Nitrogen-containing heterocyclic compound and medical application thereof

Abstract

The invention discloses a nitrogen-containing heterocyclic ring compound and medical application thereof. Specifically, the invention relates to a nitrogen-containing heterocyclic ring compound as shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the nitrogen-containing heterocyclic ring compound and application of the nitrogen-containing heterocyclic ring compound serving as a poly ADP ribose polymerase 1 (PARP1) inhibitor to treatment of diseases related to PARP1 activity. Wherein the definition of each group in the general formula (I) is the same as that in the specification.

Description

Nitrogen-containing heterocyclic compounds and their medical uses Technical Field

[0001] The present invention relates to nitrogen-containing heterocyclic compounds and their medical uses. Specifically, the present invention relates to nitrogen-containing heterocyclic compounds represented by general formula (I), methods for preparing the same, pharmaceutical compositions containing the same, and their use as poly (ADP-ribose) polymerase 1 (PARP1) inhibitors for treating diseases associated with PARP1 activity. Background Art

[0002] Poly (ADP-ribose) polymerases (PARPs) play essential roles in DNA replication, recombination, chromatin remodeling, and DNA damage repair. This family of enzymes comprises 18 members that possess ADP-ribosyltransferase activity, catalyzing the addition of ADP-ribose units to DNA or various receptor proteins, impacting diverse cellular processes. PARP1 and PARP2 are the most extensively studied PARPs due to their roles in DNA damage repair. PARP1, the most prominent member of the PARP family, is a nuclear protein composed of three domains: an N-terminal DNA-binding domain containing two zinc fingers, an automodification domain, and a C-terminal catalytic domain. It carries out over 90% of the functions of the PARP family in cells and is a key player in DNA damage repair. PARP2 has similar functions to PARP1, but differs in their substrate selection. PARP1 and PARP2 can repair single-strand breaks (SSBs), while PARP1 can also repair double-strand breaks (DSBs) and replication fork damage. As a sensor for DNA breaks, PARP1 is activated after DNA damage. It recognizes and binds to DNA breaks through its zinc finger domains, reducing recombination and protecting damaged DNA from exonucleases. After binding to the DNA nick, it catalyzes the breakdown of nicotinamide adenine dinucleotide (NAD+) into nicotinamide and ADP-ribose through its own glycosylation. Using ADP-ribose as a substrate, it causes the receptor protein and PARP1 itself to undergo "PARylation," forming PARP-ADP-ribose side chains. This prevents nearby DNA molecules from recombination with the damaged DNA, while also attracting DNA repair proteins to bind and reduce the affinity of PARP1 for DNA, causing PARP1 to dissociate from the DNA break. DNA repair proteins then bind to the DNA nick and repair the damaged site. PARP1's "PARylation" is then cleared by other enzymes, allowing PARP1 to regain activity and search for the next DNA break. In eukaryotic cells, PAR chains are not only formed but also degraded, catalyzed by poly(ADP-ribose)glycohydrolase (PARG) and type 3 ADP-ribosylhydrolase (ARH3). Four enzymes, PARP1, PARP2, PARP5A, and PARP5B, catalyze the synthesis of PAR chains. The vast majority of other enzymes in the superfamily catalyze the synthesis of only a single ADP-ribose unit, and are therefore also referred to as mono(ADP-ribosyl)ases (MARs).

[0003] PARP binding to sites of DNA damage, its catalytic activity, and its release from DNA are all crucial steps in the tumor cell response to DNA damage induced by chemotherapeutic agents and radiation. Inhibition of PARP family enzymes has been explored as a strategy to selectively kill tumor cells by inhibiting DNA repair pathways. Small molecule inhibition of PARP1 has been shown to sensitize tumor cells to cytotoxic therapies (e.g., temozolomide, platinum, topoisomerase inhibitors, and radiation). Numerous preclinical and clinical studies have demonstrated that tumor cells harboring deleterious BRCA1 or BRCA2 mutations are sensitive to PARP inhibitors. Tumors arising from mutation carriers typically lack the wild-type allele, resulting in tumor-specific homologous recombination repair (HRR) dysfunction at double-strand breaks and, therefore, dependence on PARP function for survival. When PARP1 is inhibited, base excision repair is reduced, single-strand breaks generated during the normal cell cycle persist, and double-strand breaks can form when replication forks encounter unrepaired breaks. Consequently, tumor cells deficient in homologous recombination repair, such as BRCA1 and BRCA2 mutants, are highly sensitive to PARP inhibition compared to wild-type cells. Currently, PARP inhibitor therapy is primarily targeted at cancer patients with BRCA mutations. However, for cancers with homologous recombination repair defects, every gene associated with them could be a potential target for synthetic lethality with PARP inhibitors, and PARP inhibitors hold immense therapeutic value. For example, ATM deletions have been found in patients with T-cell leukemia, B-cell chronic lymphocytic leukemia, and breast cancer; CHK2 germline mutations have been found in sarcomas, breast cancer, ovarian cancer, and brain tumors; FANCC and FANCG mutations have been confirmed in pancreatic cancer; and FANCF promoter hypermethylation has also been observed in ovarian, breast, cervical, and lung cancers. Other homologous recombination repair-related genes have also been shown to cause synthetic lethality with PARP. Homologous recombination repair is a multifactorial process that ensures the repair of DNA double-bond breaks at damaged replication forks. PARP1 recruits MRE11 to replication forks to promote base excision. PARP1 / 2 bind to 5'-deoxyribonucleic acid. After PARP activation, it recruits the BER scaffold protein XRCC1 using DNA polymerase β (Polβ) and ligase III. Cells deficient in XRCC1 and Polβ are highly sensitive to PARPis. The PARP-DNA complex is a barrier to replication. In response to replication damage and stress, ataxia telangiectasia and rad3-related protein kinase (ATR) and cycle checkpoint kinase 1 (CHK1) activate the S phase checkpoint, slowing replication forks and blocking replication initiation to maintain genomic stability. Inhibition of ATR or CHK1 leads to loss of the S phase checkpoint, replication initiation, and double-bond breaks. Combination therapy with PARP inhibitors has shown synergistic effects.FANCI-FANCD2 stabilizes the RAD51-DNA complex, PALB2 binds to BRCA2, promoting BRCA2 nuclear stability and accumulation. BRCA1 interacts with numerous HRR-associated factors (BARD1, CtIP, RAD51, BRCA2, PALB2, Abraxas, and RAP80) and accelerates HRR at multiple steps. The BRD family and BET proteins recognize and recruit multiple proteins to chromatin and transcription sites, as well as bind to acetylated histones. BET / BRD4 inhibitors inhibit HRR by blocking transcription of DNA repair genes (such as CtIP, BRCA1, WEE1, TOPBP1, and RAD51), and exhibit synergistic effects with PARPis in cells with normal BRCA expression.

[0004] PARP1 / 2 inhibitors currently on the market or in clinical trials have severe hematological toxicity as monotherapy drugs, which limits chronic treatment plans or combination therapies. Therefore, there is a need to develop compounds with high selectivity for PARP1 and less toxicity to meet clinical needs.

[0005] Summary of the Invention

[0006] After intensive research, the present inventors have designed and synthesized a series of nitrogen-containing heterocyclic compounds, which exhibit inhibitory activity against poly (ADP-ribose) polymerase 1 (PARP1) and can be developed as drugs for preventing or treating diseases associated with PARP1 activity.

[0007] Therefore, the object of the present invention is to provide a compound represented by general formula (I) or its meso-, racemic-, enantiomer-, diastereoisomer-, or mixture thereof, or a pharmaceutically acceptable salt thereof.

[0008] in:

[0009] is a single bond or a double bond;

[0010] X 1 、X 2 are each independently selected from N or C, and X 1 、X 2 Not all N at the same time;

[0011] Y 1 、Y 2 are the same or different and are each independently selected from a bond, -(CR a R b ) m -、-O-、-O(CR c R d ) n -、-NR 5 -、-NR5 (CR c R d ) n -、-C(O)NR 5 -、-NR 5 C(O)- and -C(O)-;

[0012] Z 1 、Z 2 、Z 3 are each independently selected from N or C, and Z 1 、Z 2 、Z 3 Not all N at the same time;

[0013] Ring A is selected from cycloalkyl, heterocyclic, aryl, heteroaryl, and the cycloalkyl, heterocyclic, aryl, heteroaryl may be further substituted by one or more R 3 replace;

[0014] Ring B is selected from cycloalkyl, heterocyclic, aryl, heteroaryl, and the cycloalkyl, heterocyclic, aryl, heteroaryl may be further substituted by one or more R 4 replace;

[0015] R 1 is selected from hydrogen, alkyl, cycloalkyl, and heterocyclyl, wherein the alkyl, cycloalkyl, and heterocyclyl are optionally further substituted with one or more substituents selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0016] R 2 is selected from hydrogen, alkyl, cycloalkyl, and heterocyclyl, wherein the alkyl, cycloalkyl, and heterocyclyl are optionally further substituted with one or more substituents selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0017] R 3 selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, amino, oxo, thioxo, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0018] R 4 selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, amino, oxo, thioxo, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0019] R 5 is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, amino, oxo, thioxo, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0020] R a and R b each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, amino, oxo, thioxo, nitro, cyano, hydroxyl, thiol, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0021] R c and R d each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, amino, oxo, thioxo, nitro, cyano, hydroxyl, thiol, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0022] m is 1, 2, 3 or 4;

[0023] n is 1, 2, 3 or 4.

[0024] In a specific embodiment, the compound represented by general formula (I) according to the present invention or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (II) or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0025] in, X 1 、X 2 、Y 1 、Y 2 , Ring A, Ring B, R 1 、R 2 As defined in general formula (I).

[0026] In a preferred embodiment, according to the compound represented by general formula (I) or general formula (II) of the present invention, or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein Y 1 、Y 2 are the same or different and are each independently selected from a bond, -(CR a R b ) m -、-O-、-O(CR c R d ) n -, preferably; -(CR a R b ) m -、-O-、-O(CR c R d ) n -;

[0027] where R a 、R b 、R e 、R f , m, and r are as defined in the general formula (I).

[0028] In another preferred embodiment, according to the compound represented by general formula (I) or general formula (II) of the present invention, or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein Y 1 、Y 2 The same or different, and each independently selected from -NR 5 (CR c R d ) n -、-C(O)NR 5 -、-NR 5C(O)- and -C(O)-, preferably -NR 5 (CR c R d ) n -;

[0029] where R c 、R d 、R 5 , n are as defined in the general formula (I).

[0030] In a preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (III) or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0031] Among them, Y 3 Selected from-CR e R f -、-O-、-NR 5 -;

[0032] R 5 is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, amino, oxo, thioxo, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0033] R a and R b each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, amino, oxo, thioxo, nitro, cyano, hydroxyl, thiol, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0034] R c and R deach independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, amino, oxo, thioxo, nitro, cyano, hydroxyl, thiol, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0035] R e and R f each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, amino, oxo, thioxo, nitro, cyano, hydroxyl, thiol, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0036] s is 0, 1, 2, 3, 4, preferably 0, 1, 2;

[0037] t is 0, 1, 2, 3, 4, preferably 0, 1, 2;

[0038] Ring A, Ring B, X 1 、X 2 、R 1 、R 2 As defined in general formula (I).

[0039] In another preferred embodiment, the compound represented by general formula (III) according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0040] Among them, Y 3 is selected from -O-; s is 1; t is 0 or 1;

[0041] R a and R b are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclyl, phenyl and 5 to 6 membered heteroaryl, wherein the C 3-6Cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0042] R c and R d are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclyl, phenyl and 5 to 6 membered heteroaryl, wherein the C 3-6 Cycloalkyl, 4- to 6-membered heterocyclyl, phenyl and 5- to 6-membered heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0043] In another preferred embodiment, the compound represented by general formula (III) according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0044] Among them, Y 3 is selected from -O-; s is 1; t is 0 or 1;

[0045] R a and R b are each independently selected from hydrogen, deuterium, C 1-6 Alkyl, preferably hydrogen;

[0046] R c and R d are each independently selected from hydrogen, deuterium, C 1-6 Alkyl, preferably hydrogen.

[0047] In another preferred embodiment, according to the compound represented by general formula (III) of the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, Y 3 Select from bond or -CR e R f -; s is 0 or 1; t is 0 or 1;

[0048] R e and R f are each independently selected from hydrogen, deuterium, C 1-6alkyl.

[0049] In another preferred embodiment, the compound represented by general formula (I), general formula (II), general formula (III) or its meso-, racemic-, enantiomer-, diastereomer-, or mixture thereof, or pharmaceutically acceptable salt thereof according to the present invention is a compound represented by general formula (IV) or its meso-, racemic-, enantiomer-, diastereomer-, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0050] in,

[0051] t is 0 or 1, preferably 1;

[0052] Ring A, Ring B, X 1 、X 2 、R 1 、R 2 As defined in general formula (I).

[0053] In another preferred embodiment, according to the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV) or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein ring A is selected from C 4-7 Cycloalkyl, 5- to 7-membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl, said C 4-7 Cycloalkyl, 5- to 7-membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further substituted with one or more R 3 Replacement; R 3 As defined in general formula (I).

[0054] In another preferred embodiment, according to the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV) or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein ring B is selected from C 4-7 Cycloalkyl, 5- to 7-membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl, said C 4-7 Cycloalkyl, 5- to 7-membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further substituted with one or more R 4 Replacement; R 4 As defined in general formula (I).

[0055] In another preferred embodiment, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV) or its meso-, racemic-, enantiomer-, diastereomer-, or mixture thereof, or pharmaceutically acceptable salt thereof according to the present invention is a compound represented by general formula (V) or its meso-, racemic-, enantiomer-, diastereomer-, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0056] in,

[0057] is a single bond or a double bond;

[0058] X 1 N or C;

[0059] X 2 N or C;

[0060] G1 is selected from C, N, S, O;

[0061] G2 is selected from C, N, S, O;

[0062] G3 is selected from C, N, S, O;

[0063] G4 is selected from C, N, S;

[0064] G5 is selected from C, N, S;

[0065] G6 is selected from a bond, C, N;

[0066] Ring A is selected from C 5-6 Cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, which may be further substituted by one or more R 3 replace;

[0067] Ring B is selected from phenyl or 5-6 membered heteroaryl, which is optionally further substituted by one or more R 4 replace;

[0068] t is 0 or 1, preferably 1;

[0069] v is 0 or 1;

[0070] R 1 、R 2 、R 3 、R 4 As defined in general formula (I).

[0071] In another preferred embodiment, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV) according to the present invention, or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0072] is a single bond;

[0073] X 1 、X 2 are each independently selected from N or C, and X 1 、X 2 Not all N at the same time;

[0074] Ring A is selected from C 4-7 Cycloalkyl, 5- to 7-membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl, said C 4-7 Cycloalkyl, 5- to 7-membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further substituted with one or more R 3 Replacement; R 3 As defined in general formula (I).

[0075] In another preferred embodiment, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V) according to the present invention, or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0076] is a single bond;

[0077] X 1 、X 2 are each independently selected from N or C, and X 1 、X 2 Not all N at the same time;

[0078] Ring A is selected from pyrrolyl, imidazolyl, triazolyl, pyrazolyl, thienyl, pyridinyl, pyrimidinyl; Ring A is optionally further substituted with one or more R 3 Replacement; R 3 As defined in general formula (I).

[0079] In another preferred embodiment, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV) according to the present invention, or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0080] is a double bond;

[0081] X 1 、X 2 are each independently selected from N or C, and X 1 、X 2 Not all N at the same time;

[0082] Ring A is selected from C 4-7 Cycloalkyl, 5- to 7-membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl, said C 4-7 Cycloalkyl, 5- to 7-membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl are optionally further substituted with one or more R 3 Replacement; R 3 As defined in general formula (I).

[0083] In another preferred embodiment, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V) according to the present invention, or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0084] is a double bond;

[0085] X 1 、X 2 are each independently selected from C;

[0086] Ring A is selected from cyclopentenyl, dihydrofuranyl, furanyl, thienyl, thiazolyl, phenyl, pyridinyl, pyrimidinyl; Ring A is optionally further substituted by one or more R 3 Replacement; R 3 As defined in general formula (I).

[0087] In another preferred embodiment, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V) or its meso form, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof according to the present invention, wherein, is a single bond;

[0088] Ring A is selected from:

[0089] Ring A is optionally further substituted with one or more R 3 Replaced by; R 3 As defined in general formula (I).

[0090] In another preferred embodiment, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V) or its meso form, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof according to the present invention, wherein, is a double bond;

[0091] Ring A is selected from:

[0092] Ring A is optionally further substituted with one or more R 3 Replaced by; R 3 As defined in claim 1.

[0093] In another preferred embodiment, according to the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V) or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 3 Selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C 3-6 Cycloalkyl.

[0094] In another preferred embodiment, according to the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V) or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 3 Selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl.

[0095] In another preferred embodiment, according to the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V) or its meso form, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein ring B is selected from:

[0096] Ring B is optionally further substituted with one or more R 4 Replaced by; R 4 As defined in general formula (I).

[0097] In another preferred embodiment, according to the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, ring B is selected from phenyl.

[0098] According to the compounds represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V) or their mesomorphs, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring B is selected from 6-membered heteroaryl groups, preferably

[0099] According to the compounds represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V) or their mesomorphs, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring B is selected from 5-membered heteroaryl groups, preferably Further optimization More preferred

[0100] In another preferred embodiment, according to the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V) or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 4 Selected from halogen, C1-C6 alkyl or C1-C6 haloalkyl.

[0101] In another preferred embodiment, according to the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V) or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 4 Selected from halogen.

[0102] In another preferred embodiment, according to the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V) or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl.

[0103] In another preferred embodiment, according to the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V) or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen and C 1-6 Alkyl, preferably hydrogen.

[0104] In another preferred embodiment, according to the compound represented by general formula (I) or general formula (II) of the present invention, or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 5Selected from hydrogen, deuterium, C 1-6 alkyl.

[0105] In another preferred embodiment, the compound represented by the general formula (III) according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R e and R f are each independently selected from hydrogen, deuterium, C 1-6 alkyl.

[0106] In another preferred embodiment, according to the compound of formula (I), formula (II), formula (III), or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R a and R b is hydrogen, and s is 1.

[0107] In another preferred embodiment, according to the compound represented by general formula (I), general formula (II), general formula (III) of the present invention, or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R c and R d is hydrogen, and t is 1.

[0108] Typical compounds of the present invention include, but are not limited to:

[0109] or its meso-, racemic-, enantiomer-, diastereomer-, or mixture thereof, or its pharmaceutically acceptable salt.

[0110] The present invention further provides a method for preparing the compound represented by general formula (II) according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, comprising the following steps:

[0111] In the presence of a base, a compound of formula IIa undergoes a substitution reaction with a compound of formula IIb to obtain a compound represented by formula (II) or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

[0112] in, Ring A, Ring B, X 1 、X 2 、Y 1 、Y 2 、R 1 、R 2 As defined in general formula (II).

[0113] The present invention further provides a method for preparing a compound represented by general formula (V) or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0114] In the presence of a base, a compound of formula Va undergoes a substitution reaction with a compound of formula Vb to obtain a compound represented by formula (V) or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

[0115] in, Ring A, Ring B, X 1 、X 2 、G1~G6、R 1 、R 2 , t are as defined in general formula (V).

[0116] The present invention further provides a pharmaceutical composition comprising the compound according to the present invention or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0117] The present invention further relates to the use of the compound according to the present invention or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, in the preparation of poly (ADP-ribose) polymerase 1 (PARP1) inhibitors.

[0118] The present invention further relates to the use of the compound according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, in the preparation of a medicament for preventing and / or treating diseases related to poly (ADP-ribose) polymerase 1 (PARP1) activity, preferably tumor diseases, such as ovarian cancer, breast cancer, prostate cancer, etc.

[0119] The present invention further relates to a compound according to the present invention or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a poly (ADP-ribose) polymerase 1 (PARP1) inhibitor.

[0120] The present invention further relates to a compound according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for preventing and / or treating diseases related to poly (ADP-ribose) polymerase 1 (PARP1) activity, preferably tumor diseases, such as ovarian cancer, breast cancer, prostate cancer, etc.

[0121] The present invention further relates to a compound according to the present invention or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for preventing and / or treating diseases associated with poly ADP-ribose polymerase 1 (PARP1) activity, such as ovarian cancer, breast cancer, prostate cancer, and the like.

[0122] The present invention further relates to a method for inhibiting poly (ADP-ribose) polymerase 1 (PARP1), comprising administering to a patient in need thereof an effective amount of a compound according to the present invention or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0123] The present invention further relates to a method for preventing and / or treating diseases related to poly (ADP-ribose) polymerase 1 (PARP1) activity, comprising administering to a patient in need thereof a preventively or therapeutically effective amount of a compound according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; wherein the disease is preferably a tumor disease, such as ovarian cancer, breast cancer, prostate cancer, etc.

[0124] Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions and may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants, and preservatives to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with nontoxic, pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may include inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as microcrystalline cellulose, croscarmellose sodium, corn starch, or alginic acid; binders such as starch, gelatin, polyvinyl pyrrolidone, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. These tablets may be uncoated or may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release over a longer period of time. For example, water-soluble taste masking substances such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time-extending substances such as ethylcellulose, cellulose acetate butyrate may be used.

[0125] Oral preparations may also be provided in hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oily vehicle such as peanut oil, liquid paraffin or olive oil.

[0126] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersants or wetting agents, which may be naturally occurring phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyethylene oxide sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene oxide dehydrated sorbitan monooleate. The aqueous suspension may also contain one or more preservatives, for example ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.

[0127] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. Oil suspensions can contain thickeners such as beeswax, hard paraffin or cetyl alcohol. The above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

[0128] The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as polyethylene oxide sorbitol monooleate. Emulsions can also contain sweeteners, flavorings, preservatives, and antioxidants. Syrups and elixirs prepared with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose can be used. Such preparations can also contain demulcents, preservatives, colorants, and antioxidants.

[0129] The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile injectable formulations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oil phase. For example, the active ingredient may be dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerol to form a microemulsion. The injection or microemulsion may be injected into the patient's bloodstream via local, bolus injection. Alternatively, the solution or microemulsion may be administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device may be used.

[0130] The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. Such suspensions may be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in a nontoxic, parenterally acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol. Furthermore, sterile fixed oils may conveniently be used as solvents or suspending media. For this purpose, any blended fixed oil, including synthetic mono- or diglycerides, may be used. Furthermore, fatty acids, such as oleic acid, may also be used to prepare injectable formulations.

[0131] The compounds of this invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thereby dissolves and releases the drug in the rectum. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights, and mixtures of fatty acid esters of polyethylene glycol.

[0132] It is well known to those skilled in the art that the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health condition, the patient's behavior, the patient's diet, the time of administration, the route of administration, the rate of excretion, the combination of drugs, etc. In addition, the optimal treatment method, such as the mode of treatment, the daily dosage of the general formula compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment protocols.

[0133] The present invention may contain a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to form a composition, and then prepared into a clinically acceptable dosage form. The derivatives of the present invention may be used in combination with other active ingredients, as long as they do not produce other adverse effects, such as allergic reactions. The compounds of the present invention may be used as the sole active ingredient or in combination with other drugs for treating diseases associated with tyrosine kinase activity. Combination therapy may be achieved by administering the individual therapeutic components simultaneously, separately, or sequentially.

[0134] Terminology

[0135] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0136] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group 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, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 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 preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0137] The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

[0138] The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, for example, ethynyl, propynyl, butynyl, etc. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0139] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0140] The term "spiroalkyl" refers to a polycyclic group having a carbon atom (called a spiro atom) shared between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spiroalkyl group is divided into a single spiroalkyl group, a double spiroalkyl group or a multi-spiroalkyl group, preferably a single spiroalkyl group and a double spiroalkyl group. More preferably, it is a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiroalkyl group. Non-limiting examples of spiroalkyl groups include:

[0141] The term "fused cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0142] The term "bridged cycloalkyl" refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6-14 members, more preferably 7-10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups include:

[0143] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0144] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably, it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably, it contains 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged heterocyclic groups.

[0145] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m(wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiral atoms between the rings, the spiro heterocyclic group is divided into a monospiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a monospiro heterocyclic group and a dispiro heterocyclic group. It is more preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospiro heterocyclic group. Non-limiting examples of spiro heterocyclic groups include:

[0146] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 8 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0147] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 8 to 10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include:

[0148] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0149] wait.

[0150] The heterocyclyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0151] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. Phenyl is more preferred. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, i.e., a fused ring aryl, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

[0152] The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0153] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10-membered, containing 1 to 3 heteroatoms; more preferably 5 or 6-membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, i.e., a fused ring heteroaryl, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0154] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0155] The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl and cycloalkyl is as described above. The limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituent is preferably one or more following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0156] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or or include both and Two configurations.

[0157] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0158] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0159] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium groups, wherein alkyl is as defined above.

[0160] The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium groups, wherein alkoxy is as defined above.

[0161] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0162] The term "hydroxy" refers to an -OH group.

[0163] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0164] The term "amino" refers to -NH2.

[0165] The term "cyano" refers to -CN.

[0166] The term "nitro" refers to -NO2.

[0167] The term "oxo" refers to =0.

[0168] The term "thio" refers to =S.

[0169] The term "carboxy" refers to -C(O)OH.

[0170] The term "mercapto" refers to -SH.

[0171] The term "ester group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0172] The compounds of the present invention may be in deuterated form. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom. Those skilled in the art are able to synthesize deuterated compounds with reference to the relevant literature. Commercially available deuterated starting materials may be used to prepare deuterated compounds, or they may be synthesized using conventional techniques employing deuterated reagents.

[0173] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0174] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0175] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0176] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

[0177] Synthesis method of the compound of the present invention

[0178] The compound represented by the general formula (II) of the present invention can be prepared by the following scheme.

[0179] Step 1) In the presence of a reducing agent, the compound of formula IIc undergoes a reduction reaction to obtain a compound of formula IId;

[0180] Step 2) Under catalyst conditions, the compound of formula IId undergoes functional group conversion reaction to obtain the compound of formula IIa;

[0181] Step 3) Transesterifying the compound of formula IIe with the compound of formula IIg to obtain the compound of formula IIf;

[0182] Step 4) Under acidic conditions, the compound of formula IIf undergoes a deprotection reaction to obtain a compound of formula IIb;

[0183] Step 5) Under alkaline conditions, the compound of formula IIa undergoes a substitution reaction with the compound of formula IIb to obtain the compound represented by formula (II) or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

[0184] in, Ring A, Ring B, X 1 、X 2 、Y 1 、Y 2 、R 1 、R 2 As defined in general formula (II).

[0185] Reagents that provide acidic conditions include, but are not limited to, a 1,4-dioxane solution of hydrogen chloride, trifluoroacetic acid, and formic acid.

[0186] Reagents that provide alkaline conditions include, but are not limited to, sodium hydroxide and lithium hydroxide.

[0187] The catalysts include, but are not limited to, Pd2(dba)3, RuPhos Pd G3, Pd(t-Bu3P)2, and Pd(OAc)2.

[0188] The above reaction can be carried out in a solvent, and the solvent used includes but is not limited to: methanol, toluene, acetonitrile, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, or N,N-dimethylformamide and mixtures thereof. DETAILED DESCRIPTION

[0189] The compounds of the present invention and their preparation will be further understood by way of the examples, which illustrate some methods of preparing or using the compounds. However, it will be appreciated that these examples do not limit the scope of the present invention. Variations of the present invention as now known or further developed are considered to fall within the scope of the invention as described herein and as claimed.

[0190] The compounds of the present invention are prepared using convenient starting materials and general preparation procedures. Typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, and molar ratio of reactants, are provided herein. However, other reaction conditions may be employed unless otherwise specified. Optimized conditions may vary depending on the specific reactants or solvents used, but generally, optimized reaction procedures and conditions are determined.

[0191] In addition, some protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions. Protecting groups suitable for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art. For example, TW Greene and GM Wuts' "Protective Groups in Organic Preparations" (3rd edition, Wiley, New York, 1999 and references therein) describes in detail the protection or deprotection of a large number of protecting groups.

[0192] The separation and purification of compounds and intermediates can be performed using appropriate methods and steps depending on specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin layer plate chromatography, preparative high performance liquid chromatography, or a combination of the above methods. Specific methods of use can be found in the examples described herein. Of course, other similar separation and purification methods can also be used. Conventional methods (including physical constants and spectral data) can be used to characterize the compounds and intermediates.

[0193] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Brukerdps 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0194] MS was measured using LC (Agilent 1260 Infinity) / MS (G6125B) mass spectrometer (manufacturer: Agilent).

[0195] Preparative liquid chromatography was performed using an LC6000 high performance liquid chromatograph (manufacturer: Chuangxin Tongheng), with a Daisogel C18 10 μm 100A column (30 mm × 250 mm) and acetonitrile / water as the mobile phase.

[0196] Thin layer chromatography (TLC) used Qingdao Ocean Chemical GF254 silica gel plates. The silica gel plates used for reaction monitoring were of a size of 0.20 mm to 0.25 mm, and the silica gel plates used for separation and purification were of a size of 0.5 mm.

[0197] Silica gel column chromatography method uses Qingdao marine silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.

[0198] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from online shopping malls, Beijing Coupling, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Shanghai Yinuokai, Anaiji Chemical, Shanghai Bid, Nanjing Yaoshi and other companies.

[0199] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0200] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0201] Reaction solvent, organic solvent or inert solvent are each expressed as the solvent used that does not participate in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, ether, methanol, nitrogen-methylpyrrolidone (NMP), pyridine, etc. Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0202] The chemical reactions described herein are generally carried out under normal pressure. Reaction times and conditions are, for example, between -78°C and 200°C at atmospheric pressure, and are complete within approximately 1 to 24 hours. If the reaction is allowed to proceed overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0203] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent systems used in the reactions were: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, and C: acetone. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0204] The eluent system for column chromatography and the developing solvent system for thin-layer chromatography used to purify the compound include: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and trifluoroacetic acid can also be added for adjustment.

[0205] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention.

[0206] Example

[0207] Example 1: Preparation of (R)-N-methyl-3-((6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (1)

[0208] Step 1: Preparation of methyl 6-(2-methoxycarbonyl)-1H-pyrrol-1-yl)-5-nitronicotinate (1a)

[0209] Methyl 6-chloro-5-nitronicotinate (4.34 g, 20.0 mmol) was dissolved in N,N-dimethylformamide (40 mL) at room temperature. Methyl 1H-pyrrole-2-carboxylate (3.01 g, 24.0 mmol) and cesium carbonate (8.15 g, 25.0 mmol) were added. The mixture was stirred at 60°C under a nitrogen atmosphere for 16 hours. Water (100 mL) was added for dilution and extraction with ethyl acetate (60 mL x 3). The organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 9 / 1) to obtain 1.73 g of the title compound as a yellow oil in a 28.3% yield.

[0210] LC-MS: m / z 306 [M+H] + .

[0211] Step 2: Preparation of methyl 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylate (1b)

[0212] Methyl 6-(2-methoxycarbonyl)-1H-pyrrol-1-yl)-5-nitronicotinate (1a) (1.54 g, 5.07 mmol) was dissolved in glacial acetic acid (15 mL) at room temperature, and iron powder (1.14 g, 20.3 mmol) was added. The mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure, and methanol (45 mL) was added. The mixture was stirred for 1 hour and filtered. The filter cake was washed with methanol (60 mL). The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM / MeOH = 100 / 1 to 19 / 1) to obtain 110 mg of the title compound as a yellow solid in an 8.9% yield.

[0213] LC-MS: m / z 244 [M+H] + .

[0214] Step 3: Preparation of 3-(hydroxymethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (1c)

[0215] Methyl 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylate (1b) (110 mg, 0.451 mmol) was dissolved in tetrahydrofuran (5 mL). A 2.5 mol / L solution of lithium aluminum hydride in tetrahydrofuran (0.36 mL, 0.902 mmol) was added dropwise at 0°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of sodium sulfate decahydrate, filtered, and the filter cake was washed with methanol (30 mL). The filtrate was concentrated under reduced pressure, and the residue was isolated and purified by silica gel column chromatography (mobile phase: DCM / MeOH = 100 / 1 to 94 / 6) to obtain 90.1 mg of the title compound as a white solid in a yield of 92.8%.

[0216] LC-MS: m / z 216 [M+H] + .

[0217] Step 4: Preparation of 3-(chloromethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (1d)

[0218] 3-(Hydroxymethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (1c) (80.1 mg, 0.372 mmol) was dissolved in dichloromethane (4 mL) at room temperature. Sulfonyl chloride (0.27 mL, 3.72 mmol) was added dropwise at 0°C under a nitrogen atmosphere, followed by one drop of DMF. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: DCM / MeOH = 100 / 1 to 19 / 1) to obtain 55.3 mg of the title compound as a white solid in a 63.6% yield.

[0219] LC-MS: m / z 234 [M+H] + .

[0220] Step 5: Preparation of 6-bromo-2-(bromomethyl)-3-fluoropyridine (1e)

[0221] 6-Bromo-3-fluoro-2-methylpyridine (5.00 g, 26.4 mmol) was dissolved in CCl₄ (50 mL) at room temperature. NBS (5.18 g, 29.1 mmol) and BPO (0.32 g, 1.32 mmol) were added, and the mixture was stirred at 75°C under a nitrogen atmosphere for 16 hours. Water (50 mL) was added, and the mixture was extracted with DCM (20 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 1 / 100) to obtain 6.10 g of the title compound as a light yellow solid, in a yield of 85.6%.

[0222] LC-MS: m / z 268[M+H] + .

[0223] Step 6: Preparation of (R)-tert-butyl 3-(((6-bromo-3-fluoropyridin-2-yl)methoxy)methyl)piperazine-1-carboxylate (1f)

[0224] 6-Bromo-2-(bromomethyl)-3-fluoropyridine (1e) (3.00 g, 11.2 mmol) and tert-butyl (R)-3-(hydroxymethyl)piperazine-1-carboxylate (4.23 g, 12.1 mmol) were dissolved in THF (50 mL) at room temperature. NaH (530 mg, 13.2 mmol) was added at 0°C, and the mixture was stirred at 0°C for 2 hours. Water (50 mL) was added, and the mixture was extracted with EA (50 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: EA / PE = 100%) to obtain 2.10 g of the title compound as a light yellow solid, in a yield of 46.6%.

[0225] LC-MS: m / z 404 [M+H] + .

[0226] Step 7: Preparation of (R)-tert-butyl 3-(((3-fluoro-6-(methoxycarbonyl)pyridin-2-yl)methoxy)methyl)piperazine-1-carboxylate (1 g)

[0227] (R)-tert-Butyl 3-(((6-bromo-3-fluoropyridin-2-yl)methoxy)methyl)piperazine-1-carboxylate (1f) (300 mg, 0.744 mmol) was dissolved in MeOH (5 mL) and Et3N (1 mL) at room temperature, and Pd(dppf)Cl2 (163 mg, 0.223 mmol) was added. The mixture was stirred at 50°C under a carbon monoxide atmosphere for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: EA / PE = 100%) to obtain 160 mg of the title compound as a light yellow solid, in a yield of 56.1%.

[0228] LC-MS: m / z 384 [M+H] + .

