WO2024067691A1

WO2024067691A1 - Nitrogen-containing heterocyclic compound and pharmaceutical use thereof

Info

Publication number: WO2024067691A1
Application number: PCT/CN2023/121994
Authority: WO
Inventors: 王国政; 刘国标; 闫旭; 李斌; 任越; 刘延鑫; 武勇; 赵礼坤
Original assignee: 中国医药研究开发中心有限公司
Priority date: 2022-09-30
Filing date: 2023-09-27
Publication date: 2024-04-04

Abstract

Disclosed are a nitrogen-containing heterocyclic compound and pharmaceutical use thereof. Specifically, disclosed are a nitrogen-containing heterocyclic compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition comprising the compound, and use of the compound as a poly(ADP-ribose) polymerase 1 (PARP1) inhibitor for treating diseases related to PARP1 activity. Substituents in general formula (I) have the same definitions as those in the description.

Description

Nitrogen-containing heterocyclic compounds and their medical uses

Technical Field

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), preparation methods thereof, pharmaceutical compositions containing the same, and uses thereof as poly (ADP-ribose) polymerase 1 (PARP1) inhibitors for treating diseases associated with PARP1 activity.

Background technique

Poly (ADP ribose) polymerases (PARPs) play an important role in DNA replication, recombination, chromatin remodeling, and DNA damage repair. The family includes 18 members with ADP-ribosyltransferase activity, catalyzing the addition of ADP-ribose units to DNA or different receptor proteins, affecting a variety of cellular processes. PARP1 and PARP2 are the most widely studied PARPs because of their role in DNA damage repair. PARP1 is the most important member of the PARP family. It is a nuclear protein composed of three domains: a DNA binding domain containing two zinc fingers at the N-terminus, a self-modification domain, and a C-terminal catalytic domain. It undertakes more than 90% of the functions of the PARPs family in cells and is a key factor in DNA damage repair. PARP2 has similar functions to PARP1, but the two differ in substrate selection. PARP1 and PARP2 can repair DNA single-strand breaks (SSBs), and PARP1 can also repair DNA double-strand breaks (DSBs) and replication fork damage. As a sensor of DNA breaks, PARP1 is activated after DNA damage. It recognizes and binds to the DNA break site through the zinc finger domain, reduces recombination and protects damaged DNA from the action of exonucleases. After binding to the DNA gap, it catalyzes the decomposition of nicotinamide adenine dinucleotide (NAD+) into nicotinamide and ADP ribose through its own glycosylation, and then uses ADP ribose as a substrate to "PARize" the receptor protein and PARP1 itself, forming a PARP-ADP-ribose branch chain, which can prevent nearby DNA molecules from recombination with damaged DNA on the one hand, and attract DNA repair proteins to bind and reduce the affinity of PARP1 with DNA on the other hand, so that PARP1 dissociates from the DNA break, and then DNA repair proteins bind to the DNA gap to repair the damaged site. The "PARization" of PARP1 will be cleared by other enzymes, allowing PARP1 to regain activity and look for the next DNA break. In eukaryotic cells, not only is PAR chain formed, but also its degradation is catalyzed by poly(ADP-ribose)glycohydrolase (PARG] and type 3 ADP ribose hydrolase (ADP-ribosylhydrolase 3, ARH3). Four enzymes, PARP1, PARP2, PARP5A and PARP5B, can catalyze the synthesis of PAR chains. The vast majority of other enzymes in the superfamily can only catalyze the synthesis of a single ADP ribose unit, so they are also called mono(ADP-ribosyl)ases (MARs).

PARP binding to DNA damage sites, catalytic activity, and release from DNA are all important steps in the tumor cell response to DNA damage caused by chemotherapeutic drugs and radiation. Inhibition of PARP family enzymes has been used 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). A large number of preclinical and clinical studies have shown that BRCA1 or BRCA2 with deleterious Mutated tumor cells are sensitive to PARP inhibitors. Tumors produced by mutation carriers usually lose the wild-type allele, which leads to tumor-specific homologous recombination repair (HRR) dysfunction when double-strand breaks occur, and thus rely on the function of PARP for survival. When PARP1 is inhibited, base excision repair is reduced, single-strand breaks generated in the normal cell cycle persist, and double-strand breaks can be formed when the replication fork encounters unrepaired breaks. Therefore, compared with wild-type cells, tumor cells lacking homologous recombination repair, such as BRCA1 and BRCA2 mutants, are highly sensitive to PARP inhibition. Currently, PARP inhibitor treatment is mainly aimed at cancer patients with BRCA mutations, but for cancers with homologous recombination repair defects, each related gene may become a potential target for synthetic lethality of PARP inhibitors, and PARP inhibitors have great therapeutic value. For example, ATM deletion was found in patients with T-lymphocytic leukemia, B-cell chronic lymphocytic leukemia, and breast cancer, CHK2 germline mutations were found in sarcomas, breast cancer, ovarian cancer, and brain tumors, FANCC and FANCG mutations were confirmed in pancreatic cancer, and FANCF promoter methylation also occurred in ovarian cancer, breast cancer, cervical cancer, and lung cancer. Other homologous recombination repair-related genes have also been shown to constitute 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 the replication fork to promote base excision, and PARP1/2 binds to 5'-deoxyribonucleic acid. After PARP activation, it uses DNA polymerase β (Polβ) and ligase III to recruit the BER scaffold protein XRCC1. Cells with defects in XRCC1 and Polβ are highly sensitive to PARPis. 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, slow down replication forks and block replication initiation, maintain genome stability, inhibit ATR or CHK1 leading to loss of S phase checkpoint, replication initiation, causing double bond breaks, and combined with PARP inhibitors show synergistic effects. FANCI-FANCD2 can stabilize the RAD51-DNA complex, PALB2 binds to BRCA2, promotes BRCA2 nuclear stability and accumulation, and BRCA1 interacts with many HRR-related 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 the transcription of DNA repair genes (such as CtIP, BRCA1, WEE1, TOPBP1, and RAD51), and show synergy with PARPis in cells with normal BRCA.

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 PARP1 inhibitors that are highly selective for PARP1 and less toxic to meet clinical needs.

Summary of the invention

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

Therefore, the object of the present invention is to provide a compound represented by general formula (I) or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

in:

X ¹ , X ² , X ³ , X ⁴ are independently selected from N or C(R ³ );

Y ¹ , Y ² , Y ³ , Y ⁴ , and Y ⁵ are each independently selected from N or C(R ⁴ );

Ring A is selected from heterocyclic groups, which are optionally substituted by R ² ;

R ¹ is selected from C _1-6 alkyl or C _1-6 haloalkyl;

^R2 is selected from hydrogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, deuterated alkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano;

Each R ³ is independently selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, halogen;

Each R ⁴ is independently selected from hydrogen, alkyl, halogen, amino, nitro, cyano, hydroxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)NR ^a R ^b , -C(O)R ^c , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -S(O)R ^c , -S(O) ₂ R ^c , the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, thiol, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

L is selected from a bond ^, -C( ^R5R6 )-, N( ^R7 )-, -O-, -S-, -C(O)-, -S(O)-, -S(O) _2- , -C(O)NH-, -S(O)NH-, -S(O) ₂ NH-, cycloalkylene, heterocyclylene, arylene, heteroarylene, wherein the cycloalkylene, heterocyclylene, arylene, heteroarylene are optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

R ⁵ and R ⁶ are each independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, oxo, thio, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted substituted by one or more of substituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

^R is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

^Ra and ^Rb are each independently selected from hydrogen, halogen, hydroxyl, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or,

^Ra and ^Rb together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

R ^c is selected from hydrogen, halogen, hydroxyl, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

In one embodiment of the present invention, the compound represented by the general formula (I) or its racemate, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a 4-10 membered heterocyclic group, preferably a 4-8 membered monocyclic heterocyclic group, a 6-10 membered bridged heterocyclic group, a 7-11 membered spiro heterocyclic group, or an 8-10 membered fused heterocyclic group; ring A is optionally substituted by R ² ; R ² is as defined in the general formula (I).

In another embodiment of the present invention, the compound represented by the general formula (I) or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein ring A is selected from:

Ring A is optionally substituted by R ² ; R ² is as defined in the general formula (I).

In another embodiment of the present invention, the compound represented by the general formula (I) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is the compound represented by the general formula (II) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

in,

m and n are integers from 0 to 3 respectively.

^X1 , ^X2 , ^X3 , ^X4 , ^Y1 , ^Y2 , ^Y3 , ^Y4 , ^Y5 , ^R1 and L are as defined in the general formula (I).

In another embodiment of the present invention, the compound represented by the general formula (I) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IIA) or (IIB) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

in,

p is an integer from 0 to 2;

R ¹ , R ² , R ³ , Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , L, m and n are as defined in the general formula (II).

In another embodiment of the present invention, the compound represented by the general formula (I), general formula (II) or general formula (IIA), (IIB) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

Y ¹ , Y ² , Y ³ , Y ⁴ , and Y ⁵ are independently selected from N or C(R ⁴ );

R ¹ is selected from C _1-6 alkyl or C _1-6 haloalkyl, preferably C _1-6 alkyl or C _1-6 fluoroalkyl, more preferably C _1-4 alkyl;

^R2 is selected from hydrogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, deuterated alkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano; preferably hydrogen, _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, halogen, hydroxyl, cyano;

Each ^R4 is independently selected from hydrogen, alkyl, halogen, amino, nitro, cyano, hydroxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl ^, ^heteroaryl , -C(O) ^NRaRb ^, _-C (O) ^Rc , ^-S ⁽ O)NRaRb, -S(O)2NRaRb, -S(O) ^Rc , -S(O) _2Rc ; preferably hydrogen, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 ^haloalkyl , -C(O) ^NRaRb , ^-S (O) ^NRaRb ^, -S(O) _2NRaRb , _C3-8 ^cycloalkyl , 4 to ¹⁰ membered heterocyclyl, C _6-10 membered aryl, 5 to 10 membered heteroaryl; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl may be further selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, thiol, substituted or unsubstituted alkenyl, substituted The alkyl radical is substituted with one or more substituents selected from deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylsulfonyl, alkylamino, halogen, amino, nitro, cyano, hydroxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

L is selected from a bond, -C( ^R5R6 )- ^, -N( ^R7 )-, -O-, -S-, -C(O)-, _-S (O)-, -S(O) _2- , -C(O)NH-, -S(O)NH-, -S(O)2NH-, cycloalkylene, ^{heterocyclylene} , arylene, heteroarylene, preferably a bond, -C( ^R5R6 )-, -N( ^R7 )-, -O-, cycloalkylene, heterocyclylene, arylene, heteroarylene; wherein the cycloalkylene, heterocyclylene, arylene, heteroarylene is optionally further selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl are substituted with one or more substituents; when substituted, the substituents are selected from one or more of deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylsulfonyl, alkylamino, halogen, amino, nitro, cyano, hydroxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁵ and R ⁶ are each independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, oxo, thio, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, preferably hydrogen, C _1-6 alkyl, C _1-6 deuterated alkyl, C 1-6 haloalkyl _, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 deuterated alkoxy, halogen, C _3-8 cycloalkyl, 4 to 10 membered heterocyclyl, C _6-10 membered aryl, 5 to 10 membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl , substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, when substituted, the substituent is selected from one or more of deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylsulfonyl, alkylamino, halogen, amino, nitro, cyano, hydroxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

^R7 is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, preferably hydrogen, _C1-6 alkyl, _C1-6 haloalkyl, _C3-8 cycloalkyl, 4 to 10 membered heterocyclyl, C _6-10 membered aryl, 5 to 10 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, thiol, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituents are selected from one or more of deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylsulfonyl, alkylamino, halogen, amino, nitro, cyano, hydroxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R ^c is selected from hydrogen, halogen, hydroxyl, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

p is an integer from 0 to 2;

m and n are integers from 0 to 3 respectively.

In another embodiment of the present invention, the compound represented by the general formula (I), general formula (II) or general formula (IIA), (IIB) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IIIA) or (IIIB) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

in,

p is an integer from 0 to 2;

Y ⁴ and Y ⁵ are each independently selected from N or CH;

R ^4a and R ^4b are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, -C(O)NR ^a R ^b , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , C _3-8 cycloalkyl, 4 to 10 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl; preferably halogen, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, -C(O)NR ^a R ^b , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , C _3-8 cycloalkyl; the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from deuterated, substituted or unsubstituted substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, when substituted, the substituent is selected from one or more of deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylsulfonyl, alkylamino, halogen, amino, nitro, cyano, hydroxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R ¹ , R ² , R ³ , ^Ra , R ^b , L, m and n are as defined in the general formula (II).

In another embodiment of the present invention, the compound represented by the general formula (IIIA) or (IIIB) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^4a is selected from -C(O)NR ^a R ^b , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , preferably -C(O)NR ^a R ^b ; ^Ra and R ^b are as defined in the general formula (I).

In another embodiment of the present invention, the compound represented by the general formula (I) or the general formula (II), (IIA), (IIB), (IIIA), (IIIB) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, is a compound represented by the general formula (IVA) or (IVB) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt,

in,

p is an integer from 0 to 2;

Y ⁴ and Y ⁵ are each independently selected from N or CH;

R ^4b is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 1-6} _haloalkyl , -C(O)NR ^a R ^b , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R b , C _{3-8 cycloalkyl, 4 to 10 membered heterocyclyl, C 6-10 aryl, 5 to 10 membered heteroaryl; preferably halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, -C(O)NR a R b , -S(O) 2 NR a R b , C 3-8} _{cycloalkyl, 4 to 10 membered heterocyclyl, C 6-10} _aryl _, ⁵ _to 10 membered heteroaryl; alkyl, -C(O)NR ^a R ^b , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , C _3-8 cycloalkyl; the alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally further substituted by one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, thiol, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituents are selected from one or more of deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylsulfonyl, alkylamino, halogen, amino, nitro, cyano, hydroxyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl;

R ¹ , R ² , R ³ , L, m and n are as defined in the general formula (II).

