBS, and 25 µL of the coating solution was transferred to a 384-well reaction plate and coated overnight at 4°C.

[0634] 2) After coating was completed, the coating solution was discarded and washed with PBST solution (1x PBS, 0.05% Tween-20), the method was to transfer 50μL of PBST into the 384-well reaction plate, leave it for 5 minutes, discard the washing solution, refill, and wash three times repeatedly, and finally tap the reaction plate to dry and wait for the next blocking step.

[0635] 3) 50 μL of blocking solution was transferred to a 384-well reaction plate and allowed to stand for 1 hour.

[0636] 4) After blocking was completed, discard the blocking solution (1x PBS, 0.05% Tween-20, 5% BSA), wash with PBST solution three times according to step 2, and finally tap the reaction plate dry.

[0637] 5) Prepare 25 / 10x PARP2 solution, transfer 10 μL of PARP2 solution to a 384-well reaction plate, and transfer 10 μL of reaction buffer (50 mM HEPES (pH 7.5), 0.002% Tween-20, 0.1% BSA, 100 mM NaCl, 2 mM DTT) to the negative control wells, and the final concentration of PARP2 was 1.5 nM.

[0638] 6) Prepare 2000-fold compound, transfer 50 nL of compound to echo, add 19.95 μL of reaction buffer to compound, mix evenly, and transfer 5 μL of mixed compound to 384-well reaction plate.

[0639] 7) A 25 / 10x Biotin-NAD+ solution was prepared, and 10 μL of the NAD+ solution was transferred to a 384-well reaction plate, the final concentration of NAD+ was 2 μM, and incubated at room temperature for 60 min.

[0640] 8) After the reaction was completed, discard the reaction solution and wash three times with PBST solution according to step 2.

[0641] 9) Prepare Stre-HRP solution by diluting with blocking solution, transfer 25 μL of Stre-HRP solution to the reaction plate and incubate at room temperature for 1 hour, and the final concentration of Stre-HRP was 0.1 μg / mL.

[0642] 10) Discard the Stre-HRP solution and wash three times with PBST solution according to step 2.

[0643] 11) Femto-ECL Substrate A, Femto-ECL Substrate B, and QuantaRed ADHP were mixed in a ratio of 50:50:1, and 25 μL was transferred to a 384 reaction plate and incubated at room temperature for 10 minutes. 2.5 μL of QuantaRed Stop Solution was added, and the fluorescence value was read on a Paradigm (Ex550 / Em620).

[0644] 4. Experimental results: The enzyme inhibitory activity of the compound of the present invention against PARP1 and PARP2 was measured by the above tests, and the obtained IC 50 The values ​​are as shown in Table 1 below.

[0645] [Table 3]

[0646] JPEG2025503798000203.jpg160169

[0647] Structure of AZD5305

[0648] [ka]

[0649] 5. Experimental conclusion: From the above data, it is evident that the example compounds of the present invention have good inhibitory activity against PARP1, but low inhibitory activity against PARP2, and thus have good selectivity for inhibitory activity against PARP1 / PARP2.

[0650] 2. Cell proliferation activity experiment MDA-MB-436 cell proliferation activity test 1. Purpose of the experiment: The purpose is to test the enzyme inhibitory activity of the example compounds of the present invention on MDA-MB-436 cell proliferation.

[0651] 2. Laboratory equipment and reagents: Cell line:

[0652] [Table 4]

[0653] 3. Experimental Method: 3.1 Cell plating Complete medium was prepared and mixed thoroughly. Cells were resuscitated and passaged for approximately two generations to select cell lines with good growth status. Cell culture flasks were removed from the incubator. Adherent cells: Aspirated medium, washed once with trypsin, discarded waste liquid, and added 3mL of fresh trypsin to the culture flask for digestion. Once the cells were loosely detached from the flask walls, 8mL of complete medium was added to stop trypsin digestion and gently mixed evenly. Cell suspension was transferred to a centrifuge tube using a pipette and centrifuged at 1000rpm for 5 minutes. The supernatant was discarded. An appropriate amount of medium was added to the centrifuge tube and cells were resuspended evenly by gently pipetting. Counted with a Vi-Cell XR cell counter. Cell suspension was adjusted to an appropriate concentration. Cell suspension was added to a 96-well plate at 100μL / well. Details such as cell name, plating density, and date were marked and the culture plate was placed in a CO2 incubator overnight.