[0229] Step 8: Preparation of 3-(tert-butyl)9-methyl(R)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3,9(4H)-dicarboxylate (1h)

[0230] At room temperature, tert-butyl (R)-3-(((3-fluoro-6-(methoxycarbonyl)pyridin-2-yl)methoxy)methyl)piperazine-1-carboxylate (1 g) (200 mg, 0.522 mmol) was dissolved in DMF (5 mL), and Cs2CO3 (510 mg, 1.56 mmol) was added. The mixture was stirred at 80°C under a nitrogen atmosphere for 16 hours. Water (20 mL) was added, and the mixture was extracted with EA (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 1 / 1) to obtain 150 mg of the title compound as a light yellow solid, yield: 78.9%.

[0231] LC-MS: m / z 364 [M+H] + .

[0232] Step 9: Preparation of (R)-9-(methylcarbamoyl)-1,2,4α,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (1i)

[0233] 3-(tert-Butyl)-9-methyl (R)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3,9(4H)-dicarboxylate (1h) (150 mg, 0.412 mmol) was dissolved in MeOH (1 mL) at room temperature. Aqueous methylamine solution (1 mL) was added and the mixture was stirred at room temperature for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 150 mg (crude) of the title compound as a light yellow solid.

[0234] LC-MS: m / z 363[M+H] + .

[0235] Step 10: Preparation of (R)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (1j)

[0236] At room temperature, tert-butyl (R)-9-(methylcarbamoyl)-1,2,4α,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylate (1i) (150 mg, 0.411 mmol) was dissolved in DCM (2 mL). A solution of HCl in 1,4-dioxane (4 M, 0.5 mL) was added and stirred at 25°C for 16 hours. The mixture was filtered and concentrated under reduced pressure to afford 90 mg of the title compound (crude) as a light yellow solid.

[0237] LC-MS: m / z 263 [M+H] + .

[0238] Step 11: Preparation of (R)-N-methyl-3-((6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (1)

[0239] (R)-N-Methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (1j) (50.0 mg, 0.190 mmol) and 3-(chloromethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (1d) (44.0 mg, 0.190 mmol) were dissolved in acetonitrile (2 mL) at room temperature. DIEA (116 mg, 0.909 mmol) and sodium iodide (9.00 mg, 0.060 mmol) were added, and the mixture was stirred at 80°C for 4 hours. The residue was concentrated under reduced pressure, and separated by high pressure preparative liquid chromatography (column model: Daisogei 30 mm*250 mm, C18, 10 μm 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid, 30 min) to afford 23 mg of the title compound as a white solid, in a yield of 26.1%.

[0240] LC-MS: m / z 460 [M+H] + .

[0241] 1 H NMR (400MHz, DMSO-d6) δ11.35(s,1H),8.39(q,J=4.6Hz,1H),8.18-8.08(m,2H),7.82(d,J=8.5Hz,1H),7.66(d,J=1.9Hz,1H),7.50(d,J=8.6Hz, 1H),7.10(dd,J=3.8,1.6Hz,1H),6.72(dd,J=3.8,2.8Hz,1H),4.94(d,J=13.9Hz ,1H),4.74(d,J=13.9Hz,1H),4.02(dd,J=12.4,7.5Hz,1H),3.79(dd,J=12.3,3. 9Hz,1H),3.63(s,2H),3.54-3.46(m,1H),3.40-3.34(m,2H),2.78(d,J=4.8Hz,3 H),2.71-2.63(m,1H),2.61-2.56(m,1H),2.55-2.52(m,1H),2.44-2.36(m,1H).

[0242] Example 2: Preparation of (R)-N-methyl-3-((6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (2)

[0243] Step 1: Preparation of tert-butyl (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylate (2a)

[0244] At room temperature, tert-butyl (R)-3-(hydroxymethyl)piperazine-1-carboxylate (10.0 g, 46.3 mmol) was dissolved in DCM (240 mL). TEA (9.35 g, 92.6 mmol), tert-butyldimethylsilyl chloride (6.99 g, 46.3 mmol), and 4-dimethylaminopyridine (282 mg, 2.31 mmol) were added, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 1 / 1) to obtain 10.9 g of the title compound as a yellow oil in a yield of 71.1%.

[0245] LC-MS: m / z 331[M+H] + .

[0246] Step 2: Preparation of methyl 5-bromo-6-fluoropicolinate (2b)

[0247] Methyl 5-bromopicolinate (2.20 g, 10.2 mmol) was dissolved in acetonitrile (50 mL) at room temperature, and AgF (5.00 g, 34.2 mmol) was added. The mixture was stirred at 30°C overnight under a nitrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 5 / 1) to obtain 2.18 g of the title compound as a white solid in a yield of 91.3%.

[0248] LC-MS: m / z 234 [M+H] + .

[0249] Step 3: Preparation of (R)-tert-butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(2-fluoro-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (2c)

[0250] Methyl 5-bromo-6-fluoropicolinate (2b) (3.13 g, 13.4 mmol) was dissolved in 1,4-dioxane (40 mL) at room temperature. Tert-butyl (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylate (2a) (4.87 g, 14.7 mmol), Ruphos Pd G3 (1.12 g, 1.34 mmol), and cesium carbonate (8.72 g, 26.7 mmol) were added. The mixture was stirred at 110°C overnight under a nitrogen atmosphere. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 3 / 1) to obtain 1.89 g of the title compound as a yellow semisolid in a yield of 29.1%.

[0251] LC-MS: m / z 484 [M+H] + .

[0252] Step 4: Preparation of 3-(tert-butyl)8-methyl(R)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3,8(4H)-dicarboxylate (2d)

[0253] At room temperature, tert-butyl (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(2-fluoro-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (2c) (1.89 g, 3.90 mmol) was dissolved in THF (12 mL). A 1 M solution of TBAF in THF (12 mL) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 4 / 1) to give 850 mg of the title compound as a light yellow solid, in a yield of 62.3%.

[0254] LC-MS: m / z 350 [M+H] + .

[0255] Step 5: Preparation of (R)-8-(methylcarbamoyl)-1,2,4α-5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester (2e)

[0256] 3-(tert-Butyl) 8-methyl (R)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3,8(4H)-dicarboxylate (2d) (850 mg, 2.43 mmol) was dissolved in MeOH (10 mL) at room temperature. Aqueous methylamine solution (6 mL) was added and stirred at room temperature overnight. The mixture was concentrated under reduced pressure to afford 860 mg (crude) of the title compound as a pale yellow solid.

[0257] LC-MS: m / z 349[M+H] + .

[0258] Step 6: Preparation of (R)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (2f)

[0259] At room temperature, tert-butyl (R)-8-(methylcarbamoyl)-1,2,4α-5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3(4H)-carboxylate (2e) (860 mg, 2.43 mmol) was dissolved in DCM (15 mL). A solution of HCl in 1,4-dioxane (3 mL) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to afford 850 mg of the title compound (crude) as a light yellow solid.

[0260] LC-MS: m / z 249 [M+H] + .

[0261] Step 7: Preparation of (R)-N-methyl-3-((6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (2)

[0262] (R)-N-Methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (2f) (30.0 mg, 0.128 mmol) and 3-(chloromethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (1d) (31.9 mg, 0.128 mmol) were dissolved in acetonitrile (2 mL) at room temperature. DIEA (49.6 mg, 0.385 mmol) and sodium iodide (3.85 mg, 0.0256 mmol) were added, and the mixture was stirred at room temperature overnight. The residue was concentrated under reduced pressure, and separated by high pressure preparative liquid chromatography (column model: Daisogei 30 mm*250 mm, C18, 10 μm 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid, 30 min) to afford 18 mg of the title compound as a white solid, in a yield of 31.6%.

[0263] LC-MS: m / z 446[M+H] + .

[0264] 1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),8.19-8.09(m,3H),7.64(d,1H),7.53(d,1H),7.29(d,1H),7.10(dd,1H),6.72(dd,1H),4.40(dd,1H),4.06( dd,1H),3.79(d,1H),3.69(d,1H),3.60(d,1H),3.24-3.15(s,1H),2.95( dd,2H),2.84-2.77(m,1H),2.74(d,3H),2.29-2.18(m,1H),1.83(t,1H).

[0265] Example 3: Preparation of (R)-N-methyl-3-((6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,5]naphthyridin-3-yl)methyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (3)

[0266] Step 1: Preparation of methyl 5-amino-6-bromonicotinate (3a)

[0267] Methyl 5-aminonicotinate (10.0 g, 65.7 mmol) and N-bromosuccinimide (NBS) (17.6 g, 98.7 mmol) were dissolved in DMF (100 mL) and stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate. The filter cake was then dissolved in DMSO and separated by high-pressure preparative liquid chromatography (column model: Daisogei 30 mm x 250 mm, C18, 10 μm 100A, mobile phase: acetonitrile / water, gradient: 20%-50%, 0.05% formic acid, 30 min) to obtain 3.5 g of the title compound as a white solid, in a yield of 23.1%.

[0268] LC-MS: m / z 231.0 [M+H] + .

[0269] Step 2: Preparation of methyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-1-ene-1-carboxylate (3b)

[0270] Methyl 2-oxocyclopentane-1-carboxylate (10.0 g, 70.4 mmol) was dissolved in DCM (100 mL) at room temperature. Sodium hydroxide (3.38 g, 84.5 mmol) was added at 0°C and stirred at 0°C for 1 hour under a nitrogen atmosphere. Trifluoromethanesulfonic anhydride (23.8 g, 84.5 mmol) was added and stirred at room temperature for 2 hours. The mixture was quenched with water, extracted with DCM, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 5 / 1) to obtain 19.0 g of the title compound as a yellow oil in a yield of 98.5%.

[0271] Step 3: Preparation of methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-1-ene-1-carboxylate (3c)

[0272] Methyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-1-ene-1-carboxylate (3b) (4.40 g, 16.1 mmol) was dissolved in dioxane (90 mL) at room temperature. Bis(pinacol)diboron (4.47 g, 17.6 mmol), triphenylphosphine (252 mg, 0.961 mmol), Pd(pph3)2Cl2 (337 mg, 0.481 mmol), and potassium carbonate (3.31 g, 24.2 mmol) were added, and the mixture was stirred at 80°C for 16 hours. The mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 10 / 1) to obtain 2.80 g of the title compound as a yellow oil (yield: 69.2%).

[0273] LC-MS: m / z 253.2 [M+H] + .

[0274] Step 4: Preparation of methyl 6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,5]naphthyridine-3-carboxylate (3d): methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-1-ene-1-carboxylate (3c) (3.16 g, 12.5 mmol) was dissolved in dioxane (40 mL) and water (10 mL) at room temperature, and methyl 5-amino-6-bromonicotinate (3a) (2.40 g, 10.4 mmol), potassium carbonate (2.88 g, 20.9 mmol), and Pd(dppf)Cl2 (763 mg, 1.04 mmol) were added. The mixture was stirred at 100°C under a nitrogen atmosphere for 2 hours. The mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was separated by high-pressure preparative liquid chromatography (column model: Daisogei 30 mm*250 mm, C18, 10 μm 100A, mobile phase: acetonitrile / water, gradient: 20%-50%, 0.05% formic acid, 30 min) to give 300 mg of the title compound as a white solid, in a yield of 11.8%.

[0275] LC-MS: m / z 245.1 [M+H] + .

[0276] Step 5: Preparation of 3-(hydroxymethyl)-5,7,8,9-tetrahydro-6H-cyclopenta[c][1,5]naphthyridin-6-one (3e)

[0277] Methyl 6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,5]naphthyridine-3-carboxylate (3d) (300 mg, 1.23 mmol) was dissolved in THF (8 mL) at room temperature. Under a nitrogen atmosphere, lithium aluminum tetrahydride (187 mg, 4.92 mmol) was added at 0°C, and the mixture was stirred at 0°C for 30 minutes. Water (0.5 mL) was added, followed by 10% sodium hydroxide solution (0.5 mL) and water (1.5 mL). The mixture was filtered, and the filter cake was washed with DCM / MeOH (5 / 1). The filtrate was concentrated under reduced pressure to give 500 mg of the title compound as a yellow solid (crude product).

[0278] LC-MS: m / z 217.1 [M+H] + .

[0279] Step 6: Preparation of 3-(chloromethyl)-5,7,8,9-tetrahydro-6H-cyclopenta[c][1,5]naphthyridin-6-one (3f)

[0280] 3-(Hydroxymethyl)-5,7,8,9-tetrahydro-6H-cyclopenta[c][1,5]naphthyridin-6-one (3e) (500 mg, 2.31 mmol) was dissolved in DCM (15 mL) at room temperature. Thionyl chloride (826 mg, 6.94 mmol) and a drop of DMF were added at 0°C, and the mixture was stirred at room temperature for 16 hours. The mixture was quenched by the addition of saturated aqueous sodium bicarbonate (20 mL), extracted with DCM (20 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to obtain 70 mg of the title compound as a yellow solid, in a yield of 12.9%.

[0281] LC-MS: m / z 235.1 [M+H] + .

[0282] Step 7: Preparation of (R)-N-methyl-3-((6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,5]naphthyridin-3-yl)methyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (3).

[0283] 3-(Chloromethyl)-5,7,8,9-tetrahydro-6H-cyclopenta[c][1,5]naphthyridin-6-one (3f) (50.0 mg, 0.214 mmol) was dissolved in acetonitrile (3 mL) at room temperature. (R)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (2f) (52.9 mg, 0.214 mmol), sodium iodide (3.21 mg, 0.0214 mmol) and DIEA (82.7 mg, 0.641 mmol) were added, and the mixture was stirred at room temperature under nitrogen atmosphere for 16 hours. The product was concentrated under reduced pressure, and the residue was separated by high pressure preparative liquid chromatography (column model: Daisogei 30 mm*250 mm, C18, 10 μm 100A, mobile phase: acetonitrile / water, gradient: 30%-60%, 0.05% ammonia water, 30 min) to obtain 32 mg of the title compound as a white solid, in a yield of 33.6%.

[0284] LC-MS: m / z 447.2 [M+H] + .

[0285] 1H NMR (400MHz, DMSO-d6) δ11.68(s,1H),8.42(d,J=1.8Hz,1H),8.14(q,J=4.7Hz,1H),7. 65(d,J=1.9Hz,1H),7.52(d,J=8.2Hz,1H),7.28(d,J=8.3Hz,1H),4.40(dd,J=11.0,2. 9Hz,1H),4.05(dd,J=11.0,8.9Hz,1H),3.84-3.58(m,3H),3.25-3.12(m,3H),3.00-2. 70(m,8H),2.24(td,J=11.6,3.2Hz,1H),2.11(p,J=7.7Hz,2H),1.83(t,J=10.8Hz,1H).

[0286] Example 4: Preparation of (R)-N-methyl-3-((6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,6]naphthyridin-3-yl)methyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (4)

[0287] Step 1: Preparation of methyl 4-amino-5-bromopicolinate (4a)

[0288] Methyl 5-aminonicotinate (5.00 g, 32.9 mmol) and N-bromosuccinimide (5.86 g, 32.9 mmol) were dissolved in DCE (50 mL) and stirred at room temperature under a nitrogen atmosphere for 16 hours. Saturated aqueous sodium bicarbonate (50 mL) was added, and the mixture was extracted with DCM (50 mL x 3). The mixture was washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to obtain 3.8 g of the title compound as a yellow solid in a yield of 50.2%.

[0289] LC-MS: m / z 231.0 [M+H] + .

[0290] Step 2: Preparation of methyl 6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,6]naphthyridine-3-carboxylate (4b)

[0291] Methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-1-ene-1-carboxylate (3c) (3.42 g, 13.6 mmol) and methyl 4-amino-5-bromopicolinate (4a) (2.60 g, 11.3 mmol) were dissolved in dioxane (40 mL) and water (10 mL) at room temperature. Potassium carbonate (3.12 g, 22.6 mmol) and Pd(dppf)Cl2 (826 mg, 1.13 mmol) were added, and the mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was separated by high-pressure preparative liquid chromatography (column model: Daisogei 30 mm*250 mm, C18, 10 μm 100A, mobile phase: acetonitrile / water, gradient: 20%-50%, 0.05% formic acid, 30 min) to give 80 mg of the title compound as a white solid, in a yield of 2.90%.

[0292] LC-MS: m / z 245.1 [M+H] + .

[0293] The other steps were the same as the preparation method of Example 3, except that 6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,6]naphthyridine-3-carboxylic acid methyl ester (4b) was used instead of 6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,5]naphthyridine-3-carboxylic acid methyl ester (3d) in step 4 to obtain the title compound 4.

[0294] LC-MS: m / z 447.2 [M+H] + .

[0295] 1 H NMR (400MHz, DMSO-d6) δ11.78(s,1H),8.68(s,1H),8.15(q,J=4.7Hz,1H),7.53(d,J=8.1 Hz, 1H), 7.37 (s, 1H), 7.29 (d, J = 8.3Hz, 1H), 4.41 (dd, J = 11.0, 2.9Hz, 1H), 4.06 (dd, J = 11. 0,8.9Hz,1H),3.83-3.65(m,3H),3.19(dt,J=29.9,8.6Hz,3H),2.97(dd,J=22.8,11.2Hz, 2H), 2.84-2.71 (m, 6H), 2.34-2.26 (m, 1H), 2.12 (p, J = 7.6Hz, 2H), 1.90 (t, J = 10.8Hz, 1H).

[0296] Example 5: Preparation of (R)-N-(methyl-d3)-3-((6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-1,2,3,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (5)

[0297] Step 1: Preparation of (R)-3-(tert-Butyloxycarbonyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxylic acid (5a)

[0298] 3-(tert-Butyl) 8-methyl (R)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3,8(4H)-dicarboxylate (2d) (60.0 mg, 0.171 mmol) was dissolved in THF (1 mL) and water (0.2 mL) at room temperature. Lithium hydroxide (12.3 mg, 0.514 mmol) was added and the mixture was stirred at 50°C for 2 hours. The mixture was concentrated under reduced pressure to afford 80 mg of the title compound (crude) as a light yellow solid.

[0299] LC-MS: m / z 336.1[M+H] + .

[0300] Step 2: Preparation of tert-butyl (R)-8-((methyl-d3)carbamoyl)-1,2,4α,15-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3(4H)-carboxylate (5b)

[0301] (R)-3-(tert-Butyloxycarbonyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxylic acid (5a) (80.0 mg, 0.171 mmol) and deuterated methylamine hydrochloride (14.4 mg, 0.205 mmol) were dissolved in DMF (2 mL) at room temperature. DIEA (66.2 mg, 0.513 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. HATU (97.3 mg, 0.256 mmol) was added, and the mixture was stirred at room temperature overnight. 20 mL of water was added, and the mixture was extracted with EA (10 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 74 mg of the title compound as a yellow oil (crude product).

[0302] LC-MS: m / z 352 [M+H] + .

[0303] The other steps were the same as the preparation method of Example 2, except that (R)-8-((methyl-d3)carbamoyl)-1,2,4α25-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester (5b) was used instead of (R)-8-((methyl-d3)carbamoyl)-1,2,4α25-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester (2e) in step 6 to obtain the title compound 5.

[0304] LC-MS: m / z 449.2 [M+H] + .

[0305] 1 H NMR(400MHz,DMSO-d6)δ11.34(s,1H),8.20-8.06(m,3H),7.64(d,1H),7.53(d,1H),7.29(d,1H),7.10(dd,1H),6.72(dd,1H),4.40(dd,1H) ,4.06(dd,1H),3.79(d,1H),3.69(d,1H),3.60(d,1H),3.24-3.15(s,1H),2.95(dd,2H),2.84-2.74(m,1H),2.29-2.18(m,1H),1.83(t,1H).

[0306] Example 6: Preparation of (R)-N-(methyl-d3)-3-((6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-1,2,3,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (6)

[0307] Step 1: Preparation of (R)-3-(tert-Butoxycarbonyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxylic acid (6a)

[0308] 3-(tert-Butyl)-9-methyl (R)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3,9(4H)-dicarboxylate (1h) (50.0 mg, 0.138 mmol) was dissolved in THF (1 mL) and water (0.2 mL) at room temperature. Lithium hydroxide (9.92 mg, 0.413 mmol) was added to the solution, and the mixture was stirred at 50°C for 2 hours. The mixture was concentrated under reduced pressure to give 75 mg of the title compound (crude) as a light yellow solid.

[0309] LC-MS: m / z 336.1[M+H] + .

[0310] Step 2: Preparation of (R)-9-((methyl-d3)carbamoyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (6b)

[0311] (R)-3-(tert-Butyloxycarbonyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxylic acid (6a) (75.0 mg, 0.138 mmol) and deuterated methylamine hydrochloride (11.6 mg, 0.166 mmol) were dissolved in DMF (2 mL) at room temperature. DIEA (53.4 mg, 0.414 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. HATU (78.7 mg, 0.207 mmol) was added, and the mixture was stirred at room temperature overnight. 20 mL of water was added, and the mixture was extracted with EA (10 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 55 mg of the title compound as a yellow oil (crude product).

[0312] LC-MS: m / z 366.2 [M+H] + .

[0313] The other steps were the same as the preparation method of Example 1, except that (R)-9-((methyl-d3)carbamoyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (6b) was used instead of (R)-9-(methylcarbamoyl)-1,2,4α,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (1i) in step 10 to obtain the title compound 6.

[0314] LC-MS: m / z 463.2 [M+H] + .

[0315] 1H NMR (400MHz, DMSO-d6) δ11.33(s,1H),8.36(q,J=4.6Hz,1H),8.18-8.08(m,2H),7.82(d,J=8.5Hz,1H),7.66(d ,J=1.9Hz,1H),7.50(d,J=8.6Hz,1H),7.10(dd,J=3.8,1.6Hz,1H),6.72(dd,J=3.8,2.8Hz,1H),4.94(d,J=13. 9Hz,1H),4.74(d,J=13.9Hz,1H),4.02(dd,J=12.4,7.5Hz,1H),3.79(dd,J=12.3,3.9Hz,1H),3.63(s,2H),3.5 4-3.46(m,1H),3.40-3.34(m,2H),2.71-2.63(m,1H),2.61-2.56(m,1H),2.55-2.52(m,1H),2.44-2.36(m,1H).

[0316] Example 7: Preparation of (R)-N-methyl-3-((1-methyl-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]isoquinolin-2-yl)methyl)-1,2,3,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (7)

[0317] Step 1: Preparation of 1-methyl-4-nitro-1H-pyrrole-2-carbaldehyde (7a)

[0318] 1-Methyl-1H-pyrrole-2-carbaldehyde (1.00 g, 9.17 mmol) was dissolved in 2.5 mL of concentrated sulfuric acid at 0°C. Concentrated nitric acid (0.5 mL) was slowly added dropwise at 0°C. After stirring for 1 minute, the reaction mixture was poured into ice water. The mixture was extracted with EA (50 mL x 3), washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 99 / 1 to 1 / 99) to obtain 800 mg of the title compound as a yellow solid in a yield of 55.4%.

[0319] LC-MS: m / z 155.0 [M+H] + .

[0320] Step 2: Preparation of 5-bromo-1-methyl-4-nitro-1H-pyrrole-2-carbaldehyde (7b)

[0321] 1-Methyl-4-nitro-1H-pyrrole-2-carbaldehyde (7a) (3.80 g, 24.7 mmol) was dissolved in 38 mL of DMF, and bromine (4.74 g, 29.6 mmol) was added. The mixture was stirred at 100°C overnight. 200 mL of water was added to quench the mixture, and the mixture was extracted with EA (100 mL x 3). The mixture was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by thin-layer chromatography (mobile phase: PE / EA = 100 / 1 to 10 / 1) to obtain 2 g of the title compound as a light yellow solid in a yield of 34.9%.

[0322] LC-MS: m / z 232.9 [M+H] + .

[0323] Step 3: Preparation of methyl 2-(5-formyl-1-methyl-3-nitro-1H-pyrrol-2-yl)benzoate (7c)

[0324] 5-Bromo-1-methyl-4-nitro-1H-pyrrole-2-carbaldehyde (7b) (200 mg, 0.860 mmol) was dissolved in 1,4-dioxane and water (5 / 0.5 mL), and methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (271 mg, 1.03 mmol), potassium carbonate (237 mg, 1.72 mmol) and PdCl2(dppf) (31.4 mg, 0.0430 mmol) were added. The mixture was stirred at 110 ° C. overnight under nitrogen atmosphere. The mixture was quenched by adding 20 mL of water, extracted with EA (30 mL x 3), washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by high-pressure preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 μm 100A, mobile phase: acetonitrile / water (0.05% formic acid), gradient: 30%-70%) to obtain 100 mg of the title compound as a black solid, in a yield of 40.3%.

[0325] LC-MS: m / z 289.1 [M+H] + .

[0326] Step 4: Preparation of 1-methyl-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]isoquinoline-2-carbaldehyde (7d)

[0327] Methyl 2-(5-formyl-1-methyl-3-nitro-1H-pyrrol-2-yl)benzoate (80 mg, 0.280 mmol) was dissolved in 2.5 mL of AcOH, and Fe powder (77.8 mg, 1.40 mmol) was added. The mixture was stirred at 80°C overnight. 10 mL of water was added to quench the mixture, and the pH was adjusted to >7 with saturated NaHCO3 solution. The mixture was extracted with EA (20 mL x 3), washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 64 mg of the title compound as a gray solid (crude product).

[0328] LC-MS: m / z 227.1[M+H] + .

[0329] Step 5: Preparation of (R)-N-methyl-3-((1-methyl-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]isoquinolin-2-yl)methyl)-1,2,3,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (7)

[0330] (R)-N-Methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (1j) (34.8 mg, 0.130 mmol) was dissolved in 2.5 mL of THF, and 1-methyl-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]isoquinoline-2-carbaldehyde (25.0 mg, 0.110 mmol) and Ti(OEt)4 (50.2 mg, 0.220 mmol) were added, followed by stirring at room temperature for 1 hour. NaBH3CN (13.8 mg, 0.220 mmol) and MeOH (2.5 mL) were then added, and the mixture was stirred at room temperature overnight. The mixture was quenched by the addition of 20 mL of saturated aqueous sodium bicarbonate solution, extracted with EA (10 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated twice by high pressure preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 μm 100A, mobile phase: acetonitrile / water (0.05% formic acid), gradient: 30%-70%) to give 4 mg of the title compound as a white solid, yield: 7.69%.

[0331] LC-MS: m / z 473.1[M+H] + .

[0332] 1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),8.37(q,1H),8.31(dd,1H),8.17(d,1H ),7.81(d,1H),7.74-7.70(m,1H),7.49(d,1H),7.37(t,1H),5.99(s,1H),4. 94(d,1H),4.73(d,1H),4.05(s,3H),4.01(t,1H),3.78(q,1H),3.63(q,2H), 3.52(t,1H),3.40-3.34(m,2H),2.78(d,3H),2.67-2.56(m,3H),2.41(q,1H).

[0333] Example 8: Preparation of (R)-N-methyl-3-((7-methyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-1,2,3,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (8)

[0334] Step 1: Preparation of 1-(5-bromo-3-nitropyridin-2-yl)-3-methyl-1H-pyrrole-2-carboxylic acid methyl ester (8a)

[0335] 5-Bromo-2-fluoro-3-nitropyridine (1.00 g, 4.55 mmol), methyl 3-methyl-1H-pyrrole-2-carboxylate (758 mg, 5.45 mmol), and cesium carbonate (3.69 g, 11.4 mmol) were dissolved in acetonitrile (15 mL) and stirred at 25°C for 2 hours. The mixture was extracted with ethyl acetate (50 mL x 3), washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 96 / 4) to obtain 720 mg of the title compound as a yellow oil, in a yield of 46.7%.

[0336] LC-MS: m / z 340.0 [M+H] + .

[0337] Step 2: Preparation of 3-bromo-7-methylpyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (8b)

[0338] Methyl 1-(5-bromo-3-nitropyridin-2-yl)-3-methyl-1H-pyrrole-2-carboxylate (8a) (680 mg, 2.01 mmol) was dissolved in acetic acid (30 mL), and iron powder (1.12 g, 20.1 mmol) was added. The mixture was stirred at 100°C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM / MeOH = 100 / 1 to 94 / 6) to obtain 480 mg of the title compound as a white solid in a yield of 86.2%.

[0339] LC-MS: m / z 278.0 [M+H] + .

[0340] Step 3: Preparation of 7-methyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carbonitrile (8c)

[0341] 3-Bromo-7-methylpyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (8b) (800 mg, 2.89 mmol), zinc cyanide (507 mg, 4.33 mmol), and Pd(t-Bu3P)2 (148 mg, 0.289 mmol) were dissolved in DMAc (12 mL) and stirred at 100°C for 16 hours. Water (50 mL) was added, the mixture was filtered, and the filter cake was collected and dried to give 1.30 g (crude) of the title compound as a white solid.

[0342] LC-MS: m / z 225.1 [M+H] + .

[0343] Step 4: Preparation of 7-methyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid (8d)

[0344] 7-Methyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carbonitrile (8c) (1.30 g, 5.80 mmol) was dissolved in ethanol / water (30 mL / 10 mL), and lithium hydroxide (557 mg, 23.2 mmol) was added. The mixture was stirred at 100°C for 16 hours. The mixture was concentrated under reduced pressure, and water (20 mL) was added. The pH was adjusted to acidic with 6 M HCl, and the mixture was filtered. The filter cake was collected and dried to give 450 mg (crude) of the title compound as a white solid.

[0345] LC-MS: m / z 244.1[M+H] + .

[0346] Step 5: Preparation of methyl 7-methyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylate (8e)

[0347] 7-Methyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid (8d) (450 mg, 1.85 mmol) was dissolved in MeOH / DCM (3 mL / 10 mL), and TMSCHN2 (1.9 mL, 3.70 mmol) was added. The mixture was stirred at 25°C for 16 hours. The mixture was concentrated under reduced pressure, slurried with PE / EA = 1 / 10 (5 mL), filtered, and the filter cake was collected and dried to give 400 mg (crude) of the title compound as a white solid.

[0348] LC-MS: m / z 258.1[M+H] + .

[0349] Step 6: Preparation of 3-(hydroxymethyl)-7-methylpyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (8f)

[0350] Methyl 7-methyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylate (8e) (400 mg, 1.56 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium borohydride (177 mg, 4.67 mmol) was added. The mixture was stirred at 60°C for 16 hours. Water (20 mL) was added, and the pH was adjusted to acidic with 6M hydrochloric acid. The mixture was filtered, and the filter cake was collected and dried to obtain 320 mg of the title compound as a white solid (crude product).

[0351] LC-MS: m / z 230.1 [M+H] + .

[0352] Step 7: Preparation of 7-methyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carbaldehyde (8 g)

[0353] 3-(Hydroxymethyl)-7-methylpyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (8f) (35.0 mg, 0.153 mmol) was dissolved in 1,4-dioxane (2 mL), and manganese dioxide (266 mg, 3.06 mmol) was added. The mixture was stirred at 100°C for 48 hours. The filtrate was collected by filtration and dried to give 30.0 mg of the title compound as a white solid (crude product).

[0354] LC-MS: m / z 228.1[M+H] + .

[0355] The other steps were the same as the preparation method of Example 7, except that 7-methyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxaldehyde (8 g) was used instead of (R)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxadiazine-9-carboxamide (1j) in step 5 to obtain the title compound 8.

[0356] LC-MS: m / z 474.1[M+H] + .

[0357] 1 H NMR (400MHz, DMSO-d6) δ11.10(s,1H),8.38(q,J=4.8Hz,1H),8.08(d,J=2.0Hz,1H),7.97(d,J=2.8Hz,1H),7.82(d,J= 8.4Hz,1H),7.58(d,J=2.0Hz,1H),7.50(d,J=8.4Hz,1H),6.54(d,J=2.8Hz,1H),4.94(d,J=14.0Hz,1H),4.74(d,J=14 .0Hz,1H),4.02(dd,J=12.0,7.6Hz,1H),3.79(dd,J=12.4,3.6Hz,1H),3.60(s,2H),3.50(tt,J=7.2,3.6Hz,2H),3.39 -3.38(m,1H),2.79(d,J=4.8Hz,3H),2.66(dt,J=10.0,4.4Hz,1H),2.62-2.52(m,2H),2.50(s,3H),2.42-2.35(m,1H).

[0358] Example 9: Preparation of (R)-3-((7-chloro-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (9)

[0359] The title compound 9 was prepared in the same manner as in Example 1, except that 3-chloro-1H-pyrrole-2-carboxylic acid methyl ester was used instead of 1H-pyrrole-2-carboxylic acid methyl ester in step 1.

[0360] LC-MS: m / z 494.1[M+H] + .

[0361] 1H NMR (400MHz, DMSO-d6) δ11.36(s,1H),8.38(q,J=4.8Hz,1H),8.12(dd,J=12.8,2.4Hz,2H),7.82(d,J=8.4 Hz,1H),7.62(d,J=2.0Hz,1H),7.50(d,J=8.4Hz,1H),6.78(d,J=3.2Hz,1H),4.94(d,J=13.6Hz,1H),4.74 (d,J=13.6Hz,1H),4.02(dd,J=12.4,7.6Hz,1H),3.79(dd,J=12.4,4.0Hz,1H),3.62(s,2H),3.50(dt,J=7 .2,3.6Hz,1H),3.40-3.34(m,3H),2.78(d,J=4.8Hz,3H),2.70-2.56(m,2H),2.40(dd,J=11.2,6.8Hz,1H).

[0362] Example 10: Preparation of (R)-N-methyl-3-((6-oxo-5,6-dihydrothieno[2,3-c][1,5]naphthyridin-3-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxapyridine-9-carboxamide (10)

[0363] Step 1: Preparation of methyl 5-amino-6-bromonicotinate (10a)

[0364] Methyl 5-aminonicotinate (6.00 g, 39.5 mmol) was dissolved in DCE (100 mL), and NBS (7.03 g, 39.5 mmol) was added. The mixture was stirred at 25°C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: DCM / MeOH = 100 / 1 to 98 / 2) to obtain 3.30 g of the title compound as a black solid, in a yield of 36.2%.

[0365] LC-MS: m / z 231.0 [M+H] + .

[0366] Step 2: Preparation of methyl 6-oxo-5,6-dihydrothieno[2,3-c][1,5]naphthyridine-3-carboxylate (10b)

[0367] Methyl 5-amino-6-bromonicotinate (10a) (1.00 g, 4.35 mmol), (2-(methoxycarbonyl)thiophen-3-yl)boronic acid (1.05 g, 5.65 mmol), Pd(PPh3)4 (502 mg, 0.435 mmol), and potassium carbonate (1.20 g, 8.70 mmol) were dissolved in water / 1,4-dioxane (2 mL / 10 mL) and stirred at 90°C under a nitrogen atmosphere for 16 hours. Water (30 mL) was added, the mixture was filtered, and the filter cake was slurried with EA / PE = 1 / 5 to give 750 mg of the title compound (crude) as a brown solid.

[0368] LC-MS: m / z 261.0 [M+H] + .

[0369] The other steps were the same as those in Example 1, except that 6-oxo-5,6-dihydrothieno[2,3-c][1,5]naphthyridine-3-carboxylic acid methyl ester (10b) was used instead of 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3 to obtain the title compound 10.

[0370] LC-MS: m / z 477.1[M+H] + .