In another embodiment of the present invention, the compound represented by the general formula (I), general formula (II), general formula (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (V) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

L is selected from a bond ^, -C( ^R5R6 )-, -N( ^R7 )-, -O-, -S-, a _C3-8 cycloalkylene group, a 4- to 10-membered heterocyclylene group, a _C6-10 arylene group, and a 5- to 10-membered heteroarylene group, preferably ^a bond, -C( ^R5R6 )-, -N( ^R7 )-, -O-, 4 to 10 membered heterocyclylene, wherein the 4 to 10 membered heterocyclylene is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituent is selected from C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _{1-6 alkoxy, C 1-6} _haloalkoxy , halogen, cyano, hydroxyl;

R ⁵ and R ⁶ are each independently selected from hydrogen, C _1-6 alkyl, C _1-6 deuterated alkyl, C 1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 deuterated alkoxy, halogen, C _3-8 cycloalkyl, 4 to 10 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl _{, preferably hydrogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6} _haloalkyl _, _halogen , _C3-8 cycloalkyl, 4 to 10 membered heterocyclyl, wherein the _C3-8 cycloalkyl, 4 to 10 membered heterocyclyl is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, and when substituted, the substituent is selected from deuterium, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, hydroxyalkyl, alkylsulfonyl, halogen, cyano, hydroxyl;

^R is selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, 4 to 10 membered heterocyclyl, preferably hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, wherein the C _3-8 cycloalkyl is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituent is selected from deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, C 3-8 C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, hydroxyalkyl, alkylsulfonyl, alkylamino, halogen, amino, nitro, cyano, hydroxy, alkenyl, alkynyl, C _3-8 cycloalkyl, 4 to 10 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl.

In another embodiment of the present invention, the compound represented by the general formula (I), general formula (II), general formula (IIA), (IIIA), (IVA) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is the compound represented by the general formula (VA) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

wherein R ¹ , Y ₄ , Y ₅ , R ² , R ³ , R ^4b , L, m, n and p are as defined in the general formula (IVA).

^R is selected from _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C3-8 cycloalkyl, 4 to 10 membered heterocyclyl, _C6-10 aryl, 5 to 10 membered heteroaryl, wherein the _C3-8 cycloalkyl, 4 to 10 membered heterocyclyl, _C6-10 aryl, 5 to 10 membered heteroaryl is further selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. substituted by multiple substituents; when substituted, the substituents are selected from deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, and halogen.

In another embodiment of the present invention, the compound represented by the general formula (I) or the general formula (II), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA) or its racemate, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ^Y4 is N and ^Y5 is CH; or ^Y4 is CH and ^Y5 is N.

In another embodiment of the present invention, the compound represented by the general formula (I) or the general formula (II), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

L is selected ^from a bond, -C( ^R5R6 )-, -N( ^R7 )-, -O-, a 4 to 10 membered heterocyclylene, wherein the 4 to 10 membered heterocyclylene is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituents are selected from _C1-6 alkyl, C1-6 haloalkyl, _C1-6 alkoxy, C1-6 haloalkoxy, halogen, further preferably C1-6 alkyl, _C1-6 haloalkyl, C1-6 alkoxy, _C1-6 haloalkoxy, halogen, further preferably _C1-6 alkyl, C1-6 _1-6 alkoxy, halogen;

R ⁵ and R ⁶ are each independently selected from hydrogen, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, halogen, C _3-8 cycloalkyl, and 4 to 10 membered heterocyclic groups, and are further preferably selected from hydrogen, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, halogen, and C _3-8 cycloalkyl, wherein the C _3-8 cycloalkyl is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, and when substituted, the substituent is selected from C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _{1-6 alkoxy, C 1-6} _haloalkoxy , halogen;

^R is selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, further preferably hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, wherein the C _3-8 cycloalkyl is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituent is selected from deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C 3-8 _1-6 haloalkoxy, halogen;

^R is selected from C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, 4 to 10 membered heterocyclic group, C _6-10 aryl, 5 to 10 membered heteroaryl, preferably C _1-6 alkyl, C _3-8 cycloalkyl, 4 to 10 membered heterocyclic group wherein the _C3-8 cycloalkyl, 4-10 membered heterocyclyl, _C6-10 aryl, _5-10 membered heteroaryl is further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituent is selected from deuterium, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, C1-6 _1-6 haloalkoxy, halogen.

L is selected ^from a bond, -C( ^R5R6 )-, -N( ^R7 )-, -O-, a 4- to 10-membered heterocyclyl, preferably a bond, -N( ^R7 )-, -O-, a 4- to 10-membered heterocyclyl, wherein the 4- to 10-membered heterocyclyl is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituents are selected from _C1-6 alkyl, _C1-6 alkoxy, halogen;

^R5 and ^R6 are each independently selected from hydrogen, _C1-6 alkyl, _{C1-6 deuterated alkyl, C1-6} _haloalkyl , halogen, _C3-8 cycloalkyl, wherein the _C3-8 cycloalkyl is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, thiol, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituent is selected from _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, C3-8 _1-6 haloalkoxy, halogen;

^R is selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, wherein the C _3-8 cycloalkyl is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituent is selected from deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, halogen;

^Rb is selected from _C1-6 alkyl, _C3-8 cycloalkyl, 4- to 10-membered heterocyclyl, _C6-10 aryl, 5- to 10-membered heteroaryl The group is preferably selected from C _1-6 alkyl, C _3-8 cycloalkyl, 4 to 10 membered heterocyclyl, wherein the C _3-8 cycloalkyl, 4 to 10 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl is further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituent is selected from deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, halogen, preferably selected from C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, halogen.

L is selected from a bond, -N(R ⁷ )-, O, a 4 to 10 membered heterocyclyl, wherein the 4 to 10 membered heterocyclyl is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituents are selected from C _1-6 alkyl, C _1-6 alkoxy, halogen;

^R is selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, preferably hydrogen, C _1-6 alkyl, wherein the C _3-8 cycloalkyl is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituent is selected from deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, halogen;

^R is selected from _C1-6 alkyl, _C3-8 cycloalkyl, 4 to 10 membered heterocyclyl, wherein the _C3-8 cycloalkyl, 4 to 10 membered heterocyclyl is further substituted by one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituent is selected from _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, halogen.

In another embodiment of the present invention, the general formula (I) or general formula (II), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA) or its mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

L is selected from a bond, -N(R ⁷ )-, -O-, a 4 to 10 membered heterocyclyl, wherein the 4 to 10 membered heterocyclyl is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituents are selected from C _1-6 alkyl, C _1-6 alkoxy, halogen;

^R7 is selected from hydrogen, _C1-6 alkyl.

In another embodiment of the present invention, the compound represented by the general formula (I) or the general formula (II), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA) or its racemate, racemate, enantiomer, diastereomer _, or a mixture thereof _, or a pharmaceutically acceptable salt thereof, wherein: ^R2 is selected from hydrogen, _C1-6 alkyl, _C1-6 deuterated alkyl _, _C1-6 _haloalkyl , _C1-6 alkoxy _, _C1-6 haloalkoxy _{, C1-6} _deuterated alkoxy, halogen, amino, thiol, hydroxyl, cyano.

In another embodiment of the present invention, the compound represented by the general formula (I) or the general formula (II), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA) or its racemate, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R ³ is selected from hydrogen or halogen, and p is 0 or 1.

In another embodiment of the present invention, the compound represented by the general formula (IIIA), (IIIB), (IVA), (IVB), (VA) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: R ^4b is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, 4 to 10 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl; preferably selected from halogen, C _1-4 alkyl, C _1-4 deuterated alkyl, C _1-4 haloalkyl, C _3-8 membered cycloalkyl, 4 to 10 membered heterocyclyl; the alkyl, cycloalkyl, heterocyclyl is optionally further substituted by one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, thiol, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituent is selected from one or more of deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylsulfonyl, alkylamino, halogen, amino, nitro, cyano, hydroxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.

In another embodiment of the present invention, the compound represented by the general formula (I) or the general formula (II), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: m is 1 or 2, n is 1 or 2.

In another embodiment of the present invention, the compound represented by the general formula (I) or the general formula (II), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA) or its racemate, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: m is 1 and n is 1 or 2.

In another embodiment of the present invention, the compound represented by the general formula (I) or the general formula (II), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (VA) or its racemate, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: L is -O-.

In another embodiment of the present invention, the compound represented by the general formula (IIIA), (IIIB), (IVA), (IVB), (VA) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: R ^4b is selected from hydrogen, halogen, C _1-6 alkyl.

In a specific embodiment, ^Ra and ^Rb according to the present invention are each independently selected from hydrogen, _C1-6 alkyl, _C3-6 cycloalkyl, preferably ^Ra is hydrogen, and ^Rb is selected from _C1-6 alkyl and _C3-6 cycloalkyl.

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

or its meso form, racemate, enantiomer, diastereomer, or mixture form, or its pharmaceutically acceptable salt.

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

Under alkaline conditions, compound IVe and compound IVf undergo a substitution reaction to obtain a compound represented by general formula (IVA) or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

Wherein, Y ⁴ , Y ⁵ , R ¹ , R ² , R ³ , R ^4b , ^Ra , R ^b , L, m, n, and p are as defined in the general formula (IVA): righteous.

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

The present invention further relates to the use of the compound according to the present invention or its mesomorph, 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.

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 drug for preventing and/or treating a disease associated with poly (ADP-ribose) polymerase 1 activity, wherein the disease is preferably a tumor disease, such as ovarian cancer, breast cancer, prostate cancer, etc.

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, which is used as a poly ADP-ribose polymerase 1 (PARP1) inhibitor.

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, which is used for preventing and/or treating diseases associated with poly (ADP-ribose) polymerase 1 activity, preferably tumor diseases, such as ovarian cancer, breast cancer, prostate cancer, etc.

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, which is used as a medicament for preventing and/or treating a disease associated with poly (ADP-ribose) polymerase 1 activity, preferably a tumor disease, such as ovarian cancer, breast cancer, prostate cancer, etc.

The present invention further relates to a method for inhibiting poly ADP-ribose polymerase 1 (PARP1), which comprises administering to a patient in need thereof an 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.

The present invention further relates to a method for preventing and/or treating a disease associated with poly (ADP-ribose) polymerase 1 activity, comprising administering to a patient in need thereof a preventive or therapeutically effective amount of 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; wherein the disease is preferably a tumor disease, such as ovarian cancer, breast cancer, prostate cancer, etc.

The pharmaceutical composition 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 such compositions may contain one or more ingredients selected from the following: sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasing taste. and palatable pharmaceutical preparations. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets in admixture. These excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrants such as microcrystalline cellulose, crosslinked sodium carboxymethyl cellulose, corn starch or alginic acid; binders such as starch, gelatin, polyvinyl pyrrolidone or acacia; and lubricants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time. For example, water-soluble taste masking substances such as hydroxypropyl methylcellulose or hydroxypropyl cellulose, or time-extending substances such as ethyl cellulose, cellulose acetate butyrate may be used.

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.

Aqueous suspensions contain the active substance and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersing agents or wetting agents, which may be naturally occurring phosphatides such as lecithin, or condensation products of alkylene oxides with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain fatty alcohols, for example heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, for example polyethylene oxide sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example 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, for example sucrose, saccharin or aspartame.

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. The oil suspension may contain a thickener such as beeswax, hard paraffin or cetyl alcohol. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant such as butylated hydroxyanisole or alpha-tocopherol.

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, flavoring agents, 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 a demulcent, a preservative, a coloring agent and an antioxidant.

The pharmaceutical composition of the present invention may be in the form of a sterile injectable aqueous solution. Acceptable solvents and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase. For example, the active ingredient is 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 microemulsion may be injected locally in large quantities. The injection solution or microemulsion is injected into the patient's bloodstream. Alternatively, it is best to administer the solution and microemulsion 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 can be used.

The pharmaceutical composition of the present invention can be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared according to known techniques with the above-mentioned suitable dispersants or wetting agents and suspending agents. The sterile injection preparation can also be a sterile injection solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils including synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid can also be used to prepare injections.

The compounds of the invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and which will dissolve in the rectum to release the drug. 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.

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 factors: 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 administration time, the administration method, the excretion rate, the combination of drugs, etc. In addition, the best treatment method, such as the mode of treatment, the daily dosage of the general compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment plans.

The present invention may contain the compound represented by the general formula (I), and a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and 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, etc. 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 poly ADP-ribose polymerase 1. Combination therapy is achieved by administering the individual therapeutic components simultaneously, separately or sequentially.

Terminology

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

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, and 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-methylbutyl, 2-ethylbutyl, 2-methylpentyl, 2-methylpentyl, 2-methylpentyl, 2-methylpentyl, 2-methylpentyl, 2-methylpentyl, 2-methylpentyl, 2-methylpentyl, 2-ethylbutyl ... -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-ethyl 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, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

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, such as vinyl, 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, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

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, such as ethynyl, propynyl, butynyl, etc. Alkynyl 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, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and further preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spirocyclic, condensed and bridged rings.

The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called a spiral atom) 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 6 to 10 yuan. According to the number of spiral atoms shared between rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl. 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 spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

The term "condensed 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 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 6 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl. Non-limiting examples of condensed cycloalkyls include:

The term "bridged cycloalkyl" refers to a 5 to 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 to 14 members, and more preferably 6 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic or tetracyclic, and more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

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, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

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 are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 4 to 10 ring atoms, of which 1 to 3 are heteroatoms; more preferably, it contains 4 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably, it contains 5 to 6 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. The limiting examples of monocyclic heterocyclic radicals 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 radicals include spirocyclic, condensed ring and bridged heterocyclic radicals.

The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group in which one atom (called a spiral atom) is shared between 5 to 20 monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), 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 yuan, more preferably 6 to 10 yuan. According to the number of shared spiral atoms between rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic 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 spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

The term "fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, 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 heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 6 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 6 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

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:

wait.

The heterocyclyl group 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, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

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

The aryl 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, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

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 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

The heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen The invention further comprises a halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate group.

The term "alkoxy" refers to-O-(alkyl) and-O-(non-substituted cycloalkyl), wherein the definitions of alkyl and cycloalkyl are as described above. The non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or non-substituted, and when substituted, substituents are preferably one or more of the 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.

The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived from a parent ring atom by removing one hydrogen atom, or residues derived from the same ring atom or two different ring atoms of the parent by removing two hydrogen atoms, namely "cycloalkylene", "heterocyclylene", "arylene" and "heteroarylene".

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

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

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

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

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

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

The term "hydroxy" refers to an -OH group.

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

The term "amino" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "oxo" refers to =0.

The term "thio" refers to =S.

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

The term "thiol" refers to -SH.

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

The term "alkylacyl" refers to a -C(O)R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl as defined above.

The term "alkylsulfonyl" refers to a -S(O) ₂ R group, wherein R is alkyl, cycloalkyl, Heterocyclyl, aryl, heteroaryl.

The term "aminoacyl" refers to a -C(O)NHR group, where R is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl as defined above.

The compounds of the present invention can be in deuterated form. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated compounds with reference to the relevant literature. Commercially available deuterated starting materials can be used when preparing deuterated compounds, or they can be synthesized using conventional techniques using deuterated reagents.

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

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

"Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and 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, facilitate the absorption of the active ingredient, and thus exert biological activity.