[0654] 3.2 Preparation and loading of compound plates Test compounds were prepared in 10 mM stock solutions, aliquoted and stored in a refrigerator at -20°C. Compound solutions were added to 96-well plates using HPD300. Culture was continued in a carbon dioxide incubator for a total of 6 days.

[0655] 3.3 Reagent preparation and detection CellTiter-Glo Buffer was thawed at room temperature. Lyophilized CellTiterglo substrate was equilibrated to room temperature. CellTiter-Glo Buffer was added to CellTiterglo substrate and mixed thoroughly. Cell plates were removed and equilibrated to room temperature. 100 μL of mixed CellTiterglo reagent was added to each well, shaken for 10 minutes in the dark, and incubated for 20 minutes. Culture plates were placed in an Enspire plate reader, luminescence readings were recorded, and percent inhibition was calculated according to the following formula: % Inhibition = (1-(RLU) compound -RLU blank ) / (RLU DMSO -RLU blank )) × 100%. XLFit was used to plot the drug inhibition curve and calculate the IC 50 Values ​​were calculated using a four parameter model [fit=(A+((BA) / (1+((C / x)^D))))].

[0656] 4. Experimental results: The cell proliferation inhibitory activity of the compounds of the present invention against MDA-MB-436 was measured by the above test, and the obtained IC 50 The values ​​are as shown in Table 2 below.

[0657] [Table 5]

[0658] 5. Experimental conclusion: The above data show that the compounds of the present invention have good cell proliferation inhibitory activity against MDA-MB-436 cells.

[0659] 3. Pharmacokinetic studies Purpose of the experiment: To test the pharmacokinetics of the compound in ICR (CD-1) mice.

[0660] Experimental material: Mouse (male, ICR (CD-1)) Experimental Procedure: ICR (CD-1) male mice, 3 in each group. One group was injected into the tail vein with the test compound at a dose of 1 mg / kg, and the other group was orally administered a single dose of the test compound at a dose of 3 mg / kg. In the tail vein injection group, saphenous vein blood sampling was performed 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h after the end of dosing. In the single oral administration group, saphenous vein blood sampling was performed 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h after the end of dosing. Blood was collected and placed into EDTA-K2 anticoagulant tubes, and 30 μL of whole blood was collected at each time point. After blood samples were collected, they were immediately placed on wet ice for centrifugation. Samples were centrifuged within 30 min (settings were maintained at 4 degrees, 4600 rpm for 5 min) to obtain plasma. Plasma samples were placed into test tubes (target 12-20 μL). Waiting for analysis, 50μL of plasma was collected, 5μL of MeOH was added, then 200μL of MeOH / ACN solution containing 5ng / mL ISTD (Terfenadine) was added, and the mixture was shaken to mix uniformly, then centrifuged at 4000rpm for 15min, the supernatant was taken, diluted 5 times with MeOH / water (1:1, v / v, 0.1% FA), and injected into LC-MS / MS, and the blood drug concentration was quantitatively analyzed using analytical methods, and the pharmacokinetic parameters were calculated.

[0661] Test Results: The pharmacokinetic data of the example compounds of the present invention obtained through the above scheme are shown in Table 3 below.

[0662] [Table 6]

[0663] Test conclusion: The above data show that the example compounds of the present invention have favorable pharmacokinetic parameters in mice, with 5-6 times lower clearance and 5-7 times longer half-life compared to the reference compound AZD-5305.