[0371] 1 H NMR (400MHz, DMSO-d6) δ11.97(s,1H),8.49(d,J=1.6Hz,1H),8.38(q,J=4.8Hz,1H),8.22(d,J=5.2H z,1H),8.00(d,J=5.2Hz,1H),7.84-7.76(m,2H),7.51(d,J=8.4Hz,1H),4.95(d,J=14.0Hz,1H),4.74 (d,J=13.6Hz,1H),4.05(dd,J=12.4,7.6Hz,1H),3.80(dd,J=12.4,3.6Hz,1H),3.70(s,2H),3.52(dq ,J=7.2,3.6Hz,1H),3.40-3.34(m,2H),2.79(d,J=4.8Hz,3H),2.70-2.59(m,3H),2.45-2.41(m,1H).

[0372] Example 11: Preparation of (R)-N-ethyl-3-((6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-1,2,3,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (11)

[0373] The title compound 11 was prepared in the same manner as in Example 1, except that an aqueous solution of ethylamine was used instead of an aqueous solution of methylamine in step 9.

[0374] LC-MS: m / z 474.2 [M+H] + .

[0375] 1 H NMR (400MHz, DMSO-d6) δ11.34(s,1H),8.36(s,1H),8.18-8.05(m,2H),7.82(d,J=8.4Hz,1H),7.66(d, J=1.9Hz,1H),7.50(d,J=8.5Hz,1H),7.10(dd,J=3.8,1.6Hz,1H),6.72(dd,J=3.8,2.8Hz,1H),4.94(d ,J=13.9Hz,1H),4.74(d,J=13.9Hz,1H),4.02(dd,J=12.4,7.6Hz,1H),3.79(dd,J=12.3,3.8Hz,1H),3 .63(s,2H),3.59-3.48(m,2H),3.31-3.25(m,3H),2.69-2.58(m,3H),2.42-2.37(m,1H),1.10(t,3H).

[0376] Example 12: Preparation of (R)-3-((7-fluoro-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (12)

[0377] The title compound 12 was prepared in the same manner as in Example 1, except that 3-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester was used instead of 1H-pyrrole-2-carboxylic acid methyl ester in step 1.

[0378] LC-MS: m / z 478.1[M+H] + .

[0379] 1H NMR (400MHz, DMSO-d6) δ11.27(s,1H),8.39(q,J=4.8Hz,1H),8.12(d,J=2.0Hz,1H),7.97(dd,J=4.8,3.2Hz,1H) ,7.82(d,J=8.4Hz,1H),7.61(d,J=2.0Hz,1H),7.50(d,J=8.4Hz,1H),6.65(d,J=3.2Hz,1H),4.94(d,J=13.6Hz,1 H),4.74(d,J=13.6Hz,1H),4.02(dd,J=12.4,7.6Hz,1H),3.79(dd,J=12.4,4.0Hz,1H),3.61(s,2H),3.50(tt,J= 7.2, 3.6Hz, 2H), 2.79 (d, J = 4.8Hz, 3H), 2.67 (d, J = 16.0Hz, 1H), 2.62-2.52 (m, 3H), 2.39 (dd, J = 11.2, 6.8Hz, 1H).

[0380] Example 13: Preparation of (R)-N-methyl-3-((6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a][1,5]naphthyridine-8-carboxamide (13)

[0381] Step 1: Preparation of 4-benzyl 1-(tert-butyl)(S)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (13a)

[0382] (S)-tert-Butyl 2-(hydroxymethyl)piperazine-1-carboxylate (5.00 g, 23.0 mmol) was dissolved in DCM (50 mL), and triethylamine (7.00 g, 69.0 mmol) and benzyl chloroformate (7.87 g, 46.0 mmol) were added. The mixture was stirred at 25°C for 16 hours. The mixture was extracted with DCM (50 mL x 3), washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 7 / 3) to obtain 5.8 g of the title compound as a yellow oil in a yield of 62.3%.

[0383] LC-MS: m / z 351.0 [M+H] + .

[0384] Step 2: Preparation of 4-benzyl 1-(tert-butyl)(S)-2-formylpiperazine-1,4-dicarboxylate (13b)

[0385] Dissolve 4-benzyl 1-(tert-butyl)(S)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (13a) (5.20 g, 0.0148 mol) in DCM (50 mL). Add Dess-Martin periodinane (9.40 g, 0.0222 mmol) and stir at room temperature for 16 hours. Extract with DCM (50 mL x 3), wash with saturated brine (50 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 6.9 g (crude) of the title compound as a yellow oil.

[0386] LC-MS: m / z 349.2 [M+H] + .

[0387] Step 3: Preparation of 4-benzyl 1-(tert-butyl)(R)-2-vinylpiperazine-1,4-dicarboxylate (13c)

[0388] Methyltriphenylphosphonium bromide (12.3 g, 0.0345 mol) was dissolved in THF (50 mL). NaHMDS (2N) (15.3 mL, 0.0306 mmol) was added at 0°C, and the mixture was stirred at 0°C for half an hour. 4-Benzyl 1-(tert-butyl)(S)-2-formylpiperazine-1,4-dicarboxylate (13b) (6.00 g, 0.0177 mmol) was added, and the mixture was stirred at 0°C for half an hour. The mixture was extracted with EA (50 mL x 3), washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA / PE = 100 / 1 to 7 / 3) to obtain 1.8 g of the title compound as a yellow oil, in a yield of 62.3%.

[0389] LC-MS: m / z 347.2 [M+H] + .

[0390] Step 4: Preparation of 4-benzyl-1-(tert-butyl)(R,E)-2-(2-(3-fluoro-6-(methoxycarbonyl)pyridin-2-yl)vinyl)piperazine-1,4-dicarboxylate (13d)

[0391] 4-Benzyl 1-(tert-butyl)(R)-2-vinylpiperazine-1,4-dicarboxylate (13c) (500 mg, 1.45 mmol) was dissolved in DMA (10 mL), and methyl 6-bromo-5-fluoropicolinate (370 mg, 1.55 mmol), K3PO4 (920 mg, 4.35 mmol), and Pd(OAc)2 (120 mg, 0.730 mmol) were added. The mixture was stirred at 100°C for 16 hours. The mixture was extracted with EA (50 mL x 3), washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 1 / 4) to obtain 220 mg of the title compound as a yellow oil, in a yield of 30.5%.

[0392] LC-MS: m / z 500.2 [M+H] + .

[0393] Step 5: Preparation of (R)-tert-butyl 2-(2-(3-fluoro-6-(methoxycarbonyl)pyridin-2-yl)ethyl)piperazine-1-carboxylate (13e)

[0394] Dissolve 4-benzyl-1-(tert-butyl)(R,E)-2-(2-(3-fluoro-6-(methoxycarbonyl)pyridin-2-yl)vinyl)piperazine-1,4-dicarboxylate (13d) (200 mg, 0.400 mmol) in DCM (10 mL). Add Pd / C and stir at room temperature under a hydrogen atmosphere for 16 hours. Concentrate under reduced pressure to afford 120 mg (crude) of the title compound as a white solid.

[0395] LC-MS: m / z 368.2 [M+H] + .

[0396] Step 6: Preparation of 4-benzyl-1-(tert-butyl)(R)-2-(2-(3-fluoro-6-(methoxycarbonyl)pyridin-2-yl)ethyl)piperazine-1,4-dicarboxylate (13f)

[0397] Tert-butyl (R)-2-(2-(3-fluoro-6-(methoxycarbonyl)pyridin-2-yl)ethyl)piperazine-1-carboxylate (13e) (100 mg, 0.271 mmol) was dissolved in DCM (3 mL), and DIEA (83.0 mg, 0.640 mmol) and benzyl chloroformate (69.0 mg, 0.320 mmol) were added. The mixture was stirred at room temperature for 16 hours. The mixture was quenched by the addition of 20 mL of water, extracted with DCM (5 mL x 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 1 / 100) to obtain 110 mg of the title compound as a yellow oil in a yield of 78%.

[0398] LC-MS: m / z 502.2 [M+H] + .

[0399] Step 7: Preparation of (R)-benzyl 3-(2-(3-fluoro-6-(methoxycarbonyl)pyridin-2-yl)ethyl)piperazine-1-carboxylate (13 g)

[0400] Dissolve 4-benzyl-1-(tert-butyl)(R)-2-(2-(3-fluoro-6-(methoxycarbonyl)pyridin-2-yl)ethyl)piperazine-1,4-dicarboxylate (13f) (100 mg, 0.199 mmol) in DCM (1 mL). Add dioxane hydrochloride solution (4 mol / L, 0.4 mL) and stir at room temperature for 16 hours. Concentrate under reduced pressure to give 80 mg of the title compound as a white solid (crude product).

[0401] LC-MS: m / z 402.2 [M+H] + .

[0402] Step 8: Preparation of 3-benzyl 8-methyl (R)-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a][1,5]naphthyridine-3,8-dicarboxylate (13h)

[0403] Benzyl (R)-3-(2-(3-fluoro-6-(methoxycarbonyl)pyridin-2-yl)ethyl)piperazine-1-carboxylate (13 g) (50.0 mg, 0.125 mmol) was dissolved in DMF (2 mL), and CsCO (120 mg, 0.374 mmol) was added. The mixture was stirred at 80°C for 16 hours. 20 mL of water was added for dilution, and the mixture was extracted with EA (5 mL x 3). The mixture was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 1 / 100) to obtain 30 mg of the title compound as a yellow oil in a yield of 78%.

[0404] LC-MS: m / z 382.2 [M+H] + .

[0405] Step 9: Preparation of (R)-8-(methylcarbamoyl)-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a][1,5]naphthyridine-3-carboxylate (13i)

[0406] Dissolve 3-benzyl 8-methyl (R)-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a][1,5]naphthyridine-3,8-dicarboxylate (13h) (80.0 mg, 0.209 mmol) in MeOH (1 mL), add aqueous methylamine (0.4 mL), and stir at room temperature for 16 hours. Concentrate under reduced pressure to obtain 70 mg (crude) of the title compound as a white solid.

[0407] LC-MS: m / z 381.2 [M+H] + .

[0408] Step 10: Preparation of (R)-N-methyl-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a][1,5]naphthyridine-8-carboxamide (13j)

[0409] Benzyl (R)-8-(Methylcarbamoyl)-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a][1,5]naphthyridine-3-carboxylate (13i) (50.0 mg, 0.131 mmol) was dissolved in DCM (10 mL). Pd / C was added and the mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The mixture was concentrated under reduced pressure to afford 30 mg (crude) of the title compound as a white solid.

[0410] LC-MS: m / z 247.1[M+H] + .

[0411] Step 11: Preparation of (R)-N-methyl-3-((6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a][1,5]naphthyridine-8-carboxamide (13)

[0412] (R)-N-Methyl-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a][1,5]naphthyridine-8-carboxamide (13j) (30.0 mg, 0.121 mmol), 3-(chloromethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (1d) (32.0 mg, 0.121 mmol), sodium iodide (4.00 mg, 0.0240 mmol) and DIEA (47.0 mg, 0.363 mmol) were dissolved in acetonitrile (2 mL) and stirred at room temperature for 16 hours. The residue was filtered and separated by high-pressure preparative liquid chromatography (column model: Daisogei 30 mm*250 mm, C18, 10 μm 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid, 30 min) to obtain 4.8 mg of the title compound as a white solid, in a yield of 17.8%.

[0413] LC-MS: m / z 444.1[M+H] + .

[0414] 1 H NMR(400MHz, DMSO-d6)δ11.32(s,1H),8.22-8.08(m,3H),7.71-7.60(m,2H),7.26(d,J=8.8Hz,1H), 7.10(dd,J=3.8,1.6Hz,1H),6.73(dd,J=3.8,2.8Hz,1H),3.86(d,J=12.4Hz,1H),3.62(q,J=13.4Hz, 2H),3.19-3.09(m,1H),2.91(d,J=11.7Hz,2H),2.88-2.80(m,2H),2.77(d,J=4.8Hz,3H),2.24-2.14 (m,1H),2.01-1.94(m,1H),1.90(d,J=10.7Hz,1H),1.71(qd,J=12.6,12.0,5.4Hz,1H),1.23(s,1H).

[0415] Example 14: Preparation of (R)-3-((8-fluoro-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (14)

[0416] The title compound 14 was prepared in the same manner as in Example 1, except that 4-fluoro-1H-pyrrole-2-carboxylic acid methyl ester was used instead of 1H-pyrrole-2-carboxylic acid methyl ester in step 1.

[0417] LC-MS: m / z 478.1[M+H] + .

[0418] 1 H NMR (400MHz, DMSO-d6) δ11.55(s,1H),8.39(q,J=4.8Hz,1H),8.17(d,J=2.0Hz,1H),8.06(dd,J=3.2,2.0Hz,1H) ,7.82(d,J=8.4Hz,1H),7.67(d,J=1.6Hz,1H),7.50(d,J=8.4Hz,1H),6.98(d,J=2.0Hz,1H),4.94(d,J=13.6Hz,1 H),4.74(d,J=14.0Hz,1H),4.02(dd,J=12.3,7.6Hz,1H),3.79(dd,J=12.4,3.6Hz,1H),3.63(s,2H),3.49(dd,J= 7.2, 4.0Hz, 2H), 2.79 (d, J = 4.8Hz, 3H), 2.67 (d, J = 10.4Hz, 1H), 2.63-2.53 (m, 3H), 2.40 (dd, J = 11.2, 6.8Hz, 1H).

[0419] Example 15: Preparation of (R)-N-methyl-3-((5-oxo-4,5-dihydrothieno[2,3-c]isoquinolin-2-yl)methyl)-1,2,3,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (15)

[0420] Step 1: Preparation of methyl 2-(5-formyl-2-nitrothiophen-3-yl)benzoate (15a)

[0421] 4-Bromo-5-nitrothiophene-2-carbaldehyde (100 mg, 0.430 mmol) was dissolved in 1,4-dioxane (2.5 mL) and water (0.5 mL), and methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (134 mg, 0.51 mmol), potassium carbonate (119 mg, 0.86 mmol) and PdCl2(dppf) (16.1 mg, 0.022 mmol) were added. The mixture was stirred at 100 ° C overnight under a nitrogen atmosphere. The mixture was quenched by adding 20 mL of water, extracted with EA (10 mL x 3), washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by high pressure preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 μm 100A, mobile phase: acetonitrile / water (0.05% formic acid), gradient: 30%-70%) to give 75.0 mg of the title compound as a brown oil, yield: 60.0%.

[0422] LC-MS: m / z 292.0 [M+H] + .

[0423] Step 2: Preparation of 5-oxo-4,5-dihydrothieno[2,3-c]isoquinoline-2-carbaldehyde (15b)

[0424] Methyl 2-(5-formyl-2-nitrothiophen-3-yl)benzoate (15a) (120 mg, 0.410 mmol) was dissolved in 5 mL of AcOH, and Fe powder (115 mg, 2.06 mmol) was added. The mixture was stirred at 50°C overnight. 10 mL of water was added to quench the mixture, and the pH was adjusted to >7 with saturated sodium bicarbonate solution. The mixture was extracted with EA (20 mL x 3), washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 150 mg of the title compound as a dark yellow solid (crude product).

[0425] LC-MS: m / z 230.0 [M+H] + .

[0426] Step 3: Preparation of (R)-N-methyl-3-((5-oxo-4,5-dihydrothieno[2,3-c]isoquinolin-2-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxadiazine-9-carboxamide (15)

[0427] 5-Oxo-4,5-dihydrothieno[2,3-c]isoquinoline-2-carbaldehyde (15b) (25.0 mg, 0.110 mmol) was dissolved in 3 ml of THF, and (R)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (1j) (34.8 mg, 0.130 mmol) and Ti(OEt)4 (50.2 mg, 0.220 mmol) were added. The mixture was stirred at room temperature for 0.5 hours, and NaBH3CN (13.8 mg, 0.220 mmol) and MeOH (2 mL) were added. The mixture was stirred at room temperature overnight. The mixture was quenched by adding 10 mL of water, adjusted to pH>7 with saturated sodium carbonate solution, extracted with EA (10 mL x 3), washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated twice by high pressure preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 μm 100A, mobile phase: acetonitrile / water (0.05% formic acid), gradient: 30%-70%) to give 4 mg of the title compound as a white solid, yield: 3.80%.

[0428] LC-MS: m / z 476.0 [M+H] + .

[0429] 1 H NMR(400MHz,DMSO-d6)δ12.31(s,1H),8.39(d,1H),8.24(dd,1H),8.05(d,1H),7.82-7.75(m,2H),7.60(s,1H),7.52-7.48( m,2H),4.85(dd,2H),4.05(q,1H),3.82-3.77(m,3H),3.54-3.51(m,2H),3.41-3.36(m,2H),2.78(d,3H),2.73-2.56(m,3H).

[0430] Example 16: Preparation of (R)-3-((7,8-diethyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (16)

[0431] The title compound 16 was prepared in the same manner as in Example 1, except that 3,4-diethyl-1H-pyrrole-2-carboxylic acid ethyl ester was used instead of 1H-pyrrole-2-carboxylic acid methyl ester in step 1.

[0432] LC-MS: m / z 516.3 [M+H] + .

[0433] 1 H NMR (400MHz, DMSO-d6) δ11.06(s,1H),8.38(q,J=4.8Hz,1H),8.06(d,J=1.9Hz,1H),7.85-7.79(m,2H),7.56(d,J =1.9Hz,1H),7.50(d,J=8.5Hz,1H),4.94(d,J=14.0Hz,1H),4.74(d,J=13.9Hz,1H),4.02(dd,J=12.3,7.6Hz,1H), 3.78(dd,J=12.3,3.8Hz,1H),3.59(s,2H),3.53-3.46(m,1H),3.34(s,2H),2.90(q,J=7.4Hz,2H),2.79(d,J =4.8Hz,3H),2.69-2.53(m,5H),2.38(dd,J=11.2,6.9Hz,1H),1.24(t,J=7.5Hz,3H),1.14(t,J=7.4Hz,3H).

[0434] Example 17: Preparation of (R)-N-methyl-3-((5-oxo-4,5-dihydrothieno[3,2-c]isoquinolin-2-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (17)

[0435] Step 1: Preparation of methyl 5-(2-(methoxycarbonyl)phenyl)-4-nitrothiophene-2-carboxylate (17a)

[0436] Methyl 5-bromo-4-nitrothiophene-2-carboxylate (1.00 g, 3.76 mmol), methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1j) (1.18 g, 4.52 mmol), potassium carbonate (1.04 g, 7.52 mmol), and Ruphos-Pd-G3 (312 mg, 0.376 mmol) were dissolved in toluene (10 mL) and stirred at 110°C under a nitrogen atmosphere for 16 hours. The mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE / EA = 100 / 1 to 7 / 3) to obtain 970 mg of the title compound as a yellow oil, in a yield of 80.4%.

[0437] LC-MS: m / z 322.0 [M+H]+ .

[0438] Step 2: Preparation of methyl 5-oxo-4,5-dihydrothieno[3,2-c]isoquinoline-2-carboxylate (17b)

[0439] Methyl 5-(2-(methoxycarbonyl)phenyl)-4-nitrothiophene-2-carboxylate (17a) (970 mg, 3.02 mmol) was dissolved in acetic acid (12 mL) at room temperature. Zinc powder (982 mg, 15.1 mmol) was added and stirred at 100°C for 2 hours. The mixture was concentrated under reduced pressure, DMSO (10 mL) was added, and the mixture was stirred at 60°C for 1 hour. The mixture was filtered, and the filtrate was added with a large amount of water and stirred for 30 minutes. The mixture was filtered and the filter cake was washed with acetonitrile to obtain 800 mg of the title compound (crude) as a white solid.

[0440] LC-MS: m / z 260.0 [M+H] + .

[0441] The other steps were the same as those in Example 1, except that 5-oxo-4,5-dihydrothieno[3,2-c]isoquinoline-2-carboxylic acid methyl ester (17b) was used instead of 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3 to obtain the title compound 17.

[0442] LC-MS: m / z 476.0 [M+H] + .

[0443] 1 H NMR (400MHz, DMSO-d6) δ11.95 (s, 1H), 8.39 (q, J = 4.8Hz, 1H), 8.25 (dt, J = 8.1, 1.0Hz,1H),7.82(d,J=8.5Hz,1H),7.78-7.70(m,2H),7.55-7.46(m,2H),6.96 (s,1H),4.95(d,J=14.0Hz,1H),4.75(d,J=14.0Hz,1H),4.05(dd,J=12.3,7.6 Hz,1H),3.83(d,J=7.6Hz,2H),3.53(tt,J=7.2,3.5Hz,1H),3.43-3.34(m,3H), 2.83-2.52 (m, 7H).

[0444] Example 18: Preparation of (R)-3-((8-fluoro-5-oxo-4,5-dihydrothieno[2,3-c]isoquinolin-2-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (18)

[0445] Step 1: Preparation of (4-bromo-5-nitrothiophen-2-yl)methanol (18a)

[0446] Dissolve 4-bromo-5-nitrothiophene-2-carbaldehyde (1.20 g, 5.11 mmol) in 15 mL of MeOH, add NaBH4 (194 mg, 5.11 mmol) at 0°C, and stir at room temperature overnight. Quench with 30 mL of water, extract with EA (20 mL x 3), wash with saturated brine (50 mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to afford 1.00 g of the crude title compound as a light yellow solid (yield: 82.5%).

[0447] LC-MS: m / z 237.9 [M+H] + .

[0448] Step 2: Preparation of methyl 4-fluoro-2-(5-(hydroxymethyl)-2-nitrothiophen-3-yl)benzoate (18b)

[0449] (4-Bromo-5-nitrothiophen-2-yl)methanol (18a) (500 mg, 2.11 mmol) was dissolved in dioxane (20 mL) and water (2 mL), and methyl 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (709 mg, 2.53 mmol), potassium carbonate (582 mg, 4.22 mmol) and PdCl2(dppf) (77.2 mg, 0.110 mmol) were added. The mixture was stirred at 100 ° C. under nitrogen atmosphere overnight. The mixture was quenched by adding 50 mL of water, extracted with EA (50 mL x 3), washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 1 / 100) to give 620 mg of the title compound as a brown oil, yield: 94.5%.

[0450] LC-MS: m / z 282.1[M+H] + .

[0451] Step 3: Preparation of 8-fluoro-2-(hydroxymethyl)thieno[2,3-c]isoquinolin-5(4H)-one (18c)

[0452] Methyl 4-fluoro-2-(5-(hydroxymethyl)-2-nitrothiophen-3-yl)benzoate (18b) (620 mg, 1.99 mmol) was dissolved in ethanol and water (12 mL / 1.2 mL). Iron powder (558 mg, 9.97 mmol) and ammonium chloride (316 mg, 5.97 mmol) were added, and the mixture was stirred at 60°C overnight. The mixture was diluted with 60 mL of water, extracted with EA (30 mL x 3), washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 1 / 100) to obtain 200 mg of the title compound as a white solid in a yield of 40.3%.

[0453] LC-MS: m / z 250.0 [M+H] + .

[0454] The other steps were the same as those in Example 1, except that 8-fluoro-2-(hydroxymethyl)thieno[2,3-c]isoquinolin-5(4H)-one (18c) was used instead of 3-(hydroxymethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (1c) in step 4 to obtain the title compound 18.

[0455] LC-MS: m / z 494.1[M+H] + .

[0456] 1 H NMR(400MHz,DMSO-d6)δ12.38(s,1H),8.39(q,1H),8.20(s,1H),7.91(dd,1H),7.82(d,1H),7.62(s,1H),7.51(d,1H),7.3 3(ddd,1H),4.95(d,1H),4.74(d,1H),4.05(q,1H),3.82-3.72(m,4H),3.54-3.53(m,2H),2.78(d,3H),2.70-2.59(m,4H).

[0457] Example 19: Preparation of (R)-N-methyl-3-((8-methyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-1,2,3,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (19)

[0458] Step 1: Preparation of ethyl 1-(5-bromo-3-nitropyridin-2-yl)-4-methyl-1H-pyrrole-2-carboxylate (19a)

[0459] Dissolve 5-bromo-2-fluoro-3-nitropyridine (1.50 g, 6.82 mmol), ethyl 4-methyl-1H-pyrrole-2-carboxylate (1.15 g, 7.50 mmol), and cesium carbonate (4.43 g, 13.6 mmol) in acetonitrile (20 mL) and stir at room temperature for 16 hours. Filter and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 93 / 7) to obtain 1.40 g of the title compound as a yellow oil, in a yield of 58.2%.

[0460] LC-MS: m / z 354.0 [M+H] + .

[0461] Step 2: Preparation of 3-bromo-8-methylpyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (19b)

[0462] Ethyl 1-(5-bromo-3-nitropyridin-2-yl)-4-methyl-1H-pyrrole-2-carboxylate (19a) (400 mg, 1.13 mmol) was dissolved in acetic acid (10 mL), and zinc powder (1.47 g, 22.7 mmol) was added. The mixture was stirred at 100°C for 16 hours. DMSO (8 mL) was added, and the mixture was stirred at 60°C for 10 minutes. The mixture was filtered, and water (50 mL) was added to the filtrate. The mixture was filtered, and the filter cake was collected and dried to give 350 mg of the title compound as a white solid (crude product).

[0463] LC-MS: m / z 278.0 [M+H] + .

[0464] Step 3: Preparation of 8-methyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carbonitrile (19c)

[0465] 3-Bromo-8-methylpyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (19b) (330 mg, 1.19 mmol), zinc cyanide (209 mg, 1.79 mmol), and Pd(t-Bu3P)2 (61.1 mg, 0.119 mmol) were dissolved in DMAc (8 mL) and stirred at 100°C for 16 hours. Water (50 mL) was added, the mixture was filtered, and the filter cake was collected and dried to afford 450 mg of the title compound as a white solid (crude product).

[0466] LC-MS: m / z 225.1 [M+H] + .

[0467] Step 4: Preparation of 8-methyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid (19d)

[0468] 8-Methyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carbonitrile (19c) (350 mg, 1.56 mmol) was dissolved in ethanol / water (15 mL / 5 mL), and lithium hydroxide (75.0 mg, 3.13 mmol) was added. The mixture was stirred at 100°C for 48 hours. The mixture was concentrated under reduced pressure, and water (80 mL) was added. The pH was adjusted to acidic with 6 M HCl, and the mixture was filtered. The filter cake was collected and dried to afford 150 mg (crude) of the title compound as a white solid.

[0469] LC-MS: m / z 244.1[M+H] + .

[0470] Step 5: Preparation of 8-methyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (19e)

[0471] 8-Methyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid (19d) (100 mg, 1.85 mmol) was dissolved in DCM / MeOH (10 mL / 3 mL), and TMSCHN2 (0.31 mL, 0.617 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, slurried with PE / EA = 1 / 10 (5 mL), filtered, and the filter cake was collected and dried to afford 110 mg (crude) of the title compound as a white solid.

[0472] LC-MS: m / z 258.1[M+H] + .

[0473] The other steps were the same as those in Example 1, except that 8-methyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (19e) was used instead of 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3 to obtain the title compound 19.

[0474] LC-MS: m / z 474.2 [M+H] + .

[0475] 1H NMR (400MHz, DMSO-d6) δ11.28(s,1H),8.38(d,J=4.8Hz,1H),8.12(d,J=2.0Hz,1H),7.90(dd,J=1.6,1.2Hz,1H),7.8 2(d,J=8.4Hz,1H),7.62(d,J=2.0Hz,1H),7.50(d,J=8.4Hz,1H),6.92(d,J=1.6Hz,1H),4.94(d,J=13.6Hz,1H),4.74( d,J=13.6Hz,1H),4.02(dd,J=12.4,7.6Hz,1H),3.79(dd,J=12.4,4.0Hz,1H),3.61(s,2H),3.55-3.45(m,1H),3.40- 3.30(m,3H),2.78(d,J=4.8Hz,3H),2.65-2.63(m,1H),2.62-2.57(m,1H),2.39(dd,J=11.2,7.2Hz,1H),2.24(s,3H).

[0476] Example 20: Preparation of (R)-3-((8-chloro-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (20)

[0477] The title compound 20 was prepared in the same manner as in Example 1, except that 4-chloro-1H-pyrrole-2-carboxylic acid methyl ester was used instead of 1H-pyrrole-2-carboxylic acid methyl ester in step 1.

[0478] LC-MS: m / z 494.1[M+H] + .

[0479] 1H NMR (400MHz, DMSO-d6) δ11.52(s,1H),8.38(d,J=4.8Hz,1H),8.18(dd,J=7.2,1.6Hz,2H),7.82(d,J=8.4Hz,1H ),7.67(d,J=2.0Hz,1H),7.50(d,J=8.4Hz,1H),7.11(d,J=1.6Hz,1H),4.94(d,J=14.0Hz,1H),4.74(d,J=14.0 Hz,1H),4.02(dd,J=12.4,7.6Hz,1H),3.79(dd,J=12.4,3.6Hz,1H),3.63(s,2H),3.51(s,1H),3.38-3.34(m,3 H), 2.79 (d, J = 4.8Hz, 3H), 2.67 (d, J = 11.2Hz, 1H), 2.59 (dd, J = 11.2, 3.2Hz, 1H), 2.40 (dd, J = 11.2, 6.8Hz, 1H).

[0480] Example 21: Preparation of (R)-N-methyl-3-((5-oxo-4,5-dihydrothiazolo[4,5-c]isoquinolin-2-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (21)

[0481] Step 1: Preparation of (5-bromothiazol-2-yl)methanol (21a)

[0482] Dissolve 5-bromothiazole-2-carboxaldehyde (800 mg, 4.19 mmol) in 20 mL of methanol and slowly add NaBH4 (159 mg, 4.19 mmol) at 0°C. Stir at room temperature overnight. Quench with 50 mL of water, extract with EA (50 mL x 3), wash with saturated brine (100 mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 900 mg of the title compound (crude) as a light yellow solid.

[0483] LC-MS: m / z 193.9 [M+H] + .

[0484] Step 2: Preparation of (5-bromo-4-nitrothiazol-2-yl)methanol (21b)

[0485] (5-Bromothiazol-2-yl)methanol (21a) (900 mg, 4.66 mmol) was dissolved in 5 mL of concentrated sulfuric acid at 0°C. Concentrated nitric acid (0.5 mL) was slowly added at 0°C, and the mixture was stirred at room temperature overnight. Additional nitric acid (0.50 mL) was added, and the mixture was stirred at 60°C overnight. The reaction mixture was poured into ice water, extracted with EA (50 mL x 3), washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 1 / 100) to obtain 400 mg of the title compound as a yellow solid, yield: 36.0%.

[0486] LC-MS: m / z 238.9 [M+H] + .

[0487] Step 3: Preparation of methyl 2-(2-(hydroxymethyl)-4-nitrothiazol-5-yl)benzoate (21c)

[0488] (5-Bromo-4-nitrothiazol-2-yl)methanol (21b) (380 mg, 1.60 mmol) was dissolved in dioxane / H2O (20 / 2 mL), and methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (502 mg, 1.92 mmol), potassium carbonate (442 mg, 3.20 mmol), and PdCl2(dppf) (58.6 mg, 0.08 mmol) were added. The mixture was stirred at 100°C overnight under a nitrogen atmosphere. The reaction mixture was quenched by adding 50 mL of water, extracted with EA (30 mL x 3), washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 1 / 100) to obtain 400 mg of the title compound as a dark yellow semisolid. Yield: 84.7%.

[0489] LC-MS: m / z 295.0 [M+H] + .

[0490] Step 4: Preparation of 2-(hydroxymethyl)thiazolo[4,5-c]isoquinolin-5(4H)-one (21d)

[0491] Methyl 2-(2-(hydroxymethyl)-4-nitrothiazol-5-yl)benzoate (21c) (350 mg, 1.19 mmol) was dissolved in 5 mL of AcOH, and Fe powder (266 mg, 4.74 mmol) was added. The mixture was stirred at 50°C overnight. The mixture was concentrated under reduced pressure, and 20 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with EA (20 mL x 3), washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 55 mg of the title compound as a brown solid (crude product).

[0492] LC-MS: m / z 233.0 [M+H] + .

[0493] The other steps were the same as those in Example 1, except that 2-(hydroxymethyl)thiazolo[4,5-c]isoquinolin-5(4H)-one (21d) was used instead of 3-(hydroxymethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (1c) in step 4 to obtain the title compound 21.

[0494] LC-MS: m / z 477.1[M+H] + .

[0495] 1 H NMR(400MHz,DMSO-d6)δ12.58(s,1H),8.39(d,1H),8.29(d,1H),7.84-7.78(m,3H),7.60-7.51(m,2H),4.97(d,1H) ,4.76(d,1H),4.12(dd,1H),4.00(s,2H),3.85(dd,1H),3.60(d,1H),3.42(d,3H),2.79(dd,5H),2.67-2.61(m,1H).

[0496] Example 22: Preparation of (R)-N-(methyl-d3)-3-((7-methyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-1,2,3,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (22)

[0497] Step 1: Preparation of (R)-N-(methyl-d3)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (22a)

[0498] At room temperature, tert-butyl (R)-9-((methyl-d3)carbamoyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylate (6b) (2.00 g, 5.48 mmol) was dissolved in DCM (20 mL). A 1,4-dioxane solution of HCl (4 M, 5 mL) was added, and the mixture was stirred at 25°C overnight. The mixture was concentrated under reduced pressure, slurried with PE / EA = 1 / 1, and filtered. The filter cake was collected to afford 2.3 g (crude) of the title compound as a yellow solid.

[0499] LC-MS: m / z 266.2 [M+H] + .

[0500] Step 2: Preparation of (R)-N-(methyl-d3)-3-((7-methyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-1,2,3,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (22)

[0501] 7-Methyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carbaldehyde (8 g) (30.0 mg, 0.132 mmol) and (R)-N-(methyl-d3)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (22a) (34.6 mg, 0.132 mmol) were dissolved in DCM (2 mL), acetic acid (1 drop) was added, and the mixture was stirred at room temperature for 0.5 hours. Sodium cyanoborohydride (16.7 mg, 0.264 mmol) was added and stirred at room temperature for 16 hours. The residue was filtered and separated by high-pressure preparative liquid chromatography (column model: Daisogei 30 mm*250 mm, C18, 10 μm 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid, 30 min) to afford 17.0 mg of the title compound as a white solid, in a yield of 27.1%.

[0502] LC-MS: m / z 477.1[M+H] + .

[0503] 1H NMR (400MHz, DMSO-d6) δ11.10(s,1H),8.36(s,1H),8.08(d,J=2.0Hz,1H),7.97(d,J=2.8Hz,1H),7.82(d,J=8. 4Hz,1H),7.58(d,J=2.0Hz,1H),7.50(d,J=8.4Hz,1H),6.54(d,J=2.8Hz,1H),4.94(d,J=13.6Hz,1H),4.74(d,J =14.0Hz,1H),4.02(dd,J=12.4,7.6Hz,1H),3.79(dd,J=12.4,3.6Hz,1H),3.60(s,2H),3.53-3.45(m,1H),3.3 4(s,3H),2.65(d,J=5.6Hz,1H),2.59(dd,J=11.2,3.2Hz,1H),2.55-2.52(m,3H),2.39(dd,J=11.2,6.8Hz,1H).