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

Synthesis method of the compound of the present invention

The compound of the general formula (IVA) of the present invention can be prepared by the following scheme.

plan 1

Step 1) In the presence of a base, the compound of formula IVa undergoes hydrolysis to obtain a compound of formula IVb;

Step 2) In the presence of a condensation agent, the compound of formula IVb and the compound of formula IVc undergo a condensation reaction to obtain a compound of formula IVd;

Step 3) Under acidic conditions, the compound of formula IVd undergoes a deprotection reaction to obtain a compound of formula IVe;

Step 4) Under alkaline conditions, the compound of formula IVe undergoes a substitution reaction with the compound of formula IVf to obtain a compound represented by formula (IVA) or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein R ¹ , R ² , R ³ , R ^4b , ^Ra , R ^b , Y ⁴ , Y ⁵ , L, m, n and p are as defined in the general formula (IVA).

Reagents that provide acidic conditions include, but are not limited to, hydrogen chloride in 1,4-dioxane, trifluoroacetic acid, and formic acid.

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

The condensing agent includes but is not limited to EDCI and HOBT, HATU, DCC, and FDPP.

The above reaction can be carried out in a solvent, and the solvent used includes but is not limited to: methanol, ethanol, acetonitrile, tetrahydrofuran, dichloromethane, water or N,N-dimethylformamide and a mixture thereof.

Detailed ways

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

The compounds of the present invention are prepared using convenient starting materials and common preparation steps. The present invention provides typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, and molar ratio of reactants. However, unless otherwise specified, other reaction conditions can also be adopted. The optimized conditions may change with the use of specific reactants or solvents, but in general, the reaction optimized steps and conditions can be determined.

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, T. W. Greene and G. M. Wuts's "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.

The separation and purification of compounds and intermediates can be carried out by appropriate methods and steps according to 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. The specific use method can refer to the examples described in the present invention. Of course, other similar separation and purification means can also be adopted. Conventional methods (including physical constants and spectral data) can be used to characterize them.

The structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts were given in units of 10 ^-6 (ppm). NMR measurements were made using a Bruker 300 NMR spectrometer to measure the solvent. The reagents were deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was tetramethylsilane (TMS).

MS was determined using LC (Agilent 1260 Infinity)/MS (G6125B) mass spectrometer (manufacturer: Agilent).

The preparative liquid chromatography method used an LC6000 high performance liquid chromatograph (manufacturer: Chuangxin Tongheng). The chromatographic column was Daisogel C18 10 μm 100A (30 mm × 250 mm), and the mobile phase was acetonitrile/water.

Thin layer chromatography (TLC) used Qingdao Ocean Chemical GF254 silica gel plate. The silica gel plate used in reaction monitoring thin layer chromatography adopted a specification of 0.20 mm to 0.25 mm, and the silica gel plate used in separation and purification thin layer chromatography adopted a specification of 0.5 mm.

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

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 Inokai, Anaiji Chemical, Shanghai Bid, Nanjing Yaoshi and other companies.

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

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

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.

The chemical reactions described in the present invention are generally carried out under normal pressure. The reaction time and conditions are, for example, between -78°C and 200°C at one atmosphere, and completed within about 1 to 24 hours. If the reaction is 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.

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

The eluent system of column chromatography and the developing solvent system of thin layer chromatography used for purifying compounds 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.

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 method and material similar or equivalent to the described content can be applied to the method of the present invention.

Example

Example 1: Preparation of 5-((1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)azetidin-3-yl)(methyl)amino)-N-methylpicolinamide (1)

Step 1: Preparation of ethyl 6-formyl-5-nitronicotinate (1a)

Dissolve 6-methyl-5-nitro-pyridine-3-carboxylic acid ethyl ester (10.0 g, 47.6 mmol) in 1,4-dioxane (50 mL), add selenium dioxide (7.92 g, 71.4 mmol), and stir at 110 °C for 12 hours under nitrogen atmosphere. Cool the reaction solution to room temperature, filter it with diatomaceous earth, wash the filter cake with EA (10 mL x 2), and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase PE/EA=3:1) to obtain 9.65 g of the title compound as a light yellow solid with a yield of 90.6%.

LC-MS: m/z 225 [M+H] ⁺ .

Step 2: Preparation of 6-[(E)-2-ethoxycarbonylbut-1-enyl]-5-nitro-pyridine-3-carboxylic acid ethyl ester (1b)

Sodium hydride (2.03 g, 51.1 mmol) was dissolved in THF (100 mL), and ethyl (diethoxyphosphoryl)butyrate (13.9 g, 55.1 mmol) was slowly added at 0°C, stirred at 0°C for 10 minutes, stirred at 40°C for 5 minutes, and slowly added a THF solution (20 ml) of ethyl 6-formyl-5-nitronicotinate (1a) (9.50 g, 42.4 mmol) at -78°C. The mixture was quenched with saturated NH ₄ Cl solution (100 mL), and extracted with EA (100 mL x 3). The mixture was 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=4:1) to obtain 9.40 g of the title compound as a light yellow solid, with a yield of 69.1%.

LC-MS: m/z 323 [M+H] ⁺ .

Step 3: Preparation of ethyl 5-amino-6-(2-(ethoxycarbonyl)butyl)nicotinate (1c).

At room temperature, 6-[(E)-2-ethoxycarbonylbut-1-enyl]-5-nitro-pyridine-3-carboxylic acid ethyl ester (1b) (8.40 g, 26.5 mmol) was dissolved in 100 mL of ethanol, Pd/C (1.25 g) was added to the reaction solution, and stirred at room temperature overnight under a hydrogen atmosphere. Filtered through celite, the filter cake was washed with MeOH (50 mL x 1), and the filtrate was concentrated under reduced pressure to obtain 6.40 g (crude) of the title compound as a yellow oil.

LC-MS: m/z 295 [M+H] ⁺ .

Step 4: Preparation of ethyl 7-ethyl-6-oxo-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxylate (1d)

At room temperature, dissolve 5-amino-6-(2-(ethoxycarbonyl)butyl)nicotinate ethyl ester (1c) (1.00 g, 3.40 mmol) in a hydrochloric acid dioxane solution (10 ml) and stir at room temperature overnight under a nitrogen atmosphere. Add 30 mL of a mixed solution of PE and EA (PE/EA = 5:1) and stir at room temperature for 1 hour. Filter and wash the filter cake with a mixed solution of PE/EA = 5:1 (5 mL x 3) to obtain 600 mg (crude) of the title compound as a yellow solid.

LC-MS: m/z 249 [M+H] ⁺ .

Step 5: Preparation of ethyl 7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate (1e)

At room temperature, ethyl 7-ethyl-6-oxo-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxylate (1d) (3.60 g, 14.5 mmol) was dissolved in 40 mL 1,4-dioxane. DDQ (3.95 g, 17.4 mmol) was added to the reaction solution, and the mixture was stirred at 110 °C for 4 hours under nitrogen atmosphere. 50 mL of water was added, and the mixture was extracted with EA (50 mL x 3), washed with saturated brine (40 mL x 2), 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=100:1-1:1) to give 2.8 g of the title compound as a light yellow solid. Yield: 77.7%.

LC-MS: m/z 247 [M+H] ⁺ .

Step 6: Preparation of 3-ethyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one (1f)

Dissolve ethyl 7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate (1e) (2.60 g, 1.02 mmol) in THF (40 ml), add LiAlH ₄ (12.5 mL, 1 mol/L) at 0°C, and stir at 0°C for 1 hour. Add 0.5 mL of water, 0.5 mL of 4 mol/L sodium hydroxide solution, and 1.5 mL of water to quench, stir at room temperature for 1 hour, filter, wash the filter cake with THF (20 mL x 4), and concentrate the filtrate under reduced pressure to obtain 1.8 g of the crude title compound as a yellow oil.

LC-MS: m/z 205 [M+H] ⁺ .

Step 7: Preparation of 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (1 g)

At room temperature, 3-ethyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one (1f) (720 mg, 3.53 mmol) was dissolved in 10 mL of DCM, SOCl ₂ (2.50 g, 21.2 mmol) and DMF (51.0 mg, 0.353 mmol) were added to the reaction solution, and stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure to obtain 760 mg (crude) of the title compound as a white solid.

LC-MS: m/z 223 [M+H] ⁺ .

Step 8: Preparation of methyl 5-((1-(tert-butyloxycarbonyl)azetidin-3-yl)(methyl)amino)picolinate (1h)

Dissolve 5-bromopicolinic acid methyl ester (500 mg, 2.33 mmol) in 1,4-dioxane (5 mL), add tert-butyl 3-(methylamino)azetidine-1-carboxylate (476 mg, 2.56 mmol), cesium carbonate (1.51 g, 4.65 mmol), Ruphos pd G3 (68.1 mg, 0.0814 mmol). Stir at 110°C for 16 hours under nitrogen atmosphere. Add water (20 mL), extract with ethyl acetate (20.0 mL x 3), wash with saturated brine (20 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate and purify the residue by silica gel column chromatography (mobile phase: EA/PE=100:1-7:3) to obtain 600 mg of the title compound as a light yellow solid, yield: 67.4%.

LC-MS: m/z 322.2 [M+H] ⁺ .

Step 9: Preparation of 5-((1-(tert-butyloxycarbonyl)azetidin-3-yl)(methyl)amino)picolinic acid (1i)

Dissolve methyl 5-((1-(tert-butyloxycarbonyl)azetidin-3-yl)(methyl)amino)picolinate (1h) (600 mg, 1.87 mmol) in water (2 mL) and methanol (6 mL), and add lithium hydroxide (89.7 mg, 3.74 mmol). Stir at room temperature for 16 hours. Concentrate under reduced pressure to obtain 730 mg (crude) of the title compound as a white solid.

LC-MS: m/z 308.2 [M+H] ⁺ .

Step 10: Preparation of tert-butyl 3-(methyl(6-(methylcarbamoyl)pyridin-3-yl)amino)azetidine-1-carboxylate (1j)

5-((1-(tert-Butyloxycarbonyl)azetidin-3-yl)(methyl)amino)picolinic acid (1i) (680 mg, 2.21 mmol) was dissolved in DMF (7 mL), and methylamine hydrochloride (223 mg, 3.32 mmol), DIEA (857 mg, 6.64 mmol), and HATU (1.26 g, 3.32 mmol) were added, and stirred at room temperature for 16 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (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 separated and purified by silica gel column chromatography (mobile phase: EA/PE = 100%) to obtain 550 mg of the title compound as a light yellow solid, with a yield of (71.3%).

LC-MS: m/z 321.2 [M+H] ⁺ .

Step 11: Preparation of 5-(azetidin-3-yl(methyl)amino)-N-methylpicolinamide (1k)

At room temperature, tert-butyl 3-(methyl(6-(methylcarbamoyl)pyridin-3-yl)amino)azetidine-1-carboxylate (1j) (80.0 mg, 0.250 mmol) was dissolved in methanol (0.5 mL), and a dioxane hydrochloride solution (4 mol/L, 1.5 mL) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to obtain 60 mg (crude) of the title compound as a light yellow solid.

LC-MS: m/z 221.1 [M+H] ⁺ .

Step 12: Preparation of 5-((1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)azetidin-3-yl)(methyl)amino)-N-methylpicolinamide (1)

At room temperature, 5-(azetidin-3-yl(methyl)amino)-N-methylpicolinamide (1k) (55.0 mg, 0.250 mmol) and 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (1g) (55.5 mg, 0.250 mmol) were dissolved in acetonitrile (2 mL), DIEA (161 mg, 1.25 mmol) and sodium iodide (7.50 mg, 0.0500 mmol) were added, and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was separated by high pressure preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um 100A, mobile phase: acetonitrile/water, gradient: 10%-50%, 0.05% formic acid, 30 min) to obtain 13.0 mg of the title compound as a white solid, with a yield of 11.5%.

LC-MS: m/z 407.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ )δ11.85(s,1H),8.39-8.31(m,2H),8.04(d,J＝2.8Hz,1H),7.80(d,J＝8.8Hz,1H),7.74(s,1H),7.58(d,J＝1.6Hz,1H),7.16(dd,J＝8.8,3.2Hz,1H),4.34(p,J＝6.8Hz,1H),3.74(s,2H),3.68(td,J＝6.8,1.6Hz,2H),3.13(td,J＝6.8,1.6Hz,2H),2.98(s,3H),2.77(d,J＝4.8Hz,3H),2.57-2.52(m,2H),1.18(t,J＝7.2Hz,3H).

Example 2: Preparation of 5-(1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-[3,3'-diazetidine]-1-yl)-N-methylpicolinamide (2)

Step 1: Preparation of 1-dibenzylazetidin-3-yl methanesulfonate (2a)

Methanesulfonyl chloride (11.4 g, 100 mmol) was added to a solution of 1-benzhydrylazetidine-3-ol (20.0 g, 83.7 mmol) and pyridine (9.90 g, 125 mmol) in dichloromethane (200 mL) at -20°C, and stirred at -20°C for 30 minutes under a nitrogen atmosphere. The reaction solution was added to water (500 mL), extracted with dichloromethane (300 mL x 3), washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 28.3 g of the title compound (crude product) as a white solid.

LC-MS: m/z 318.1 [M+H] ⁺ .

Step 2: Preparation of diethyl 2-(1-diphenylmethylazetidin-3-yl)malonate (2b)

Sodium hydride (7.07 g, 177 mmol) was added to a solution of diethyl malonate (31.1 g, 194 mmol) in N,N-dimethylformamide (150 mL) at 0°C, and the mixture was stirred at 0°C for 1 hour. A solution of 1-dibenzylazetidin-3-yl methanesulfonate (2a) (28.0 g, 88.3 mmol) in N,N-dimethylformamide (50 mL) was added, and the mixture was stirred at 70°C overnight under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (500 mL), and the organic phase was washed with water (300 mL x 4), washed with saturated brine (300 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 = 100:1-4:1) to obtain 34.0 g of the title compound (crude product) as a colorless oily liquid.

LC-MS: m/z 382.1 [M+H] ⁺ .

Step 3: Preparation of 2-(1-diphenylmethylazetidin-3-yl)propane-1,3-diol (2c)

At 0°C, add lithium aluminum hydride (8.14 g, 214 mmol) to a solution of diethyl 2-(1-dibenzylazetidin-3-yl)malonate (2b) (34.0 g, 89.2 mmol) in tetrahydrofuran (400 mL). Stir at room temperature overnight under a nitrogen atmosphere, add 8 mL of water to quench, add 8 mL of 15% sodium hydroxide solution, add 24 mL of water, stir for half an hour, filter, and concentrate the filtrate under reduced pressure to obtain 16.0 g of the title compound (crude) as a colorless oily liquid.

LC-MS: m/z 298.2 [M+H] ⁺ .