Claims

1. A compound represented by the general formula (I), a prodrug thereof, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 (however, Ring A is a 3- to 18-membered heterocyclyl or a 5- to 18-membered heteroaryl, which may be further optionally substituted; Ring B is C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ aryl or 5- to 14-membered heteroaryl, ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ The aryl and 5- to 14-membered heteroaryl may be further optionally substituted; Ring C is C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ aryl or 5- to 14-membered heteroaryl, ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ The aryl and 5- to 14-membered heteroaryl may be further optionally substituted; R １ are independently hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ Aryloxy, 5-14 membered heteroaryloxy, C ３－１２ Cycloalkyl-C １－６ Alkyl, 3- to 12-membered heterocyclyl-C １－６ Alkyl, C ６－１４ Aryl-C １－６ Alkyl or 5- to 14-membered heteroaryl-C １－６ alkyl, and the amino, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ Aryloxy and 5- to 14-membered heteroaryloxy can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ optionally substituted by one or more substituents selected from aryloxy and 5- to 14-membered heteroaryloxy; Or, any two R １ C together with the atom on which they are located ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ aryl or 5- to 14-membered heteroaryl; ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl and 5- to 14-membered heteroaryl can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ optionally substituted by one or more substituents selected from aryloxy and 5- to 14-membered heteroaryloxy; R ２ are independently hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ Aryloxy, 5-14 membered heteroaryloxy, C ３－１２ Cycloalkyl-C １－６ Alkyl, 3- to 12-membered heterocyclyl-C １－６ Alkyl, C ６－１４ Aryl-C １－６ Alkyl or 5- to 14-membered heteroaryl-C １－６ alkyl, and the amino, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ Aryloxy and 5- to 14-membered heteroaryloxy can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ optionally substituted by one or more substituents selected from aryloxy and 5- to 14-membered heteroaryloxy; R ３ are independently hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ Aryloxy, 5- to 14-membered heteroaryloxy, -(CH ２ ) ｎ１ R ａ , -(CH ２ ) ｎ１ OR ａ , -(CH ２ ) ｎ１ S.R. ａ , -(CH ２ ) ｎ１ N.R. ｂ R ａ , -(CH ２ ) ｎ１ C(O)R ａ , -(CH ２ ) ｎ１ C(O)NR ｂ R ａ , -(CH ２ ) ｎ１ N.R. ｂ C(O)R ａ , -(CH ２ ) ｎ１ S (O) ｍ１ R ａ , -(CH ２ ) ｎ１ S (O) ｍ１ N.R. ｂ R ａ , -(CH ２ ) ｎ１ S(O)(=NR ｂ ) R ａ , -(CH ２ ) ｎ１ N=S(=O)R ａ R ｂ or -(CH ２ ) ｎ１ N.R. ｂ S (O) ｍ１ R ａ and the amino, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ Aryloxy and 5- to 14-membered heteroaryloxy can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl and 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ Optionally substituted by one or more substituents selected from the group consisting of aryloxy, 5- to 14-membered heteroaryloxy; Or, any two R ３ are linked together with the atom on which they are located to form C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ aryl or 5- to 14-membered heteroaryl; ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl and 5- to 14-membered heteroaryl can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ optionally substituted by one or more substituents selected from aryloxy and 5- to 14-membered heteroaryloxy; R ａ and R ｂ are each independently hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ aryloxy or 5- to 14-membered heteroaryloxy; １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ Aryloxy and 5- to 14-membered heteroaryloxy can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl and 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ optionally substituted by one or more substituents selected from aryloxy and 5- to 14-membered heteroaryloxy; L is -(CR ４ R ５ ) ｎ２ -, -C(O)-, -C(O)NR ４ -or- (CR ４ R ５ ) ２ O, R ４ and R ５ are each independently hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ aryloxy or 5- to 14-membered heteroaryloxy; １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ Aryloxy and 5- to 14-membered heteroaryloxy can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl and 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ optionally substituted by one or more substituents selected from aryloxy and 5- to 14-membered heteroaryloxy; Or, R ４ and R ５ are linked together with the atom on which they are located to form C ３－１２ cycloalkyl or 3- to 12-membered heterocyclyl, ３－１２ Cycloalkyl and 3- to 12-membered heterocyclyl can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ optionally substituted by one or more substituents selected from aryloxy and 5- to 14-membered heteroaryloxy; x, y, and z are each independently an integer from 0 to 10; n1 is an integer from 0 to 10, n2 is 0, 1, 2 or 3; and m1 is 0, 1 or 2.