[0504] Example 23: Preparation of (R)-N-methyl-3-((6-oxo-5,6-dihydrobenzo[c][1,5]naphthyridin-3-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (23)

[0505] Step 1: Preparation of 6-(2-(methoxycarbonyl)phenyl)-5-nitronicotinic acid (23a)

[0506] Methyl 2-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)benzoate (100 mg, 0.463 mmol) was dissolved in 1,4-dioxane (2 mL). Potassium carbonate (160 mg, 1.16 mmol), methyl 6-chloro-5-nitronicotinate (115 mg, 0.463 mmol), and Pd(pph3)4 (25.0 mg, 0.232 mmol) were added. The mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. The product was used directly in the next step without further treatment.

[0507] LC-MS: m / z 303.0 [M+H] + .

[0508] Step 2: Preparation of methyl 6-(2-(methoxycarbonyl)phenyl)-5-nitronicotinate (23b)

[0509] To the reaction mixture from the previous step was added iodomethane (132 mg, 0.926 mmol), stirred at 25°C for 16 hours, extracted with ethyl acetate (10 mL x 3), washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 82 / 18) to give 80 mg of the title compound as a yellow oil, with a two-step yield of 54.7%.

[0510] LC-MS: m / z 317.0 [M+H] + .

[0511] Step 3: Preparation of methyl 6-oxo-5,6-dihydrobenzo[c][1,5]naphthyridine-3-carboxylate (23c)

[0512] Methyl 6-(2-(methoxycarbonyl)phenyl)-5-nitronicotinate (23b) (220 mg, 0.696 mmol) was dissolved in acetic acid (3 mL), and zinc powder (450 mg, 6.96 mmol) was added. The mixture was stirred at 120°C for 16 hours. After filtration, the filter cake was dissolved in DMSO (8 mL), stirred at 60°C for 10 minutes, and filtered. Water (20 mL) was added to the filtrate, filtered, and the filter cake was collected and dried to give 160 mg of the title compound as a white solid (crude product).

[0513] LC-MS: m / z 255.0 [M+H] + .

[0514] The other steps were the same as the preparation method of Example 1, except that 6-oxo-5,6-dihydrobenzo[c][1,5]naphthyridine-3-carboxylic acid methyl ester (23c) was used instead of 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3 to obtain the title compound 23.

[0515] LC-MS: m / z 471.1 [M+H] + .

[0516] 1H NMR (400MHz, DMSO-d6) δ11.76(s,1H),8.75(dd,J=8.1,1.1Hz,1H),8.50(d,J=1.8Hz,1H),8.39(q,J=4.8Hz,1H),8.3 1(dd,J=7.9,1.2Hz,1H),7.92(ddd,J=8.3,7.2,1.4Hz,1H),7.82(d,J=8.6Hz,1H),7.78-7.70(m,2H),7.51(d,J=8.5 Hz,1H),4.95(d,J=13.9Hz,1H),4.75(d,J=14.0Hz,1H),4.05(dd,J=12.3,7.6Hz,1H),3.80(dd,J=12.3,3.9Hz,1H), 3.69(s,2H),3.57-3.49(m,1H),3.36(s,2H),2.79(d,J=4.8Hz,3H),2.72-2.55(m,3H),2.43(dd,J=11.2,6.8Hz,1H).

[0517] Example 24: Preparation of (R)-3-((9-fluoro-6-oxo-5,6-dihydrobenzo[c][1,5]naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (24)

[0518] The title compound 24 was prepared in the same manner as in Example 23, except that methyl 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate was used instead of methyl 2-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)benzoate in step 1.

[0519] LC-MS: m / z 489.1[M+H] + .

[0520] 1H NMR (400MHz, DMSO-d6) δ11.80(s,1H),8.51(d,J=1.8Hz,1H),8.43-8.32(m,3H),7.82(d,J=8.4Hz,1H ),7.73(d,J=1.9Hz,1H),7.59(td,J=8.7,2.7Hz,1H),7.51(d,J=8.6Hz,1H),4.95(d,J=13.9Hz,1H),4 .75(d,J=14.0Hz,1H),4.06(dd,J=12.3,7.6Hz,1H),3.80(dd,J=12.3,3.9Hz,1H),3.70(s,2H),3.36( s, 2H), 2.79 (d, J = 4.9Hz, 3H), 2.69 (d, J = 6.2Hz, 1H), 2.66-2.53 (m, 3H), 2.43 (dd, J = 11.2, 6.9Hz, 1H).

[0521] Example 25: Preparation of (R)-N-methyl-3-((5-oxo-5,6-dihydrobenzo[h][1,6]naphthyridin-8-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (25)

[0522] Step 1: Preparation of (2-amino-4-(methoxycarbonyl)phenyl)boronic acid (25a)

[0523] Dissolve (4-(Methoxycarbonyl)-2-nitrophenyl)boronic acid (1.50 g, 6.67 mmol) in methanol (15 mL), add Pd / C (150 mg) and hydrochloric acid (940 mg), and stir at 25°C under a hydrogen atmosphere for 16 hours. Filter and slurry with ethyl acetate to obtain 1.50 g (crude) of the title compound as a white solid.

[0524] LC-MS: m / z 196.1 [M+H] + .

[0525] Step 2: Preparation of methyl 5-oxo-5,6-dihydrobenzo[h][1,6]naphthyridine-8-carboxylate (25b)

[0526] Methyl 2-bromonicotinate (500 mg, 2.33 mmol) was dissolved in water / 1,4-dioxane (2 mL / 10 mL), and (2-amino-4-(methoxycarbonyl)phenyl)boronic acid (25a) (695 mg, 3.02 mmol), Pd(PPh3)4 (269 mg, 0.233 mmol), and potassium carbonate (642 mg, 4.65 mmol) were added. The mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. Water (30 mL) was added, the mixture was filtered, and the filter cake was collected. The mixture was slurried with EA / PE = 1 / 5, filtered, and the filter cake was collected and dried to obtain 600 mg of the title compound as a yellow solid (crude product).

[0527] LC-MS: m / z 255.1 [M+H] + .

[0528] The other steps were the same as those in Example 1, except that 5-oxo-5,6-dihydrobenzo[h][1,6]naphthyridine-8-carboxylic acid methyl ester (25b) was used instead of 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3 to obtain the title compound 25.

[0529] LC-MS: m / z 471.1 [M+H] + .

[0530] 1 H NMR (400MHz, DMSO-d6) δ11.86 (s, 1H), 9.05 (dd, J = 4.4, 1.6Hz, 1H), 8.64-8.54(m,2H),8.39(q,J=4.8Hz,1H),7.82(d,J=8.4Hz,1H),7.66(dd,J=8.0,4.4Hz,1H),7.51(d,J=8.4Hz,1H), 7.42(d,J=1.6Hz,1H),7.29(dd,J=8.0,1.6Hz,1H),4.96(d,J=14.0Hz,1H),4.74(d,J=14.0Hz,1H),4.09(dd,J=12.0 ,7.6Hz,1H),3.80(dd,J=12.0,3.6Hz,1H),3.64(d,J=3.6Hz,2H),3.58-3.50(m,1H),3.40-3.35(m,2H),2.79(d,J=4 .8Hz, 3H), 2.66 (d, J = 7.2Hz, 1H), 2.60 (dd, J = 11.2, 3.2Hz, 1H), 2.55 (d, J = 7.2Hz, 1H), 2.42 (dd, J = 11.2, 6.8Hz, 1H).

[0531] Example 26: Preparation of (R)-3-((7-cyclopropyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (26)

[0532] The title compound 26 was prepared in the same manner as in Example 19, except that ethyl 3-cyclopropyl-1H-pyrrole-2-carboxylate was used instead of ethyl 4-methyl-1H-pyrrole-2-carboxylate in step 1.

[0533] LC-MS: m / z 500.1[M+H] + .

[0534] 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),8.38(q,J=4.8Hz,1H),8.07(d,J=2.0Hz,1H),7.95(d,J=2.8Hz,1H),7.82(d,J=8 .4Hz,1H),7.57(d,J=2.0Hz,1H),7.50(d,J=8.4Hz,1H),6.28(d,J=3.2Hz,1H),4.94(d,J=14.0Hz,1H),4.74(d,J=14.0H z,1H),4.01(dd,J=12.4,7.6Hz,1H),3.79(dd,J=12.4,3.6Hz,1H),3.59(s,2H),3.55-3.35(m,3H),2.87(td,J=8.4,4. 4Hz, 1H), 2.79 (d, J = 4.8Hz, 3H), 2.70-2.53 (m, 3H), 2.39 (dd, J = 11.2, 6.8Hz, 1H), 1.04-0.95 (m, 2H), 0.71-0.62 (m, 2H).

[0535] Example 27: Preparation of (R)-N-(methyl-d3)-3-((6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,5]naphthyridin-3-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (27)

[0536] Step 1: Preparation of methyl 2-((trifluoromethanesulfonyl)oxy)cyclopent-1-ene-1-carboxylate (27a)

[0537] Methyl 2-oxocyclopentane-1-carboxylate (10.0 g, 70.4 mmol) was dissolved in DCM (100 mL) at room temperature. Sodium hydride (3.38 g, 84.5 mmol) was added at 0°C, and the mixture was stirred at 0°C for 1 hour under a nitrogen atmosphere. Trifluoromethanesulfonic anhydride (23.8 g, 84.5 mmol) was added at 0°C. The mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The mixture was quenched with water, extracted with DCM (100 mL x 3), washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 5 / 1) to obtain 16.0 g of the title compound as a yellow oil in a yield of 82.9%.

[0538] Step 2: Preparation of methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-1-ene-1-carboxylate (27b)

[0539] Methyl 2-((trifluoromethanesulfonyl)oxy)cyclopent-1-ene-1-carboxylate (27a) (10.0 g, 36.5 mmol), pinacol diboron (11.1 g, 43.8 mmol), Pd(dppf)Cl2 (2.67 g, 3.65 mmol), and potassium acetate (7.15 g, 72.9 mmol) were dissolved in dioxane (240 mL) at room temperature. The mixture was stirred at 80°C under a nitrogen atmosphere for 16 hours. The mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 9 / 1) to obtain 8.0 g of the title compound as a yellow oil in a yield of 86.9%.

[0540] LC-MS: m / z 253.2 [M+H] + .

[0541] Step 3: Preparation of methyl 6-(2-(methoxycarbonyl)cyclopent-1-en-1-yl)-5-nitronicotinate (27c)

[0542] Methyl 6-chloro-5-nitronicotinate (3.12 g, 14.4 mmol), methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-1-ene-1-carboxylate (4.0 g, 15.9 mmol), Pd(dppf)Cl2 (1.05 g, 1.44 mmol), and potassium phosphate (6.12 g, 28.9 mmol) were dissolved in dioxane (90 mL) at room temperature and stirred at 80°C under a nitrogen atmosphere for 3 hours. The mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 5 / 1) to obtain 2.4 g of the title compound as a yellow oil in a yield of 68.5%.

[0543] LC-MS: m / z 307.1[M+H] + .

[0544] Step 4: Preparation of methyl 5-hydroxy-6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,5]naphthyridine-3-carboxylate (27d)

[0545] Methyl 6-(2-(methoxycarbonyl)cyclopent-1-en-1-yl)-5-nitronicotinate (27c) (2.40 g, 7.84 mmol) and zinc powder (2.55 g, 39.2 mmol) were dissolved in acetic acid (30 mL) at room temperature and stirred at 100°C for 3 hours. The mixture was filtered, the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure. The residue was slurried with water and filtered to afford 2.10 g (crude) of the title compound as a brown solid.

[0546] LC-MS: m / z 261.1 [M+H] + .

[0547] Step 5: Preparation of methyl 6-oxo-6,6a,7,8,9,9a-hexahydro-5H-cyclopenta[c][1,5]naphthyridine-3-carboxylate (27e)

[0548] Methyl 5-hydroxy-6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,5]naphthyridine-3-carboxylate (27d) (2.00 g, 7.69 mmol) was dissolved in acetic acid (50 mL) at room temperature. Zinc powder (2.50 g, 38.5 mmol) was added and stirred at 120°C for 3 hours. The mixture was filtered, the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure. The residue was slurried with water and filtered to obtain 1.30 g (crude) of the title compound as a brown solid.

[0549] LC-MS: m / z 247.1[M+H] + .

[0550] Step 6: Preparation of 6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,5]naphthyridine-3-carboxylic acid methyl ester (27f) 6-oxo-6,6a,7,8,9,9a-hexahydro-5H-cyclopenta[c][1,5]naphthyridine-3-carboxylic acid methyl ester (27e) (1.30 g, 5.28 mmol) was dissolved in dioxane (25 mL) at room temperature, DDQ (1.44 g, 6.34 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched by addition of saturated sodium bicarbonate solution, concentrated under reduced pressure, and the residue was separated by high pressure preparative liquid chromatography (column model: Daisogei 30 mm*250 mm, C18, 10 μm 100A, mobile phase: acetonitrile / water, gradient: 10%-60%, 0.05% formic acid, 30 min) to afford 320 mg of the title compound as a brown solid, in a yield of 24.8%.

[0551] LC-MS: m / z 245.1 [M+H] + .

[0552] Step 7: Preparation of 3-(hydroxymethyl)-5,7,8,9-tetrahydro-6H-cyclopenta[c][1,5]naphthyridin-6-one (27 g)

[0553] Methyl 6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,5]naphthyridine-3-carboxylate (27f) (300 mg, 1.23 mmol) was dissolved in THF (8 mL) at room temperature. Under a nitrogen atmosphere, lithium aluminum tetrahydride (187 mg, 4.92 mmol) was added at 0°C, and the mixture was stirred at 0°C for 30 minutes. Water (0.2 mL) was added, followed by 15% sodium hydroxide solution (0.2 mL) and water (0.6 mL). The mixture was filtered, and the filter cake was washed with DCM / MeOH = 10 / 1. The filtrate was concentrated under reduced pressure to obtain 350 mg of the title compound (crude) as a brown solid.

[0554] LC-MS: m / z 217.1 [M+H] + .

[0555] Step 8: Preparation of 3-(chloromethyl)-5,7,8,9-tetrahydro-6H-cyclopenta[c][1,5]naphthyridin-6-one (27h)

[0556] 3-(Hydroxymethyl)-5,7,8,9-tetrahydro-6H-cyclopenta[c][1,5]naphthyridin-6-one (27 g) (300 mg, 1.39 mmol) was dissolved in DCM (20 mL) at room temperature. Thionyl chloride (496 mg, 4.17 mmol) and one drop of DMF were added at 0°C and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was slurried with dichloromethane / methanol (10 / 1), filtered, and the filtrate was concentrated to afford 180 mg of the title compound as a brown solid in a 55.4% yield.

[0557] LC-MS: m / z 235.1 [M+H] + .

[0558] Step 9: Preparation of (R)-N-(methyl-d3)-3-((6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,5]naphthyridin-3-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxapyridine-9-carboxamide (27)

[0559] 3-(Chloromethyl)-5,7,8,9-tetrahydro-6H-cyclopenta[c][1,5]naphthyridin-6-one (27h) (180 mg, 0.769 mmol) and (R)-N-(methyl-d3)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (22a) (203 mg, 0.769 mmol) were dissolved in acetonitrile (15 mL) at room temperature. DIEA (0.5 mL) and sodium iodide (23.1 mg, 0.154 mmol) were added, and the mixture was stirred at room temperature under nitrogen atmosphere for 16 hours. The product was concentrated under reduced pressure, and the residue was separated by high pressure preparative liquid chromatography (column model: Daisogei 30 mm*250 mm, C18, 10 μm 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid, 30 min) to afford 86 mg of the title compound as a white solid, in a yield of 24.1%.

[0560] LC-MS: m / z 464.2 [M+H] + .

[0561] 1H NMR (400MHz, DMSO-d6) δ11.68(s,1H),8.44-8.33(m,2H),7.82(d,J=8.4Hz,1H),7.66(d,J=1.8Hz,1H),7 .50(d,J=8.5Hz,1H),4.94(d,J=14.0Hz,1H),4.74(d,J=13.9Hz,1H),4.03(dd,J=12.4,7.6Hz,1H),3.78 (dd,J=12.3,3.9Hz,1H),3.65(s,2H),3.51(dq,J=7.2,3.6Hz,1H),3.40-3.34(m,2H),3.17(tt,J=8.5,1 .8Hz,2H),2.81(t,J=7.4Hz,2H),2.70-2.51(m,3H),2.39(dd,J=11.2,6.8Hz,1H),2.11(p,J=7.8Hz,2H).

[0562] Example 28: Preparation of (R)-3-((7-ethyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (28)

[0563] Step 1: Preparation of glycine methyl ester (28a)

[0564] Methyl 2-((tert-butoxycarbonyl)amino)acetate (10.0 g, 41.1 mmol) was dissolved in DCM (60 mL), TFA (10 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain 3.8 g (crude) of the title compound as a pale yellow oil.

[0565] Step 2: Preparation of tosylglycine methyl ester (28b)

[0566] Glycine methyl ester (28a) (3.8 g, 42.7 mmol) was dissolved in DCM (80 mL), and 4-methylbenzenesulfonyl chloride (8.93 g, 46.9 mmol) and triethylamine (8 mL) were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in EA (20 mL). A large amount of petroleum ether was added to precipitate a solid. The solid was filtered, and the filter cake was washed with petroleum ether to obtain 6.5 g of the title compound as a white solid in a yield of 62.6%.

[0567] LC-MS: m / z 244.1[M+H] + .

[0568] Step 3: Preparation of methyl 3-ethyl-3-hydroxy-1-tolylpyrrolidine-2-carboxylate (28c)

[0569] Tosylglycine methyl ester (28b) (5.00 g, 20.6 mmol) and 1-penten-3-one (2.07 g, 24.7 mmol) were dissolved in THF (50 mL) at room temperature. Under a nitrogen atmosphere, DBU (5.00 g, 32.9 mmol) was slowly added at 0°C and stirred at room temperature for 16 hours. The reaction was quenched by the addition of ice water and the pH was adjusted to less than 7 with 2 mol / L hydrochloric acid. The product was extracted with ethyl acetate (50 mL x 3), washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE / EA = 100 / 1 to 65 / 35) to obtain 4.9 g of the title compound as a yellow oil in a yield of 72.8%.

[0570] LC-MS: m / z 328.1[M+H] + .

[0571] Step 4: Preparation of methyl 3-ethyl-1-toluenesulfonyl-2,5-dihydro-1H-pyrrole-2-carboxylate (28d)

[0572] Methyl 3-ethyl-3-hydroxy-1-tolylpyrrolidine-2-carboxylate (28c) (4.90 g, 16.2 mmol) was dissolved in pyridine (10 mL) at room temperature. Phosphorus oxychloride (3.97 g, 25.9 mmol) was slowly added at 0°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 16 hours. The reaction was quenched by the addition of ice water, and the mixture was extracted with ethyl acetate (30 mL x 3), washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4.5 g (crude) of the title compound as a yellow oil.

[0573] LC-MS: m / z 310.1 [M+H] + .

[0574] Step 5: Preparation of methyl 3-ethyl-1H-pyrrole-2-carboxylate (28e)

[0575] Methyl 3-ethyl-1-tosyl-2,5-dihydro-1H-pyrrole-2-carboxylate (28d) (4.50 g, 14.6 mmol) and DBU (6.64 g, 43.7 mmol) were dissolved in toluene (20 mL) and stirred at 100°C under a nitrogen atmosphere for 16 hours. The mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE / EA = 100 / 1 to 7 / 3) to obtain 2.0 g of the title compound as a yellow oil in a yield of 89.8%.

[0576] LC-MS: m / z 154.1 [M+H] + .

[0577] The other steps were the same as those in Example 1, except that 3-ethyl-1H-pyrrole-2-carboxylic acid methyl ester (28e) was used instead of 1H-pyrrole-2-carboxylic acid methyl ester in step 1 to obtain the title compound 28.

[0578] LC-MS: m / z 488.1[M+H] + .

[0579] 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),8.38(q,J=4.8Hz,1H),8.08(d,J=1.9Hz,1H),7.99(d,J=2.8Hz,1H),7.82(d,J=8.4H z,1H),7.58(d,J=1.9Hz,1H),7.50(d,J=8.5Hz,1H),6.61(d,J=2.9Hz,1H),4.94(d,J=13.9Hz,1H),4.74(d,J=13.9Hz,1H), 4.02(dd,J=12.4,7.6Hz,1H),3.79(dd,J=12.4,3.8Hz,1H),3.60(s,2H),3.50(tt,J=7.2,3.5Hz,1H),3.35(q,J=5.0,4.1Hz ,2H),2.97(q,J=7.5Hz,2H),2.79(d,J=4.8Hz,3H),2.71-2.53(m,3H),2.39(dd,J=11.2,6.9Hz,1H),1.21(t,J=7.5Hz,3H).

[0580] Example 29: Preparation of (R)-N-methyl-3-((6-methyl-5-oxo-4,5-dihydropyrrolo[1,2-a]thieno[3,2-e]pyrazin-2-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (29)

[0581] Step 1: Preparation of methyl 1-(5-methoxycarbonyl)-3-nitrothiophen-2-yl)-3-methylpyrrole-2-carboxylate (29a)

[0582] Methyl 5-chloro-4-nitrothiophene-2-carboxylate (2.22 g, 10.0 mmol) was dissolved in N,N-dimethylformamide (25 mL) at room temperature. Methyl 3-methylpyrrole-2-carboxylate (1.84 g, 12.0 mmol) and cesium carbonate (4.07 g, 12.5 mmol) were added. The mixture was stirred at 60°C under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 100 / 1 to 4 / 1) to obtain 3.20 g of the title compound as a yellow solid in a 94.5% yield.

[0583] LC-MS: m / z 338.9 [M+H] + .

[0584] Step 2: Preparation of methyl 6-methyl-5-oxo-4,5-dihydropyrrolo[1,2-a]thieno[3,2-e]pyrazine-2-carboxylate (29b)

[0585] Methyl 1-(5-methoxycarbonyl)-3-nitrothiophen-2-yl)-3-methylpyrrole-2-carboxylate (29a) (3.10 g, 9.15 mmol) was dissolved in acetic acid (30 mL) at room temperature. Iron powder (2.05 g, 36.6 mmol) was added and stirred at 80°C for 2 hours. The mixture was filtered, and the filter cake was washed with methanol (100 mL). The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 19 / 1) to obtain 995 mg of the title compound as a yellow solid, in a yield of 41.5%.

[0586] LC-MS: m / z 262.9 [M+H] + .

[0587] Step 3: Preparation of 2-hydroxymethyl-6-methylpyrrolo[1,2-a]thieno[3,2-e]pyrazin-5(4H)one (29c)

[0588] Methyl 6-methyl-5-oxo-4,5-dihydropyrrolo[1,2-a]thieno[3,2-e]pyrazine-2-carboxylate (29b) (895 mg, 3.41 mmol) was dissolved in tetrahydrofuran (20 mL). Under a nitrogen atmosphere, a 2.5 M solution of lithium aluminum hydride in tetrahydrofuran (2.73 mL, 6.82 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of sodium sulfate decahydrate, filtered, and the filter cake was washed with methanol (50 mL). The filtrate was concentrated under reduced pressure, and the residue was isolated and purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 94 / 6) to obtain 409 mg of the title compound as a yellow solid in a 51.2% yield.

[0589] LC-MS: m / z 234.9 [M+H] + .

[0590] Step 4: Preparation of 6-methyl-5-oxo-4,5-dihydropyrrolo[1,2-a]thieno[3,2-e]pyrazine-2-carbaldehyde (29d)

[0591] 2-Hydroxymethyl-6-methylpyrrolo[1,2-a]thieno[3,2-e]pyrazin-5(4H)-one (29c) (359 mg, 1.53 mmol) was dissolved in dichloromethane (20 mL), and Dess-Martin periodinane (1.30 mg, 3.06 mmol) was added. The mixture was stirred at 40°C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 19 / 1) to obtain 561.4 mg of the crude title compound as a yellow solid.

[0592] LC-MS: m / z 232.9 [M+H] + .

[0593] The other steps were the same as those in Example 7, except that 6-methyl-5-oxo-4,5-dihydropyrrolo[1,2-a]thieno[3,2-e]pyrazine-2-carbaldehyde (29d) was used instead of 1-methyl-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]isoquinoline-2-carbaldehyde (7d) in step 5 to obtain the title compound 29.

[0594] LC-MS: m / z 479.1[M+H] + .

[0595] 1H NMR(400MHz,DMSO-d6)δ11.09(br,1H),8.41-8.36(m,1H),7.82(d,1H),7.51(d ,1H),7.45(d,1H),6.77(s,1H),6.42(d,1H),4.95(d,1H),4.74(d,1H),4.06-3 .99(m,1H),3.83-3.79(m,1H),3.76(br,1H),3.55-3.49(m,1H),3.39-3.34(m, 2H), 2.78 (d, J = 4.8Hz, 3H), 2.75-2.62 (m, 3H), 2.47 (s, 3H), 2.36-2.30 (m, 1H).

[0596] Example 30: Preparation of (R)-3-((7-isopropyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (30)

[0597] Step 1: Preparation of methyl 3-(prop-1-en-2-yl)-1H-pyrrole-2-carboxylate (30a)

[0598] Methyl 3-bromo-1H-pyrrole-2-carboxylate (2.00 g, 9.85 mmol) was dissolved in dioxane (20 mL) and water (2 mL) at room temperature. 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (2.48 g, 14.8 mmol), sodium carbonate (2.09 g, 19.7 mmol), and tetrakistriphenylphosphine palladium (2.28 g, 1.97 mmol) were added. The mixture was stirred at 80°C under a nitrogen atmosphere for 48 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE / EA = 100 / 1 to 7 / 3) to obtain 930 mg of the title compound as a yellow oil in a yield of 57.2%.

[0599] LC-MS: m / z 166.1 [M+H] + .

[0600] Step 2: Preparation of methyl 3-isopropyl-1H-pyrrole-2-carboxylate (30b)

[0601] Methyl 3-(prop-1-en-2-yl)-1H-pyrrole-2-carboxylate (30a) (930 mg, 5.64 mmol) was dissolved in MeOH (10 mL) at room temperature, and aqueous Pd / C (300 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The mixture was filtered, the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE / EA = 100 / 1 to 3 / 1) to obtain 800 mg of the title compound as a yellow oil in a yield of 84.9%.

[0602] LC-MS: m / z 168.1 [M+H] + .

[0603] The other steps were the same as those in Example 1, except that 3-isopropyl-1H-pyrrole-2-carboxylic acid methyl ester (30b) was used instead of 1H-pyrrole-2-carboxylic acid methyl ester in step 1 to prepare the title compound 30.

[0604] LC-MS: m / z 502.1[M+H] + .

[0605] 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),8.38(q,J=4.8Hz,1H),8.08(d,J=1.8Hz,1H),8.00(d,J=3.0Hz,1H),7.82( d,J=8.5Hz,1H),7.58(d,J=1.9Hz,1H),7.50(d,J=8.5Hz,1H),6.67(d,J=2.9Hz,1H),4.94(d,J=13.9Hz,1H),4.7 4(d,J=13.9Hz,1H),4.02(dd,J=12.3,7.6Hz,1H),3.87-3.73(m,2H),3.60(s,2H),3.50(tt,J=7.3,3.5Hz,2H),3 .00-2.90(m,1H),2.79(d,J=4.8Hz,3H),2.70-2.53(m,3H),2.38(dd,J=11.2,6.9Hz,1H),1.23(d,J=6.9Hz,6H).

[0606] Example 31: Preparation of (R)-N-methyl-3-((2-methyl-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-7-yl)methyl)-1,2,3,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (31)

[0607] Step 1: Preparation of methyl 3-bromo-1-methyl-1H-pyrazole-4-carboxylate (31a)

[0608] 3-Bromo-1-methyl-1H-pyrazole-4-carboxylic acid (800 mg, 3.92 mmol) was dissolved in DMF (15 mL), and cesium carbonate (1.90 g, 5.88 mmol) and iodomethane (668 mg, 4.71 mmol) were added. The mixture was stirred at room temperature for 16 hours, extracted with ethyl acetate (30 mL x 3), washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 82 / 18) to obtain 780 mg of the title compound as a yellow oil, in a yield of 89.5%.

[0609] LC-MS: m / z 219.0 [M+H] + .

[0610] Step 2: Preparation of 2-methyl-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-7-carboxylic acid (31b)

[0611] Methyl 3-bromo-1-methyl-1H-pyrazole-4-carboxylate (31a) (270 mg, 1.23 mmol) was dissolved in 1,4-dioxane (5 mL). Potassium carbonate (160 mg, 1.16 mmol), (2-amino-4-(methoxycarbonyl)phenyl)boronic acid (370 mg, 1.61 mmol), and Pd(pph3)4 (142 mg, 0.123 mmol) were added. The mixture was stirred at 110°C under a nitrogen atmosphere for 16 hours. The product was used directly in the next step without further treatment.

[0612] LC-MS: m / z 244.0 [M+H] + .

[0613] Step 3: Preparation of methyl 2-methyl-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-7-carboxylate (31c)

[0614] To the reaction mixture from the previous step was added iodomethane (132 mg, 0.926 mmol), stirred at 25°C for 16 hours, extracted with ethyl acetate (20 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1-82 / 18) to give 130 mg of the title compound as a yellow oil, with a two-step yield of 41%.

[0615] LC-MS: m / z 258.0 [M+H] + .

[0616] The other steps were the same as those in Example 1, except that 2-methyl-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-7-carboxylic acid methyl ester (31c) was used instead of 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3 to obtain the title compound 31.

[0617] LC-MS: m / z 474.1[M+H] + .

[0618] 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),8.52(s,1H),8.38(q,J=4.8Hz,1H),7.95(d,J=7.9Hz,1H),7.81(d ,J=8.5Hz,1H),7.50(d,J=8.5Hz,1H),7.35(d,J=1.4Hz,1H),7.16(dd,J=8.0,1.5Hz,1H),4.95(d,J=14. 0Hz,1H),4.74(d,J=14.0Hz,1H),4.08(s,3H),4.05(d,J=7.8Hz,1H),3.79(dd,J=12.3,3.9Hz,1H),3.65 -3.48(m,3H),3.40-3.35(m,2H),2.79(d,J=4.9Hz,3H),2.68-2.53(m,3H),2.40(dd,J=11.2,6.8Hz,1H).

[0619] Example 32: Preparation of (R)-N-(methyl-d3)-3-((1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinolin-7-yl)methyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (32)

[0620] Step 1: Preparation of methyl 5-bromo-1-methyl-1H-pyrazole-4-carboxylate (32a)

[0621] Dissolve 5-bromo-1-methyl-1H-pyrazole-4-carboxylic acid (800 mg, 3.92 mmol) in DMF (15 mL), add cesium carbonate (1.90 g, 5.88 mmol) and iodomethane (668 mg, 4.71 mmol). Stir at room temperature for 16 hours. Extract with ethyl acetate (20 mL x 3), wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 82 / 18) to obtain 780 mg of the title compound as a yellow oil, yield: 89.5%.

[0622] LC-MS: m / z 219.0 [M+H] + .

[0623] Step 2: Preparation of 1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-7-carboxylic acid (32b)

[0624] Methyl 5-bromo-1-methyl-1H-pyrazole-4-carboxylate (32a) (270 mg, 1.23 mmol) was dissolved in 1,4-dioxane (5 mL). Potassium carbonate (160 mg, 1.16 mmol), (2-amino-4-(methoxycarbonyl)phenyl)boronic acid (370 mg, 1.61 mmol), and Pd(pph3)4 (142 mg, 0.123 mmol) were added. The mixture was stirred at 110°C under a nitrogen atmosphere for 16 hours. The product was used directly in the next step without further treatment.

[0625] LC-MS: m / z 244.0 [M+H] + .

[0626] Step 3: Preparation of methyl 1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-7-carboxylate (32c)

[0627] To the reaction mixture from the previous step was added iodomethane (132 mg, 0.926 mmol), stirred at 25°C for 16 hours, extracted with ethyl acetate (20 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: EA / PE / EA = 100 / 1-4 / 1) to give 130 mg of the title compound as a yellow oil, with a two-step yield of 41%.

[0628] LC-MS: m / z 258.0 [M+H] + .

[0629] The other steps were the same as those in Example 1, except that 1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-7-carboxylic acid methyl ester (32c) was used instead of 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3, and (R)-8-((methyl-d3)carbamoyl)-1,2,4α ,15-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester (5b) was used instead of (R)-9-(methylcarbamoyl)-1,2,4α,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (1i) in step 10 to give the title compound 32.

[0630] LC-MS: m / z 463.1[M+H] + .

[0631] 1 H NMR(400MHz,DMSO-d6)δ11.36(s,1H),8.17(d,J=8.3Hz,1H),8.11(s,1H),8.07(s ,1H),7.53(d,J=8.1Hz,1H),7.46(d,J=1.7Hz,1H),7.31-7.25(m,2H),4.41(dd,J =10.9,2.9Hz,1H),4.35(s,3H),4.10-4.04(m,1H),3.80(d,J=12.0Hz,1H),3.74- 3.56(m,3H),3.26-3.20(m,1H),2.99-2.90(m,2H),2.80(td,J=11.9,3.2Hz,2H).

[0632] Example 33: Preparation of (R)-N-methyl-3-((4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (33)

[0633] Step 1: Preparation of methyl 4-fluoro-3-(1H-pyrazole-5-carboxamido)benzoate (33a)

[0634] 1H-Pyrazole-5-carboxylic acid (560 mg, 5.00 mmol) and methyl 4-fluoro-3-nitrobenzoate (1.27 mg, 7.50 mmol) were dissolved in pyridine (40 mL) at room temperature. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.92 mg, 10.0 mmol) was added. The mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM / MeOH = 100 / 1-98 / 2) to give 1.05 g of the title compound as a light yellow solid. Yield: 79.8%.

[0635] LC-MS: m / z 263.9 [M+H] + .

[0636] Step 2: Preparation of methyl 4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxylate (33b)

[0637] Methyl 4-fluoro-3-(1H-pyrazole-5-carboxamido)benzoate (33a) (150 mg, 0.570 mmol) was dissolved in acetonitrile (10 mL) at room temperature, and potassium carbonate (157 mg, 1.14 mmol) was added. The mixture was stirred at 90°C under a nitrogen atmosphere for 18 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: DCM / MeOH = 100 / 1 to 10 / 1) to afford 132 mg of the title compound as a light brown solid in a yield of 95.2%.

[0638] LC-MS: m / z 244.1[M+H] + .

[0639] The other steps were the same as the preparation method of Example 1, except that 4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxylic acid methyl ester (33b) was used instead of 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3, and (R)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (2f) was used instead of (R)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (1j) in step 11 to obtain the title compound 33.

[0640] LC-MS: m / z 446.1[M+H] + .

[0641] 1H NMR (400MHz, DMSO-d6) δ11.86(s,1H),8.20-8.07(m,2H),8.07(d,J=2.0Hz,1H),7.53(d,J=8.0Hz,1H ),7.40(d,J=1.6Hz,1H),7.33-7.21(m,2H),7.15(d,J=2.0Hz,1H),4.40(dd,J=10.8,2.8Hz,1H),4.06 (dd,J=11.2,8.8Hz,1H),3.80(d,J=12.0Hz,1H),3.66(d,J=13.2Hz,1H),3.59(d,J=13.2Hz,1H),3.2 2(s,1H),3.01-2.87(m,2H),2.85-2.72(m,4H),2.22(td,J=11.6,3.2Hz,1H),1.83(t,J=10.8Hz,1H).