Step 4: Preparation of 1-diphenylmethyl-3-(1,3-dibromopropan-2-yl)azetidine (2d)

Bromine (25.9 g, 162 mmol) was dissolved in dichloromethane (200 mL) at 0°C, triphenylphosphine (42.3 g, 162 mmol) was added, and the mixture was stirred at 0°C overnight for 1 hour under nitrogen atmosphere. Triethylamine (16.3 mg, 162 mmol) was added, and the mixture was stirred at 0°C overnight for 1 hour. A solution of 2-(1-dibenzylazetidin-3-yl)propane-1,3-diol (2c) (16.0 g, 53.9 mmol) in dichloromethane (200 mL) was added, and the mixture was stirred at room temperature overnight. Saturated sodium sulfite solution (300 mL) was added to quench the reaction mixture, extracted with dichloromethane (300 mL x 3), washed with saturated brine (300 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=100/1-9/1) to give 17.7 g of the title compound as a colorless oily liquid. Yield: 78.0%.

LC-MS: m/z 422.1 [M+H] ⁺ .

Step 5: Preparation of 1-diphenylmethyl-1'-(3,4-dimethylbenzyl)-3,3'-diazetidine (2e)

At room temperature, (3,4-dimethylphenyl)methanamine (6.94 g, 41.6 mmol) was added to 1-diphenylmethyl-3-(1,3-dibromopropan-2-yl)azetidine (2d) (17.5 g, 41.6 mmol) and N,N-diisopropylethylamine (16.1 g, 125 mmol) in acetonitrile (600 mL), stirred at 70 ° C overnight under nitrogen atmosphere, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=100/1-15/1) to obtain 16.0 g of the title compound as a yellow solid. Yield: 89.9%.

LC-MS: m/z 397.3 [M+H] ⁺ .

Step 6: Preparation of tert-butyl 1'-(3,4-dimethylbenzyl)-[3,3'-diazetidine]-1-carboxylate (2f)

Palladium on carbon (4.0 g) was added to a solution of 1-benzhydryl-1'-(3,4-dimethylbenzyl)-3,3'-diazetidine (2e) (16.0 g, 37.4 mmol) and di-tert-butyl dicarbonate (16.3 g, 74.5 mmol) in ethanol (150 mL) at room temperature. The mixture was stirred at room temperature overnight under a hydrogen atmosphere, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=100/1-10/1) to give 6.79 g of the title compound as an off-white solid. Yield: 50.0%.

LC-MS: m/z 331.2 [M+H] ⁺ .

Step 7: Preparation of [3,3'-diazetidine]-1-carboxylic acid tert-butyl ester (2 g)

At 0°C, 1-chloroethyl chloroformate (2.36 g, 16.5 mmol) was added to a solution of tert-butyl 1'-(3,4-dimethylbenzyl)-[3,3'-diazetidine]-1-carboxylate (2f) (3.00 g, 8.26 mmol) and triethylamine (3.34 g, 33.1 mmol) in dichloroethane (100 mL), stirred at 80°C for 3 hours, concentrated under reduced pressure, and the residue was dissolved in methanol (20 mL), and stirred at 80°C overnight. Concentrated under reduced pressure, the residue was dissolved in water (50 mL), and washed with dichloromethane (50 mL x 3). The aqueous phase was concentrated under reduced pressure to obtain 1.20 g of the crude title compound as a yellow oily liquid.

LC-MS: m/z 213 [M+H] ⁺ .

Step 8: Preparation of tert-butyl 1'-(6-(methoxycarbonyl)pyridin-3-yl)-[3,3'-diazetidine]-1-carboxylate (2i)

At room temperature, methyl 5-fluoropicolinate (200 mg, 1.29 mmol) was dissolved in DMF (5 mL), and tert-butyl [3,3'-diazetidine]-1-carboxylate (270 mg, 1.29 mmol) and potassium carbonate (530 mg, 3.87 mmol) were added, and stirred at 80°C for 16 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (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: EA/PE = 1/99-99/1) to obtain 120 mg of the title compound as a light yellow solid, yield: 26.7%.

LC-MS: m/z 348.2 [M+H] ⁺ .

The remaining steps were the same as the preparation method of Example 1, except that 1'-(6-(methoxycarbonyl)pyridin-3-yl)-[3,3'-diazetidine]-1-carboxylic acid tert-butyl ester (2i) was used instead of 5-((1-(tert-butyloxycarbonyl)azetidine-3-yl)(methyl)amino)picolinic acid methyl ester (1h) in step 9 to obtain the title compound 2.

LC-MS: m/z 433.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.83 (s, 1H), 8.41 (d, J = 1.8 Hz, 1H), 8.29 (q, J = 5.3, 4.9 Hz, 1H), 7.85 (d, J＝2.8Hz,1H),7.79(d,J＝8.7Hz,1H),7.75(d,J＝1.4Hz,1H),7.62(d,J＝1.8Hz,1H),6.93(dd,J＝ 8.7,2.9Hz,1H), 3.99 (d, J = 6.6 Hz, 1H), 3.51 (dt, J = 6.6, 4.2 Hz, 3H), 3.08 (dd, J = 10.3, 8.5 Hz, 2H), 2.91 (dd, J = 8.7, 5.5 Hz ,2H),2.77(d,J＝4.8Hz,2H),2.67(dd,J＝10.4,8.3Hz,2H),2.55(td,J＝7.4,1.2Hz, 3H), 2.40(t, J = 5.2 Hz, 2H), 1.18(t, J = 7.4 Hz, 3H).

Example 3: Preparation of 5-((1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperidin-4-yl)(methyl)amino)-N-methylpicolinamide (3)

Step 1: Preparation of methyl 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)(methyl)amino)picolinate (3a)

Dissolve 5-bromopyridine-2-carboxylic acid methyl ester (2.00 g, 9.30 mmol) in 50 mL of dioxane, add 4-(methylamino)piperidine-1-carboxylic acid tert-butyl ester (2.38 g, 11.2 mmol), cesium carbonate (6.08 g, 18.6 mmol), Ruphos-Pd-G3 (389 mg, 0.470 mmol), and stir at 105°C overnight. Add 100 mL of EA to dilute, wash with saturated brine (100 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=100/1-1/1) to obtain 1.50 g of the title compound as a yellow oil, with a yield of 46.8%.

LC-MS: m/z 350.2 [M+H] ⁺ .

The remaining steps were the same as the preparation method of Example 1, except that 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)(methyl)amino)picolinic acid methyl ester (3a) was used instead of 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)(methyl)amino)picolinic acid methyl ester (1h) in step 9 to obtain the title compound 3.

LC-MS: m/z 435.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.84 (s, 1H), 8.39 (d, 1H), 8.27 (q, 1H), 8.11 (d, 1H), 7.78-7.75 (m, 2H), 7.60 (d, 1H), 7.26-7.23 (dd, 1H), 3.61 (s, 2H), 2.90 (d, 2H), 2.84 (s, 3H), 2.78 (d, 3H), 2.57-2.53 (m, 2H), 2.49 (s, 1H), 2.22-2.17 (m, 2H), 1.82-1.74 (m, 2H), 1.62 (d, 2H), 1.18 (t, 3H).

Example 4: Preparation of 5-((1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-N-methylpicolinamide (4)

Step 1: Preparation of 5-((1-(tert-Butyloxycarbonyl)pyrrolidin-3-yl)(methyl)amino)picolinate (4a)

Dissolve 5-bromopyridine-2-carboxylic acid methyl ester (500 mg, 2.33 mmol) in 5 mL of dioxane, add tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (558 mg, 2.79 mmol), cesium carbonate (1.52 g, 4.66 mmol), Ruphos-Pd-G3 (97.5 mg, 0.12 mmol), and stir at 105°C overnight. Add 50 mL of EA to dilute, wash with saturated brine (50 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA = 10:1-1:1) to obtain 107 mg of the title compound as a yellow oil, with a yield of 13.7%.

LC-MS: m/z 336.2 [M+H] ⁺ .

The remaining steps were the same as the preparation method of Example 1, except that 5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(methyl)amino)picolinate (4a) was used instead of 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)(methyl)amino)picolinic acid methyl ester (1h) in step 9 to obtain the title compound 4.

LC-MS: m/z 421.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.41 (d, 1H), 8.30 (d, 1H), 8.11 (d, 1H), 7.77-7.74 (m, 2H), 7.63 (s, 1H), 7.23 (dd, 1H), 4.64-4.62 (m, 1H), 3.79 (d, 1H), 3.65 (d, 1H), 2.97-2.89 (m, 4H), 2.78-2.71 (m, 4H), 2.58-2.53 (m, 3H), 2.36-2.22 (m, 2H), 1.74 (dd, 1H), 1.18 (t, 3H).

Example 5: Preparation of 5-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-4-hydroxypiperidin-4-yl)-N-methylpicolinamide (5)

Step 1: Preparation of tert-butyl 4-(6-bromopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (5a)

2-Bromo-5-iodopyridine (1.00 g, 3.52 mmol) was dissolved in dry tetrahydrofuran (15 mL). Under nitrogen atmosphere, isopropylmagnesium chloride (2 mol/L, 1.76 mL) was slowly added at -20°C. The mixture was stirred for 20 minutes. A tetrahydrofuran solution (5 mL) of tert-butyl 4-oxopiperidine-1-carboxylate (841 mg, 4.22 mmol) was slowly added at -20°C. Stir at room temperature overnight. At 0°C, add 10% citric acid solution to quench (20 mL), extract with ethyl acetate (20 mL x 3), wash with saturated sodium bicarbonate solution (30 mL x 1), wash with saturated brine (30 mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: EA/PE=100/1-9/1) to obtain 310 mg of the title compound as a colorless oil, yield: 24.7%.

LC-MS: m/z 357.1 [M+H] ⁺ .

Step 2: Preparation of methyl 5-(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)picolinate (5b)

Dissolve tert-butyl 4-(6-bromopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (5a) (260 mg, 0.728 mmol) in methanol (3 mL), add Pd(dppf)Cl ₂ (26.6 mg, 0.0363 mmol) and triethylamine (1.2 mL), stir overnight at 90°C under a carbon monoxide atmosphere (pressure of about 0.5 kPa). Concentrate under reduced pressure, and separate and purify the residue by silica gel column chromatography (mobile phase: EA/PE=100/1-1/1) to obtain 180 mg of the title compound as a reddish brown solid, yield: 73.4%.

LC-MS: m/z 337.2 [M+H] ⁺ .

The remaining steps were the same as the preparation method of Example 1, except that 5-(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)picolinic acid methyl ester (5b) was used instead of 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)(methyl)amino)picolinic acid methyl ester (1h) in step 9 to obtain the title compound 5.

LC-MS: m/z 422.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.85 (br, 1H), 8.78-8.68 (m, 2H), 8.40 (d, J=2.8 Hz, 1H), 8.08-8.02 (m, 1H), 7.99-7.94 (m, 1H), 7.74 (s, 1H), 7.63 (s, 1H), 5.19 (s, 1H), 3.64 (s, 2H), 2.83 (d, J=4.8 Hz, 3H), 2.70-2.62 (m, 2H), 2.58-2.52 (m, 4H), 2.06-1.94 (m, 2H), 1.71-1.60 (m, 2H), 1.18 (t, J=7.2 Hz, 3H).

Example 6: Preparation of 5-((1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)azetidin-3-yl)oxy)-N-methylpicolinamide (6)

Step 1: Preparation of methyl 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)picolinate (6a)

Dissolve 5-hydroxypicolinic acid methyl ester (100 mg, 0.653 mmol) in DMF (2 mL), add 3-iodoazetidine-1-carboxylic acid tert-butyl ester (221 mg, 0.784 mmol) and potassium carbonate (135 mg, 0.980 mmol), and stir at 80°C for 16 hours under nitrogen atmosphere. Add water (10 mL) and use ethyl acetate (10 mL) to obtain the mixture. The residue was extracted with saturated sodium chloride (20 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 150 mg (crude) of the title compound as a light yellow solid.

LC-MS: m/z 309.1 [M+H] ⁺ .

The remaining steps were the same as the preparation method of Example 1, except that 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)picolinic acid methyl ester (6a) was used instead of 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)(methyl)amino)picolinic acid methyl ester (1h) in step 9 to obtain the title compound 6.

LC-MS: m/z 394.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.56 (q, J = 4.7 Hz, 1H), 8.37 (d, J = 1.9 Hz, 1H), 8.22 (d, J = 2.8 Hz, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.73 (s, 1H), 7.57 (d, J = 1.8 Hz, 1H), 7.40 (dd, J = 8.7, 2.9 Hz, 1H), 5.02 (p, J = 5.5 Hz, 1H), 3.83-3.74 (m, 4H), 3.21-3.13 (m, 2H), 2.79 (d, J = 4.8 Hz, 3H), 2.59-2.52 (m, 2H), 1.18 (t, J = 7.4 Hz, 3H).

Example 7: Preparation of 5-((1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)azetidin-3-yl)(methyl)amino)-6-fluoro-N-methylpicolinamide (7)

Step 1: Preparation of methyl 5-bromo-6-fluoropicolinate (7a)

Dissolve methyl 5-bromopiperidincarboxylate (2.00 g, 9.30 mmol) in acetonitrile (25 mL), add silver fluoride (5.43 g, 37.2 mmol), and stir at room temperature for 16 hours under nitrogen atmosphere. Extract with ethyl acetate (50 mL x 3), wash with saturated brine (50 mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=100/1-1/1) to obtain 1.0 g of the title compound as a white solid, yield: 46.1%.

LC-MS: m/z 233.9 [M+H] ⁺ .

Step 2: Preparation of methyl 5-(1-(tert-butoxycarbonyl)azetidin-3-yl)(methyl)amino)-6-fluoropicolinate (7b)

5-Bromo-6-fluoropicolinic acid methyl ester (7a) (500 mg, 2.15 mmol) was dissolved in 1,4-dioxane (10 mL), tert-butyl 3-(methylamino)azetidine-1-carboxylate (439 mg, 2.36 mmol), cesium carbonate (1.39 g, 4.29 mmol), Ruphos pd G3 (62.9 mg, 0.0751 mmol) were added, and the mixture was stirred at 40 °C under nitrogen atmosphere. Stir at 110°C for 16 hours. Extract with ethyl acetate (20 mL x 3), wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate and purify the residue by silica gel column chromatography (mobile phase: PE/EA=100/1-1/1) to obtain 620 mg of the title compound as a yellow oil, yield: 85.1%.

LC-MS: m/z 340.2 [M+H] ⁺ .

The remaining steps are the same as the preparation method of Example 1, except that 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)(methyl)amino)-6-fluoropicolinic acid methyl ester (7b) is used to replace 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)(methyl)amino)picolinic acid methyl ester (1h) in step 9 to obtain the title compound 7.