2. said ring A is a 5- to 6-membered monocyclic heteroaryl, a 6- to 10-membered bicyclic fused-ring heterocyclyl, an 8- to 10-membered bicyclic fused-ring heteroaryl, an 8- to 14-membered tricyclic fused-ring heterocyclyl, or a 10- to 14-membered tricyclic fused-ring heteroaryl; The ring A may further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ The compound according to claim 1, its prodrug, stereoisomer or pharma- ceutically acceptable salt, optionally substituted with one or more of the following substituents: aryloxy and 5- to 14-membered heteroaryloxy.

3. The compound according to claim 1 or 2, characterized in that the general formula (I) is further represented by general formula (II), or a prodrug, stereoisomer or pharma- ceutically acceptable salt thereof. 【Chemistry 2】 (however, X １ is O, S, N, NR ６ , C.R. ６ Or CR ６ R ７ and X ２ is O, S, N, C(O), NR ８ , C.R. ８ Or CR ８ R ９ and X ３ is N or CR １０ and X ４ is N or CR １１ and R ６ , R ７ , R ８ , R ９ , R １０ and R １１ are each independently hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ Aryloxy, 5- to 14-membered heteroaryloxy or -(CH ２ ) ｎ３ R ｃ and the amino, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ Aryloxy and 5- to 14-membered heteroaryloxy can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl and 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ optionally substituted by one or more substituents selected from aryloxy and 5- to 14-membered heteroaryloxy; Or, R ６ , R ７ , R ８ , R ９ , R １０ and R １１ Any two of the atoms on which they are located are linked together to form C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ aryl or 5- to 14-membered heteroaryl; ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl and 5- to 14-membered heteroaryl can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ optionally substituted by one or more substituents selected from aryloxy and 5- to 14-membered heteroaryloxy; R ｃ is hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ aryloxy or 5- to 14-membered heteroaryloxy; １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ Aryloxy and 5- to 14-membered heteroaryloxy can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl and 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ Optionally substituted by one or more substituents selected from aryloxy and 5- to 14-membered heteroaryloxy; and n3 is 0, 1, 2, 3 or 4; Ring B, Ring C, R １ , R ２ , R ３ , R ４ , R ５ , y and z are as defined in claims 1 and 2.

4. The ring B is C ３－６ cycloalkyl or 3- to 6-membered heterocyclyl; The ring B may further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ The compound according to claim 1, its prodrug, stereoisomer or pharma- ceutically acceptable salt, optionally substituted with one or more of the following substituents: aryloxy and 5- to 14-membered heteroaryloxy.

5. The compound according to any one of claims 1 to 4, characterized in that the general formula (I) is further represented by general formula (III), or a prodrug, stereoisomer or pharma- ceutically acceptable salt thereof. 【Chemistry 3】 (however, n is 1, 2, 3, 4, 5 or 6; X ２ is N or CR ８ and R ６ and R ８ are each independently hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ Aryloxy, 5- to 14-membered heteroaryloxy or -(CH ２ ) ｎ３ R ｃ and the amino, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ Aryloxy and 5- to 14-membered heteroaryloxy can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl and 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ optionally substituted by one or more substituents selected from aryloxy and 5- to 14-membered heteroaryloxy; Or, R ６ and R ８ are linked together with the atom on which they are located to form C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ aryl or 5- to 14-membered heteroaryl; ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl and 5- to 14-membered heteroaryl can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Deuterated alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ optionally substituted by one or more substituents selected from aryloxy and 5- to 14-membered heteroaryloxy; X ３ , X ４ , ring C, R １ , R ２ , R ３ , y and z are as defined in claims 1 to 4.