[0642] Example 34: Preparation of (R)-N-methyl-3-((1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinolin-7-yl)methyl)-1,2,3,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (34)

[0643] The title compound 34 was prepared in the same manner as in Example 1, except that 1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-7-carboxylic acid methyl ester (32c) was used instead of 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3.

[0644] LC-MS: m / z 474.10 [M+H] + .

[0645] 1H NMR (400MHz, DMSO-d6) δ11.38(s,1H),8.38(q,J=4.8Hz,1H),8.17(d,J=8.3Hz,1H),8.06(s,1H),7.81(d,J =8.4Hz,1H),7.60-7.42(m,2H),7.27(dd,J=8.3,1.6Hz,1H),4.95(d,J=14.0Hz,1H),4.74(d,J=14.0Hz,1H) ,4.35(s,3H),4.08(dd,J=12.3,7.7Hz,1H),3.80(dd,J=12.3,3.9Hz,1H),3.63(s,2H),3.53(dq,J=7.6,3. 6Hz, 1H), 3.36 (s, 2H), 2.79 (d, J = 4.9Hz, 3H), 2.67-2.56 (m, 2H), 2.53 (s, 2H), 2.41 (dd, J = 11.2, 6.7Hz, 1H).

[0646] Example 35: Preparation of (R)-N-methyl-3-((4-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrazin-7-yl)methyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (35)

[0647] Step 1: Preparation of N-(5-bromo-2-fluoropyridin-3-yl)-1H-pyrazole-5-carboxamide (35a)

[0648] 5-Bromo-2-fluoropyridin-3-amine (1.50 g, 7.89 mmol) and 1H-pyrazole-5-carboxylic acid (1.06 g, 9.47 mmol) were dissolved in DMF (25 mL). HATU (4.50 g, 11.8 mmol) and DIEA (3.06 g, 23.7 mmol) were added, and the mixture was stirred at 80°C for 16 hours. 50 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The mixture was washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE / EA = 100 / 1 to 1 / 1) to obtain 1.70 g of the title compound as a white solid in a yield of 75.8%.

[0649] LC-MS: m / z 285.0 [M+H] + .

[0650] Step 2: Preparation of 7-bromopyrazolo[1,5-a]pyrido[3,2-e]pyrazin-4(5H)-one (35b)

[0651] N-(5-Bromo-2-fluoropyridin-3-yl)-1H-pyrazole-5-carboxamide (35a) (1.60 g, 5.63 mmol) was dissolved in DMSO (25 mL) at room temperature. Potassium carbonate (2.33 g, 16.9 mmol) was added and the mixture was stirred at 120°C for 16 hours. A solid precipitated upon addition of water. The solid was filtered and the filter cake washed with EA to afford 930 mg of the title compound as a white solid (crude product).

[0652] LC-MS: m / z 265.0 [M+H] + .

[0653] Step 3: Preparation of 7-(Hydroxymethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrazin-4(5H)-one (35c)

[0654] 7-Bromopyrazolo[1,5-a]pyrido[3,2-e]pyrazin-4(5H)-one (35b) (830 mg, 3.14 mmol) and (tributyltinyl)methanol (2.02 g, 6.29 mmol) were dissolved in dioxane (30 mL). Potassium carbonate (1.04 g, 7.52 mmol) and Ruphos-Pd-G2 (247 mg, 0.314 mmol) were added. The mixture was stirred at 120°C under a nitrogen atmosphere for 16 hours. The mixture was filtered and the filter cake was washed with EA to obtain 800 mg of the title compound as a white solid (crude product).

[0655] LC-MS: m / z 217.1 [M+H] + .

[0656] The other steps were the same as those in Example 1, except that 7-(hydroxymethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrazin-4(5H)-one (35c) was used instead of 3-(hydroxymethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (1c) in step 4, and (R)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (2f) was used instead of (R)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (1j) in step 11 to give the title compound 35.

[0657] LC-MS: m / z 447.0 [M+H] + .

[0658] 1H NMR (400MHz, DMSO-d6) δ11.89(s,1H),8.28(d,J=1.8Hz,1H),8.18-8.11(m,2H),7.75(d,J =1.8Hz,1H),7.53(d,J=8.1Hz,1H),7.29(d,J=8.2Hz,1H),7.21(d,J=1.9Hz,1H),4.39(dd, J=11.0,2.9Hz,1H),4.07(dd,J=10.9,8.9Hz,1H),3.84-3.62(m,3H),3.25-3.18(m,1H),3 .03-2.89(m,2H),2.83-2.72(m,4H),2.25(td,J=11.7,3.3Hz,1H),1.85(t,J=10.8Hz,1H).

[0659] Example 36: Preparation of (R)-3-((9-fluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (36)

[0660] Step 1: Preparation of 5-bromo-2,3-difluoroaniline (36a)

[0661] Dissolve 5-bromo-1,2-difluoro-3-nitrobenzene (3.00 g, 12.7 mmol) in water (20 mL) and ethanol (40 mL). Add iron powder (1.42 g, 25.3 mmol) and ammonium chloride (6.84 g, 126 mmol). Stir at 80°C for 16 hours. Filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (PE / EA = 100 / 1-3 / 2) to obtain 1.60 g of the title compound as a yellow oil (yield: 61.1%).

[0662] LC-MS: m / z 207.9 [M+H] + .

[0663] Step 2: Preparation of N-(5-bromo-2,3-difluorophenyl)-1H-pyrazole-5-carboxamide (36b)

[0664] 5-Bromo-2,3-difluoroaniline (36a) (1.60 g, 7.73 mmol) and 1H-pyrazole-5-carboxylic acid (952 mg, 8.50 mmol) were dissolved in DMF (25 mL). HATU (4.41 g, 11.6 mmol) and DIEA (2.99 g, 23.2 mmol) were added, and the mixture was stirred at 80°C for 16 hours. 50 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE / EA = 100 / 1 to 1 / 1) to obtain 1.30 g of the title compound as a yellow oil in a yield of 55.9%.

[0665] LC-MS: m / z 302.0 [M+H] + .

[0666] Step 3: Preparation of 7-bromo-9-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (36c)

[0667] N-(5-Bromo-2,3-difluorophenyl)-1H-pyrazole-5-carboxamide (36b) (1.30 g, 4.32 mmol) was dissolved in DMSO (15 mL) at room temperature, and potassium carbonate (1.79 g, 12.9 mmol) was added. The mixture was stirred at 120°C for 16 hours. Water was added to precipitate a solid, which was filtered and the filter cake washed with EA to give 450 mg of the title compound as a white solid (crude product).

[0668] LC-MS: m / z 282.0 [M+H] + .

[0669] Step 4: Preparation of 9-fluoro-7-(hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (36d)

[0670] 7-Bromo-9-fluoropyrazolo[1,5-a]quinoxaline-4(5H)-one (36c) (430 mg, 1.53 mmol) and (tributyltinyl)methanol (982 mg, 3.06 mmol) were dissolved in dioxane (12 mL). Ruphos-Pd-G2 (120 mg, 0.0153 mmol) was added and stirred at 90°C under a nitrogen atmosphere for 16 hours. Filter and wash the filter cake with EA to obtain 180 mg of the title compound as a white solid (crude product).

[0671] LC-MS: m / z 234.1[M+H] + .

[0672] The other steps were the same as those in Example 1, except that 9-fluoro-7-(hydroxymethyl)pyrazolo[1,5-a]quinoxaline-4(5H)-one (36d) was used instead of 3-(hydroxymethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (1c) in step 4, and (R)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (2f) was used instead of (R)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (1j) in step 11 to give the title compound 36.

[0673] LC-MS: m / z 464.1[M+H] + .

[0674] 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H),8.18-8.08(m,2H),7.53(d,J=8.1Hz,1H),7.29(d,J=8 .3Hz,1H),7.24(d,J=1.6Hz,1H),7.21-7.15(m,2H),4.41(dd,J=10.9,2.9Hz,1H),4.07(dd,J =11.0,8.9Hz,1H),3.87-3.76(m,1H),3.68-3.55(m,2H),3.23(ddd,J=11.5,5.8,3.0Hz,1H) ,3.01-2.88(m,2H),2.85-2.71(m,4H),2.24(td,J=11.6,3.2Hz,1H),1.84(t,J=10.8Hz,1H).

[0675] Example 37: Preparation of (R)-N-methyl-3-((5-oxo-5,6-dihydropyrrolo[1,2-c]quinazolin-8-yl)methyl)-1,2,3,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (37)

[0676] Step 1: Preparation of methyl 5-oxo-5,6-dihydropyrrolo[1,2-c]quinazoline-8-carboxylate (37a)

[0677] Methyl 3-amino-4-bromobenzoate (500 mg, 2.13 mmol) was dissolved in 1,4-dioxane (10 mL) and water (2 mL). Sodium carbonate (691 mg, 6.52 mmol), (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid (550 mg, 2.61 mmol), and Pd(dppf)Cl2 (159 mg, 0.217 mmol) were added. The mixture was stirred at 85°C overnight under a nitrogen atmosphere. The mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 2 / 1) to obtain 230 mg of the title compound as a reddish-brown solid in a yield of 44.6%.

[0678] LC-MS: m / z 243.1[M+H] + .

[0679] The other steps were the same as those in Example 1, except that 5-oxo-5,6-dihydropyrrolo[1,2-c]quinazoline-8-carboxylic acid methyl ester (37a) was used instead of 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3 to obtain the title compound 37.

[0680] LC-MS: m / z 459.1[M+H] + .

[0681] 1 H NMR(400MHz,DMSO-d6)δ11.45(s,1H),8.42-8.36(m,1H),7.87(d,1H),7.81(d,1 H),7.60-7.55(m,1H),7.50(d,1H),7.26(s,1H),7.17(dd,1H),6.98(dd,1H),6. 67(t,1H),4.95(d,1H),4.74(d,1H),4.09-4.02(m,1H),3.79(dd,1H),3.59-3.4 9(m,3H),3.40-3.35(m,2H),2.79(d,3H),2.68-2.57(m,3H),2.43-2.35(m,1H).

[0682] Example 38: Preparation of (R)-N-methyl-3-((6-oxo-5,6-dihydrothieno[3,4-c][1,5]naphthyridin-3-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (38)

[0683] Step 1: Preparation of methyl 6-oxo-5,6-dihydrothieno[3,4-c][1,5]naphthyridine-3-carboxylate (38a)

[0684] Methyl 5-amino-6-bromonicotinate (10a) (180 mg, 0.818 mmol) and (4-(methoxycarbonyl)thiophen-3-yl)boronic acid (198 mg, 1.06 mmol) were dissolved in water / 1,4-dioxane (1 mL / 5 mL). Pd(PPh3)4 (94.5 mg, 0.0818 mmol) and potassium carbonate (226 mg, 1.64 mmol) were added. The mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. Water (50 mL) was added, the mixture was filtered, and the filter cake was slurried with EA / PE = 1 / 5 to obtain 100 mg (crude) of the title compound as a yellow solid.

[0685] LC-MS: m / z 261.0 [M+H] + .

[0686] The other steps were the same as those in Example 1, except that 6-oxo-5,6-dihydrothieno[3,4-c][1,5]naphthyridine-3-carboxylic acid methyl ester (38a) was used instead of 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3 to obtain the title compound 38.

[0687] LC-MS: m / z 477.1[M+H] + .

[0688] 1 H NMR (400MHz, DMSO-d6) δ11.26(s,1H),8.56(d,J=3.2Hz,1H),8.44(d,J=3.2Hz,1H),8.38(q,J=4.8Hz,1 H),8.35(d,J=1.6Hz,1H),7.82(d,J=8.4Hz,1H),7.63(d,J=1.6Hz,1H),7.50(d,J=8.4Hz,1H),4.95(d, J=14.0Hz,1H),4.74(d,J=14.0Hz,1H),4.04(dd,J=12.4,7.6Hz,1H),3.79(dd,J=12.4,4.0Hz,1H),3.6 4(s,2H),3.55-3.48(m,1H),3.35(s,2H),2.78(d,J=4.8Hz,3H),2.68-2.57(m,3H),2.43-2.38(m,1H).

[0689] Example 39: Preparation of (R)-N-methyl-3-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)-1,2,3,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (39)

[0690] Step 1: Preparation of methyl 6-(1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)-5-nitronicotinate (39a)

[0691] Methyl 6-chloro-5-nitronicotinate (2.00 g, 9.26 mmol) and (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid (3.91 g, 18.5 mmol) were dissolved in dioxane (40 mL) at room temperature. 2N sodium carbonate solution (13.9 mL, 27.8 mmol) and Pd(pph3)2Cl2 (650 mg, 0.926 mmol) were added. Under a nitrogen atmosphere, the mixture was stirred at 100°C for 1 hour. Water (40 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE / EA = 100 / 1 to 72 / 28) to obtain 1.5 g of the title compound as a yellow solid in a yield of 46.7%.

[0692] LC-MS: m / z 348.1[M+H] + .

[0693] Step 2: Preparation of methyl 6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidine-3-carboxylate (39b)

[0694] Methyl 6-(1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)-5-nitronicotinate (39a) (1.50 g, 4.32 mmol) was dissolved in acetic acid (15 mL) at room temperature. Zinc powder (1.41 g, 21.6 mmol) was added, and the mixture was stirred at 100°C for 3 hours. The mixture was filtered, the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE / EA = 100 / 1 to 1 / 1) to obtain 360 mg of the title compound as a yellow-brown solid, in a yield of 34.3%.

[0695] LC-MS: m / z 244.1[M+H] + .

[0696] The other steps were the same as those in Example 1, except that 6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidine-3-carboxylic acid methyl ester (39b) was used instead of 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3 to obtain the title compound 39.

[0697] LC-MS: m / z 460.1 [M+H] + .

[0698] 1 H NMR (400MHz, DMSO-d6) δ11.61(s,1H),8.37(dd,J=13.3,3.4Hz,2H),7.82(d,J=8.5Hz,1H),7.67(dd,J=3.0,1.6 Hz,1H),7.59(d,J=1.8Hz,1H),7.50(d,J=8.5Hz,1H),7.07(dd,J=3.6,1.6Hz,1H),6.74(t,J=3.3Hz,1H),4.94( d,J=13.9Hz,1H),4.74(d,J=13.9Hz,1H),4.07-3.98(m,1H),3.79(dd,J=12.3,3.8Hz,1H),3.63(s,2H),3.55-3 .48(m,1H),3.41-3.35(m,2H),2.79(d,J=4.9Hz,3H),2.70-2.64(m,1H),2.62-2.53(m,2H),2.43-2.36(m,1H).

[0699] Example 40: Preparation of (R)-N-isopropyl-3-((6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-1,2,3,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (40)

[0700] Step 1: Preparation of (R)-9-(isopropylcarbamoyl)-1,2,4α15-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (40a)

[0701] (R)-3-(tert-Butoxycarbonyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[1,2-d]pyrido[2,3-b][1,4]oxazepane-9-carboxylic acid (6a) (300 mg, 0.859 mmol) and isopropylamine (101 mg, 1.72 mmol) were dissolved in DMF (3 mL) at room temperature. DIEA (333 mg, 2.58 mmol) was added and the mixture was stirred at room temperature for 20 minutes. HATU (654 mg, 1.72 mmol) was added, followed by 20 mL of water. The mixture was extracted with EA (10 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 290 mg of the title compound as a yellow oil (crude product).

[0702] LC-MS: m / z 391.2 [M+H] + .

[0703] The other steps were the same as the preparation method of Example 1, except that (R)-9-(isopropylcarbamoyl)-1,2,4α,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (40a) was used instead of (R)-9-(methylcarbamoyl)-1,2,4α,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (1i) in step 10 to obtain the title compound 40.

[0704] LC-MS: m / z 488.2 [M+H] + .

[0705] 1 H NMR(400MHz,DMSO-d6)δ11.34(s,1H),8.15(d,1H),8.11(dd,1H),8.06(d,1H),7.82(d,1H),7.66(d,1H),7.50(d,1H),7 .10(dd,1H),6.72(dd,1H),4.95(d,1H),4.76(d,1H),4.10-3.97(m,2H),3.79(dd,1H),3.62(s,2H),3.52-3.44(m,1H), 3.38-3.34(m,2H),2.72-2.58(m,3H),2.42-2.36(m,1H),1.17(d,1H).

[0706] Example 41: Preparation of (R)-N-methyl-3-((6-oxo-5,6-dihydrothieno[3,4-c][1,5]naphthyridin-3-yl)methyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (41)

[0707] The title compound 41 was prepared by the same preparation method as in Example 1, except that 6-oxo-5,6-dihydrothieno[3,4-c][1,5]naphthyridine-3-carboxylic acid methyl ester (38a) was used instead of 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3, and (R)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (2f) was used instead of (R)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (1j) in step 11.

[0708] LC-MS: m / z 463.1[M+H] + .

[0709] 1 H NMR (400MHz, DMSO-d6) δ11.25(s,1H),8.57(d,J=3.2Hz,1H),8.45(d,J=3.2Hz,1H),8.36(d,J=1.6Hz,1H),8.14( d,J=4.8Hz,1H),7.62(d,J=1.6Hz,1H),7.53(d,J=8.0Hz,1H),7.29(d,J=8.0Hz,1H),4.40(dd,J=11.2,3.2Hz,1H) ,4.06(dd,J=11.2,8.8Hz,1H),3.80(d,J=12.4Hz,1H),3.70(d,J=13.6Hz,1H),3.60(d,J=13.6Hz,1H),3.22(s,1 H), 2.99 (d, J = 11.2Hz, 1H), 2.92 (d, J = 10.4Hz, 1H), 2.85-2.71 (m, 4H), 2.30-2.20 (m, 1H), 1.84 (t, J = 10.8Hz, 1H).

[0710] Example 42: Preparation of (R)-3-((2-chloro-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrazin-7-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (42)

[0711] Step 1: Preparation of 3-chloro-1H-pyrazole-5-carboxylic acid (42a)

[0712] Dissolve methyl 3-chloro-1H-pyrazole-5-carboxylate (3.00 g, 18.8 mmol) in methanol (25 mL), add 2 mol / L sodium hydroxide solution (18.8 mL), and stir at room temperature for 16 hours. Add 2 mol / L hydrochloric acid to adjust the pH to <3, then concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (DCM / MeOH = 100 / 1 to 5 / 1) to obtain 1.80 g of the title compound as a white solid, in a yield of 65.8%.

[0713] LC-MS: m / z 147.0 [M+H] + .

[0714] Step 2: Preparation of 3-chloro-1H-pyrazole-5-carbonyl chloride (42b)

[0715] 3-Chloro-1H-pyrazole-5-carboxylic acid (42a) (1.70 g, 11.6 mmol) was dissolved in DCM (25 mL). Oxalyl chloride (5.92 g, 46.6 mmol) and DMF (0.1 mL) were added at 0°C. The mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours and concentrated under reduced pressure to afford 1.80 g (crude) of the title compound as a yellow oil.

[0716] LC-MS: m / z 165.0 [M+H] + .

[0717] Step 3: Preparation of N-(5-bromo-2-fluoropyridin-3-yl)-3-chloro-1H-pyrazole-5-carboxamide (42c)

[0718] 5-Bromo-2-fluoropyridin-3-amine (1.50 g, 7.89 mmol) and potassium carbonate (3.48 g, 23.7 mmol) were dissolved in THF (25 mL). 3-Chloro-1H-pyrazole-5-carbonyl chloride (42b) (1.94 g, 11.8 mmol) was added at 0°C. The mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (PE / EA = 100 / 1 to 73 / 17) to obtain 600 mg of the title compound as a white solid in a yield of 23.9%.

[0719] LC-MS: m / z 318.9 [M+H] + .

[0720] Step 4: Preparation of 7-bromo-2-chloropyrazolo[1,5-a]pyrido[3,2-e]pyrazin-4(5H)-one (42d)

[0721] N-(5-Bromo-2-fluoropyridin-3-yl)-3-chloro-1H-pyrazole-5-carboxamide (42c) (600 mg, 1.89 mmol) and potassium carbonate (781 mg, 5.66 mmol) were dissolved in DMSO (8 mL) at room temperature and stirred at 120°C for 16 hours. Water was added to precipitate a solid, which was filtered and the filter cake washed with acetonitrile to afford 330 mg of the title compound as a white solid (crude product).

[0722] LC-MS: m / z 298.9 [M+H] + .

[0723] Step 5: Preparation of 2-chloro-7-(hydroxymethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrazin-4(5H)-one (42e)

[0724] 7-Bromo-2-chloropyrazolo[1,5-a]pyrido[3,2-e]pyrazin-4(5H)-one (42d) (330 mg, 1.11 mmol) and (tributyltinyl)methanol (711 mg, 2.21 mmol) were dissolved in dioxane (10 mL), and Ruphos-Pd-G2 (87.0 mg, 0.110 mmol) was added. The mixture was stirred at 120°C under a nitrogen atmosphere for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by high-pressure preparative liquid chromatography (column model: Daisogei 30 mm*250 mm, C18, 10 μm 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% pure water) over 30 minutes to afford 60 mg of the title compound as a yellow solid, in a yield of 21.7%.

[0725] LC-MS: m / z 251.0 [M+H] + .

[0726] The other steps were the same as those in Example 1, except that 2-chloro-7-(hydroxymethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrazin-4(5H)-one (42e) was used instead of 3-(hydroxymethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (1c) in step 4, and (R)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (2f) was used instead of (R)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (1j) in step 11 to give the title compound 42.

[0727] LC-MS: m / z 481.1 [M+H] + .

[0728] 1 H NMR (400MHz, DMSO-d6) δ12.08(s,1H),8.27(d,J=1.8Hz,1H),8.14(q,J=4.8Hz,1H),7.74(d,J=1.9Hz,1H),7.53(d,J=8.1Hz,1H),7.34-7.24(m,2H), 4.39(dd,J=11.0,2.9Hz,1H),4.07(dd,J=11.0,8.9Hz,1H),3.81(d,J=11.9Hz,1H),3.69(q,J=13.6Hz,2H),3.25-3.19(m,1 H),3.02-2.88(m,2H),2.80(dd,J=12.0,3.2Hz,1H),2.75(d,J=4.8Hz,3H),2.25(td,J=11.6,3.2Hz,1H),1.91-1.82(m,1H).

[0729] Example 43: Preparation of (R)-N-methyl-3-((6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,5]naphthyridin-3-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (43)

[0730] The title compound 43 was prepared by the same preparation method as in Example 1, except that 6-oxo-6,7,8,9-tetrahydro-5H-cyclopenta[c][1,5]naphthyridine-3-carboxylic acid methyl ester (27f) was used instead of 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 2.

[0731] LC-MS: m / z 461.2 [M+H] + .

[0732] 1 H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.46-8.34(m,2H),7.82(d,J=8.4Hz,1H),7.67(s,1H),7 .50(d,J=8.5Hz,1H),4.94(d,J=13.9Hz,1H),4.74(d,J=14.0Hz,1H),4.03(dd,J=12.2,7.7Hz,1 H),3.78(dd,J=12.4,3.8Hz,1H),3.65(s,2H),3.50(s,1H),3.35(s,2H),3.17(t,J=7.5Hz,2H) ,2.80(dd,J=13.2,6.2Hz,5H),2.68-2.53(m,3H),2.39(t,J=9.1Hz,1H),2.11(q,J=7.5Hz,2H).

[0733] Example 44: Preparation of (R)-N-methyl-3-((4-oxo-4,5-dihydrothieno[3,4-c]quinolin-7-yl)methyl)-1,2,3,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (44)

[0734] Step 1: Preparation of methyl 4-oxo-4,5-dihydrothieno[3,4-c]quinoline-7-carboxylate (44a)

[0735] Methyl 4-bromothiophene-3-carboxylate (500 mg, 2.27 mmol) was dissolved in 20 mL of 1,4-dioxane and 2 mL of water (20 mL / 2 mL). (2-amino-4-(methoxycarbonyl)phenyl)boronic acid (630 mg, 2.72 mmol), potassium carbonate (626 mg, 4.54 mmol), and Ruphos-Pd-G3 (92.1 mg, 0.110 mmol) were added. The mixture was stirred at 100°C overnight under a nitrogen atmosphere. The mixture was quenched by the addition of 50 mL of water, extracted with EA (50 mL x 3), washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: DCM / MeOH = 100 / 1 to 10 / 1) to obtain 270 mg of the title compound as a brown oil in a yield of 45.9%.

[0736] LC-MS: m / z 260.0 [M+H] + .

[0737] The other steps were the same as those in Example 1, except that 4-oxo-4,5-dihydrothieno[3,4-c]quinoline-7-carboxylic acid methyl ester (44a) was used instead of 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3 to obtain the title compound 44.

[0738] LC-MS: m / z 476.1[M+H] + .

[0739] 1 H NMR(400MHz,DMSO-d6)δ8.50(d,1H),8.41-8.35(m,2H),8.04(d,1H),7.81(d,1H),7.50(d,1H),7.29(s,1H),7.14(d,1H),4.95(d,1H),4.7 3(d,1H),4.06(q,1H),3.79(dd,1H),3.57(d,2H),3.54-3.49(m,1H), 3.37-3.34(m,2H),2.78(d,3H),2.61-2.53(m,3H),2.41-2.33(m,1H).

[0740] Example 45: Preparation of (R)-N-methyl-3-((4-oxo-4,5-dihydrothieno[3,4-c]quinolin-7-yl)methyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (45)

[0741] The title compound 45 was prepared by the same preparation method as in Example 1, except that 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3 was replaced by 4-oxo-4,5-dihydrothieno[3,4-c]quinoline-7-carboxylic acid methyl ester (44a) and (R)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (2f) in step 11 was replaced by (R)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (1j) to obtain the title compound 45.

[0742] LC-MS: m / z 462.1[M+H] + .

[0743] 1 H NMR(400MHz,DMSO-d6)δ8.51-8.49(m,1H),8.38(d,1H),8.17-8.11(m,1H) ,8.05(d,1H),7.53(d,1H),7.31-7.26(m,2H),7.15(dd,1H),4.41(dd,1H) ,4.06(q,1H),3.79(d,1H),3.58(q,2H),3.26-3.18(m,1H),3.01-2.88(m, 2H),2.82-2.79(m,1H),2.74(d,3H),2.24-2.18(m,1H),1.85-1.72(m,1H).

[0744] Example 46: Preparation of (R)-3-((7-fluoro-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-N-(methyl-d3)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (46)

[0745] The title compound 46 was prepared by the same preparation method as in Example 1, except that 1H-pyrrole-2-carboxylic acid methyl ester in step 1 was replaced with 3-fluoro-1H-pyrrole-2-carboxylic acid ethyl ester, and (R)-9-((methyl-d3)carbamoyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (6b) was used instead of (R)-9-(methylcarbamoyl)-1,2,4α,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (1i) in step 10.

[0746] LC-MS: m / z 481.1 [M+H] + .

[0747] 1 H NMR (400MHz, DMSO-d6) δ11.22(s,1H),8.36(s,1H),8.12(d,J=1.6Hz,1H),7.97(dd,J=4.8,3.2Hz,1H), 7.82(d,J=8.4Hz,1H),7.61(d,J=1.6Hz,1H),7.50(d,J=8.4Hz,1H),6.65(d,J=3.2Hz,1H),4.94(d,J=1 3.6Hz,1H),4.74(d,J=13.6Hz,1H),4.02(dd,J=12.4,7.6Hz,1H),3.79(dd,J=12.4,3.6Hz,1H),3.61(s ,2H),3.50(dq,J=7.2,3.6Hz,1H),3.40-3.33(m,2H),2.72-2.53(m,3H),2.39(dd,J=11.2,6.8Hz,1H).

[0748] Example 47: Preparation of (R)-3-((8-fluoro-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-N-(methyl-d3)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (47)

[0749] The title compound 47 was prepared by the same preparation method as in Example 1, except that 1H-pyrrole-2-carboxylic acid methyl ester was used instead of 1H-pyrrole-2-carboxylic acid methyl ester in step 1, and (R)-9-((methyl-d3)carbamoyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (6b) was used instead of (R)-9-(methylcarbamoyl)-1,2,4α,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (1i) in step 10.

[0750] LC-MS: m / z 481.1 [M+H] + .

[0751] 1 H NMR (400MHz, DMSO-d6) δ11.55(s,1H),8.36(s,1H),8.17(d,J=1.6Hz,1H),8.06(dd,J=3.2,2.0Hz,1H) ,7.82(d,J=8.4Hz,1H),7.67(d,J=1.6Hz,1H),7.50(d,J=8.4Hz,1H),6.98(d,J=2.0Hz,1H),4.96-4.9 2(m,1H),4.74(d,J=13.6Hz,1H),4.02(dd,J=12.4,7.6Hz,1H),3.79(dd,J=12.4,3.6Hz,1H),3.63(s, 2H), 3.50 (dt, J=7.2, 3.6Hz, 1H), 3.36-3.33 (m, 2H), 2.69-2.58 (m, 3H), 2.40 (dd, J=11.2, 6.8Hz, 1H).

[0752] Example 48: Preparation of (R)-3-((8-ethyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (48)

[0753] Step 1: Preparation of methyl 4-vinyl-1H-pyrrole-2-carboxylate (48a)

[0754] Methyl 4-bromo-1H-pyrrole-2-carboxylate (3.00 g, 14.8 mmol), ethylene boronic anhydride pyridine complex (4.63 g, 19.2 mmol), Pd2(dba)3 (1.35 g, 1.48 mmol), dtbpf (1.40 g, 2.96 mmol), and K2CO3 (6.12 g, 44.3 mmol) were dissolved in H2O / 1,4-dioxane (30 mL / 90 mL) and stirred at 90°C for 16 hours under a nitrogen atmosphere. The product was extracted with ethyl acetate (50 mL x 3), washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 5 / 1) to obtain 1.13 g of the title compound as a yellow oil, in a yield of 50.6%.

[0755] LC-MS: m / z 152.1[M+H] + .

[0756] Step 2: Preparation of methyl 4-ethyl-1H-pyrrole-2-carboxylate (48b)

[0757] Methyl 4-vinyl-1H-pyrrole-2-carboxylate (48a) (1.08 g, 7.15 mmol) was dissolved in ethanol (15 mL), and aqueous palladium on carbon (110 mg) was added. The mixture was stirred at 25°C under a hydrogen atmosphere for 16 hours, filtered, and concentrated under reduced pressure to obtain 1.12 g (crude) of the title compound as a yellow oil.

[0758] LC-MS: m / z 154.1 [M+H] + .

[0759] The other steps were the same as those in Example 1, except that 4-ethyl-1H-pyrrole-2-carboxylic acid methyl ester (48b) was used instead of 1H-pyrrole-2-carboxylic acid methyl ester in step 1 to prepare the title compound 48.

[0760] LC-MS: m / z 488.2 [M+H] + .

[0761] 1H NMR (400MHz, DMSO-d6) δ11.26(s,1H),8.38(t,J=4.8Hz,1H),8.12(d,J=1.6Hz,1H),7.92(d,J=1.2Hz,1H),7.82 (d,J=8.4Hz,1H),7.62(d,J=1.6Hz,1H),7.50(d,J=8.4Hz,1H),6.96(d,J=1.6Hz,1H),4.94(d,J=13.6Hz,1H),4 .74(d,J=13.6Hz,1H),4.01(dd,J=12.0,7.6Hz,1H),3.79(dd,J=12.4,3.6Hz,1H),3.61(s,2H),3.50(s,1H),3. 34(s,3H),2.78(d,J=4.8Hz,3H),2.61(dd,J=14.0,8.4Hz,4H),2.39(dd,J=11.2,6.8Hz,1H),1.29-1.17(m,3H).

[0762] Example 49: Preparation of (R)-3-((8-cyclopropyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (49)

[0763] Step 1: Preparation of methyl 6-(4-bromo-2-(methoxycarbonyl)-1H-pyrrol-1-yl)-5-nitronicotinate (49a)

[0764] Methyl 4-bromo-1H-pyrrole-2-carboxylate (3.00 g, 14.8 mmol) and methyl 6-chloro-5-nitronicotinate (3.83 g, 17.7 mmol) were dissolved in acetonitrile (40 mL). Cesium carbonate (9.61 g, 29.6 mmol) was added and stirred at room temperature for 16 hours. The mixture was filtered, the filter cake was washed with acetonitrile, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE / EA = 100 / 1 to 7 / 3) to obtain 5.50 g of the title compound as a yellow solid in a yield of 97.2%.

[0765] LC-MS: m / z 384.0 [M+H] + .

[0766] Step 2: Preparation of 8-bromo-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (49b)

[0767] Methyl 6-(4-bromo-2-(methoxycarbonyl)-1H-pyrrol-1-yl)-5-nitronicotinate (49a) (5.40 g, 14.1 mmol) was dissolved in acetic acid (60 mL) at room temperature. Zinc powder (4.58 g, 70.5 mmol) was added and stirred at 100°C for 3 hours. A large amount of methanol was added and filtered. The filtrate was concentrated under reduced pressure. The residue was slurried in water, filtered, and the filter cake was washed with water to obtain 2.30 g (crude) of the title compound as a white solid.

[0768] LC-MS: m / z 322.0 [M+H] + .

[0769] Step 3: Preparation of 8-cyclopropyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (49c)

[0770] Methyl 8-bromo-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylate (49b) (600 mg, 1.87 mmol) and cyclopropylboronic acid (321 mg, 3.73 mmol) were dissolved in toluene / water (10 / 1) (18 mL) at room temperature. Potassium phosphate (1.19 g, 5.61 mmol) and Sphos-Pd-G1 (126 mg, 0.187 mmol) were added and microwaved at 130 °C under nitrogen atmosphere for 1 hour. The mixture was filtered and concentrated under reduced pressure. The residue was separated by high-pressure preparative liquid chromatography (column model: Daisogei 30 mm*250 mm, C18, 10 μm 100A, mobile phase: acetonitrile / water, gradient: 20%-50%, 0.05% formic acid, 30 min) to obtain 40 mg of the title compound as a white solid, yield: 7.6%.

[0771] LC-MS: m / z 284.1 [M+H] + .

[0772] The other steps were the same as those in Example 1, except that 8-cyclopropyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (49c) was used instead of 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3 to obtain the title compound 49.

[0773] LC-MS: m / z 500.2 [M+H] + .

[0774] 1H NMR (400MHz, DMSO-d6) δ11.28(s,1H),8.38(q,J=4.8Hz,1H),8.12(d,J =1.8Hz,1H),7.91(d,J=1.7Hz,1H),7.82(d,J=8.4Hz,1H),7.62(d,J=1.9Hz,1H),7.50(d,J=8.5Hz,1H),6 .84(d,J=1.8Hz,1H),4.94(d,J=13.9Hz,1H),4.74(d,J=13.9Hz,1H),4.01(dd,J=12.4,7.5Hz,1H),3.79(d d,J=12.3,3.8Hz,1H),3.61(s,2H),3.50(dq,J=7.4,3.6Hz,1H),2.78(d,J=4.8Hz,3H),2.71-2.55(m,3H) ,2.43-2.32(m,2H),1.94(ddd,J=8.4,5.1,3.3Hz,1H),1.24(s,1H),0.95-0.88(m,2H),0.70-0.62(m,2H).