LC-MS: m/z 425.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.42-8.31 (m, 2H), 7.82-7.70 (m, 2H), 7.61-7.54 (m, 1H), 7.34 (dd, J = 10.4, 8.0 Hz, 1H), 4.14 (d, J = 7.6 Hz, 1H), 3.75 (d, J = 43.6 Hz, 4H), 3.14 (s, 2H), 2.85 (d, J = 1.6 Hz, 3H), 2.76 (d, J = 4.8 Hz, 3H), 2.57-2.52 (m, 2H), 1.18 (t, J = 7.2 Hz, 3H).

Example 8: Preparation of 5-(ethyl(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)azetidin-3-yl)amino)-N-methylpicolinamide (8)

Step 1: Preparation of methyl 5-(1-(tert-butyloxycarbonyl)azetidin-3-yl)amino)picolinate (8a)

Dissolve 5-bromopicolinic acid methyl ester (1.00 g, 4.65 mmol) in 1,4-dioxane (15 mL), add 3-aminoazetidine-1-carboxylic acid tert-butyl ester (880 mg, 5.12 mmol), cesium carbonate (3.02 g, 9.30 mmol), Ruphos pd G3 (136 mg, 0.163 mmol). Stir at 110°C for 4 hours under nitrogen atmosphere. Add water (20 mL), extract with ethyl acetate (20 mL x 3), wash with saturated brine (20 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate and purify the residue by silica gel column chromatography (mobile phase: PE/EA=100/1-3/7) to obtain 900 mg of the title compound as a light yellow solid, yield: 63.0%.

LC-MS: m/z 308.2 [M+H] ⁺ .

Step 2: Preparation of 5-((1-(tert-butyloxycarbonyl)azetidin-3-yl)amino)picolinic acid (8b)

Methyl 5-(1-(tert-butyloxycarbonyl)azetidin-3-yl)amino)picolinate (8a) (900 mg, 2.93 mmol) was dissolved in water (3 mL) and tetrahydrofuran (10 mL), and lithium hydroxide (141 mg, 5.86 mmol) was added, and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to obtain 820 mg (crude) of the title compound as a white solid.

LC-MS; m/z 294.1 [M+H] ⁺ .

Step 3: Preparation of tert-butyl 3-(6-(methylcarbamoyl)pyridin-3-yl)amino)azetidine-1-carboxylate (8c)

5-((1-(tert-Butyloxycarbonyl)azetidin-3-yl)amino)picolinic acid (8b) (770 mg, 2.63 mmol) was dissolved in DMF (10 mL), and methylamine hydrochloride (211 mg, 3.15 mmol), DIEA (1.02 g, 7.88 mmol), and HATU (1.50 g, 3.94 mmol) were added, and stirred at room temperature for 16 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 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=100/1-1/9) to obtain 810 mg of the title compound as a light yellow solid, with a two-step yield of 90.3%.

LC-MS: m/z 307.2 [M+H] ⁺ .

Step 4: Preparation of tert-butyl 3-(ethyl(6-(methylcarbamoyl)pyridin-3-yl)amino)azetidine-1-carboxylate (8d)

Tert-butyl 3-(6-(methylcarbamoyl)pyridin-3-yl)amino)azetidine-1-carboxylate (8c) (200 mg, 0.654 mmol) was dissolved in DMF (4 mL), sodium hydride (52.3 mg, 1.31 mmol) and iodoethane (71.4 mg, 0.458 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 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: EA/PE/EA=100/1-1/1) to obtain 120 mg of the title compound as a light yellow solid, with a yield of 54.9%.

LC-MS: m/z 335.2 [M+H] ⁺ .

The remaining steps were the same as the preparation method of Example 1, except that tert-butyl 3-(6-(methylcarbamoyl)pyridin-3-yl)amino)azetidine-1-carboxylate (8d) was used instead of tert-butyl 3-(methyl(6-(methylcarbamoyl)pyridin-3-yl)amino)azetidine-1-carboxylate (1j) in step 11 to obtain the title compound 8.

LC-MS: m/z 421.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.85 (s, 1H), 8.37 (d, J = 1.6 Hz, 1H), 8.33 (q, J = 4.8 Hz, 1H), 8.00 (d, J = 2.8Hz,1H),7.79(d,J＝8.8Hz,1H),7.74(s,1H),7.60-7.55(m,1H),7.14(dd,J＝8.8,3.2Hz,1H ),4.25(p,J＝6.8Hz,1H),3.80-3.68(m,4H),3.51(q,J＝6.8Hz,2H),3.05(s,2H),2.77(d,J＝4.8Hz , 3H), 2.58-2.52(m, 2H), 1.18(t, J＝7.2Hz, 3H), 1.04(t, J＝6.8Hz, 3H).

Example 9: Preparation of 5-((1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)azetidine-3-alkyl)(isopropyl)amino)-N-methylpicolinamide (9)

The title compound 9 was prepared in the same manner as in Example 8, except that iodopropane was used instead of iodoethane in step 4.

LC-MS: m/z 435.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.84 (s, 1H), 8.44 (q, J=4.8 Hz, 1H), 8.34 (d, J=1.6 Hz, 1H), 8.12 (d, J=2.8 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 7.54 (d, J=1.6 Hz, 1H), 7.33 (dd, J=8.4, 2.8 Hz, 1H), 4.23 (p, J=6.8 Hz, 1H), 3.74-3.62 (m, 5H), 2.89 (t, J=7.2 Hz, 2H), 2.78 (d, J=4.8 Hz, 3H), 2.55 (dd, J=7.2, 1.2 Hz, 2H), 1.22-1.09 (m, 9H).

Example 10: Preparation of 5-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3-hydroxyazetidin-3-yl)-N-methylpicolinamide (10)

Step 1: Preparation of tert-butyl 3-(6-bromopyridin-3-yl)-3-hydroxyazetidine-1-carboxylate (10a)

2-Bromo-5-iodopyridine (2.00 g, 7.04 mmol) was dissolved in dry tetrahydrofuran (15 mL). Isopropylmagnesium chloride (2 mol/L, 3.9 mL) was slowly added at -20 °C under nitrogen atmosphere. The mixture was stirred for 20 minutes. A solution of tert-butyl 3-oxoazetidine-1-carboxylate (1.44 g, 8.42 mmol) in tetrahydrofuran (5 mL) was slowly added at -20 °C. The mixture was stirred at room temperature overnight. 10% citric acid solution (20 mL) was added to quench the mixture at 0 °C. The mixture was extracted with ethyl acetate (20 mL x 3), washed with saturated sodium bicarbonate solution (30 mL x 1), 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: EA/PE = 100/1-10/1) to obtain 660 mg of the title compound as a yellow oil. The yield was 28.5%.

LC-MS: m/z 329.0 [M+H] ⁺ .

Step 2: Preparation of 5-(1-(tert-butoxycarbonyl)-3-hydroxyazetidin-3-yl)picolinic acid methyl ester (10b) preparation

Dissolve tert-butyl 3-(6-bromopyridin-3-yl)-3-hydroxyazetidine-1-carboxylate (10a) (560 mg, 1.70 mmol) in methanol (5 mL), add Pd(dppf)Cl ₂ (62.3 mg, 0.0851 mmol) and triethylamine (2 mL), stir overnight at 90°C under a carbon monoxide atmosphere (pressure of about 0.5 kPa). Concentrate under reduced pressure, and separate and purify the residue by silica gel column chromatography (mobile phase: EA/PE=100/1-1/1) to obtain 240 mg of the title compound as a reddish brown semisolid, yield: 45.8%.

LC-MS: m/z 309.1 [M+H] ⁺ .

The remaining steps were the same as the preparation method of Example 1, except that 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)(methyl)amino)picolinic acid methyl ester (10b) was used instead of 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)(methyl)amino)picolinic acid methyl ester (1h) in step 9 to obtain the title compound 10.

LC-MS: m/z 394.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.85 (br, 1H), 8.88 (d, 1H), 8.78-8.70 (m, 1H), 8.40 (d, J=2.8 Hz, 1H), 8.27-8.21 (m, 1H), 8.08-8.02 (m, 1H), 7.74 (s, 1H), 7.63 (s, 1H), 6.31 (s, 1H), 3.85 (s, 2H), 3.67-3.59 (m, 2H), 3.44-3.38 (m, 2H), 2.83 (d, J=4.8 Hz, 3H), 2.59-2.54 (m, 2H), 1.18 (t, J=7.2 Hz, 3H).

Example 11: Preparation of 5-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)pyrrolidin-3-yl)-N-methylpicolinamide (11)

Step 1: Preparation of methyl 5-(1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)picolinate (11a)

Methyl 5-bromopicolinate (500 mg, 2.33 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (819 mg, 2.78 mmol) and Pd(dppf) ₂ Cl ₂ (84.9 mg, 0.116 mmol) were dissolved in acetonitrile (15 mL), potassium phosphate solution (2 mol/L, 3.5 mL) was added, and the mixture was stirred at 85°C for 3 hours under nitrogen atmosphere. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (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: EA/PE=100/1-3/2) to obtain 360 mg of the title compound as an off-white solid, with a yield of 50.6%.

LC-MS: m/z 305.1 [M+H] ⁺ .

Step 2: Preparation of methyl 5-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)picolinate (11b)

Dissolve 5-(1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)picolinic acid methyl ester (11a) (150 mg, 0.492 mmol) in methanol (3 mL), add Pd/C (50 mg), and stir at room temperature overnight under a hydrogen atmosphere. Filter, wash the filter cake with methanol, and concentrate under reduced pressure to obtain 190 mg (crude) of the title compound as a yellow oil.

LC-MS: m/z 307.2 [M+H] ⁺ .

The remaining steps were the same as the preparation method of Example 1, except that 5-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)picolinic acid methyl ester (11b) was used instead of 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)(methyl)amino)picolinic acid methyl ester (1h) in step 9 to obtain the title compound 11.

LC-MS: m/z 392.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ )δ11.85(br,1H),8.72-8.63(m,1H),8.53(d,J＝2.8Hz,1H),8.42(d,J＝2.8Hz,1H),8.01-7.90(m,2H),7.74(s,1H),7.63(s,1H),3.84-3.70(m,2H),3.51-3.43(m,1H),2.94-2.88(m,1H),2.81(d,J＝4.8Hz,3H),2.70-2.63(m,1H),2.60-2.52(m,4H),2.41-2.38(m,1H),1.81-1.77(m,1H),1.18(t,J＝7.2Hz,3H).

Example 12: Preparation of 5-(1-(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinolin-6-yl)methyl)azetidin-3-yl)(methyl)amino)-N-methylpicolinamide (12)

Step 1: Preparation of 1-bromo-2,4-difluoro-3-nitrobenzene (12a)

Dissolve 1,3-difluoro-2-nitrobenzene (20.0 g, 126 mmol) in concentrated sulfuric acid (150 mL), add NBS (26.9 g, 151 mmol), and stir at 80 ° C for 16 hours. Pour the reaction solution into ice water, extract with ethyl acetate (300 mL x 3), wash with saturated brine (100 mL x 2), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: EA/PE = 5%) to obtain 27.6 g of the title compound as a yellow oil, with a yield of 94.2%.

LC-MS: m/z 237.9 [M+H] ⁺ .

Step 2: Preparation of (4-bromo-3-fluoro-2-nitrophenyl)alanine methyl ester (12b)

1-Bromo-2,4-difluoro-3-nitrobenzene (12a) (27.6 g, 116 mmol) and alanine methyl ester hydrochloride (16.2 g, 116 mmol) were dissolved in DMF (220 mL), DIEA (45.1 g, 349 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was extracted with ethyl acetate (300 mL x 3), washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and slurried with DCM (20 mL) to obtain 14.5 g of the title compound as a red solid, with a yield of 39.1%.

LC-MS: m/z 321.0 [M+H] ⁺ .

Step 3: Preparation of (2-amino-4-bromo-3-fluorophenyl)alanine methyl ester (12c)

Dissolve (4-bromo-3-fluoro-2-nitrophenyl)alanine methyl ester (12b) (14.5 g, 45.3 mmol), zinc powder (23.6 g, 363 mmol), and ammonium chloride (19.2 g, 363 mmol) in water (5 mL) and methanol (150 mL), and stir at 0°C for 0.5 hours and at room temperature for 3 hours. Filter, concentrate under reduced pressure, extract with ethyl acetate (300 mL x 3), wash with saturated brine (100 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 13.5 g (crude) of the title compound as a black oil.

LC-MS: m/z 291.0 [M+H] ⁺ .

Step 4: Preparation of 7-bromo-8-fluoro-3-methyl-3,4-dihydroquinolin-2(1H)-one (12d)

Dissolve (2-amino-4-bromo-3-fluorophenyl)alanine methyl ester (12c) (12.5 g, 43.1 mmol) in ethyl acetate (12.5 mL) and methanol (12.5 mL), add concentrated hydrochloric acid (0.5 mL), and stir at room temperature for 1 hour. Adjust pH>7 with saturated sodium bicarbonate, extract with ethyl acetate (100 mL x 3), wash with saturated brine (100 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 11.5 g (crude) of the title compound as a brown solid.

LC-MS: m/z 259.0 [M+H] ⁺ .

Step 5: Preparation of 7-bromo-8-fluoro-3-methylquinolin-2(1H)-one (12e)

7-Bromo-8-fluoro-3-methyl-3,4-dihydroquinolin-2(1H)-one (12d) (10.5 g, 40.7 mmol) and manganese dioxide (35.4 g, 407 mmol) were dissolved in 1,4-dioxane (210 mL) and stirred at 85°C for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 10.5 g (crude) of the title compound as a brown solid.

LC-MS: m/z 257.0 [M+H] ⁺ .

Step 6: Preparation of 8-fluoro-7-(hydroxymethyl)-3-methylquinolin-2(1H)-one (12f)

7-Bromo-8-fluoro-3-methylquinolin-2(1H)-one (12e) (6.72 g, 26.3 mmol), (tributyltinyl)methanol (9.30 g, 28.9 mmol), and Xphos Pd G2 (1.03 g, 1.32 mmol) were dissolved in 1,4-dioxane (135 mL) and stirred at 0°C for 16 hours. The residue was concentrated under reduced pressure and separated by silica gel column chromatography. The residue was purified by centrifugation (mobile phase: MeOH/DCM=10%) to obtain 5.0 g of the title compound as a brown solid. Yield: 91.4%.

LC-MS: m/z 209.1 [M+H] ⁺ .