6. The compound, its prodrug, stereoisomer or pharma- ceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that general formula (I) is further represented by general formula (IIIA), general formula (IIIB), general formula (IIIC) or general formula (IIID). 【Chemistry 4】 (however, X ２ , X ３ , X ４ , ring C, R １ , R ２ , R ３ , R ６ , n, y and z are as defined in claim 5.

7. General formula (I) is further represented by general formula (IV), general formula (V), general formula (VI), general formula (V), general formula (VII), general formula (VIII) or general formula (IX), 【Chemistry 5】 however, X ２ , X ３ , X ４ , ring B, ring C, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , n, y and z are as defined in any one of claims 1 to 5, Preferably, general formula (IV) is as represented by general formula (IVA), general formula (IVB), general formula (IVC) or general formula (IVD), 【Chemistry 6】 however, X ２ , X ３ , X ４ , ring B, ring C, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , n, y and z are as defined in any one of claims 1 to 5. The compound according to any one of claims 1 to 3, a prodrug thereof, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

8. The ring C is phenyl, 3- to 6-membered nitrogen-, oxygen- or sulfur-containing heterocyclyl, 5- to 6-membered nitrogen-containing heteroaryl, 5- to 6-membered nitrogen-containing heteroaryl-fused 5- to 6-membered heteroaryl, or 5- to 6-membered nitrogen-containing heteroaryl-fused 5- to 6-membered heterocyclyl, and the ring C is preferably 【Chemistry 7】 and ring C is more preferably 【Chemistry 8】 and The ring C may further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ Aryl, 5-14 membered heteroaryl, C ３－１２ Cycloalkyloxy, 3- to 12-membered heterocyclyloxy, C ６－１４ The compound according to any one of claims 1 to 7, its prodrug, stereoisomer or pharma- ceutically acceptable salt, optionally substituted with one or more of the following substituents: aryloxy and 5- to 14-membered heteroaryloxy.

9. The ring C is 【Chemistry 9】 and Preferably, the ring C is 【Chemistry 10】 and More preferably, the ring C is 【Chemistry 11】 and however, M １ , M. ２ , M. ３ , M. ４ and M. ５ Each independently represents N or CR ３ and M ６ are each independently N, NR ３ Or CR ３ R ３ and M ７ are each independently N or C; R ３ A compound according to any one of claims 1 to 8, a prodrug thereof, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, characterized in that it is as described in claims 1 to 7.