[0775] Example 50: Preparation of (R)-3-((9-fluoro-6-oxo-5,6-dihydrobenzo[c][1,5]naphthyridin-3-yl)methyl)-N-(methyl-d3)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (50)

[0776] Step 1: Preparation of 6-(2-(methoxycarbonyl)phenyl)-5-nitronicotinic acid (50a)

[0777] Methyl 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (100 mg, 0.357 mmol) was dissolved in 1,4-dioxane (2 mL). Potassium carbonate (160 mg, 1.16 mmol), methyl 6-chloro-5-nitronicotinate (115 mg, 0.463 mmol), and Pd(pph3)4 (25.0 mg, 0.232 mmol) were added. The mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. The product was used directly in the next step without further treatment.

[0778] LC-MS: m / z 321.0 [M+H] + .

[0779] Step 2: Preparation of methyl 6-(5-fluoro-2-(methoxycarbonyl)phenyl)-5-nitronicotinate (50b)

[0780] To the reaction mixture from the previous step was added iodomethane (132 mg, 0.926 mmol), stirred at 25°C for 16 hours, extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1-5 / 1) to give 80 mg of the title compound as a yellow oil, with a two-step yield of 54.7%.

[0781] LC-MS: m / z 335.1[M+H] + .

[0782] Step 3: Preparation of methyl 9-fluoro-6-oxo-5,6-dihydrobenzo[c][1,5]naphthyridine-3-carboxylate (50c)

[0783] Methyl 6-(2-(methoxycarbonyl)phenyl)-5-nitronicotinate (50b) (300 mg, 0.896 mmol) was dissolved in acetic acid (3 mL), and zinc powder (450 mg, 6.96 mmol) was added. The mixture was stirred at 120°C for 16 hours. After filtration, the filter cake was dissolved in DMSO (8 mL), stirred at 60°C for 10 minutes, and filtered. Water (50 mL) was added to the filtrate, filtered, and the filter cake was collected and dried to give 160 mg of the title compound as a white solid (crude product).

[0784] LC-MS: m / z 273.0 [M+H] + .

[0785] The other steps were the same as those in Example 1, except that 9-fluoro-6-oxo-5,6-dihydrobenzo[c][1,5] Methyl naphthyridine-3-carboxylate (50c) was used instead of methyl 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylate (1b) in step 3, and tert-butyl (R)-9-((methyl-d3)carbamoyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylate (6b) was used instead of tert-butyl (R)-9-(methylcarbamoyl)-1,2,4α,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylate (1i) in step 10 to give the title compound 50.

[0786] LC-MS: m / z 492.1[M+H] + .

[0787] 1H NMR (400MHz, DMSO-d6) δ11.81(s,1H),8.51(d,J=1.8Hz,1H),8.43-8.28(m,2H),7.82(d,J=8.4Hz ,1H),7.73(d,J=1.9Hz,1H),7.59(td,J=8.6,2.7Hz,1H),7.51(d,J=8.5Hz,1H),4.96-4.92(m,1H) ,4.74(d,J=13.6Hz,1H),4.02(dd,J=12.4,7.6Hz,1H),3.79(dd,J=12.4,3.6Hz,1H),3.63(s,2H) ,3.50(dt,J=7.2,3.6Hz,1H),3.36-3.33(m,2H),2.69-2.58(m,3H),2.40(dd,J=11.2,6.8Hz,1H).

[0788] Example 51: Preparation of (R)-N-(methyl-d3)-3-((5-oxo-5,6-dihydrobenzo[h][1,6]naphthyridin-8-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (51)

[0789] The preparation method is the same as that of Example 1, except that 5-oxo-5,6-dihydrobenzo[h][1,6]naphthyridine-8-carboxylic acid methyl ester (25b) is used instead of 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3, and (R)-9-((methyl-d3)carbamoyl)-1,2,4a,5-tetrahydro-7H-pyrazine is used. The title compound 51 was prepared by replacing (R)-9-(methylcarbamoyl)-1,2,4α,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (6b) in step 10 with (R)-9-(methylcarbamoyl)-1,2,4α,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (1i).

[0790] LC-MS: m / z 474.2 [M+H] + .

[0791] 1H NMR (400MHz, DMSO-d6) δ11.86(s,1H),9.05(dd,J=4.6,1.6Hz,1H),8.63-8.53(m,2H),8.36(s,1H),7.82(d,J=8. 4Hz,1H),7.66(dd,J=8.0,4.4Hz,1H),7.51(d,J=8.4Hz,1H),7.42(d,J=1.6Hz,1H),7.29(dd,J=8.0,1.6Hz,1H),4 .96(d,J=14.0Hz,1H),4.74(d,J=14.0Hz,1H),4.09(dd,J=12.4,7.6Hz,1H),3.80(dd,J=12.4,3.6Hz,1H),3.64( d,J=3.2Hz,2H),3.55(dt,J=7.2,3.6Hz,1H),3.43-3.34(m,2H),2.72-2.57(m,3H),2.42(dd,J=11.2,6.6Hz,1H).

[0792] Example 52: Preparation of (R)-3-((8-chloro-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-N-(methyl-d3)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (52)

[0793] The title compound 52 was prepared by the same preparation method as in Example 1, except that 4-chloro-1H-pyrrole-2-carboxylic acid methyl ester was used instead of 1H-pyrrole-2-carboxylic acid methyl ester in step 1, and (R)-9-((methyl-d3)carbamoyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (6b) was used instead of (R)-9-(methylcarbamoyl)-1,2,4α,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (1i) in step 10.

[0794] LC-MS: m / z 497.1[M+H] + .

[0795] 1H NMR (400MHz, DMSO-d6) δ11.54(s,1H),8.36(s,1H),8.18(dd,J=6.8,1.6Hz,2H),7.82(d,J=8.4Hz,1H) ,7.67(d,J=1.6Hz,1H),7.50(d,J=8.4Hz,1H),7.11(d,J=1.6Hz,1H),4.94(d,J=14.0Hz,1H),4.74(d,J =13.6Hz,1H),4.02(dd,J=12.4,7.6Hz,1H),3.79(dd,J=12.4,3.6Hz,1H),3.63(s,2H),3.50(tt,J=7.2 ,3.6Hz,1H),3.34(d,J=4.8Hz,2H),2.63(ddt,J=26.4,15.2,8.0Hz,3H),2.40(dd,J=11.2,6.8Hz,1H).

[0796] Example 53: Preparation of (R)-3-((6-fluoro-2-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (53)

[0797] Step 1: Preparation of 3-methyl-1H-pyrazole-5-carboxylic acid (53a)

[0798] Ethyl 3-methyl-1H-pyrazole-5-carboxylate (3.00 g, 19.2 mmol) was dissolved in methanol (25 mL), and 2 mol / L sodium hydroxide (10 mL) was added. The mixture was stirred at room temperature for 16 hours. The pH was adjusted to 5-6 with 2 mol / L hydrochloric acid, and the mixture was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (DCM / MeOH = 100 / 1 to 8 / 1) to obtain 1.80 g of the title compound as a white solid, in a yield of 69.5%.

[0799] LC-MS: m / z 127.0 [M+H] + .

[0800] Step 2: Preparation of 3-methyl-1H-pyrazole-5-carbonyl chloride (53b)

[0801] 3-Methyl-1H-pyrazole-5-carboxylic acid (53a) (1.80 g, 12.6 mmol) was dissolved in DCM (25 mL). Oxalyl chloride (5.92 g, 46.6 mmol) and a drop of DMF were added at 0°C. The mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours and concentrated under reduced pressure to afford 1.90 g of the title compound as a yellow oil (crude product).

[0802] LC-MS: m / z 145.0 [M+H] + .

[0803] Step 3: Preparation of N-(3-bromo-2,6-difluorophenyl)-3-methyl-1H-pyrazole-5-carboxamide (53c)

[0804] 3-Methyl-1H-pyrazole-5-carbonyl chloride (53b) (1.40 g, 6.74 mmol) was dissolved in THF (25 mL), and potassium carbonate (3.48 g, 23.7 mmol) and 3-bromo-2,6-difluoroaniline (1.94 g, 11.8 mmol) were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 100 / 1 to 83 / 17) to obtain 660 mg of the title compound as a white solid, in a yield of 33.1%.

[0805] LC-MS: m / z 316.0 [M+H] + .

[0806] Step 4: Preparation of 7-bromo-6-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (53d)

[0807] N-(3-Bromo-2,6-difluorophenyl)-3-methyl-1H-pyrazole-5-carboxamide (53c) (500 mg, 1.58 mmol) and potassium carbonate (781 mg, 5.66 mmol) were dissolved in DMSO (8 mL) at room temperature and stirred at 120°C for 16 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 1 / 100) to obtain 120 mg of the title compound as a light yellow solid, in a yield of 25.7%.

[0808] LC-MS: m / z 296.0 [M+H] + .

[0809] Step 5: Preparation of 6-fluoro-7-(hydroxymethyl)-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (53e)

[0810] 7-Bromo-6-fluoro-2-methylpyrazolo[1,5-a]quinoxalin-4(5H)-one (53d) (120 mg, 0.407 mmol), (tributyltinyl)methanol (195 mg, 0.610 mmol), and Ruphos-Pd-G2 (87.0 mg, 0.110 mmol) were dissolved in dioxane (10.0 mL) and stirred at 100°C under a nitrogen atmosphere for 16 hours. The mixture was concentrated under reduced pressure, and 10 mL of EA / PE (1 / 3) was added to precipitate a solid. The solid was filtered and the filter cake was collected to give 70 mg of the title compound as a light yellow solid (crude product).

[0811] LC-MS: m / z 248.0 [M+H] + .

[0812] The other steps were the same as those in Example 1, except that 6-fluoro-7-(hydroxymethyl)-2-methylpyrazolo[1,5-a]quinoxaline-4(5H)-one (53e) was used instead of 3-(hydroxymethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (1c) in step 4 to obtain the title compound 53.

[0813] LC-MS: m / z 492.1[M+H] + .

[0814] 1 H NMR (400MHz, DMSO-d6) δ11.89(s,1H),8.38(q,J=4.8Hz,1H),7.87(dd,J=8.5,1.2Hz,1H),7.81(d,J=8.5Hz, 1H),7.48(d,J=8.5Hz,1H),7.32(dd,J=8.5,6.8Hz,1H),6.98(s,1H),4.92(d,J=13.8Hz,1H),4.74(d,J=13.8 Hz,1H),3.96(dd,J=12.4,7.2Hz,1H),3.78(dd,J=12.4,3.8Hz,1H),3.67(s,2H),3.50(tt,J=7.2,3.6Hz,1H) ,3.34(d,J=4.8Hz,2H),2.78(d,J=4.8Hz,3H),2.71-2.56(m,3H),2.43(s,3H),2.40(dd,J=11.2,6.8Hz,1H).

[0815] Example 54: Preparation of (R)-N-methyl-3-((2-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrazin-7-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[2,2-e][1,4]oxazepane-9-carboxamide (54)

[0816] The title compound 54 was prepared in the same manner as in Example 53, except that 5-bromo-2-fluoropyridin-3-amine was used instead of 3-bromo-2,6-difluoroaniline in step 3.

[0817] LC-MS: m / z 475.1 [M+H] + .

[0818] 1 H NMR (400MHz, DMSO-d6) δ11.80(s,1H),8.38(q,J=4.8Hz,1H),8.22(d,J=1.9Hz,1H),7.82(d,J=8.4Hz,1 H),7.72(d,J=1.9Hz,1H),7.51(d,J=8.6Hz,1H),6.98(s,1H),4.95(d,J=13.9Hz,1H),4.74(d,J=14.0H z,1H),4.03(dd,J=12.3,7.6Hz,1H),3.79(dd,J=12.3,3.9Hz,1H),3.65(s,2H),3.52(dd,J=7.2,3.6Hz ,1H),3.35(s,2H),2.78(d,J=4.9Hz,3H),2.71-2.56(m,3H),2.43(s,3H),2.40(dd,J=11.2,6.8Hz,1H).

[0819] Example 55: Preparation of (R)-N-methyl-3-((4-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrazin-7-yl)methyl)-1,2,3,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[2,2-e][1,4]oxazepane-9-carboxamide (55)

[0820] The title compound 55 was prepared in the same manner as in Example 1, except that 7-(hydroxymethyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrazin-4(5H)-one (35c) was used instead of 3-(hydroxymethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (1c) in step 4.

[0821] LC-MS: m / z 461.1 [M+H] + .

[0822] 1 H NMR (400MHz, DMSO-d6) δ11.93(s,1H),8.39(q,J=4.9Hz,1H),8.28(d,J=1.7Hz,1H),8.13(d,J=1.9Hz,1H),7.82(d,J =8.4Hz,1H),7.76(d,J=1.8Hz,1H),7.51(d,J=8.5Hz,1H),7.21(d,J=1.9Hz,1H),4.95(d,J=13.9Hz,1H),4.75(d,J= 13.9Hz,1H),4.03(dd,J=12.4,7.6Hz,1H),3.79(dd,J=12.3,3.8Hz,1H),3.67(s,2H),3.52(dq,J=7.3,3.6Hz,1H),3 .39-3.35(m,2H),2.79(d,J=4.7Hz,3H),2.68(q,J=5.5,4.7Hz,1H),2.63-2.56(m,2H),2.42(dd,J=11.2,6.8Hz,1H).

[0823] Example 56: Preparation of (R)-N-methyl-3-((4-oxo-4,5-dihydrofuro[2,3-c]quinolin-7-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (56)

[0824] Step 1: Preparation of methyl 3-bromofuran-2-carboxylate (56a)

[0825] Dissolve 3-bromofuran-2-carboxylic acid (4.0 g, 21.1 mmol) in methanol (5 mL) and dichloromethane (35 mL), add trimethylsilylated diazomethane (4.79 g, 42.1 mmol), and stir at room temperature for 2 hours. Concentrate under reduced pressure, and the residue is purified by silica gel column chromatography (PE / EA = 100 / 1 to 5 / 1) to obtain 5.0 g of the title compound as a white solid (yield: 99%).

[0826] LC-MS: m / z 204.9 [M+H] + .

[0827] Step 2: Preparation of (2-(methoxycarbonyl)furan-3-yl)boronic acid (56b)

[0828] Methyl 3-bromofuran-2-carboxylate (56a) (5.00 g, 24.5 mmol) and bispinacol boronate (18.7 g, 73.5 mmol) were dissolved in dioxane (120 mL). Pd(dppf)Cl2 (1.79 g, 2.45 mmol) and potassium acetate (7.21 g, 73.5 mmol) were added, and the mixture was stirred at 80°C under a nitrogen atmosphere for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE / EA = 100 / 1 to 5 / 1) to obtain 4.1 g of the title compound as a yellow solid in a yield of 97.8%.

[0829] LC-MS: m / z 171.0 [M+H] + .

[0830] Step 3: Preparation of methyl 4-oxo-4,5-dihydrofuro[2,3-c]quinoline-7-carboxylate (56c)

[0831] (2-(Methoxycarbonyl)furan-3-yl)boronic acid (56b) (736 mg, 4.33 mmol) and methyl 3-amino-4-iodobenzoate (1.00 g, 3.61 mmol) were dissolved in dioxane / water (6 / 1) (20 mL). Cesium carbonate (1.76 g, 5.42 mmol), Pd(dppf)Cl2 (264 mg, 0.361 mmol), and S-phos (148 mg, 0.361 mmol) were added. The mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure, slurried with water, filtered, and the filter cake washed with acetonitrile to obtain 550 mg (crude) of the title compound as a white solid.

[0832] LC-MS: m / z 244.1[M+H] + .

[0833] The other steps were the same as those in Example 1, except that 4-oxo-4,5-dihydrofuro[2,3-c]quinoline-7-carboxylic acid methyl ester (56c) was used instead of 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3 to obtain the title compound 56.

[0834] LC-MS: m / z 460.1 [M+H] + .

[0835] 1H NMR (400MHz, DMSO-d6) δ11.84(s,1H),8.38(q,J=4.8Hz,1H),8.23(d,J=2.0Hz,1H),7.97(d,J=8.0Hz,1H) ,7.81(d,J=8.4Hz,1H),7.53-7.43(m,3H),7.25(dd,J=8.0,1.6Hz,1H),4.95(d,J=14.0Hz,1H),4.74(d,J= 14.0Hz,1H),4.07(dd,J=12.3,7.8Hz,1H),3.79(dd,J=12.3,3.9Hz,1H),3.68-3.57(m,2H),3.53(dt,J=7 .3,3.6Hz,1H),3.41-3.35(m,2H),2.79(d,J=4.8Hz,3H),2.69-2.54(m,3H),2.40(dd,J=11.2,6.7Hz,1H).

[0836] Example 57: Preparation of (R)-N-methyl-3-((6-oxo-5,6-dihydrofuro[2,3-c][1,5]naphthyridin-3-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (57)

[0837] The title compound 57 was prepared in the same manner as in Example 56, except that 5-amino-6-bromonicotinate was used instead of 3-amino-4-iodobenzoic acid methyl ester in step 3.

[0838] LC-MS: m / z 461.1 [M+H] + .

[0839] 1H NMR (400MHz, DMSO-d6) δ12.02(s,1H),8.49(d,J=1.8Hz,1H),8.38(d,J=4.9Hz,1H),8.31(d,J=1.9Hz,1H) ,7.80(d,J=1.9Hz,1H),7.50(d,J=8.5Hz,1H),7.39(d,J=1.9Hz,1H),7.25(t,J=7.5Hz,1H),4.95(d,J=14 .0Hz,1H),4.74(d,J=14.0Hz,1H),4.05(dd,J=12.3,7.6Hz,1H),3.79(dd,J=12.3,3.8Hz,1H),3.69(s,2H ),3.54-3.50(m,1H),3.37(d,J=3.3Hz,2H),2.79(d,J=4.9Hz,3H),2.71-2.58(m,3H),2.44-2.39(m,1H).

[0840] Example 58: Preparation of (R)-N-methyl-3-((4-oxo-4,5-dihydrofuro[3,2-c]quinolin-7-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (58)

[0841] Step 1: Preparation of methyl 2-(4-bromo-2-nitrophenyl)furan-3-carboxylate (58a)

[0842] Dissolve 1,4-dibromo-2-nitrobenzene (4.40 g, 15.9 mmol) and methyl furan-3-carboxylate (2.00 g, 15.9 mmol) in toluene (25 mL). Add potassium acetate (4.67 g, 47.7 mmol) and tetrakistriphenylphosphine palladium (900 mg, 0.790 mmol). Stir at 100°C under a nitrogen atmosphere for 16 hours. Concentrate under reduced pressure, and purify the residue by silica gel column chromatography (PE / EA = 100 / 1 to 7 / 3) to obtain 1.2 g of the title compound as a white solid (yield: 24.3%).

[0843] LC-MS: m / z 326.0 [M+H] + .

[0844] Step 2: Preparation of 7-bromofuro[3,2-c]quinolin-(5H)-one (58b)

[0845] Methyl 2-(4-bromo-2-nitrophenyl)furan-3-carboxylate (58a) (1.00 g, 3.08 mmol) was dissolved in EtOH (20 mL) at room temperature. Zinc powder (990 mg, 15.4 mmol) and NH4Cl (172 mg, 30.8 mmol) were added, and the mixture was stirred at 80°C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 100 / 1 to 1 / 1) to give 350 mg of the title compound as a white solid in a yield of 43.2%.

[0846] LC-MS: m / z 264 [M+H] + .

[0847] Step 3: Preparation of 7-(hydroxymethyl)furo[3,2-c]quinolin-4(5H)-one (58c)

[0848] 7-Bromofuro[3,2-c]quinolin-(5H)-one (58b) (300 mg, 1.14 mmol) and (tributyltinyl)methanol (549 mg, 1.71 mmol) were dissolved in dioxane (10 mL). Ruphos-Pd-G2 (87.0 mg, 0.110 mmol) was added and stirred at 100°C under a nitrogen atmosphere for 16 hours. The mixture was concentrated under reduced pressure and 10 mL of EA / PE (1 / 3) was added to precipitate a solid, which was filtered to yield 150 mg of the crude product (the filter cake).

[0849] LC-MS: m / z 216.0 [M+H] + .

[0850] The other steps were the same as those in Example 1, except that 7-(hydroxymethyl)furo[3,2-c]quinolin-4(5H)-one (58c) was used instead of 3-(hydroxymethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (1c) in step 4 to obtain the title compound 58.

[0851] LC-MS: m / z 460.2 [M+H] + .

[0852] 1H NMR (400MHz, DMSO-d6) δ11.70(s,1H),8.38(q,J=4.7Hz,1H),8.07(d,J=2.0Hz,1H),7.88(d,J=8.1Hz,1H),7.8 1(d,J=8.5Hz,1H),7.61-7.45(m,2H),7.26(dd,J=8.1,1.5Hz,1H),7.05(d,J=2.0Hz,1H),4.95(d,J=14.1Hz,1H ),4.74(d,J=14.0Hz,1H),4.07(dd,J=12.3,7.8Hz,1H),3.79(dd,J=12.3,3.9Hz,1H),3.62(d,J=2.6Hz,2H),3. 54(dd,J=7.9,4.4Hz,1H),3.35(s,2H),2.79(d,J=4.8Hz,3H),2.67-2.53(m,3H),2.41(dd,J=11.2,6.8Hz,1H).

[0853] Example 59: Preparation of (R)-3-((7,9-dimethyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (59)

[0854] The title compound 59 was prepared by the same method as in Example 35, except that 3,5-dimethyl-1H-pyrrole-2-carboxylic acid was used instead of 1H-pyrazole-5-carboxylic acid in step 1.

[0855] LC-MS: m / z 488.2 [M+H] + .

[0856] 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.39(d,J=4.9Hz,1H),8.05(d,J=2.0Hz,1H),7.82(d,J=8.4Hz, 1H),7.55(d,J=2.0Hz,1H),7.50(d,J=8.5Hz,1H),6.28(s,1H),4.94(d,J=13.9Hz,1H),4.74(d,J=13.9 Hz,1H),4.02(dd,J=12.4,7.6Hz,1H),3.79(dd,J=12.3,3.8Hz,1H),3.58(s,2H),3.49(dt,J=7.2,3.6 Hz, 1H), 3.35 (s, 2H), 2.84-2.75 (m, 6H), 2.69-2.54 (m, 3H), 2.45 (s, 3H), 2.39 (dd, J = 11.2, 7.0Hz, 1H).

[0857] Example 60: Preparation of (R)-3-((8-isopropyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (60)

[0858] Step 1: Preparation of methyl 6-(4-bromo-2-(methoxycarbonyl)-1H-pyrrol-1-yl)-5-nitronicotinate (60a)

[0859] Methyl 4-bromo-1H-pyrrole-2-carboxylate (1.00 g, 4.93 mmol), methyl 6-chloro-5-nitronicotinate (1.17 g, 5.42 mmol), and cesium carbonate (3.20 g, 9.85 mmol) were dissolved in acetonitrile (30 mL) and stirred at room temperature for 16 hours. The mixture was filtered, the filter cake washed with acetonitrile, and the filtrate concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE / EA = 30%) to obtain 1.90 g of the title compound as a yellow oil (yield: 100%).

[0860] LC-MS: m / z 384.0 [M+H] + .

[0861] Step 2: Preparation of 6-(2-(methoxycarbonyl)-4-(prop-1-en-2-yl)-1H-pyrrol-1-yl)-5-nitronicotinic acid (60b)

[0862] Methyl 6-(4-bromo-2-(methoxycarbonyl)-1H-pyrrol-1-yl)-5-nitronicotinate (60a) (1.90 g, 4.96 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.67 g, 9.92 mmol), and sodium carbonate (1.05 g, 9.92 mmol) were dissolved in 1,4-dioxane (30 mL) and water (3 mL) at room temperature, and tetrakistriphenylphosphine palladium (1.15 g, 0.992 mmol) was added. The mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. Water (30 mL) was added, extracted with ethyl acetate (30 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE / EA = 30%) to give 1.0 g of the title compound as a white solid, yield: 60.9%.

[0863] LC-MS: m / z 332.1[M+H] + .

[0864] Step 3: Preparation of methyl 6-(2-(methoxycarbonyl)-4-(prop-1-en-2-yl)-1H-pyrrol-1-yl)-5-nitronicotinate (60c)

[0865] 6-(2-(Methoxycarbonyl)-4-(prop-1-en-2-yl)-1H-pyrrol-1-yl)-5-nitronicotinic acid (60b) (1.00 g, 3.02 mmol) was dissolved in DCM / MeOH (20 mL / 2 mL) at room temperature. (Diazomethyl)trimethylsilane (3 mL, 6.04 mmol) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 30%) to give 400 mg of the title compound as a yellow solid, in a 38.4% yield.

[0866] LC-MS: m / z 346.1[M+H] + .

[0867] Step 4: Preparation of methyl 6-oxo-8-(prop-1-en-2-yl)-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylate (60d)

[0868] Methyl 6-(2-(methoxycarbonyl)-4-(prop-1-en-2-yl)-1H-pyrrol-1-yl)-5-nitronicotinate (60c) (400 mg, 1.16 mmol) was dissolved in acetic acid (15 mL) at room temperature. Zinc powder (371 mg, 5.59 mmol) was added, and the mixture was stirred at 120°C for 16 hours. 100 mL of methanol was added, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried in water, filtered, and the filter cake was washed with water to obtain 350 mg of the title compound as a yellow solid (crude product).

[0869] LC-MS: m / z 284.1 [M+H] + .

[0870] Step 5: Preparation of 8-isopropyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (60e)

[0871] Methyl 6-oxo-8-(prop-1-en-2-yl)-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylate (60d) (300 mg, 1.06 mmol) was dissolved in MeOH (10 mL) at room temperature. Aqueous Pd / C (150 mg) was added and stirred at room temperature under a hydrogen atmosphere for 16 hours. The mixture was filtered, the filter cake was washed with copious amounts of ethanol, and the filtrate was concentrated under reduced pressure to afford 100 mg (crude) of the title compound as a white solid.

[0872] LC-MS: m / z 286.1[M+H] + .

[0873] The other steps were the same as those in Example 1, except that 8-isopropyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (60e) was used instead of 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3 to obtain the title compound 60.

[0874] LC-MS: m / z 502.2 [M+H] + .

[0875] 1H NMR (400MHz, DMSO-d6) δ11.27(s,1H),8.38(d,J=4.9Hz,1H),8.12(d,J=1.9Hz,1H),7.91(dd,J=1.8,0.8Hz,1H),7.82 (d,J=8.4Hz,1H),7.63(d,J=1.9Hz,1H),7.50(d,J=8.5Hz,1H),7.00(d,J=1.8Hz,1H),4.94(d,J=13.9Hz,1H),4.74(d ,J=13.9Hz,1H),4.02(dd,J=12.4,7.6Hz,1H),3.79(dd,J=12.3,3.8Hz,1H),3.62(s,2H),3.53-3.48(m,1H),3.34(d, J=5.8Hz,2H),3.01-2.93(m,1H),2.78(d,J=4.8Hz,3H),2.70-2.56(m,3H),2.41-2.36(m,1H),1.27(d,J=6.9Hz,6H).

[0876] Example 61: Preparation of (R)-N-methyl-3-((4-oxo-4,5-dihydrooxazolo[4,5-c]quinolin-7-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (61)

[0877] Step 1: Preparation of ethyl 5-(2-amino-4-bromophenyl)oxazole-4-carboxylate (61a)

[0878] 2-Amino-4-bromobenzoic acid (2.00 g, 9.31 mmol) and cesium carbonate (6.05 g, 18.6 mmol) were dissolved in DMF (40 mL). DPPA (5.12 g, 18.6 mmol) was added at 0°C and stirred at room temperature under a nitrogen atmosphere for 1 hour. Ethyl 2-isocyanate (1.10 g, 9.31 mmol) was added at 0°C and stirred at room temperature for 16 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 50%) to obtain 500 mg of the title compound as a yellow solid in a yield of 17.3%.

[0879] LC-MS: m / z 311.0 [M+H] + .

[0880] Step 2: Preparation of 7-bromooxazolo[4,5-c]quinolin-4(5H)-one (61b)

[0881] Ethyl 5-(2-amino-4-bromophenyl)oxazole-4-carboxylate (61a) (500 mg, 1.61 mmol) was dissolved in DMF (10 mL), and cesium carbonate (1.57 g, 4.84 mmol) was added. The mixture was stirred at 60°C under a nitrogen atmosphere for 16 hours. The reaction mixture was poured into water, filtered, and the filter cake was washed with acetonitrile to obtain 180 mg of the title compound as a white solid (crude product).

[0882] LC-MS: m / z 265.0 [M+H] + .

[0883] Step 3: Preparation of 7-(hydroxymethyl)oxazolo[4,5-c]quinolin-4(5H)-one (61c)

[0884] Dissolve 7-bromooxazolo[4,5-c]quinolin-4(5H)-one (61b) (150 mg, 0.568 mmol), (tributyltinyl)methanol (365 mg, 1.14 mmol), and Ruphos-Pd-G2 (44.7 mg, 0.0568 mmol) in 1,4-dioxane (5 mL) and stir at 120°C under a nitrogen atmosphere for 16 hours. Filter and wash the filter cake with DCM to afford 100 mg (crude) of the title compound as a dark brown solid.

[0885] LC-MS: m / z 217.1 [M+H] + .

[0886] The other steps were the same as those in Example 1, except that 7-(hydroxymethyl)oxazolo[4,5-c]quinolin-4(5H)-one (61c) was used instead of 3-(hydroxymethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (1c) in step 4 to obtain the title compound 61.

[0887] LC-MS: m / z 461.2 [M+H] +

[0888] 1H NMR (400MHz, DMSO-d6) δ11.98(s,1H),8.81(s,1H),8.38(q,J=4.9Hz,1H),7.90(d,J=8.1Hz,1 H),7.81(d,J=8.4Hz,1H),7.53-7.49(m,2H),7.31(dd,J=8.2,1.4Hz,1H),4.96(d,J=14.0Hz, 1H),4.74(d,J=14.0Hz,1H),4.11-4.04(m,1H),3.81-3.77(m,1H),3.65(s,2H),3.55(dq,J=7 .5,3.7Hz,1H),3.39-3.35(m,2H),2.79(d,J=4.7Hz,3H),2.60(s,3H),2.42(d,J=4.5Hz,1H).

[0889] Example 62: Preparation of (R)-N-methyl-3-((4-oxo-4,5-dihydrooxazolo[4,5-c][1,5]naphthyridin-7-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (62)

[0890] The other steps were the same as those of Example 61, except that 3-amino-5-bromopyridinic acid replaced 2-amino-4-bromobenzoic acid in Step 1, to obtain the title compound 62.

[0891] LC-MS: m / z 462.1[M+H] + .

[0892] 1H NMR (400MHz, DMSO-d6) δ12.12(s,1H),8.91(s,1H),8.54(d,J=1.6Hz,1H),8.39(q,J=4.8Hz,1H),7.86(d,J=1.6Hz,1H),7 .82(d,J=8.4Hz,1H),7.51(d,J=8.4Hz,1H),4.95(d,J=14.0Hz,1H),4.75(d,J=14.0Hz,1H),4.06(dd,J=12.3,7.6Hz,1H) ,3.80(dd,J=12.4,3.6Hz,1H),3.72(s,2H),3.53(tt,J=7.2,3.6Hz,1H),3.37(q,J=5.2,4.4Hz,2H),2.79(d,J=4.8Hz,3H ), 2.69(dd,J=11.2,4.8Hz,1H), 2.61(dd,J=11.2,3.2Hz,1H), 2.56(dd,J=6.8,4.0Hz,1H), 2.43(dd,J=11.2,6.8Hz,1H).

[0893] Example 63: Preparation of (R)-N-methyl-3-((1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]quinolin-7-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (63)

[0894] Step 1: Preparation of 1-methyl-1H-pyrrole-3-carboxylic acid (63a)

[0895] Methyl 1-methyl-1H-pyrrole-3-carboxylate (600 mg, 4.32 mmol) was dissolved in 15 / 2 / 2 mL THF / MeOH / H2O, and LiOH (544 mg, 12.9 mmol) was added. The mixture was stirred at 70°C overnight. 30 mL of water was added for dilution, and the pH was adjusted to 5-6 with saturated citric acid. The mixture was extracted with DCM (30 mL x 3), washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 750 mg of the title compound as a khaki solid (crude product).

[0896] LC-MS: m / z 126.0 [M+H] + .

[0897] Step 2: Preparation of 1-methyl-1H-pyrrole-3-carbonyl chloride (63b)

[0898] 1-Methyl-1H-pyrrole-3-carboxylic acid (63a) (750 mg, 6.00 mmol) was dissolved in 20 mL of DCM, and oxalyl chloride (838 mg, 6.60 mmol) and 1 drop of DMF were slowly added at 0°C. The mixture was stirred at room temperature overnight and concentrated under reduced pressure to afford 617 mg of the title compound as a yellow oil (crude product).

[0899] Step 3: Preparation of methyl 4-bromo-3-(1-methyl-1H-pyrrole-3-carboxamido)benzoate (63c)

[0900] Methyl 3-amino-4-bromobenzoate (941 mg, 4.11 mmol) was dissolved in 20 ml of DCM, and DIPEA (1.59 g, 12.3 mmol) and 1-methyl-1H-pyrrole-3-carbonyl chloride (63b) (617 mg, 4.31 mmol) were added. The mixture was stirred at room temperature overnight and quenched by the addition of 50 mL of water. The mixture was extracted with EA (30 mL x 3), washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 1 / 1) to give 300 mg of the title compound as a yellow solid in a yield of 21.7%.

[0901] LC-MS: m / z 337.0 [M+H] + .

[0902] Step 4: Preparation of methyl 1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]quinoline-7-carboxylate (63d)

[0903] Methyl 4-bromo-3-(1-methyl-1H-pyrrole-3-carboxamido)benzoate (63c) (300 mg, 0.890 mmol) was dissolved in 15 mL of 1,4-dioxane, and potassium acetate (175 mg, 1.78 mmol) and Pd(dppf)Cl2 (32.6 mg, 0.0400 mmol) were added. The mixture was stirred at 100°C overnight under a nitrogen atmosphere. 50 mL of water was added, and the mixture was extracted with EA (30 mL x 3), washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: DCM / MeOH = 100 / 1 to 10 / 1) to obtain 100 mg of the title compound as a dark gray solid in a yield of 43.8%.

[0904] LC-MS: m / z 257.1[M+H] + .

[0905] The other steps were the same as those in Example 1, except that 1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]quinoline-7-carboxylic acid methyl ester (63d) was used instead of 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3 to obtain the title compound 63.

[0906] LC-MS: m / z 473.2 [M+H] + .

[0907] 1 H NMR(400MHz,DMSO-d6)δ11.20(s,1H),8.39(d,1H),8.11(d,1H),7.81(d,1H),7.50(d,1H),7.41(s,1H),7.19-7.17(m,2H),6.58(d,1H),4.95(d ,1H),4.73(d,1H),4.14(s,3H),4.05(q,1H),3.79(dd,1H),3.59(d,2H) ,3.55-3.51(m,3H),2.79(d,3H),2.63-2.56(m,3H),2.42-2.39(m,1H).