Step 7: Preparation of 7-(bromomethyl)-8-fluoro-3-methylquinolin-2(1H)-one (12 g)

8-Fluoro-7-(hydroxymethyl)-3-methylquinolin-2(1H)-one (12f) (500 mg, 2.40 mmol) was dissolved in DCM (10 mL), phosphorus tribromide (714 mg, 2.64 mmol) was added at 0°C, and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and slurried with EA/PE = 1/10 (10 mL) to obtain 1.0 g of the title compound as a brown solid, with a yield of 98.2%.

LC-MS: m/z 271.0 [M+H] ⁺ .

The other steps were the same as the preparation method of Example 1, except that 7-(bromomethyl)-8-fluoro-3-methylquinolin-2(1H)-one (12 g) was used instead of 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (1 g) in step 12 to obtain the title compound 12.

LC-MS: m/z 411.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ )δ12.43(s,1H),8.35(q,J＝4.8Hz,1H),8.02(d,J＝2.8Hz,1H),7.79(d,J＝8.8Hz,1H),7.50(dd,J＝8.4,1.2Hz,1H),7.27(dd,J＝8.4,7.2Hz,1H),7.15(dd,J＝8.8,3.2Hz,1H),4.31(p,J＝6.8Hz,1H),3.75(d,J＝1.6Hz,2H),3.68(td,J＝6.4,1.8Hz,2H),3.14(t,J＝7.2Hz,2H),2.96(s,3H),2.77(d,J＝4.8Hz,3H),2.41(s,3H).

Example 13: Preparation of 6-fluoro-5-(1-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinolin-6-yl)methyl)azetidin-3-yl)(methyl)amino)-N-methylpicolinamide (13)

Step 1: Preparation of 5-(azetidin-3-yl(methyl)amino)-6-fluoro-picolinic acid methyl ester (13a)

At room temperature, methyl 5-(1-(tert-butoxycarbonyl)azetidin-3-yl)(methyl)amino)-6-fluoropicolinate (7b) (80.0 mg, 0.236 mmol) was dissolved in dichloromethane (1 mL). TFA (0.2 mL) was added and the mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure to give 150 mg (crude) of the title compound as a pale yellow oil.

LC-MS: m/z 239.1 [M+H] ⁺ .

Step 2: Preparation of 6-fluoro-5-(1-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinolin-6-yl)methyl)azetidin-3-yl)(methyl)amino)-N-methylpicolinamide (13)

At room temperature, 5-(azetidin-3-yl(methyl)amino)-6-fluoro-picolinic acid methyl ester (13a) (55.0 mg, 0.250 mmol), 7-(bromomethyl)-8-fluoro-3-methylquinolin-2(1H)-one (12 g) (67.5 mg, 0.250 mmol) were dissolved in acetonitrile (3 mL), DIEA (161 mg, 1.25 mmol) and sodium iodide (7.5 mg, 0.050 mmol) were added, and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was separated by high pressure preparative liquid phase separation (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um 100A, mobile phase: acetonitrile/water, gradient: 10%-50%, 0.05% formic acid, 30 min) to obtain 30.0 mg of the title compound as a white solid, with a yield of 29.6%.

LC-MS: m/z 429.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.41 (s, 1H), 8.36 (q, J=4.4 Hz, 1H), 7.76 (dd, J=8.0, 1.6 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.33 (dd, J=10.4, 8.0 Hz, 1H), 7.24 (dd, J=8.4, 7.2 Hz, 1H), 4.07 (p, J=6.4 Hz, 1H), 3.72 (s, 2H), 3.62 (dd, J=7.6, 6.0 Hz, 2H), 3.02 (t, J=7.2 Hz, 2H), 2.83 (d, J=1.6 Hz, 3H), 2.76 (d, J=4.8 Hz, 3H), 2.41 (s, 3H).

Example 14: 6-(1-(7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)azetidin-3-yl)(methyl)amino)-N-methylnicotinamide

The title compound 14 was prepared in the same manner as in Example 1, except that methyl 6-chloronicotinate was used instead of methyl 5-bromopicolinate in step 8.

LC-MS: m/z 407.2 [M+H] ⁺ .

¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.60-8.53 (m, 2H), 8.42 (d, J＝2.0 Hz, 1H), 8.28 (dd, J＝9.2, 1.9 Hz, 1H), 7.80 ( q, J = 1.2 Hz, 1H), 7.64 (dd, J = 1.6, 0.8 Hz, 1H), 7.08 (dd, J = 9.6, 0.8 Hz, 1H), 4.79 (d, J = 11.2 Hz, 1H ),4.68(dd,J＝12.4,6.8Hz,1H),4.37(ddt,J＝10.8,7.2,3.6Hz,1H),3.95(d,J＝3.2Hz,2H),3.19-3.09(m, 4H), 2.91(s, 4H), 2.65(qd, J＝7.2,1.2Hz,2H), 1.27(t, J＝7.6Hz,3H).

Example 15: Preparation of 4-(1-(7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)azetidin-3-yl)(methyl)amino)-N-methylbenzamide (15)

The title compound 15 was prepared in the same manner as in Example 1, except that methyl 4-bromobenzoate was used instead of methyl 5-bromopicolinate in step 8.

LC-MS: m/z 406.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.91 (s, 1H), 8.41 (s, 1H), 8.10 (d, J=4.8 Hz, 1H), 7.75 (s, 1H), 7.73-7.65 (m, 2H), 7.62 (s, 1H), 6.72 (d, J=8.4 Hz, 2H), 4.30 (s, 1H), 3.81 (s, 6H), 2.92 (s, 3H), 2.73 (d, J=4.4 Hz, 3H), 2.58-2.52 (m, 2H), 1.18 (t, J=7.2 Hz, 3H).

Example 16: Preparation of 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (16)

Step 1: Preparation of 1'-(tert-butyl)6-methyl 3',6'-dihydro-[3,4'-bipyridyl]-1',6(2'H)-dicarboxylate (16a)

Methyl 5-bromopyridine-2-carboxylate (500 mg, 2.33 mmol) was dissolved in a mixed solvent of 7.5 mL of dioxane and 0.75 mL of water, and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (862 mg, 2.79 mmol), potassium carbonate (643 mg, 4.66 mmol) and Pd(dppf)Cl ₂ (85.3 mg, 0.120 mmol) were added. The mixture was stirred at 120° C. overnight under a nitrogen atmosphere. Add 10 mL of EA to dilute, wash with saturated brine (10 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated by high-pressure preparative liquid separation (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um 100A, mobile phase: acetonitrile/water (0.05% formic acid), gradient: 30%-70%) to obtain 125 mg of the title compound as a red-brown oil, yield: 16.9%.

LC-MS: m/z 319.2[M+H]+.

The other steps were the same as those in Example 1, except that 1'-(tert-butyl)6-methyl-3',6'-dihydro-[3,4'- The title compound 16 was prepared by replacing methyl 5-((1-(tert-butyloxycarbonyl)azetidin-3-yl)(methyl)amino)picolinate (1h) with [1-(tert-butyloxycarbonyl)azetidin-3-yl)(methyl)amino]-1',6(2'H)-dicarboxylate (16a).

LC-MS: m/z 404.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.83 (br, 1H), 8.74-8.67 (m, 2H), 8.43-8.39 (m, 1H), 8.01-7.95 (m, 2H), 7.76 (s, 1H), 7.65 (s, 1H), 6.42 (s, 1H), 3.72 (s, 2H), 3.16 (br, 2H), 2.82 (d, 3H), 2.71 (t, 2H), 2.58-2.54 (m, 4H), 1.18 (t, 3H).

Example 17: Preparation of 5-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2,5-dihydro-1H-pyrrol-3-yl)-N-methylpicolinamide (17)

Step 1: Preparation of methyl 5-(1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)picolinate (17a)

LC-MS: m/z 305.1 [M+H] ⁺ .

The other steps were the same as the preparation method of Example 1, except that 5-(1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)picolinic acid methyl ester (17a) was used instead of 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)(methyl)amino)picolinic acid methyl ester (1h) in step 9 to obtain the title compound 17.

LC-MS: m/z 390.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.85 (br, 1H), 8.73-8.66 (m, 2H), 8.45 (d, J=2.8 Hz, 1H), 7.97 (d, J=8.8 Hz, 2H), 7.76 (s, 1H), 7.67 (d, J=1.6 Hz, 1H), 6.68 (t, 1H), 3.99 (br, 2H), 3.91-3.85 (m, 2H), 3.72-3.66 (m, 2H), 2.81 (d, J=4.8 Hz, 3H), 2.59-2.54 (m, 2H), 1.18 (t, J=7.2 Hz, 3H).

Example 18: Preparation of 5-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)pyrrolidin-3-yl)-N-methylpicolinamide (18)

Step 1: Preparation of methyl 5-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)picolinate (18a)

Dissolve 5-(1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)picolinic acid methyl ester (17a) (150 mg, 0.492 mmol) in methanol (3 mL), add Pd/C (50 mg), and stir at room temperature overnight under a hydrogen atmosphere. Filter, wash the filter cake with methanol, and concentrate the filtrate under reduced pressure to obtain 190 mg (crude) of the title compound as a yellow oil.

LC-MS: m/z 307.2 [M+H] ⁺ .

The other steps were the same as the preparation method of Example 1, except that 5-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)picolinic acid methyl ester (18a) was used instead of 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)(methyl)amino)picolinic acid methyl ester (1h) in step 9 to obtain the title compound 18.

LC-MS: m/z 392.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.85 (br, 1H), 8.72-8.63 (m, 1H), 8.53 (d, J=2.8 Hz, 1H), 8.42 (d, J=2.8 Hz, 1H), 8.01-7.90 (m, 2H), 7.74 (s, 1H), 7.63 (s, 1H), 3.84-3.70 (m, 2H), 3.51-3.43 (m, 1H), 2.94-2.88 (m, 1H), 2.81 (d, J=4.8 Hz, 3H), 2.70-2.63 (m, 1H), 2.60-2.52 (m, 4H), 1.18 (t, J=7.2 Hz, 3H).

Example 19: Preparation of 5-(3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-N-methylpicolinamide (19)

The preparation method was the same as in Example 1, except that tert-butyl 3,8-diazacyclo[3.2.1]octane-3-carboxylate was used instead of The title compound 19 was prepared by replacing tert-butyl 3-(methylamino)azetidine-1-carboxylate in step 8.

LC-MS: m/z 433.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ )δ11.85(s,1H),8.35-8.28(m,2H),8.15(d,J＝2.8Hz,1H),7.79(d,J＝8.8Hz,1H),7.73(d,J＝1.2Hz,1H),7.63(d,J＝1.6Hz,1H),7.28(dd,J＝8.8,2.8Hz,1H),4.45(d,J＝4.4Hz,2H),3.51(s,2H),2.78(d,J＝4.8Hz,3H),2.57-2.51(m,4H),2.38(d,J＝10.8Hz,2H),2.05(q,J＝6.0,5.2Hz,2H),1.96-1.86(m,2H),1.18(t,J＝7.2Hz,3H).

Example 20: Preparation of 5-(7-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-4,7-diazaspiro[2.5]octan-4-yl)-N-methylpicolinamide (20)

The title compound 20 was prepared in the same manner as in Example 1, except that tert-butyl 4,7-diazaspiro[2.5]octane-7-carboxylate was used instead of tert-butyl 3-(methylamino)azetidine-1-carboxylate in step 8.

LC-MS: m/z 433.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.85 (s, 1H), 8.41-8.38 (m, 1H), 8.34 (t, J=2.3 Hz, 2H), 7.82 (d, J=8.7 Hz, 1H), 7.60 (s, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.49 (dd, J=8.8, 2.8 Hz, 1H), 3.70-3.38 (m, 4H), 2.78 (d, J=4.8 Hz, 3H), 2.57-2.54 (m, 4H), 2.13 (br, 2H), 1.17 (t, J=7.4 Hz, 3H), 0.80 (br, 4H).

Example 21: Preparation of 5-(6-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2,6-diazaspiro[3.3]hept-2-yl)-N-methylpicolinamide (21)

The title compound 21 was prepared in the same manner as in Example 1, except that tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate was used instead of tert-butyl 3-(methylamino)azetidine-1-carboxylate in step 8.

LC-MS: m/z 419.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.80 (s, 1H), 8.38-8.27 (m, 2H), 7.80 (d, J=8.5 Hz, 1H), 7.76-7.70 (m, 2H), 7.55 (d, J=1.8 Hz, 1H), 6.87 (dd, J=8.6, 2.8 Hz, 1H), 4.05 (s, 4H), 3.66 (s, 2H), 3.37 (s, 4H), 2.77 (d, J=4.8 Hz, 3H), 2.58-2.52 (m, 2H), 1.18 (t, J=7.4 Hz, 3H).

Example 22: 5-(6-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2,6-diazaspiro [3.4] Preparation of octan-2-yl)-N-methylpyridine amide (22)

The title compound 22 was prepared in the same manner as in Example 1, except that tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate was used instead of tert-butyl 3-(methylamino)azetidine-1-carboxylate in step 8.

LC-MS: m/z 433.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.77 (s, 1H), 8.31 (d, J=1.8 Hz, 1H), 8.26 (q, J=4.5 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.67 (d, J=2.9 Hz, 2H), 7.53 (d, J=1.8 Hz, 1H), 6.79 (dd, J=8.6, 2.7 Hz, 1H), 3.92-3.78 (m, 4H), 3.63 (s, 2H), 2.70 (d, J=4.8 Hz, 5H), 2.57-2.44 (m, 6H), 2.02 (t, J=7.0 Hz, 2H), 1.11 (t, J=7.4 Hz, 3H).

Example 23: Preparation of 5-(2-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2,6-diazaspiro[3.4]octan-6-yl)-N-methylpicolinamide (23)

The title compound 23 was prepared in the same manner as in Example 1, except that tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate was used instead of tert-butyl 3-(methylamino)azetidine-1-carboxylate in step 8.

LC-MS: m/z 433.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.82 (s, 1H), 8.38-8.21 (m, 2H), 7.87 (d, J=2.8 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 7.57 (s, 1H), 6.95 (dd, J=8.8, 2.8 Hz, 1H), 3.71 (s, 2H), 3.49 (s, 2H), 3.35 (t, J=6.8 Hz, 2H), 3.22 (s, 4H), 2.77 (d, J=4.8 Hz, 3H), 2.55 (d, J=7.2 Hz, 2H), 2.17 (t, J=6.8 Hz, 2H), 1.18 (t, J=7.2 Hz, 3H).

Example 24: Preparation of 5-(7-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)-N-methylpicolinamide (24)

The title compound 24 was prepared in the same manner as in Example 1, except that tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate was used instead of tert-butyl 3-(methylamino)azetidine-1-carboxylate in step 8.