10. R ３ are independently hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Deuterated alkyl, C １－３ Alkoxy, C １－３ Alkylthio, C １－３ Hydroxyalkyl, C ２－３ Alkenyl, C ２－３ Alkynyl, C ３－８ Cycloalkyl, 3-8 membered heterocyclyl, C ６－１０ Aryl, 5- to 10-membered heteroaryl, -OR ａ , -SR ａ , -NR ｂ R ａ , -C(O)R ａ , -C(O)NR ｂ R ａ , -NR ｂ C(O)R ａ , -S(O)R ａ , -S(O) ２ R ａ , -S(O) ２ N.R. ｂ R ａ , -S(O)(=NR ｂ ) R ａ , -N=S(=O)R ａ R ｂ Or -NR ｂ S (O) ２ R ａ and the amino, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Deuterated alkyl, C １－３ Alkoxy, C １－３ Alkylthio, C １－３ Hydroxyalkyl, C ２－３ Alkenyl, C ２－３ Alkynyl, C ３－８ Cycloalkyl, 3-8 membered heterocyclyl, C ６－１０ Aryl and 5- to 10-membered heteroaryl can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Deuterated alkyl, C １－３ Alkoxy, C １－３ Alkylthio, C １－３ Hydroxyalkyl, C ２－３ Alkenyl, C ２－３ Alkynyl, C ３－８ Cycloalkyl, 3-8 membered heterocyclyl, C ６－１０ Aryl, 5-10 membered heteroaryl, C ３－８ Cycloalkyloxy, 3-8 membered heterocyclyloxy, C ６－１０ optionally substituted by one or more substituents selected from aryloxy and 5-10 membered heteroaryloxy; Or, any two R ３ C together with the atom on which they are located ３－８ Cycloalkyl, 3-8 membered heterocyclyl, C ６－１０ aryl or 5- to 10-membered heteroaryl; ３－８ Cycloalkyl, 3-8 membered heterocyclyl, C ６－１０ Aryl and 5- to 10-membered heteroaryl can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Deuterated alkyl, C １－３ Alkoxy, C １－３ Alkylthio, C １－３ Hydroxyalkyl, C ２－３ Alkenyl, C ２－３ Alkynyl, C ３－８ Cycloalkyl, 3-8 membered heterocyclyl, C ６－１０ Aryl, 5-10 membered heteroaryl, C ３－８ Cycloalkyloxy, 3-8 membered heterocyclyloxy, C ６－１０ optionally substituted by one or more substituents selected from aryloxy and 5-10 membered heteroaryloxy; R ａ and R ｂ are each independently hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Deuterated alkyl, C １－３ Alkoxy, C １－３ Alkylthio, C １－３ Hydroxyalkyl, C ２－３ Alkenyl, C ２－３ Alkynyl, C ３－８ Cycloalkyl, 3-8 membered heterocyclyl, C ６－１０ aryl or 5- to 10-membered heteroaryl, １－３ Alkyl, C １－３ Haloalkyl, C １－３ Deuterated alkyl, C １－３ Alkoxy, C １－３ Alkylthio, C １－３ Hydroxyalkyl, C ２－３ Alkenyl, C ２－３ Alkynyl, C ３－８ Cycloalkyl, 3-8 membered heterocyclyl, C ６－１０ Aryl and 5- to 10-membered heteroaryl can further include deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, oxo, thio, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Deuterated alkyl, C １－３ Alkoxy, C １－３ Alkylthio, C １－３ Hydroxyalkyl, C ２－３ Alkenyl, C ２－３ Alkynyl, C ３－８ Cycloalkyl, 3-8 membered heterocyclyl, C ６－１０ Aryl, 5-10 membered heteroaryl, C ３－８ Cycloalkyloxy, 3-8 membered heterocyclyloxy, C ６－１０ The compound according to any one of claims 1 to 9, characterized in that it is optionally substituted with one or more of the following substituents: aryloxy and 5-10 membered heteroaryloxy, its prodrug, stereoisomer or pharma- ceutically acceptable salt.