[0908] Example 64: Preparation of (R)-3-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (64)

[0909] Step 1: Preparation of 4-fluoro-1H-pyrazole-3-carbonyl chloride (64a)

[0910] Dissolve 4-fluoro-1H-pyrazole-3-carboxylic acid (500 mg, 3.85 mmol) in DCM (15.0 mL). Add oxalyl chloride (0.49 mL, 5.77 mmol) and a drop of DMF at 0°C. Stir at room temperature under nitrogen for 3 hours. Concentrate under reduced pressure to obtain 470 mg of the title compound as a white solid (crude product).

[0911] Step 2: Preparation of N-(3-bromo-2,6-difluorophenyl)-4-fluoro-1H-pyrazole-3-carboxamide (64b)

[0912] 4-Fluoro-1H-pyrazole-3-carbonyl chloride (64a) (500 mg, 3.14 mmol) and potassium carbonate (999 mg, 7.25 mmol) were dissolved in THF (15 mL). 4-Fluoro-1H-pyrazole-3-carbonyl chloride (465 mg, 3.14 mmol) was added at 0°C. The mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (PE / EA = 50%) to afford 300 mg of the title compound as a white solid in a yield of 38.8%.

[0913] LC-MS: m / z 320.1[M+H] + .

[0914] Step 3: Preparation of 7-bromo-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (64c)

[0915] N-(3-Bromo-2,6-difluorophenyl)-4-fluoro-1H-pyrazole-3-carboxamide (64b) (280 mg, 0.877 mmol) and potassium carbonate (363 mg, 2.63 mmol) were dissolved in DMSO (5 mL) at room temperature and stirred at 120°C for 16 hours. The reaction mixture was poured into water, adjusted to pH <7 with 4 mol / L hydrochloric acid, and filtered. The filter cake was washed with acetonitrile to obtain 120 mg (crude) of the title compound as a white solid.

[0916] LC-MS: m / z 300.0 [M+H] + .

[0917] Step 4: Preparation of 3,6-difluoro-7-(hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (64d)

[0918] 7-Bromo-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (64c) (80.0 mg, 0.268 mmol), (tributyltinyl)methanol (172 mg, 0.535 mmol), and Ruphos-Pd-G2 (21.0 mg, 0.0268 mmol) were dissolved in 1,4-dioxane (3 mL) and stirred at 120°C under a nitrogen atmosphere for 16 hours. The mixture was filtered and the filter cake was washed with DCM to afford 100 mg of the title compound (crude) as a dark brown solid.

[0919] LC-MS: m / z 252.1[M+H] + .

[0920] The other steps were the same as those in Example 1, except that 3-(hydroxymethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (1c) in step 4 was replaced with 3,6-difluoro-7-(hydroxymethyl)pyrazolo[1,5-a]quinoxaline-4(5H)-one (64d) to obtain the title compound 64.

[0921] LC-MS: m / z 496.1[M+H] + .

[0922] 1 H NMR (400MHz, DMSO-d6) δ12.31(s,1H),8.38(d,J=5.0Hz,1H),8.20(d,J=3.8Hz,1H),7.90(dd,J=8.5 ,1.1Hz,1H),7.81(d,J=8.4Hz,1H),7.48(d,J=8.5Hz,1H),7.33(dd,J=8.6,6.7Hz,1H),4.92(d,J=13 .9Hz,1H),4.74(d,J=13.8Hz,1H),3.99-3.92(m,1H),3.78(dd,J=12.4,3.8Hz,1H),3.67(s,2H),3. 48-3.44(m,1H),3.41-3.37(m,2H),2.78(d,J=4.8Hz,3H),2.71-2.54(m,3H),2.43(d,J=7.2Hz,1H).

[0923] Example 65: Preparation of (R)-3-((3-chloro-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrazin-7-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[1,2-e][1,4]oxazepane-9-carboxamide (65)

[0924] The title compound 65 was prepared in the same manner as in Example 42, except that 4-chloro-1H-pyrazole-5-carboxylic acid was used instead of 3-chloro-1H-pyrazole-5-carboxylic acid (42a) in step 2.

[0925] LC-MS: m / z 495.1 [M+H] + .

[0926] 1H NMR(400MHz,DMSO-d6)11.92(br,1H),8.42-8.37(m,1H),8.28-8.23(m,2H),7.82(d,1H),7.72(d,1H),7.50(d,1H),4.9 7(d,1H),4.74(d,1H),4.07-3.99(m,1H),3.84-3.75(m,1H),3.67(s,2H),3.54-3.49(m,1H),3.41-3.37(m,2H),2.79(d, 3H),2.71-2.58(m,3H),2.45-2.39(m,1H).

[0927] Example 66: Preparation of (R)-N-(methyl-d3)-3-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)-1,2,3,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (66)

[0928] Step 1: Preparation of 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (66a)

[0929] Methyl 6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidine-3-carboxylate (39b) (330 mg, 1.36 mmol) was dissolved in THF (15 mL) at room temperature. Lithium borohydride (258 mg, 6.79 mmol) was slowly added at room temperature and stirred at 60°C under a nitrogen atmosphere for 16 hours. The reaction mixture was poured into ice water to quench, and the pH was adjusted to less than 7 with 2 mol / L hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 150 mg of the title compound as a yellow solid (crude product).

[0930] LC-MS: m / z 216.1 [M+H] + .

[0931] Step 2: Preparation of 3-(chloromethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (66b)

[0932] 3-(Hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (66a) (100 mg, 0.465 mmol) was dissolved in DCM (5 mL) at room temperature. Thionyl chloride (166 mg, 1.39 mmol) and a drop of DMF were added at 0°C. The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was concentrated under reduced pressure to afford 100 mg (crude) of the title compound as a brown solid.

[0933] Step 3: Preparation of (R)-N-(methyl-d3)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (66c)

[0934] To the solution of tert-butyl (R)-9-((methyl-d3)carbamoyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylate (6b) (150 mg, 0.411 mmol) in DCM (2 mL) at room temperature, a 4 M HCl / 1,4-dioxane solution (0.5 mL) was added, and the mixture was stirred at 25°C for 16 hours. The mixture was filtered and concentrated under reduced pressure to afford 90 mg of the title compound as a pale yellow solid (crude product).

[0935] LC-MS: m / z 266.2 [M+H] + .

[0936] Step 4: Preparation of (R)-N-(methyl-d3)-3-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)-1,2,3,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxathiophene-9-carboxamide (66)

[0937] 3-(Chloromethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (66b) (50.0 mg, 0.215 mmol) and (R)-N-(methyl-d3)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxirane-9-carboxamide (66c) (56.9 mg, 0.215 mmol) were dissolved in acetonitrile (2 mL) at room temperature. DIEA (0.5 mL) and sodium iodide (6.44 mg, 0.0429 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The residue was concentrated under reduced pressure, and separated by high pressure preparative liquid chromatography (column model: Daisogei 30 mm*250 mm, C18, 10 μm 100A, mobile phase: acetonitrile / water, gradient: 20%-50%, 0.05% formic acid) in 30 min to afford 11 mg of the title compound as a white solid, in a yield of 11.1%.

[0938] LC-MS: m / z 463.2 [M+H] + .

[0939] 1 H NMR(400MHz, DMSO-d6)11.61(s,1H),8.39-8.32(m,2H),7.82(d,J=8.4Hz,1H),7.67(dd,J=3.0,1.6Hz,1H) ,7.58(d,J=1.8Hz,1H),7.50(d,J=8.4Hz,1H),7.07(dd,J=3.6,1.6Hz,1H),6.74(t,J=3.3Hz,1H),4.94(d, J=13.9Hz,1H),4.74(d,J=14.0Hz,1H),4.03(dd,J=12.4,7.6Hz,1H),3.79(dd,J=12.4,3.8Hz,1H),3.63(s ,2H),3.51(dq,J=7.5,3.7Hz,1H),3.35(d,J=4.8Hz,2H),2.70-2.57(m,3H),2.40(dd,J=11.2,6.9Hz,1H).

[0940] Example 67: Preparation of (R)-N-methyl-3-((8-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[3,4-c][1,5]naphthyridin-3-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (67)

[0941] Step 1: Preparation of 1-(tert-butyl)3-ethyl-4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate (67a)

[0942] 1-(tert-Butyl)-3-ethyl-4-oxopyrrolidine-1,3-dicarboxylate (5.00 g, 19.5 mmol) was dissolved in toluene (90 mL) at room temperature. DIPEA (3.77 g, 1.50 mmol) was added at 0°C and stirred for 1 hour. Trifluoromethanesulfonic anhydride (6.57 g, 23.3 mmol) was added at 0°C and stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was quenched with water, extracted with EA (50 mL x 3), washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: EA / PE = 20%) to obtain 4.0 g of the title compound as a yellow oil in a 52.9% yield.

[0943] LC-MS: m / z 390.1[M+H] + .

[0944] Step 2: Preparation of (1-(tert-Butyloxycarbonyl)-4-(ethoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)boronic acid (67b)

[0945] 1-(tert-Butyl)-3-ethyl-4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate (67a) (4.00 g, 10.3 mmol), bis(pinacolato)diboron (3.13 g, 12.3 mmol), Pd(dppf)Cl2 (752 mg, 1.03 mmol), and potassium acetate (2.02 g, 20.6 mmol) were dissolved in 1,4-dioxane (80 mL) at room temperature and stirred at 80°C under a nitrogen atmosphere for 16 hours. The mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: EA / PE = 20%) to give 4.50 g of the title compound as a yellow oil (yield: 100%).

[0946] LC-MS: m / z 286.1[M+H] + .

[0947] Step 3: Preparation of tert-butyl 3-bromo-6-oxo-5,6,7,9-tetrahydro-8H-pyrrolo[3,4-c][1,5]naphthyridine-8-carboxylate (67c)

[0948] (1-(tert-Butyloxycarbonyl)-4-(ethoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)boronic acid (67b) (4.50 g, 15.8 mmol), 2,5-dibromopyridin-3-amine (3.32 g, 13.1 mmol), potassium carbonate (3.63 g, 26.3 mmol), and Pd(PPh3)4 (1.52 g, 1.32 mmol) were dissolved in 1,4-dioxane (60 mL) and water (10 mL) at room temperature. The mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. The mixture was filtered and the filter cake was washed with acetonitrile to give 1.10 g (crude) of the title compound as a white solid.

[0949] LC-MS: m / z 286.1[M+H] + .

[0950] Step 4: Preparation of tert-butyl 3-(hydroxymethyl)-6-oxo-5,6,7,9-tetrahydro-8H-pyrrolo[3,4-c][1,5]naphthyridine-8-carboxylate (67d)

[0951] Tert-butyl 3-bromo-6-oxo-5,6,7,9-tetrahydro-8H-pyrrolo[3,4-c][1,5]naphthyridine-8-carboxylate (67c) (1.10 g, 3.01 mmol), (tributyltinyl)methanol (1.93 g, 6.03 mmol), and Ruphos-Pd-G2 (237 mg, 0.301 mmol) were dissolved in 1,4-dioxane (20 mL) at room temperature under a nitrogen atmosphere and stirred for 16 hours. The mixture was filtered, and the filtrate was slurried with petroleum ether and filtered. The filter cake was washed with dichloromethane to obtain 800 mg of the title compound as a brown solid (crude product).

[0952] LC-MS: m / z 318.1 [M+H] + .

[0953] Step 5: Preparation of tert-butyl 3-(((methylsulfonyl)oxy)methyl)-6-oxo-5,6,7,9-tetrahydro-8H-pyrrolo[3,4-c][1,5]naphthyridine-8-carboxylate (67e)

[0954] Tert-butyl 3-(hydroxymethyl)-6-oxo-5,6,7,9-tetrahydro-8H-pyrrolo[3,4-c][1,5]naphthyridine-8-carboxylate (67d) (500 mg, 1.58 mmol) and triethylamine (239 mg, 2.37 mmol) were dissolved in DCM (15 mL) at room temperature. Methanesulfonic anhydride (330 mg, 1.89 mmol) was added and stirred at room temperature for 2 hours. The mixture was quenched by the addition of saturated sodium bicarbonate solution (30 mL), extracted with DCM (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 400 mg of the title compound as a yellow solid (crude product).

[0955] LC-MS: m / z 396.1[M+H] + .

[0956] Step 6: Preparation of (R)-3-((9-(methylcarbamoyl)-1,2,4-a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepan-3(4H)-yl)methyl)-6-oxo-5,6,7,9-tetrahydro-8H-pyrrolo[3,4-c][1,5]naphthyridine-8-carboxylic acid tert-butyl ester (67f)

[0957] Tert-butyl 3-(((methylsulfonyl)oxy)methyl)-6-oxo-5,6,7,9-tetrahydro-8H-pyrrolo[3,4-c][1,5]naphthyridine-8-carboxylate (67e) (196 mg, 0.496 mmol) and (R)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (1j) (130 mg, 0.496 mmol) were dissolved in acetonitrile (8 mL) at room temperature. Sodium iodide (14.9 mg, 0.0992 mmol) and DIEA (0.8 mL) were added, and the mixture was stirred at 40°C under nitrogen atmosphere for 16 hours. The residue was concentrated under reduced pressure, and separated by high pressure preparative liquid chromatography (column model: Daisogei 30 mm*250 mm, C18, 10 μm 100A, mobile phase: acetonitrile / water, gradient: 30%-60%, 0.05% aqueous ammonia, 30 min) to afford 60 mg of the title compound as a white solid, in a yield of 21.6%.

[0958] LC-MS: m / z 562.2 [M+H] + .

[0959] Step 7: Preparation of (R)-N-methyl-3-((6-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[3,4-c][1,5]naphthyridin-3-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (67 g)

[0960] (R)-tert-Butyl 3-((9-(methylcarbamoyl)-1,2,4-a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepan-3(4H)-yl)methyl)-6-oxo-5,6,7,9-tetrahydro-8H-pyrrolo[3,4-c][1,5]naphthyridine-8-carboxylate (67f) (60.0 mg, 0.107 mmol) was dissolved in DCM (1 mL) at room temperature. 4 M hydrochloric acid in dioxane (1 mL) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to give 50 mg of the title compound as a yellow solid (crude product).

[0961] LC-MS: m / z 462.2 [M+H] + .

[0962] Step 8: Preparation of (R)-N-methyl-3-((8-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[3,4-c][1,5]naphthyridin-3-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (67)

[0963] (R)-N-Methyl-3-((6-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[3,4-c][1,5]naphthyridin-3-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (67 g) (40.0 mg, 0.0868 mmol), paraformaldehyde (21.1 mg, 0.261 mmol) and tetraethyl titanate (59.3 mg, 0.261 mmol) were dissolved in DCM / MeOH (3 mL) at room temperature and stirred at 60°C for 2 hours. Sodium cyanoborohydride (16.4 mg, 0.261 mmol) was added at room temperature, and the mixture was stirred at 60°C for 16 hours under nitrogen atmosphere. The residue was concentrated under reduced pressure, and separated by high-pressure preparative liquid chromatography (column model: Daisogei 30 mm*250 mm, C18, 10 μm 100A, mobile phase: acetonitrile / water, gradient: 30%-60%, 0.05% ammonia water) after 30 min to afford 4 mg of the title compound as a white solid, in a yield of 9.71%.

[0964] LC-MS: m / z 476.2 [M+H] + .

[0965] 1 H NMR(400MHz, DMSO-d6)11.86(s,1H),8.44-8.35(m,2H),7.82(d,J=8.4Hz,1H),7.70(d,J=1.8Hz,1H) ,7.50(d,J=8.6Hz,1H),4.94(d,J=13.9Hz,1H),4.74(d,J=13.9Hz,1H),4.24(t,J=3.7Hz,2H),4.06- 4.01(m,1H),3.89(t,J=3.5Hz,2H),3.79(dd,J=12.3,3.8Hz,1H),3.66(s,2H),3.51(dq,J=7.3,3.6H z, 1H), 3.35 (d, J = 5.1Hz, 2H), 2.79 (d, J = 4.8Hz, 3H), 2.70-2.53 (m, 6H), 2.40 (dd, J = 11.2, 6.9Hz, 1H).

[0966] Example 68: Preparation of (R)-N-methyl-3-((2-methyl-5-oxo-5,6-dihydroimidazo[1,2-c]quinazolin-8-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (68)

[0967] Step 1: Preparation of tert-butyl 2-bromo-4-methyl-1H-imidazole-1-carboxylate (68a)

[0968] Dissolve 2-bromo-4-methyl-1H-imidazole (1.00 g, 6.25 mmol) in 20 mL of DCM, add Boc2O (1.36 g, 6.25 mmol), triethylamine (631 mg, 6.25 mmol), and DMAP (38.1 mg, 0.312 mmol), and stir at room temperature overnight. Concentrate under reduced pressure, and the residue is purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 1 / 100) to obtain 1.40 g of the crude title compound as a colorless oil (yield: 87.5%).

[0969] LC-MS: m / z 261[M+H] + .

[0970] Step 2: Preparation of methyl 2-methyl-5-oxo-5,6-dihydroimidazo[1,2-c]quinazoline-8-carboxylate (68b)

[0971] Tert-butyl 2-bromo-4-methyl-1H-imidazole-1-carboxylate (68a) (500 mg, 1.32 mmol) was dissolved in 20 / 2.5 mL dioxane / H₂O. (2-amino-4-(methoxycarbonyl)phenyl)boronic acid (533 mg, 2.31 mmol), K₂CO₃ (530 mg, 3.84 mmol), and Pd(dppf)Cl₂ (70.3 mg, 0.0960 mmol) were added. The mixture was stirred at 100°C overnight under a nitrogen atmosphere. The mixture was quenched by the addition of 50 mL of water, extracted with EA (30 mL x 3), washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: PE / EA = 100 / 1 to 1 / 100) to obtain 120 mg of the crude title compound as a gray solid in a yield of 24.3%.

[0972] LC-MS: m / z 258 [M+H] + .

[0973] The other steps were the same as those in Example 1, except that 2-methyl-5-oxo-5,6-dihydroimidazo[1,2-c]quinazoline-8-carboxylic acid methyl ester (68b) was used instead of 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3 to obtain the title compound 68.

[0974] LC-MS: m / z 474.2 [M+H] + .

[0975] 1 H NMR(400MHz,DMSO-d6)δ11.20(s,1H),8.39(d,1H),8.11(d,1H),7.81(d,1H),7.50(d,1H),7.41(s,1H),7.19-7.17(m,1H),6.58(d,1H),4.95(d ,1H),4.73(d,1H),4.14(s,3H),4.05(q,1H),3.79(dd,1H),3.59(d,2H) ,3.55-3.51(m,3H),2.79(d,3H),2.63-2.56(m,3H),2.42-2.39(m,1H).

[0976] Example 69: Preparation of (R)-N-methyl-3-((3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrazin-7-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[1,2-e][1,4]oxazepane-9-carboxamide (69)

[0977] Step 1: Preparation of 4-methyl-1H-pyrazole-5-carbonyl chloride (69a)

[0978] Dissolve 4-methyl-1H-pyrazole-5-carboxylic acid (4.00 g, 31.7 mmol) in DCM (100 mL), add oxalyl chloride (6.05 g, 47.6 mmol) and a drop of DMF at 0°C, stir at room temperature under a nitrogen atmosphere for 3 hours, and concentrate under reduced pressure to obtain 4.2 g (crude) of the title compound as a yellow oil.

[0979] LC-MS: m / z 145.0 [M+H] + .

[0980] Step 2: Preparation of N-(5-bromo-2-fluoropyridin-3-yl)-4-methyl-1H-pyrazole-5-carboxamide (69b)

[0981] 5-Bromo-2-fluoropyridin-3-amine (1.32 g, 6.94 mmol) was dissolved in THF (25 mL), and potassium carbonate (3.48 g, 23.7 mmol) and 4-methyl-1H-pyrazole-5-carbonyl chloride (69a) (1.00 g, 6.94 mmol) were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 30%) to obtain 1.2 g of the title compound as a white solid (yield: 59.6%).

[0982] LC-MS: m / z 299[M+H] + .

[0983] Step 3: Preparation of 7-bromo-3-methylpyrazolo[1,5-a]pyrido[3,2-e]pyrazin-4(5H)-one (69c)

[0984] N-(5-Bromo-2-fluoropyridin-3-yl)-4-methyl-1H-pyrazole-5-carboxamide (69b) (500 mg, 1.67 mmol) and potassium carbonate (781 mg, 5.66 mmol) were dissolved in DMSO (8 mL) at room temperature and stirred at 120°C for 16 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20.0 mL x 3). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: EA / PE = 100%) to give 260 mg of the title compound as a light yellow solid, in a yield of 56.5%.

[0985] LC-MS: m / z 279[M+H] + .

[0986] Step 4: Preparation of 7-(hydroxymethyl)-3-methylpyrazolo[1,5-a]pyrido[3,2-e]pyrazin-4(5H)-one (69d)

[0987] 7-Bromo-3-methylpyrazolo[1,5-a]pyrido[3,2-e]pyrazin-4(5H)-one (69c) (200 mg, 0.760 mmol), (tributyltinyl)methanol (366 mg, 1.14 mmol), and Ruphos-Pd-G2 (60.0 mg, 0.076 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 100°C under a nitrogen atmosphere for 16 hours. The mixture was concentrated under reduced pressure, and 10 mL of EA / PE (1 / 3) was added. The filter cake was filtered to obtain 150 mg of the title compound as a dark gray solid (crude product).

[0988] LC-MS: m / z 231.0 [M+H] + .

[0989] The other steps were the same as those in Example 1, except that 7-(hydroxymethyl)-3-methylpyrazolo[1,5-a]pyrido[3,2-e]pyrazin-4(5H)-one (69d) was used instead of 3-(hydroxymethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (1c) in step 4 to obtain the title compound 69.

[0990] LC-MS: m / z 475.2 [M+H] + .

[0991] 1 H NMR (400MHz, DMSO-d6) δ11.74(s,1H),8.38(d,J=5.0Hz,1H),8.19(d,J=1.9Hz,1H),7.94(s,1H), 7.82(d,J=8.4Hz,1H),7.68(d,J=1.9Hz,1H),7.50(d,J=8.6Hz,1H),4.94(d,J=13.9Hz,1H),4.74 (d,J=13.9Hz,1H),4.03(dd,J=12.4,7.6Hz,1H),3.79(dd,J=12.3,3.8Hz,1H),3.64(s,2H),3.36 (d,J=5.1Hz,2H),2.79(d,J=4.8Hz,3H),2.67(d,J=10.9Hz,1H),2.63-2.53(m,2H),2.44(s,4H).

[0992] Example 70: Preparation of (R)-N-methyl-3-((3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (70)

[0993] Step 1: Preparation of methyl 4-fluoro-3-(4-methyl-1H-pyrazole-5-carboxamide)benzoate (70a)

[0994] Methyl 3-amino-4-fluorobenzoate (1.17 g, 6.94 mmol) was dissolved in THF (25 mL), and potassium carbonate (2.87 g, 20.8 mmol) and 3-methyl-1H-pyrazole-5-carbonyl chloride (53b) (1.00 g, 6.94 mmol) were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 30%) to obtain 1.3 g of the title compound as a white solid in a yield of 62.8%.

[0995] LC-MS: m / z 299[M+H] + .

[0996] Step 2: Preparation of methyl 3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxylate (70b)

[0997] Methyl 4-fluoro-3-(4-methyl-1H-pyrazole-5-carboxamido)benzoate (70a) (300 mg, 1.07 mmol) and potassium carbonate (448 mg, 3.25 mmol) were dissolved in DMSO (8 mL) at room temperature and stirred at 120°C for 16 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: EA / PE = 100%) to give 110 mg of the title compound as a light yellow solid, in a yield of 39.3%.

[0998] LC-MS: m / z 279[M+H] + .

[0999] The other steps were the same as those in Example 1, except that 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3 was replaced with 3-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxylic acid methyl ester (70b) to obtain the title compound 70.

[1000] LC-MS: m / z 474.2 [M+H] + .

[1001] 1 H NMR (400MHz, DMSO-d6) δ11.66(s,1H),8.38(q,J=4.8Hz,1H),8.03(d,J=8.3Hz,1H),7.88(s,1H),7.81(d,J=8.4Hz,1 H),7.50(d,J=8.5Hz,1H),7.36(d,J=1.8Hz,1H),7.23(dd,J=8.4,1.7Hz,1H),4.95(d,J=13.9Hz,1H),4.74(d,J=13. 9Hz, 1H), 4.06 (dd, J=12.3, 7.7Hz, 1H), 3.79 (dd, J=12.3, 3.8Hz, 1H), 3.58 (d, J=2.4Hz, 2H), 3.53 (dd, J=8.2, 4.5Hz, 1H), 3.36 (q, J=5.6, 4.6Hz, 2H), 2.79 (d, J=4.8Hz, 3H), 2.68-2.62 (m, 1H), 2.58 (dd, J=11.2, 3.3Hz, 2H), 2.43 (s, 4H).

[1002] Example 71: Preparation of (R)-3-((3-chloro-2-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (71)

[1003] Step 1: Preparation of ethyl 4-chloro-3-methyl-1H-pyrazole-5-carboxylate (71a)

[1004] Ethyl 3-methyl-1H-pyrazole-5-carboxylate (5.40 g, 35.1 mmol) was dissolved in DMF (50 mL). NCS (5.17 g, 38.6 mmol) was added at 0°C, and the mixture was stirred at 25°C for 16 hours. 100 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 3), washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: EA / PE = 20%) to obtain 6.20 g of the title compound as a white solid, in a yield of 94.0%.

[1005] LC-MS: m / z 189.0 [M+H] + .

[1006] Step 2: Preparation of 4-chloro-3-methyl-1H-pyrazole-5-carboxylic acid (71b)

[1007] Ethyl 4-chloro-3-methyl-1H-pyrazole-5-carboxylate (71a) (6.00 g, 31.9 mmol) was dissolved in H2O / THF (5 / 15 mL), and lithium hydroxide (1.53 g, 63.8 mmol) was added. The mixture was stirred at 70°C for 16 hours. Water (50 mL) was added, and the pH was adjusted to <7 with 6 mol / L hydrochloric acid. The mixture was extracted with ethyl acetate (50 mL x 3), washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4.10 g (crude) of the title compound as a white solid.

[1008] LC-MS: m / z 161.0 [M+H] + .

[1009] Step 3: Preparation of 4-chloro-3-methyl-1H-pyrazole-5-carbonyl chloride (71c)

[1010] 4-Chloro-3-methyl-1H-pyrazole-5-carboxylic acid (71b) (2.00 g, 12.5 mmol) was dissolved in DCM (50 mL), and oxalyl chloride (7.5 mL) and DMF (3 drops) were added at 0°C. The mixture was stirred at 25°C for 16 hours and concentrated under reduced pressure to give 3.50 g (crude) of the title compound as a yellow oil.

[1011] LC-MS: m / z 179.0 [M+H] + .

[1012] The other steps were the same as those of Example 70, except that 4-chloro-3-methyl-1H-pyrazole-5-carbonyl chloride (71c) was used instead of 3-methyl-1H-pyrazole-5-carbonyl chloride (53b) in Step 1 to give the title compound 71.

[1013] LC-MS: m / z 508.1[M+H] + .

[1014] 1 H NMR (400MHz, DMSO-d6) δ11.89(s,1H),8.38(q,J=4.8Hz,1H),8.01(d,J=8.4Hz,1H),7.81(d,J=8.4Hz, 1H),7.50(d,J=8.4Hz,1H),7.37(d,J=1.6Hz,1H),7.25(dd,J=8.4,1.6Hz,1H),4.95(d,J=14.0Hz,1H), 4.74(d,J=14.0Hz,1H),4.06(dd,J=12.4,7.6Hz,1H),3.79(dd,J=12.4,4.0Hz,1H),3.63-3.49(m,3H), 3.35(dt,J=6.4,3.6Hz,3H),2.79(d,J=4.8Hz,3H),2.67-2.54(m,2H),2.44-2.39(m,1H),2.38(s,3H).

[1015] Example 72: Preparation of (R)-3-((3-chloro-2-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrazin-7-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[1,2-e][1,4]oxazepane-9-carboxamide (72)

[1016] The title compound 72 was prepared in the same manner as in Example 69, except that 4-chloro-3-methyl-1H-pyrazole-5-carbonyl chloride (71c) was used instead of 4-methyl-1H-pyrazole-5-carbonyl chloride (69a) in step 2.

[1017] LC-MS: m / z 509.1 [M+H] + .

[1018] 1 H NMR (400MHz, DMSO-d6) δ11.95(s,1H),8.38(q,J=4.8Hz,1H),8.23(d,J=2.0Hz,1H),7.82(d,J=8.4Hz,1H),7.70 (d,J=2.0Hz,1H),7.50(d,J=8.4Hz,1H),4.95(d,J=14.0Hz,1H),4.74(d,J=14.0Hz,1H),4.03(dd,J=12.4,7.6Hz ,1H),3.79(dd,J=12.4,4.0Hz,1H),3.65(s,2H),3.54-3.49(m,1H),3.39-3.35(m,2H),2.79(d,J=4.8Hz,3H),2. 67(d,J=10.4Hz,1H),2.60(dd,J=11.2,3.2Hz,1H),2.54(dd,J=6.4,4.8Hz,1H),2.44-2.41(m,1H),2.40(s,3H).

[1019] Example 73: Preparation of (R)-3-((3-chloro-2-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrazin-7-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[1,2-e][1,4]oxazepane-9-carboxamide (73)

[1020] The title compound 73 was prepared in the same manner as in Example 1, except that 3-(hydroxymethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (1c) in step 4 was replaced by pyrazolo[1,5-a]pyrido[3,2-e]pyrazin-4(5H)-one (42e).

[1021] LC-MS: m / z 495.2 [M+H] + .

[1022] 1H NMR (400MHz, DMSO-d6) δ8.39(d,J=4.9Hz,1H),8.28(d,J=1.8Hz,1H),7.82(d,J=8.4Hz ,1H),7.76(d,J=1.7Hz,1H),7.51(d,J=8.5Hz,1H),7.31(s,1H),4.95(d,J=13.9Hz,1H) ,4.75(d,J=13.9Hz,1H),4.03(s,1H),3.79(dd,J=12.4,3.8Hz,1H),3.67(s,2H),3.54- 3.50(m,1H),3.39(s,2H),2.79(d,J=4.7Hz,3H),2.69-2.59(m,3H),2.44-2.40(m,1H).

[1023] Example 74: Preparation of (R)-N-(methyl-d3)-3-((8-methyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-1,2,3,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (74)

[1024] The preparation method was the same as that of Example 1, except that 8-methyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (19e) was used instead of 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3, and (R)-N-(methyl-d3)-1,2,3,4,4 a,5-Hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (66c) was used instead of (R)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (1j) in step 11 to give the title compound 74.

[1025] LC-MS: m / z 477.2 [M+H] + .

[1026] 1H NMR (400MHz, DMSO-d6) δ11.28(s,1H),8.36(s,1H),8.12(d,J=1.6Hz,1H),7.93-7.88(m,1H),7.82( d,J=8.4Hz,1H),7.62(d,J=2.0Hz,1H),7.50(d,J=8.4Hz,1H),6.92(d,J=1.6Hz,1H),4.94(d,J=13.6 Hz,1H),4.74(d,J=13.6Hz,1H),4.02(dd,J=12.4,7.2Hz,1H),3.79(dd,J=12.0,3.6Hz,1H),3.61(s ,2H),3.53-3.46(m,1H),3.34(s,2H),2.70-2.55(m,3H),2.39(dd,J=11.2,6.8Hz,1H),2.24(s,3H).

[1027] Example 75: Preparation of (R)-N-methyl-3-((4-oxo-2,3,4,5-tetrahydrofuro[3,2-c]quinolin-7-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (75)

[1028] Step 1: Preparation of methyl 3-(furan-3-carboxamido)-4-iodobenzoate (75a)

[1029] Furan-3-carboxylic acid (2.43 g, 21.7 mmol), methyl 3-amino-4-iodobenzoate (3.00 g, 10.8 mmol), DIPEA (6.99 g, 54.2 mmol), and propylphosphonic anhydride (17.2 g, 54.2 mmol) were dissolved in DMF (50 mL) and stirred at 60°C for 16 hours. 100 mL of water was added, and the mixture was extracted with EA (50 mL x 3). The mixture was washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE / EA = 40%) to obtain 930 mg of the title compound as a yellow solid, in a yield of 23.1%.

[1030] LC-MS: m / z 372.0 [M+H] + .

[1031] Step 2: Preparation of methyl 3-(N-(tert-butyloxycarbonyl)furan-3-carboxamido)-4-iodobenzoate (75b)

[1032] Methyl 3-(furan-3-carboxamido)-4-iodobenzoate (75a) (900 mg, 2.43 mmol) and (Boc)2O (1.06 g, 4.85 mmol) were dissolved in DCE (10 mL). DMAP (296 mg, 2.43 mmol) was added and stirred at room temperature for 16 hours. 30 mL of water was added, and the mixture was extracted with DCM (20 mL x 3). The mixture was washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (PE / EA = 30%) to obtain 710 mg of the title compound as a white solid, in a yield of 62.1%.

[1033] LC-MS: m / z 471.0 [M+H] + .

[1034] Step 3: Preparation of methyl 4-oxo-4,5-dihydrofuro[3,2-c]quinoline-7-carboxylate (75c)

[1035] Methyl 3-(N-(tert-Butyloxycarbonyl)furan-3-carboxamido)-4-iodobenzoate (75b) (680 mg, 1.44 mmol), palladium acetate (65.5 mg, 0.289 mmol), potassium carbonate (398 mg, 2.89 mmol), and Pcy3 (80.8 mg, 0.289 mmol) were dissolved in DMF (10 mL) and microwaved at 100°C for 2 hours under a nitrogen atmosphere. The reaction mixture was separated by high-pressure preparative liquid chromatography (column model: Daisogei 30 mm*250 mm, C18, 10 μm 100A, mobile phase: acetonitrile / water, gradient: 20%-50%, 0.05% formic acid, 30 min) to afford 120 mg of the title compound as a white solid in a 34.2% yield.

[1036] LC-MS: m / z 244.1[M+H] + .

[1037] Step 4: Preparation of methyl 4-oxo-2,3,4,5-tetrahydrofuro[3,2-c]quinoline-7-carboxylate (75d)

[1038] Methyl 4-oxo-4,5-dihydrofuro[3,2-c]quinoline-7-carboxylate (75c) (120 mg, 0.494 mmol) was dissolved in MeOH (10 mL) at room temperature. Aqueous palladium on carbon (80 mg) was added and stirred at room temperature under a hydrogen atmosphere for 48 hours. The mixture was filtered, the filter cake was washed with a large amount of methanol, and the filtrate was concentrated under reduced pressure to afford 80 mg (crude) of the title compound as a white solid.

[1039] LC-MS: m / z 246.1[M+H] +.

[1040] The other steps were the same as those in Example 1, except that 4-oxo-2,3,4,5-tetrahydrofuro[3,2-c]quinoline-7-carboxylic acid methyl ester (75d) was used instead of 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3 to obtain the title compound 75.

[1041] LC-MS: m / z 462.2 [M+H] + .