LC-MS: m/z 447.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.82 (s, 1H), 8.39 (d, J = 1.8 Hz, 1H), 8.30-8.20 (m, 2H), 7.85 (d, J = 2.8 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.73 (s, 1H), 7.60 (d, J = 1.8 Hz, 1H), 6.93 (dd, J = 8.8, 2.9 Hz, 1H), 3 .71(s,2H),3.40-3.28(m,4H),2.77(d,J＝4.9Hz,3H),2.70-2.60(m,2H),2.57-2.52(m,4H),2.00(ddt , J = 19.6, 12.1, 6.0 Hz, 2H), 1.88-1.78 (m, 2H), 1.17 (t, J = 7.4 Hz, 3H).

Example 25: Preparation of 5-(5-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-methylpicolinamide (25)

The title compound 25 was prepared in the same manner as in Example 1, except that tert-butyl 3-(methylamino)azetidine-1-carboxylate was replaced with tert-butyl hexahydropyrrolidine[3,4-c]pyrrole-2(1H)-carboxylate.

LC-MS: m/z 433.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ )δ11.83(s,1H),8.37-8.30(m,2H),7.96(d,J＝2.8Hz,1H),7.82(d,J＝8.8Hz,1H),7.72(s,1H),7.58(d,J＝1.6Hz,1H),7.06(dd,J＝8.8,2.8Hz,1H),3.69(s,2H),3.56(dd,J＝9.6,8.0Hz,2H),3.21(dd,J＝10.0,3.3Hz,2H),2.96(s,2H),2.78(d,J＝4.8Hz,3H),2.62(dd,J＝8.8,6.4Hz,2H),2.57-2.52(m,4H),1.17(t,J＝7.2Hz,3H).

Example 26: Preparation of 5-(3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)-N-methylpicolinamide (26)

The title compound 26 was prepared in the same manner as in Example 1, except that tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate was used instead of tert-butyl 3-(methylamino)azetidine-1-carboxylate in step 8.

LC-MS: m/z 419.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.76 (s, 1H), 8.34 (d, 1H), 8.07 (d, 1H), 7.81 (dd, 2H), 7.68 (s, 1H), 7.43 (s, 1H), 6.98 (dd, 1H), 4.42 (d, 2H), 3.59 (s, 2H), 3.07 (d, 2H), 2.79 (t, 6H), 2.59-2.53 (m, 2), 1.97 (d, 1H), 1.18 (t, 3H).

Example 27: Preparation of 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-1,4-diazepin-1-yl)-N-methylpicolinamide (27)

The title compound 27 was prepared in the same manner as in Example 1, except that tert-butyl 1,4-diazepane-1-carboxylate was used instead of tert-butyl 3-(methylamino)azetidine-1-carboxylate in step 8.

LC-MS: m/z 421.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.83 (s, 1H), 8.35-8.27 (m, 2H), 8.06 (d, 1H), 7.80-7.73 (m, 2H), 7.61 (s, 1H), 7.17 (dd, 1H), 3.74 (s, 2H), 3.62-3.58 (m, 3H), 2.79-2.75 (m, 6H), 2.56-2.52 (m, 4H), 1.89 (s, 2H), 1.18 (t, 3H).

Example 28: Preparation of 5-(5-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)-N-methylpicolinamide (28)

The title compound 28 was prepared in the same manner as in Example 1, except that tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was used instead of tert-butyl 3-(methylamino)azetidine-1-carboxylate in step 8.

LC-MS: m/z 419.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.76 (s, 1H), 8.36 (d, 1H), 8.30 (dd, 1H), 7.96 (d, 1H), 7.80 (d, 1H), 7.72 (s, 1H), 7.60 (d, 1H), 7.06 (dd, 1H), 4.56 (s, 1H), 3.80 (s, 2H), 3.63 (s, 1H), 3.47-3.44 (m, 1H), 2.78-2.71 (m, 4H), 2.55-2.51 (m, 4H), 1.99 (d, 1H), 1.83 (d, 1H), 1.17 (t, 3H).

Example 29: Preparation of 5-(1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-[1,3'-diazetidine]-3-yl)-N-methylpicolinamide (29)

Step 1: Preparation of 5-bromopyridinic acid (29a)

Dissolve methyl 5-bromopiperidinate (2.00 g, 9.30 mmol) in tetrahydrofuran (20 mL) and water (10 mL), add lithium hydroxide (446 mg, 18.6 mmol), stir at room temperature for 2 hours and concentrate under reduced pressure to obtain 2.5 g (crude) of the title compound as a white oil.

LC-MS: m/z 201.9 [M+H] ⁺ .

Step 2: Preparation of 5-bromo-N-methylpicolinamide (29b)

5-Bromopyridinic acid (29a) (2.50 g, 12.4 mmol) was dissolved in DMF (60 mL), and methylamine hydrochloride (1.00 g, 14.9 mmol), HATU (6.10 g, 16.2 mmol), and DIEA (4.80 g, 37.3 mmol) were added, and stirred at room temperature for 16 hours. 100 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 3), washed with saturated brine (50 mL x 2), 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 = 100/1-4/1) to obtain 1.90 g of the title compound as a light yellow oil, with a yield of 71.3%.

LC-MS: m/z 215.0 [M+H] ⁺ .

Step 3: Preparation of (6-(methylcarbamoyl)pyridin-3-yl)boronic acid (29c).

5-Bromo-N-methylpicolinamide (29b) (1.00 g, 4.67 mmol) was dissolved in 1,4-dioxane (4 mL), and diboronic acid pinacol ester (1.78 g, 7.01 mmol), potassium acetate (916 mg, 9.35 mmol), Pd(dppf)Cl ₂ (678 mg, 0.935 mmol) were added, and stirred at 110°C for 2 hours under 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=100/1-4/1) to obtain 700 mg of the title compound as a yellow oil, with a yield of 83.3%.

LC-MS: m/z 181.1 [M+H] ⁺ .

Step 4: Preparation of tert-butyl 3-(6-(methylcarbamoyl)pyridin-3-yl)azetidine-1-carboxylate (29d)

(6-(Methylcarbamoyl)pyridin-3-yl)boronic acid (29c) (1.40 g, 7.78 mmol) was dissolved in DMF (15 mL) and water (3 mL), and tert-butyl 3-iodoazetidine-1-carboxylate (2.20 g, 7.78 mmol), potassium carbonate (3.22 g, 23.3 mmol), and Pd(PPh ₃ ) ₄ (898 mg, 0.778 mmol) were added. The mixture was stirred at 60° C. for 16 hours under a nitrogen atmosphere. 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3), washed with saturated brine (30 mL x 2), 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=100/1-3/7) to obtain 100 mg of the title compound as a light yellow oil, with a yield of 4.42%.

LC-MS: m/z 292.2 [M+H] ⁺ .

Step 5: Preparation of 5-(azetidin-3-yl)-N-methylpicolinamide (29e)

At room temperature, tert-butyl 3-(6-(methylcarbamoyl)pyridin-3-yl)azetidine-1-carboxylate (29d) (90.0 mg, 0.309 mmol) was dissolved in dichloromethane (1 mL), TFA (0.2 mL) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to obtain 100 mg (crude) of the title compound as a pale yellow oil.

LC-MS: m/z 192.1[M+H]+.

Step 6: Preparation of tert-butyl 3-(6-(methylcarbamoyl)pyridin-3-yl)-[1,3'-aziridine]-1'-carboxylate (29f)

5-(Azetidine-3-yl)-N-methylpicolinamide (29e) (59.1 mg, 0.309 mmol) was dissolved in methanol (2 mL), tert-butyl 3-oxoazetidine-1-carboxylate (79.3 mg, 0.464 mmol) and acetic acid (1 drop) were added, and the mixture was stirred at room temperature for 0.5 hours. Sodium cyanoborohydride (39.0 mg, 0.618 mmol) was added, and the mixture was stirred at room temperature for 16 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate (10 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=100/1-1/1) to obtain 50.0 mg of the title compound as a light yellow oil, with a yield of 46.8%.

LC-MS: m/z 347.2 [M+H] ⁺ .

The other steps were the same as the preparation method of Example 1, except that 3-(6-(methylcarbamoyl)pyridin-3-yl)-[1,3'-aziridine]-1'-carboxylic acid tert-butyl ester (29f) was used instead of 3-(methyl(6-(methylcarbamoyl)pyridin-3-yl)amino)azetidine-1-carboxylic acid tert-butyl ester (1j) in step 11 to obtain the title compound 29.

LC-MS: m/z 433.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.82 (s, 1H), 8.71 (q, J = 4.8 Hz, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.29 (d, J = 1.6 Hz, 1H), 8.04 (dd, J = 8.0, 2.0 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.50 (d, J = 1.6 Hz, 1H) ,4.35(t,J＝8.0Hz,1H),3.60(s,2H),3.38-3.27 (m, 2H), 3.21 (dt, J = 14.4, 6.8 Hz, 2H), 3.15-3.06 (m, 1H), 2.91 (t, J = 6.4 Hz, 1H), 2.82 (dd, J = 9.2, 5.6 Hz, 4H), 2.55 (dd, J = 7.2, 1.2 Hz, 2H), 2.32 (dtd, J = 10.0, 7.6, 2.0 Hz, 1H), 2.02 (p, J = 9.2 Hz, 1H), 1.17 (t , J = 7.2 Hz, 3H).

Example 30: Preparation of 5-((1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)pyrrolidin-3-yl)oxy)-N-methylpicolinamide (30)

The title compound 30 was prepared in the same manner as in Example 6, except that tert-butyl 3-iodopyrrolidine-1-carboxylate was used instead of tert-butyl 3-iodoazetidine-1-carboxylate.

LC-MS: m/z 408.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.77 (s, 1H), 8.47 (q, J = 4.8 Hz, 1H), 8.32 (d, J = 1.9 Hz, 1H), 8.17 (d, J = 2.8 Hz, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 1.5 Hz, 1H), 7.53(d, J＝1.8Hz,1H),7.40(dd, J＝8.7,2.9Hz,1H),4.98(s,1H),3.66(d, J＝2.7Hz,2H),2.84(dd, J＝10.6,6.0Hz,1H),2.75-2.63(m,5H),2.49(dd, J＝7.4,1.2Hz,2H),2.42-2.24(m,2H),1.80-1.71(m,1H),1.11(t, J＝7.4Hz,3H).

Example 31: Preparation of 5-((1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)azetidin-3-yl)(methyl)amino)-N,6-dimethylpicolinamide (31)

Step 1: Preparation of 5-bromo-N,6-dimethylpicolinamide (31a)

5-Bromo-6-methylpyridine acid (300 mg, 1.40 mmol) was dissolved in DMF (4 mL), and methylamine hydrochloride (112 mg, 1.67 mmol), HATU (689 mg, 1.81 mmol), and DIEA (540 mg, 4.19 mmol) were added, and stirred at room temperature for 2 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL x 2), 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=100/1-9/1) to obtain 330 mg of the title compound as a light yellow solid, with a yield of 88.8%.

LC-MS: m/z 229.0 [M+H] ⁺ .

The other steps were the same as those of Example 1, except that 5-bromo-N,6-dimethylpicolinamide (31a) was used instead of tert-butyl 3-(methylamino)azetidine-1-carboxylate in step 8 to prepare the title compound 31.

LC-MS: m/z 421.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.81 (s, 1H), 8.41 (q, J=4.8 Hz, 1H), 8.34 (d, J=1.6 Hz, 1H), 7.76-7.69 (m, 2H), 7.57-7.51 (m, 1H), 7.31 (d, J=8.4 Hz, 1H), 3.96 (p, J=6.4 Hz, 1H), 3.68 (s, 2H), 3.53 (dd, J=7.6, 6.0 Hz, 2H), 2.95-2.85 (m, 2H), 2.80 (d, J=4.8 Hz, 3H), 2.61 (s, 3H), 2.56-2.51 (m, 5H), 1.17 (t, J=7.2 Hz, 3H).

Example 32: Preparation of N-ethyl-5-((1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)azetidin-3-yl)(methyl)amino)picolinamide (32)

The title compound 32 was prepared in the same manner as in Example 1, except that ethylamine hydrochloride was used instead of methylamine hydrochloride in step 10.

LC-MS: m/z 420.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.85 (s, 1H), 8.42-8.33 (m, 2H), 8.03 (d, J＝2.9 Hz, 1H), 7.80 (d, J＝8.8 Hz, 1H), 7.76-7.71 (m, 1H), 7.61-7.55 (m, 1H), 7.17 (dd, J = 8.8, 3.0 Hz, 1H), 4.34 (q, J = 6.8 Hz, 1H ),3.74(s,2H),3.68(td,J＝6.6,1.7Hz,2H),3.30-3.24(m,2H),3.16-3.09(m,2H),2.98(s,3H),2.55( td, J = 7.4, 1.2 Hz, 2H), 1.18 (t, J = 7.4 Hz, 3H), 1.09 (t, J = 7.2 Hz, 3H).

Example 33: Preparation of 5-((1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)azetidin-3-yl)(methyl)amino)-N,4-dimethylpicolinamide (33)

The title compound 33 was prepared in the same manner as in Example 1, except that 5-bromo-4-methylpicolinic acid methyl ester was used instead of 5-bromopicolinic acid methyl ester in step 8.

LC-MS: m/z 420.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.79 (s, 1H), 8.51 (d, J=5.1 Hz, 1H), 8.34 (d, J=1.8 Hz, 1H), 8.01 (s, 1H), 7.81 (s, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.54 (d, J=1.8 Hz, 1H), 4.10 (p, J=6.5 Hz, 1H), 3.68 (s, 2H), 3.60-3.53 (m, 2H), 2.93 (t, J=6.9 Hz, 2H), 2.78 (d, J=4.8 Hz, 3H), 2.64 (s, 3H), 2.57-2.52 (m, 2H), 2.33 (s, 3H), 1.17 (t, J=7.4 Hz, 3H).

Example 34: Preparation of N-ethyl-5-((1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)azetidin-3-yl)oxy)picolinamide (34)

The title compound 34 was prepared in the same manner as in Example 1, except that 3-((6-(ethylcarbamoyl)pyridin-3-yl)oxy)azetidine-1-carboxylic acid tert-butyl ester (6a) was used instead of 3-(methylamino)azetidine-1-carboxylic acid tert-butyl ester in step 8, and ethylamine hydrochloride was used instead of methylamine hydrochloride in step 10.

LC-MS: m/z 408.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.83 (s, 1H), 8.58 (t, J＝4.7 Hz, 1H), 8.37 (d, J =1.9 Hz, 1H), 8.22 (d, J = 2.8 Hz, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.73 (s, 1H), 7.57 (d, J = 1.8 Hz, 1H), 7.40 (dd, J = 8.7, 2.9 Hz, 1H), 5.02 (p, J = 5.5 Hz, 1H), 3.86-3.70 (m, 4H), 3.29-3.24 (m, 2H), 3.20-3.12 (m, 2H), 2.59-2.52 (m, 2H), 1.18 (t, J = 7.4 Hz, 3H), 1.10 (t, J = 7.4 Hz, 3H).