11. The compound is (1) The ring B is C ４－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ aryl or 5- to 14-membered heteroaryl, ４－１２ Cycloalkyl, 3- to 12-membered heterocyclyl, C ６－１４ The aryl and 5- to 14-membered heteroaryl are optionally further substituted, (2) the ring C is phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, pyridopyrazolyl, pyridooxazolyl, pyridoisoxazolyl, pyridothiazolyl, pyridoisothiazolyl, or pyridopyrrolyl, preferably ring C is phenyl, pyridinyl, or pyridoisoxazolyl; (3) R １ are independently halogen, C １－６ Alkyl, C substituted with one or more halogens １－６ Alkyl, C ３－６ Cycloalkyl or C １－６ alkoxy, or any two R １ C together with the atom on which they are located ３－６ A cycloalkyl or a 3- to 6-membered heterocyclyl is formed, the heteroatom of the 3- to 6-membered heterocyclyl is N or O, the number of the heteroatom is 1, and preferably R １ are independently hydrogen, deuterium, halogen, C １－６ Alkyl, C substituted with one or more halogens １－６ Alkyl, C ３－６ Cycloalkyl or C １－６ alkoxy, or any two R １ C together with the atom on which they are located ５ Form a cycloalkyl or a 6-membered heterocyclyl, the heteroatom of the 6-membered heterocyclyl is O, the number of heteroatoms is 1, more preferably R １ is independently C １－６ Alkyl or C ３－６ cycloalkyl, or any two R １ C together with the atom on which they are located ５ A cycloalkyl or a 6-membered heterocyclyl, the heteroatom of the 6-membered heterocyclyl is O, and the number of the heteroatom is 1, for example, R １ is independently C １－６ alkyl or trifluoromethyl; or any two R １ C together with the atom on which they are located ５ Conditions for forming a cycloalkyl, (4) R ２ are independently hydrogen or deuterium; (5) R ３ are independently hydrogen, deuterium, halogen, C １－６ Alkyl, 5-6 membered heteroaryl, -(CH ２ ) ｎ１ C(O)NR ｂ R ａ or -(CH ２ ) ｎ１ N.R. ｂ R ａ wherein said 5-6 membered heteroaryl is optionally C １－６ The heteroatom of the 5- to 6-membered heterocyclyl is N and / or O, and the number of heteroatoms is 1 or 2. Preferably, R ３ are independently hydrogen, halogen or -(CH ２ ) ｎ１ C(O)NR ｂ R ａ For example, hydrogen or -(CH ２ ) ｎ１ C(O)NR ｂ R ａ The condition that and (6) R ａ and R ｂ are each independently hydrogen, C １－６ Alkyl or C ３－６ cycloalkyl, R ａ and R ｂ are preferably each independently hydrogen or C １－６ alkyl, for example hydrogen or methyl; x, y, and z each independently represent an integer from 0 to 3; The n is 1, 2, 3, 4, 5 or 6, and X ２ is CH, and X ３ is N and X ４ is CH, then n is not 1; The compound according to any one of claims 1 to 10, a prodrug thereof, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, characterized in that it satisfies one or more of the following conditions:

12. The compound is (1) R １ are independently ethyl, methoxy, trifluoromethyl, difluoromethyl, cyclopropyl, fluorine or methyl; or any two R １ together with the atom on which they are located form a cyclopentyl or a 6-membered heterocyclyl, the heteroatom of said 6-membered heterocyclyl being N or O, and the number of heteroatoms being one; (2) R ３ are independently hydrogen, 【Chemistry 12】 Fluorine, methyl, 【Chemistry 13】 The condition that (3) x is an integer from 0 to 3; (4) L is -(CR ４ R ５ ) ｎ２ - and n2 is 1; （５） 【Chemistry 14】 teeth, 【Chemistry 15】 The condition that (6) y is 0; (7) Ring C is 【Chemistry 16】 For example, 【Chemistry 17】 The condition that (8) z is 1 or 2; (9) n1 is 0; (10) Ring A is 【Chemistry 18】 The condition that and (11) in a further preferred embodiment of the present invention, the compound represented by the general formula (I) is 【Chemistry 19】 Instead, Preferably, 【Chemistry 20】 teeth, 【Chemistry 21】 and and / or 【Chemical 22】 teeth, 【Chemistry 23】 The condition that The compound according to any one of claims 1 to 11, a prodrug thereof, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, characterized in that it satisfies one or more of the following conditions:

13. Ring A is 【Chemistry 24】 and Ring B is C ４－６ cycloalkyl or 5- to 6-membered heterocyclyl, the heteroatom of said 5- to 6-membered heterocyclyl is N, O or S, the number of heteroatoms is 1, Ring C is pyridinyl or pyridoisoxazolyl; R １ are independently hydrogen, deuterium, halogen, C １－６ Alkyl, C substituted with one or more halogens １－６ Alkyl, C ３－６ Cycloalkyl or C １－６ is an alkoxy; Or, any two R １ C together with the atom on which they are located ３－６ forming a cycloalkyl or a 3- to 6-membered heterocyclyl, the heteroatom of the 3- to 6-membered heterocyclyl being N or O, the number of heteroatoms being 1; R ２ are independently hydrogen or deuterium; R ３ are independently hydrogen, deuterium, halogen, C １－６ Alkyl, 5-6 membered heteroaryl, -(CH ２ ) ｎ１ C(O)NR ｂ R ａ or -(CH ２ ) ｎ１ N.R. ｂ R ａ wherein said 5-6 membered heteroaryl is optionally C １－６ substituted by alkyl, the heteroatoms of said 5- to 6-membered heterocyclyl being N and / or O, the number of heteroatoms being 1 or 2; R ａ and R ｂ are each independently hydrogen, C １－６ Alkyl or C ３－６ is cycloalkyl, L is -(CR ４ R ５ ) ｎ２ - and R ４ and R ５ are each independently hydrogen or deuterium; x, y, and z each independently represent an integer from 0 to 3; n1 is an integer from 0 to 3, n2 is 1, and The compound according to any one of claims 1 to 12, wherein m1 is 0, 1 or 2, or a prodrug, stereoisomer or pharma- ceutically acceptable salt thereof.

14. The compound, prodrug, stereoisomer or pharma- ceutically acceptable salt thereof according to any one of claims 1 to 13, characterized in that the general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (V), general formula (VII), general formula (VIII) or / and general formula (IX) are in a cis or trans configuration, preferably in a cis configuration.

15. The compound according to any one of claims 1 to 14, a prodrug, a stereoisomer or a pharma- ceutically acceptable salt thereof, selected from the following compounds: 【Table 1】

16. obtaining a compound represented by general formula (Ia) and (Ib) through one or multiple nucleophilic substitution reactions, coupling reactions or other reactions, directly or further through a deprotection reaction, a compound represented by general formula (Ic), a prodrug thereof, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof; Formula (Ic) and Formula (Id) can be prepared by one or multiple steps of nucleophilic substitution, coupling or other reactions to obtain a compound represented by general formula (I), a prodrug thereof, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, and optionally further chiral separation of the compound represented by general formula (I) to obtain a single configuration compound, a prodrug thereof, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof; A method for producing a compound represented by general formula (I) according to any one of claims 1 to 15, a prodrug thereof, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, comprising: 【Chemistry 25】 (however, X is selected from halogens, preferably X is fluorine, chlorine, bromine or iodine; X ０ is selected from halogen, preferably X ０ is fluorine, chlorine, bromine or iodine, R is hydrogen or an amino protecting group, including, but not limited to, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and the like; When R is hydrogen, after reacting the compound represented by formula (Ia) with the compound represented by formula (Ib), a compound represented by general formula (Ic), a prodrug thereof, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof is directly obtained; When R is an amino-protecting group, the compound represented by formula (Ia) is reacted with the compound represented by formula (Ib), and then a deprotection reaction is carried out to obtain a compound represented by general formula (Ic), a prodrug thereof, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof; Ring A, Ring B, Ring C, L, R １ , R ２ , R ３ , x, y and z are as defined in claims 1 to 14.

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 15, its prodrug, stereoisomer or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers or excipients.

18. Use of a compound according to any one of claims 1 to 15, a prodrug thereof, a stereoisomer or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17 in the manufacture of a medicament for treating a disease mediated by polyadenosine diphosphate ribose (ADP-ribose) polymerase (PARP), preferably in the manufacture of a medicament for treating a PARP1 inhibitor-associated disease.

19. Use of a compound according to any one of claims 1 to 15, a prodrug thereof, a stereoisomer or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, in the manufacture of a medicament for treating abnormal cell proliferation, preferably for treating related diseases such as cancer, inflammation, metabolic diseases, cardiovascular diseases, immune diseases and psychiatric diseases.

20. A compound represented by formula (IC), a stereoisomer thereof or a salt thereof: 【Chemistry 26】 (Ring B, Ring C, R ２ , R ３ , y and z are as defined in any one of claims 1 to 15.

21. A compound having any one of the following structures: 【Chemical 27】 【change】

Images