[1042] 1 H NMR (400MHz, DMSO-d6) δ11.35(s,1H),8.38(d,J=5.2Hz,1H),7.81(dd,J=8.6,1.6Hz,1H),7 .53(dd,J=22.1,8.3Hz,2H),7.36(s,1H),7.15(d,J=8.1Hz,1H),4.94(dd,J=13.9,4.3Hz,1H ),4.84-4.71(m,3H),4.06(t,J=10.2Hz,1H),3.81-3.76(m,1H),3.63-3.49(m,3H),3.35(s, 2H), 3.04 (t, J = 9.2Hz, 2H), 2.79 (d, J = 4.8Hz, 3H), 2.69-2.54 (m, 3H), 2.39 (t, J = 8.8Hz, 1H).

[1043] Example 76: Preparation of (R)-N-methyl-3-((4-oxo-3-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrazin-7-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[2,2-e][1,4]oxazepane-9-carboxamide (76)

[1044] Step 1: Preparation of 4-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (76a)

[1045] Dissolve ethyl 4-(trifluoromethyl)-1H-pyrazole-3-carboxylate (1.00 g, 18.8 mmol) in THF (10 mL), add 2 mol / L sodium hydroxide solution (7.2 mL), and stir at room temperature for 16 hours. Adjust the pH to <7 with 2 mol / L hydrochloric acid, extract with ethyl acetate (20 mL x 3), wash with saturated brine (20 mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 900 mg (crude) of the title compound as a white solid.

[1046] LC-MS: m / z 181.0 [M+H] + .

[1047] The other steps were the same as those of Example 69, except that 4-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (76a) was used instead of 4-methyl-1H-pyrazole-5-carboxylic acid in Step 1 to give the title compound 76.

[1048] LC-MS: m / z 529.2 [M+H] + .

[1049] 1 H NMR (400MHz, DMSO-d6) δ12.31(s,1H),8.54(s,1H),8.39(q,J=4.8Hz,1H),8.34(d,J=1.9Hz, 1H),7.84-7.79(m,2H),7.51(d,J=8.5Hz,1H),4.95(d,J=14.0Hz,1H),4.75(d,J=13.9Hz,1H ),4.05(dd,J=12.3,7.6Hz,1H),3.79(dd,J=12.3,3.9Hz,1H),3.70(s,2H),3.57-3.50(m,1H ),3.40-3.34(m,2H),2.79(d,J=4.9Hz,3H),2.72-2.56(m,3H),2.43(dd,J=11.2,6.8Hz,1H).

[1050] Example 77: Preparation of (R)-3-((2,3-dimethyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrazin-7-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[1,2-e][1,4]oxazepane-9-carboxamide (77)

[1051] The title compound 77 was prepared by the same method as Example 69, except that 3,4-dimethyl-1H-pyrazole-5-carboxylic acid was used instead of 4-methyl-1H-pyrazole-5-carboxylic acid in Step 1.

[1052] LC-MS: m / z 489.2 [M+H] + .

[1053] 1H NMR (400MHz, DMSO-d6) δ11.69(s,1H),8.38(q,J=4.8Hz,1H),8.18(d,J=1.9Hz,1H) ,7.82(d,J=8.4Hz,1H),7.67(d,J=1.9Hz,1H),7.50(d,J=8.6Hz,1H),4.94(d,J=13. 9Hz,1H),4.74(d,J=13.9Hz,1H),4.03(dd,J=12.3,7.6Hz,1H),3.79(dd,J=12.3,3 .9Hz, 1H), 3.63 (s, 2H), 3.35 (s, 6H), 2.78 (d, J = 4.8Hz, 3H), 2.36 (d, J = 11.6Hz, 4H).

[1054] Example 78: Preparation of (R)-3-((6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-N-propyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (78)

[1055] Step 1: Preparation of (R)-3-(tert-Butoxycarbonyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxylic acid (78a)

[1056] Dissolve 3-(tert-Butyl)-9-methyl (R)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3,9(4H)-dicarboxylate (1h) (500 mg, 1.38 mmol) in THF (10 mL). Add 1 mol / L LiOH solution (2 mL) and stir at room temperature for 16 hours. Concentrate under reduced pressure to obtain 560 mg of the title compound as a yellow oil (crude product).

[1057] LC-MS: m / z 350.0 [M+H] + .

[1058] Step 2: Preparation of (R)-9-(propylcarbamoyl)-1,2,4α15-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (78b)

[1059] (R)-3-(tert-Butoxycarbonyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxylic acid (78a) (300 mg, 0.860 mmol) was dissolved in DMF (10 mL). Triethylamine (550 mg, 4.31 mmol), n-propylamine (240 mg, 2.58 mmol), and HATU (650 mg, 4.30 mmol) were added and stirred at room temperature for 16 hours. 20 mL of water was added and the mixture was extracted with EA (10 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: EA / PE = 100%) to give 210 mg of the title compound as a yellow oil, with a two-step yield of 62.5%.

[1060] LC-MS: m / z 391.0 [M+H] + .

[1061] The other steps were the same as those in Example 1, except that (R)-9-(propylcarbamoyl)-1,2,4α,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (78b) was used instead of (R)-9-(methylcarbamoyl)-1,2,4α,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (1i) in step 10 to obtain the title compound 78.

[1062] LC-MS: m / z 488.2 [M+H] + .

[1063] 1H NMR (400MHz, DMSO-d6) δ11.34(s,1H),8.40(t,J=6.2Hz,1H),8.24-8.08(m,2H),7.82(d,J=8.5Hz,1H),7.66(d,J=1 .8Hz,1H),7.50(d,J=8.5Hz,1H),7.10(dd,J=3.7,1.5Hz,1H),6.75(s,1H),4.95(d,J=13.9Hz,1H),4.75(d,J=13.9 Hz,1H),4.02(dd,J=12.4,7.5Hz,1H),3.79(dd,J=12.4,3.8Hz,1H),3.63(s,2H),3.50(dt,J=7.3,3.9Hz,1H),3.35(q,J=4.7,3.9H z, 2H), 3.22 (dt, J = 9.0, 6.1Hz, 2H), 2.71-2.57 (m, 3H), 2.40 (dd, J = 11.2, 7.0Hz, 1H), 1.52 (q, J = 7.3Hz, 2H), 0.86 (t, J = 7.4Hz, 3H).

[1064] Example 79: Preparation of (R)-9-((6-chloro-5-oxo-4,5-dihydropyrrolo[1,2-a]thieno[3,2-e]pyrazin-2-yl)methyl)-N-methyl-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[3,4-e][1,4]oxazepane-9-carboxamide (79)

[1065] The title compound 79 was prepared in the same manner as in Example 29, except that 3-chloropyrrole-2-carboxylic acid methyl ester was used instead of 3-methylpyrrole-2-carboxylic acid methyl ester in step 1.

[1066] LC-MS: m / z 499.1[M+H] + .

[1067] 1H NMR (400MHz, DMSO-d6) δ11.45(s,1H),8.41(d,J=5.1Hz,1H),7.81(d,J=8.5Hz,1H), 7.69(s,1H),7.51(d,J=8.6Hz,1H),6.79(s,1H),6.68(d,J=2.9Hz,1H),4.95(d,J=13 .9Hz,1H),4.74(d,J=14.2Hz,1H),4.04(t,J=9.8Hz,1H),3.86-3.73(m,3H),3.52(s, 1H), 3.41-3.35 (m, 2H), 2.78 (d, J = 4.8Hz, 3H), 2.69-2.59 (m, 3H), 2.44-2.40 (m, 1H).

[1068] Example 80: Preparation of (R)-3-((6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (80)

[1069] The title compound 80 was prepared in the same manner as in Example 78, except that 1,1,1-trifluoro-2-methylpropan-2-amine was used instead of n-propylamine in step 2.

[1070] LC-MS: m / z 556.2 [M+H] + .

[1071] 1 H NMR (400MHz, DMSO-d6) δ11.34(s,1H),8.18-8.08(m,2H),8.05(s,1H),7.85(d,J=8.6Hz,1H),7.65( d,J=1.9Hz,1H),7.54(d,J=8.6Hz,1H),7.09(dd,J=3.8,1.6Hz,1H),6.72(dd,J=3.8,2.8Hz,1H),4. 95(d,J=14.0Hz,1H),4.75(d,J=14.0Hz,1H),4.03(dd,J=12.4,7.6Hz,1H),3.80(dd,J=12.4,3.8Hz ,1H),3.63(s,2H),3.37(s,2H),2.71-2.56(m,3H),2.40(dd,J=11.2,7.0Hz,1H),1.63(d,J=1.8Hz, 6H).

[1072] Example 81: Preparation of (R)-N-methyl-3-((7-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-c][1,5]naphthyridin-3-yl)methyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (81)

[1073] Step 1: Preparation of methyl 3-bromo-1-methyl-1H-pyrrole-2-carboxylate (81a)

[1074] Methyl 3-bromo-1H-pyrrole-2-carboxylate (1.00 g, 4.93 mmol) was dissolved in DMF (20 mL), and potassium carbonate (1.36 g, 9.85 mmol) and iodomethane (770 mg, 5.42 mmol) were added. The mixture was stirred at 25°C for 16 hours. 50 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: EA / PE = 20%) to obtain 900 mg of the title compound as a white solid, in a yield of 84.1%.

[1075] LC-MS: m / z 218.0 [M+H] + .

[1076] Step 2: Preparation of (2-(methoxycarbonyl)-1-methyl-1H-pyrrol-3-yl)boronic acid (81b)

[1077] Methyl 3-bromo-1-methyl-1H-pyrrole-2-carboxylate (81a) (550 mg, 2.53 mmol) was dissolved in 1,4-dioxane (10 mL). B(pin)2 (966 mg, 3.80 mmol), potassium acetate (496 mg, 5.06 mmol), and Pd(dppf)Cl2 (185 mg, 0.253 mmol) were added, and the mixture was stirred at 70°C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: EA / PE = 30%) to give 420 mg of the title compound as a yellow oil, in a yield of 90.7%.

[1078] LC-MS: m / z 184.1 [M+H] + .

[1079] Step 3: Preparation of 3-chloro-7-methyl-5,7-dihydro-6H-pyrrolo[2,3-c][1,5]naphthyridin-6-one (81c)

[1080] (2-(Methoxycarbonyl)-1-methyl-1H-pyrrol-3-yl)boronic acid (81b) (250 mg, 1.37 mmol), 2-bromo-5-chloropyridin-3-amine (281 mg, 1.37 mmol), potassium carbonate (378 mg, 2.74 mmol), and Pd(PPh3)4 (158 mg, 0.137 mmol) were dissolved in water / 1,4-dioxane (1 mL / 5 mL) and stirred at 90°C under a nitrogen atmosphere for 16 hours. The reaction mixture was poured into water and filtered. The filter cake was washed with ethyl acetate and collected and dried to give 180 mg of the title compound as a yellow solid (crude product).

[1081] LC-MS: m / z 234.0 [M+H] + .

[1082] Step 4: Preparation of 3-(hydroxymethyl)-7-methyl-5,7-dihydro-6H-pyrrolo[2,3-c][1,5]naphthyridin-6-one (81d)

[1083] Dissolve 3-chloro-7-methyl-5,7-dihydro-6H-pyrrolo[2,3-c][1,5]naphthyridin-6-one (81c) (180 mg, 0.773 mmol) in 1,4-dioxane (10 mL). Add (tributyltinyl)methanol (322 mg, 1.00 mmol) and Xphos Pd G2 (60.8 mg, 0.0773 mmol). Stir at 100°C under a nitrogen atmosphere for 16 hours. Add water (50 mL), filter, collect the filter cake, and dry to obtain 80.0 mg (crude) of the title compound as a yellow solid.

[1084] LC-MS: m / z 230.1 [M+H] + .

[1085] The other steps were the same as those in Example 1, except that 3-(hydroxymethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (1c) in step 4 was replaced with 3-(hydroxymethyl)-7-methyl-5,7-dihydro-6H-pyrrolo[2,3-c][1,5]naphthyridine-6-one (81d) to give the title compound 81.

[1086] LC-MS: m / z 474.2 [M+H] + .

[1087] 1H NMR (400MHz, DMSO-d6) δ11.33(s,1H),8.31(q,J=4.8Hz,1H),8.28(d,J=2.0Hz,1H),7.74(d,J=8.4Hz,1H),7.59(d,J= 2.0Hz,1H),7.43(d,J=8.4Hz,1H),7.35(d,J=2.8Hz,1H),6.77(d,J=2.8Hz,1H),4.87(d,J=14.0Hz,1H),4.67(d,J=14 .0Hz,1H),4.05(s,3H),3.96(dd,J=12.4,7.6Hz,1H),3.72(dd,J=12.4,3.6Hz,1H),3.56(s,2H),3.44(dq,J=7.6,3.6 Hz,1H),3.29(s,2H),2.71(d,J=4.8Hz,3H),2.58(s,1H),2.52(dd,J=11.2,3.2Hz,2H),2.33(dd,J=11.2,6.8Hz,1H).

[1088] Example 82: Preparation of (R)-3-((7-fluoro-9-methyl-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (82)

[1089] Step 1: Preparation of ethyl 5-bromo-3-fluoro-1H-pyrrole-2-carboxylate (82a)

[1090] Ethyl 3-fluoro-1H-pyrrole-2-carboxylate (1.90 g, 12.1 mmol) was dissolved in DCM (20 mL) at room temperature, and NBS (2.15 g, 12.1 mmol) was added. The mixture was protected from light and stirred at room temperature for 1 hour. The mixture was quenched with 50 mL of water, extracted with DCM (30 mL x 3), washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by high-pressure preparative liquid chromatography (Daisogei 30 mm x 250 mm, C18, 10 μm 100A column, mobile phase: acetonitrile / water, gradient: 30%-60%, 0.05% formic acid, 30 min) to afford 1.10 g of the title compound as a white solid in a yield of 38.7%.

[1091] LC-MS: m / z 236 [M+H] + .

[1092] Step 2: Preparation of ethyl 3-fluoro-5-methyl-1H-pyrrole-2-carboxylate (82b)

[1093] Ethyl 5-bromo-3-fluoro-1H-pyrrole-2-carboxylate (82a) (1.10 g, 4.68 mmol), methylboronic acid (843 mg, 14.1 mmol), potassium carbonate (3.23 g, 23.4 mmol), and Pd(dppf)Cl2 (342 mg, 0.468 mmol) were dissolved in 1,4-dioxane / water (18 mL / 2 mL) at room temperature and stirred at 90°C under a nitrogen atmosphere for 16 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (PE / EA = 20%) to give 700 mg of the title compound as a yellow solid, in a yield of 87.5%.

[1094] LC-MS: m / z 172.1[M+H] + .

[1095] Step 3: Preparation of 3-fluoro-5-methyl-1H-pyrrole-2-carboxylic acid (82c)

[1096] Ethyl 3-fluoro-5-methyl-1H-pyrrole-2-carboxylate (82b) (700 mg, 4.09 mmol) was dissolved in tetrahydrofuran / water (12 mL / 3 mL) at room temperature, and lithium hydroxide (859 mg, 20.5 mmol) was added. The mixture was stirred at 70°C for 16 hours. Water (10 mL) was added for dilution, and the pH was adjusted to <7 with 1 mol / L hydrochloric acid solution. The mixture was extracted with ethyl acetate (20 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was slurried with EA / PE = 5 / 1, filtered, and the filter cake was washed with petroleum ether to afford 390 mg of the title compound as a white solid, in a yield of 66.6%.

[1097] LC-MS: m / z 144.0 [M+H] + .

[1098] Step 4: Preparation of N-(5-bromo-2-fluoropyridin-3-yl)-3-fluoro-5-methyl-1H-pyrrole-2-carboxamide (82d)

[1099] 3-Fluoro-5-methyl-1H-pyrrole-2-carboxylic acid (82c) (360 mg, 2.52 mmol), 5-bromo-2-fluoropyridin-3-amine (398 mg, 2.09 mmol), and DIPEA (812 mg, 6.29 mmol) were dissolved in DMF (10 mL) at room temperature. Propylphosphonic anhydride (4.01 g, 6.29 mmol) was added, and the mixture was stirred at 60°C for 16 hours. Water (30 mL) was added, and the mixture was extracted with EA (20 mL x 3). The mixture was washed with saturated brine (30 mL x 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (PE / EA = 50%) to obtain 300 mg of the title compound as a yellow solid in a yield of 37.8%.

[1100] LC-MS: m / z 315.0 [M+H] + .

[1101] Step 5: Preparation of 3-bromo-7-fluoro-9-methylpyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (82e)

[1102] N-(5-Bromo-2-fluoropyridin-3-yl)-3-fluoro-5-methyl-1H-pyrrole-2-carboxamide (82d) (270 mg, 0.857 mmol) was dissolved in DMSO (4 mL) at room temperature. Potassium carbonate (355 mg, 2.57 mmol) was added, and the mixture was stirred at 120°C under a nitrogen atmosphere for 16 hours. The reaction mixture was poured into water and filtered. The filter cake was washed with acetonitrile to give 150 mg of the title compound as a white solid (crude product).

[1103] LC-MS: m / z 296.0 [M+H] + .

[1104] Step 6: Preparation of 7-fluoro-3-(hydroxymethyl)-9-methylpyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (82f)

[1105] 3-Bromo-7-fluoro-9-methylpyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (82e) (90 mg, 0.305 mmol), (tributyltinyl)methanol (196 mg, 0.610 mmol), and Ruphos-Pd-G2 (23.9 mg, 0.0310 mmol) were dissolved in 1,4-dioxane (1.5 mL) at room temperature and stirred at 120°C under a nitrogen atmosphere for 16 hours. Filtration and the filter cake were washed with DCM to afford 70 mg of the title compound as a dark brown solid (crude product).

[1106] LC-MS: m / z 248.1[M+H]+ .

[1107] The other steps were the same as the preparation method of Example 1, except that 7-fluoro-3-(hydroxymethyl)-9-methylpyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (82f) was used instead of 3-(hydroxymethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (1c) in step 4 to obtain the title compound 82.

[1108] LC-MS: m / z 492.2 [M+H] + .

[1109] 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),8.39(q,J=4.8Hz,1H),8.09(d,J=1.9Hz,1H),7.82(d,J=8.4Hz,1 H),7.58(d,J=2.0Hz,1H),7.50(d,J=8.5Hz,1H),6.43(s,1H),4.94(d,J=13.9Hz,1H),4.74(d,J=13.9Hz ,1H),4.01(dd,J=12.4,7.5Hz,1H),3.79(dd,J=12.3,3.8Hz,1H),3.59(s,2H),3.49(dq,J=7.4,3.7Hz, 1H), 3.35 (s, 2H), 2.87-2.74 (m, 6H), 2.63 (ddd, J = 27.9, 10.7, 3.6Hz, 3H), 2.39 (dd, J = 11.2, 6.9Hz, 1H).

[1110] Example 83: Preparation of (R)-3-((8-fluoro-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-N-(1,1,1-trifluoropropan-2-yl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (83)

[1111] Step 1: Preparation of tert-butyl (4aR)-9-((1,1,1-trifluoropropan-2-yl)carbamoyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylate (83a)

[1112] (R)-3-(tert-Butoxycarbonyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxylic acid (78a) (100 mg, 0.287 mmol), 1,1,1-trifluoropropane-2-amine (38.9 mg, 0.344 mmol), DIEA (111 mg, 0.860 mmol) and HATU (142 mg, 0.372 mmol) were dissolved in DMF (2 mL) and stirred at 25°C for 16 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The mixture was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: EA / PE = 8%) to obtain 100 mg of the title compound as a colorless oil. Yield: 78.5%.

[1113] LC-MS: m / z 445.2 [M+H] + .

[1114] The other steps were the same as those in Example 1, except that 4-fluoro-1H-pyrrole-2-carboxylic acid methyl ester was used instead of 1H-pyrrole-2-carboxylic acid methyl ester in step 1, and (4aR)-9-((1,1,1-trifluoropropan-2-yl)carbamoyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (83a) was used instead of (R)-9-(methylcarbamoyl)-1,2,4α,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (1i) in step 10 to give the title compound 83.

[1115] LC-MS: m / z 560.2 [M+H] + .

[1116] 1H NMR (400MHz, DMSO-d6) δ11.54(s,1H),8.65(d,J=9.2Hz,1H),8.17(d,J=2.0Hz,1H),8.06(dd,J=3.2,2.0Hz,1 H),7.86(dd,J=8.4,2.4Hz,1H),7.67(d,J=2.0Hz,1H),7.53(d,J=8.4Hz,1H),6.98(d,J=2.0Hz,1H),4.99(dd ,J=14.0,6.0Hz,1H),4.86-4.74(m,2H),4.03(dt,J=12.4,8.4Hz,1H),3.81(dt,J=12.4,3.6Hz,1H),3.64(s, 2H), 3.58-3.50 (m, 1H), 3.37 (s, 2H), 2.70-2.58 (m, 3H), 2.40 (dt, J = 11.2, 6.0Hz, 1H), 1.39 (d, J = 7.2Hz, 3H).

[1117] Example 84: Preparation of (R)-3-((8-fluoro-6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (84)

[1118] Step 1: Preparation of (R)-tert-butyl 9-((1,1,1-trifluoro-2-methylpropan-2-yl)carbamoyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylate (84a)

[1119] (R)-3-(tert-Butoxycarbonyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxylic acid (78a) (100 mg, 0.287 mmol) was dissolved in DMF (1 mL) and triethylamine (87.0 mg, 0.861 mmol), 1,1,1-trifluoro-2-methylpropan-2-amine (56.0 mg, 0.861 mmol) and HATU (163 mg, 0.430 mmol) were added. The mixture was stirred at room temperature for 16 hours, and 20 mL of water was added. The mixture was extracted with EA (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: EA / PE = 100%) to give 80 mg of the title compound as a yellow oil. Yield: 77.2%.

[1120] LC-MS: m / z 459.0 [M+H] + .

[1121] The other steps were the same as those in Example 1, except that 4-fluoro-1H-pyrrole-2-carboxylic acid methyl ester was used instead of 1H-pyrrole-2-carboxylic acid methyl ester in step 1, and (R)-9-((1,1,1-trifluoro-2-methylpropan-2-yl)carbamoyl)-1,2,4a,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (84a) was used instead of (R)-9-(methylcarbamoyl)-1,2,4α,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (1i) in step 10 to obtain the title compound 84.

[1122] LC-MS: m / z 574.2 [M+H] + .

[1123] 1H NMR (400MHz, DMSO-d6) δ11.55(s,1H),8.17(d,J=1.9Hz,1H),8.09-8.02(m,2H),7.85(d,J=8.5Hz,1H),7.67( d,J=1.9Hz,1H),7.54(d,J=8.6Hz,1H),6.98(d,J=2.0Hz,1H),4.95(d,J=14.0Hz,1H),4.74(d,J=14.0Hz,1H) ,4.02(dd,J=12.4,7.6Hz,1H),3.80(dd,J=12.4,3.8Hz,1H),3.64(s,2H),3.53(dt,J=7.4,3.8Hz,1H),3.40- 3.35(m,2H),2.65(s,1H),2.60(dd,J=11.2,3.2Hz,2H),2.40(dd,J=11.2,6.9Hz,1H),1.63(d,J=1.8Hz,6H).

[1124] Example 85: Preparation of (R)-3-((6-oxo-5,6-dihydrothieno[2,3-c][1,5]naphthyridin-3-yl)methyl)-N-(2,2,2-trifluoroethyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxamide (85)

[1125] Step 1: Preparation of (R)-9-((2,2,2-trifluoroethyl)carbamoyl)-1,2,4α,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (85a)

[1126] (R)-3-(tert-Butoxycarbonyl)-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-9-carboxylic acid (78a) (100 mg, 0.287 mmol), 2,2,2-trifluoroethane-1-amine (34.0 mg, 0.344 mmol), DIEA (111 mg, 0.860 mmol) and HATU (142 mg, 0.372 mmol) were dissolved in DMF (4 mL) and stirred at 25°C for 16 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The mixture was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: EA / PE = 8%) to give 110 mg of the title compound as a colorless oil. Yield: 89.1%.

[1127] LC-MS: m / z 431.2 [M+H] + .

[1128] The other steps were the same as those in Example 1, except that 6-oxo-5,6-dihydrothieno[2,3-c][1,5]naphthyridine-3-carboxylic acid methyl ester (10b) was used instead of 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylic acid methyl ester (1b) in step 3, and (R)-9-((2,2,2-trifluoroethyl)carbamoyl)-1,2,4α15-tetrahydro -7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (85a) was used instead of (R)-9-(methylcarbamoyl)-1,2,4α,5-tetrahydro-7H-pyrazino[2,1-c]pyrido[3,2-e][1,4]oxazepane-3(4H)-carboxylic acid tert-butyl ester (1i) in step 10 to give the title compound 85.

[1129] LC-MS: m / z 545.1[M+H] + .

[1130] 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H),8.93(t,J=6.8Hz,1H),8.49(d,J=1.6Hz,1H),8.22(d,J=5.2Hz,1 H),8.00(d,J=5.2Hz,1H),7.87(d,J=8.4Hz,1H),7.80(d,J=1.6Hz,1H),7.54(d,J=8.4Hz,1H),4.99(d, J=14.0Hz,1H),4.76(d,J=14.0Hz,1H),4.10-4.03(m,2H),3.82(dd,J=12.4,3.6Hz,1H),3.69(d,J=5.6 Hz, 2H), 3.59 (d, J = 4.4Hz, 2H), 3.39 (q, J = 5.2Hz, 2H), 2.72-2.56 (m, 3H), 2.43 (dd, J = 11.2, 6.8Hz, 1H).

[1131] Example 86: Preparation of (R)-3-((3-fluoro-2-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrazin-7-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydro-7H-pyrazino[2,1-c]pyrido[1,2-e][1,4]oxazepane-9-carboxamide (86)

[1132] Step 1: Preparation of ethyl 4-fluoro-3-methyl-1H-pyrazole-5-carboxylate (86a)

[1133] Ethyl 3-methyl-1H-pyrazole-5-carboxylate (5.00 g, 32.5 mmol) was dissolved in acetonitrile (250 mL), and a selective fluorinating agent (34.5 g, 97.4 mmol) was added. The mixture was stirred at 40°C for 16 hours. The mixture was filtered and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: MeOH / DCM = 5%) to obtain 5.20 g (crude) of the title compound as a white solid. The residue was then separated by high-pressure preparative liquid chromatography (column model: Daisogei 30 mm x 250 mm, C18, 10 μm 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid, 30 min) to obtain 1.50 g of the title compound as a white solid, in a yield of 26.8%.

[1134] LC-MS: m / z 173.1 [M+H] + .

[1135] Step 2: Preparation of 4-fluoro-3-methyl-1H-pyrazole-5-carboxylic acid (86b)

[1136] Ethyl 4-fluoro-3-methyl-1H-pyrazole-5-carboxylate (86a) (1.40 g, 8.14 mmol) was dissolved in H2O / THF (5 / 15 mL), and lithium hydroxide (391 mg, 16.3 mmol) was added. The mixture was stirred at 50°C for 16 hours. Water (50 mL) was added, and the pH was adjusted to <7 with 6 mol / L hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL x 3), washed with saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.30 g (crude) of the title compound as a white solid.

[1137] LC-MS: m / z 145.0 [M+H] + .

[1138] The other steps were the same as those of Example 69, except that 4-fluoro-3-methyl-1H-pyrazole-5-carboxylic acid (86b) was used instead of 4-methyl-1H-pyrazole-5-carboxylic acid in step 1 to give the title compound 86.

[1139] LC-MS: m / z 493.2 [M+H] + .

[1140] 1H NMR (400MHz, DMSO-d6) δ11.84(s,1H),8.38(q,J=3.6,2.4Hz,1H),8.22(d,J=1.6Hz,1H), 7.82(d,J=8.4Hz,1H),7.70(d,J=1.6Hz,1H),7.50(d,J=8.4Hz,1H),4.95(d,J=14.0Hz,1 H),4.74(d,J=13.6Hz,1H),4.03(dd,J=12.4,7.6Hz,1H),3.64(s,2H),3.52(dq,J=7.2,3 .6Hz, 1H), 3.35 (t, J = 4.0Hz, 2H), 2.79 (d, J = 4.8Hz, 3H), 2.70-2.53 (m, 4H), 2.40 (s, 4H).

[1141] Example 87: Preparation of (R)-N-methyl-3-((6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoline-8-carboxamide (87)

[1142] The other steps were the same as those in Example 13, except that methyl 3-bromo-4-fluorobenzoate was used instead of methyl 6-bromo-5-fluoropicolinate in step 4, to give the title compound 87.

[1143] LC-MS: m / z 443.1[M+H] + .

[1144] 1 H NMR(400MHz,DMSO-d6)δ11.36(s,1H),8.16(d,1H),8.13-8.10(m,1H),8.06-8.00(m,1H),7.65( d,1H),7.54-7.49(m,1H),7.45-7.42(m,1H),7.10(dd,1H),6.83(d,1H),6.73(dd,J=3.8,2.8...

Claims

1. A compound represented by the general formula (I) or its meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in: is a single bond or a double bond; X 1 , X 2 are each independently selected from N or C, and X 1 , X 2 Not all are N; Y 1 , Y 2 are the same or different and are each independently selected from a bond, -(CR a R b ) m -、-O-、-O(CR c R d ) n -、-NR 5 -、-NR 5 (CR c R d ) n -、-C(O)NR 5 -、-NR 5 C(O)- and -C(O)-; Z 1 , Z 2 , Z 3 are each independently selected from N or C, and Z 1 , Z 2 , Z 3 Not all are N; Ring A is selected from cycloalkyl, heterocyclic group, aryl, heteroaryl, and the cycloalkyl, heterocyclic group, aryl, heteroaryl may be further substituted with one or more R 3 replace; Ring B is selected from cycloalkyl, heterocyclic group, aryl, heteroaryl, and the cycloalkyl, heterocyclic group, aryl, heteroaryl may be further substituted with one or more R 4 replace; R 1 is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, wherein the alkyl, cycloalkyl, heterocyclyl is optionally further substituted with one or more substituents selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 2 is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, wherein the alkyl, cycloalkyl, heterocyclyl is optionally further substituted with one or more substituents selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 3 is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 4 is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of deuterium, halogen, amino, oxo, substituted by one or more substituents selected from the group consisting of thio, nitro, cyano, hydroxy, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 5 is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R a and R b each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R c and R d each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; m is 1, 2, 3 or 4; n is 1, 2, 3 or 4.

2. The compound of general formula (I) according to claim 1, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which is a compound of general formula (II) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, in, X 1 , X 2 , Y 1 , Y 2 , Ring A, Ring B, R 1 , R 2 As defined in claim 1.

3. The compound represented by the general formula (I) according to claim 1 or 2, or its meso form, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: Y 1 , Y 2 are the same or different and are each independently selected from a bond, -(CR a R b ) m -、-O-、-O(CR c R d ) n -, preferably; -(CR a R b ) m -、-O-、-O(CR c R d ) n -; Among them, R a , R b , R c , R d , m, n as defined in claim 1.

4. A compound of formula (I) according to any one of claims 1 to 3, or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of formula (III) or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in, Y 3 Selected from -CR e R f -、-O-、-NR 5 -; R 5 is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R a and R b each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R c and R d each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R e and R f each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; s is 0, 1, 2, 3, 4, preferably 0, 1, 2; t is 0, 1, 2, 3, 4, preferably 0, 1, 2; Ring A, Ring B, X 1 , X 2 , R 1 , R 2 As defined in claim 1.

5. A compound of the general formula (I) according to any one of claims 1 to 4, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (IV) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in, t is 0 or 1, preferably 1; Ring A, Ring B, X 1 , X 2 , R 1 , R 2 As defined in claim 1.

6. The compound represented by the general formula (I) according to any one of claims 1 to 5, or its meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from C 4-7 Cycloalkyl, 5- to 7-membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl, said C 4-7 Cycloalkyl, 5- to 7-membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl may further be substituted with one or more R 3 Replacement; R 3 As defined in claim 1.

7. The compound represented by the general formula (I) according to any one of claims 1 to 6, or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from C 4-7 Cycloalkyl, 5- to 7-membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl, said C 4-7 Cycloalkyl, 5- to 7-membered heterocyclic group, C 6-10 Aryl, 5 to 10 membered heteroaryl may further be substituted with one or more R 4 Replacement; R 4 As defined in claim 1.

8. A compound of formula (I) according to any one of claims 1 to 7, or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of formula (V) or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in, is a single bond or a double bond; X 1 N or C; X 2 N or C; G1 is selected from C, N, S, O; G2 is selected from C, N, S, O; G3 is selected from C, N, S, O; G4 is selected from C, N, S; G5 is selected from C, N, S; G6 is selected from a bond, C, N; Ring A is selected from C 5-6 Cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, which may be further substituted by one or more R 3 replace; Ring B is selected from phenyl or 5-6 membered heteroaryl, which is optionally further substituted by one or more R 4 replace; t is 0 or 1, preferably 1; v is 0 or 1; R 1 , R 2 , R 3 , R 4 As defined in claim 1.

9. A compound represented by the general formula (I) according to any one of claims 1 to 8, or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in, is a single bond; Ring A is selected from: Ring A is optionally further substituted with one or more R 3 Replaced by; R 3 As defined in claim 1; Preferably, R 3 is selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, 3-6 Cycloalkyl.

10. A compound represented by the general formula (I) according to any one of claims 1 to 8, or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in, is a double bond; Ring A is selected from: Ring A is optionally further substituted with one or more R 3 Replaced by; R 3 As defined in claim 1; Preferably, R 3 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, 3-6 Cycloalkyl.

11. A compound represented by the general formula (I) according to any one of claims 1 to 10, or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in, Ring B is selected from: Ring B is optionally further substituted with one or more R 4 Replaced by; R 4 As defined in claim 1; Preferably, R 4 Selected from halogen, C1-C6 alkyl or C1-C6 haloalkyl.

12. The compound represented by the general formula (I) according to any one of claims 1 to 11, or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl.

13. The compound of the general formula (I) according to any one of claims 1 to 12, or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen and C 1-6 alkyl.

14. A compound of the general formula (I) according to any one of claims 1 to 13, or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

15. A method for preparing a compound represented by general formula (II) or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps: In the presence of a base, a compound of the general formula IIa undergoes a substitution reaction with a compound of the general formula IIb to obtain a compound represented by the general formula (II) or its mesomorph, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof; in, Ring A, Ring B, X 1 , X 2 , Y 1 , Y 2 , R 1 , R 2 As defined in claim 2.

16. A method for preparing a compound represented by general formula (V) or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps: In the presence of a base, a compound of the general formula Va undergoes a substitution reaction with a compound of the general formula Vb to obtain a compound represented by the general formula (V) or its mesomorph, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof; in, Ring A, Ring B, X 1 , X 2 、G1~G6、R 1 , R 2 , t as defined in claim 8.

17. A pharmaceutical composition comprising a compound represented by the general formula (I) according to any one of claims 1 to 14 or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

18. Use of the compound represented by general formula (I) according to any one of claims 1 to 14 or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17 in the preparation of a poly (ADP-ribose) polymerase 1 (PARP1) inhibitor.

19. Use of the compound represented by general formula (I) according to any one of claims 1 to 14 or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17 in the preparation of a medicament for preventing and / or treating a disease associated with poly (ADP ribose) polymerase 1 (PARP1) activity, wherein the disease is preferably a tumor disease, such as ovarian cancer, breast cancer, and prostate cancer.

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