Example 35: Preparation of N-cyclopropyl-5-((1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)azetidin-3-yl)oxy)picolinamide (35)

The title compound 35 was prepared in the same manner as in Example 1, except that 3-((6-(ethylcarbamoyl)pyridin-3-yl)oxy)azetidine-1-carboxylic acid tert-butyl ester (6a) was used instead of 3-(methylamino)azetidine-1-carboxylic acid tert-butyl ester in step 8, and cyclopropylamine was used instead of methylamine hydrochloride in step 10.

LC-MS: m/z 420.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.83 (s, 1H), 8.51 (d, J=12 Hz, 1H), 8.37 (d, J=1.9 Hz, 1H), 8.22 (d, J=2.8 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.73 (s, 1H), 7.57 (br, 1H), 7.40 (dd, J=8.7, 2.9 Hz, 1H), 5.07-4.97 (m, 1H), 3.81-3.73 (m, 4H), 3.21-3.13 (m, 2H), 2.91-2.82 (m, 1H), 2.59-2.52 (m, 2H), 1.18 (t, J=7.4 Hz, 3H), 0.69-0.60 (m, 4H).

Example 36: Preparation of 5-((1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)azetidin-3-yl)oxy)-N,6-dimethylpicolinamide (36)

Step 1: Preparation of methyl 5-hydroxy-6-methylpicolinate (36a)

At room temperature, 6-chloro-2-methylpyridin-3-ol (500 mg, 3.50 mmol) was dissolved in methanol (10 mL), triethylamine (4 mL) and Pd(dppf)Cl ₂ (100 mg, 0.137 mmol) were added, and the mixture was stirred at 80°C for 16 hours under a carbon monoxide atmosphere. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography. Purification (mobile phase: DCM/MeOH=100/1-15/1) afforded the title compound as a light yellow solid (120 mg). Yield: 20.1%).

LC-MS: m/z 168.1 [M+H] ⁺ .

Step 2: Preparation of methyl 5-(1-(tert-butyloxycarbonyl)azetidin-3-yl)oxy)-6-methylpicolinate (36b)

At room temperature, methyl 5-hydroxy-6-methylpicolinate (36a) (100 mg, 0.595 mmol) was dissolved in DMF (2 mL), tert-butyl 3-iodoazetidine-1-carboxylate (238 mg, 0.835 mmol) and K ₂ CO ₃ (132 mg, 0.955 mmol) were added, and the mixture was stirred at 80° C. for 16 hours under a nitrogen atmosphere. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL x 2), 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=100/1-2/1) to obtain 90 mg of the title compound as a light yellow solid, yield: 48.3%.

LC-MS: m/z 323.2 [M+H] ⁺ .

The other steps were the same as the preparation method of Example 1, except that 5-(1-(tert-butoxycarbonyl)azetidine-3-yl)oxy)-6-methylpicolinic acid methyl ester (36b) was used instead of tert-butyl 3-(methylamino)azetidine-1-carboxylate in step 8 to prepare the title compound 36.

LC-MS: m/z 408.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.78 (s, 1H), 8.39-8.25 (m, 2H), 7.75-7.64 (m, 2H), 7.50 (d, J=1.8 Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 4.87 (p, J=5.6 Hz, 1H), 3.77-3.73 (m, 1H), 3.71 (d, J=7.0 Hz, 2H), 3.13-3.05 (m, 2H), 2.72 (d, J=4.9 Hz, 3H), 2.48 (dd, J=7.7, 6.4 Hz, 3H), 2.38 (s, 3H), 1.11 (t, J=7.4 Hz, 3H).

Example 37: Preparation of 5-((1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)azetidin-3-yl)oxy)-N,3-dimethylpicolinamide (37)

The title compound 37 was prepared in the same manner as Example 36, except that 6-bromo-5-methylpyridin-3-ol was used instead of 6-chloro-2-methylpyridin-3-ol in step 1.

LC-MS: m/z 408.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.83 (s, 1H), 8.43-8.34 (m, 2H), 8.05 (d, J=2.7 Hz, 1H), 7.74 (s, 1H), 7.57 (s, 1H), 7.18 (d, J=2.7 Hz, 1H), 4.99 (p, J=5.6 Hz, 1H), 3.78 (d, J=8.1 Hz, 4H), 3.15 (dd, J=8.0, 5.2 Hz, 2H), 2.74 (d, J=4.7 Hz, 3H), 2.53 (d, J=5.5 Hz, 5H), 1.18 (t, J=7.4 Hz, 3H).

Example 38: 5-((1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)azetidine-3- Preparation of 3-fluoro-N-methylpyridineamide (38)

The title compound 38 was prepared in the same manner as Example 36, except that 6-chloro-5-fluoropyridin-3-ol was used instead of 6-chloro-2-methylpyridin-3-ol in step 1.

LC-MS: m/z 412.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.84 (br, 1H), 8.47-8.41 (m, 1H), 8.37-8.34 (m, 1H), 8.14-8.10 (m, 1H), 7.74 (s, 1H), 7.57 (s, 1H), 7.40 (dd, J=6.0 Hz, 1H), 5.07-5.00 (m, 1H), 3.83-3.72 (m, 4H), 3.20-3.13 (m, 2H), 2.74 (d, J=4.7 Hz, 3H), 2.57-2.52 (m, 2H), 1.18 (t, J=7.4 Hz, 3H).

Example 39: Preparation of 5-(3-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)pyrrolidin-3-yl)azetidin-1-yl)-N-methylpicolinamide (39)

Step 1: Preparation of tert-butyl 3-(1-(((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)pyrrolidin-3-yl)azetidine-1-carboxylate (39a)

Tert-butyl 3-(pyrrolidin-3-yl)azetidine-1-carboxylate (60.0 mg, 0.265 mmol) and 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (1 g) (58.9 mg, 0.265 mmol) were dissolved in acetonitrile (2 mL) at room temperature, and DIEA (103 mg, 0.798 mmol) and sodium iodide (7.96 mg, 0.0531 mmol) were added. The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=100/1-92/8) to obtain 98 mg of the title compound as a yellow oil. Yield: 89.9%.

LC-MS: m/z 413.2 [M+H] ⁺ .

Step 2: Preparation of 7-((3-(azetidin-3-yl)pyrrolidin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (39b)

At room temperature, tert-butyl 3-(1-(((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)pyrrolidin-3-yl)azetidine-1-carboxylate (39a) (98.0 mg, 0.238 mmol) was dissolved in DCM (2 mL), and a dioxane hydrochloride solution (0.5 mL, 4 mol/L) was added. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, slurried with PE/EA=1/1, filtered, and the filter cake was collected to give 80 mg (crude) of the title compound as a yellow solid.

LC-MS: m/z 313.2 [M+H] ⁺ .

Step 3: Preparation of methyl 5-(3-(1-(((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)pyrrolidin-3-yl)azetidin-1-yl)picolinate (39c)

Methyl 5-fluoropicolinate (36.9 mg, 0.238 mmol) was dissolved in DMF (2 mL), and 7-((3-(azetidin-3-yl)pyrrolidin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (39b) (80.0 mg, 0.238 mmol) and cesium carbonate (155 mg, 0.476 mmol) were added. The mixture was stirred at 75 °C overnight under a nitrogen atmosphere. Water (20 mL) was added, and the mixture was 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: DCM/MeOH=100/1-10/1) to obtain 22 mg of the title compound as a light yellow oil, with a yield of 20.6%.

LC-MS: m/z 448.2 [M+H] ⁺ .

Step 4: Preparation of 5-(3-(1-(((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)pyrrolidin-3-yl)azetidin-1-yl)-N-methylpicolinamide (39)

Methyl 5-(3-(1-(((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)pyrrolidin-3-yl)azetidin-1-yl)picolinate (39c) (20.0 mg, 0.0447 mmol) was dissolved in methanol (0.5 mL), and aqueous methylamine solution (33%, 0.5 mL) was added. The mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue was separated by high performance preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um 100A, mobile phase: acetonitrile/water, gradient: 10%-50%, 0.05% formic acid, 30 min) to obtain 2.5 mg of the title compound as a white solid, yield: 12.5%.

LC-MS: m/z 447.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.80 (br, 1H), 8.36 (d, 1H), 8.34-8.28 (m, 1H), 8.22 (s, 1H), 7.78 (d, 1H), 7.74-7.69 (m, 2H), 7.59 (d, 1H), 6.83 (dd, 1H), 4.09-3.96 (m, 2H), 3.74-3.57 (m, 4H), 2.76 (d, J=4.8 Hz, 3H), 2.65-2.52 (m, 5H), 2.47-2.39 (m, 1H), 2.24-2.16 (m, 1H), 2.05-1.90 (m, 2H), 1.45-1.35 (m, 1H), 1.17 (t, J=7.4 Hz, 3H).

Example 40: Preparation of 5-(1-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)pyrrolidin-3-yl)azetidin-3-yl)-N-methylpicolinamide (40)

Step 1: Preparation of tert-butyl 3-(3-(6-(methylcarbamoyl)pyridin-3-yl)azetidin-1-yl)pyrrolidine-1-carboxylate (40a)

5-(Azetidine-3-yl)-N-methylpicolinamide (29e) (170 mg, 0.890 mmol) was dissolved in methanol (3 mL), acetic acid (3 drops) and tert-butyl 3-oxopyrrolidine-1-carboxylate (247 mg, 1.34 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (112 mg, 1.78 mmol) was added, and the mixture was stirred at room temperature for 16 hours. 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 separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=100/1-98/2) to obtain 95.0 mg of the title compound as a yellow oil, with a yield of 29.7%.

LC-MS: m/z 361.2 [M+H] ⁺ .

The other steps were the same as the preparation method of Example 1, except that tert-butyl 3-(3-(6-(methylcarbamoyl)pyridin-3-yl)azetidine-1-yl)pyrrolidine-1-carboxylate (40a) was used instead of tert-butyl 3-(methyl(6-(methylcarbamoyl)pyridin-3-yl)amino)azetidine-1-carboxylate (1j) in step 10 to obtain the title compound 40.

LC-MS: m/z 447.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.84 (s, 1H), 8.69 (q, J = 4.8 Hz, 1H), 8.53 (s, 1H), 8.37 (d, J = 1.6 Hz, 1H) ,8.24(s,1H),7.98(d,J＝1.6Hz,1H),7.74(s,1H),7.59(d,J＝1.6Hz,1H),3.66(d,J＝7.2Hz,3H) ,3.57(dt,J＝14.0,7.2Hz,2H),3 .10(q,J＝6.4Hz,2H),3.02(tt,J＝8.0,4.4Hz,1H),2.81(d,J＝4.8Hz,3H),2.64–2.52(m,4H),2.27( dd, J = 9.2, 4.0 Hz, 2H), 1.82 (dt, J = 14.4, 7.2 Hz, 1H), 1.51 (q, J = 4.8, 3.5 Hz, 1H), 1.18 (t, J = 7.2 Hz, 3H ).

Example 41: Preparation of 5-((1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)azetidin-3-yl)oxy)-N-isopropylpicolinamide (41)

The preparation method was the same as that of Example 1, except that tert-butyl 3-((6-(ethylcarbamoyl)pyridin-3-yl)oxy)azetidine-1-carboxylate (6a) was used instead of tert-butyl 3-(methylamino)azetidine-1-carboxylate in step 8. The title compound 41 was prepared by replacing the methylamine hydrochloride in step 10 with isopropylamine.

LC-MS: m/z 422.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.83 (s, 1H), 8.37 (d, 1H), 8.27-8.20 (m, 2H), 7.94 (d, 1H), 7.73 (s, 1H), 7.57 (br, 1H), 7.40 (dd, 1H), 5.07-4.97 (m, 1H), 4.14-4.02 (m, 1H), 3.84-3.73 (m, 4H), 3.21-3.13 (m, 2H), 2.91-2.82 (m, 1H), 2.59-2.52 (m, 2H), 1.22-1.12 (m, 9H).

Example 42: Preparation of 5-((1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)azetidin-3-yl)oxy)-6-fluoro-N-methylpicolinamide (42)

Step 1: Preparation of 5-fluoro-6-hydroxynicotinic acid methyl ester (42a)

At room temperature, 5-chloro-3-fluoropyridin-2-ol (500 mg, 3.38 mmol) was dissolved in methanol (10 mL), and potassium acetate (1.66 g, 16.9 mmol) and Pd(dppf)Cl ₂ (124 mg, 0.169 mmol) were added. The mixture was stirred at 90°C overnight under a carbon monoxide atmosphere. Water (20 mL) was added, and the mixture was extracted with DCM (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: DCM/MeOH=100/1-10/1) to obtain 170 mg of the title compound as a reddish brown oil, with a yield of 29.4%.

LC-MS: m/z 172.0 [M+H] ⁺ .

Step 2: Preparation of methyl 6-((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)-5-fluoronicotinate (42b)

At room temperature, 5-fluoro-6-hydroxynicotinic acid methyl ester (42a) (150 mg, 0.877 mmol) was dissolved in DMF (20 mL), and 3-iodo-azetidine-1-carboxylic acid tert-butyl ester (248 mg, 0.877 mmol) and K ₂ CO ₃ (242 mg, 1.75 mmol) were added. The mixture was stirred at 80°C overnight under a nitrogen atmosphere. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (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=100/1-1/2) to obtain 130 mg of the title compound as a yellow oil, yield: 45.5%.

LC-MS: m/z 327.1 [M+H] ⁺ .

Step 3: Preparation of tert-butyl 3-((3-fluoro-5-(methylcarbamoyl)pyridin-2-yl)oxy)azetidine-1-carboxylate (42c)

At room temperature, 6-((1-(tert-butyloxycarbonyl)azetidin-3-yl)oxy)-5-fluoronicotinic acid methyl ester (42b) (100 mg, 0.307mmol) was dissolved in methanol (2mL), and 30% aqueous methylamine solution (0.8mL) was added. Stir at room temperature overnight under nitrogen atmosphere. Concentrate under reduced pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=100/1-1/9) to obtain 15mg of the title compound as a light yellow solid, yield: 15.0%.

LC-MS: m/z 326.1 [M+H] ⁺ .

The other steps were the same as the preparation method of Example 1, except that 3-((3-fluoro-5-(methylcarbamoyl)pyridin-2-yl)oxy)azetidine-1-carboxylic acid tert-butyl ester (42c) was used instead of 3-(methyl(6-(methylcarbamoyl)pyridin-3-yl)amino)azetidine-1-carboxylic acid tert-butyl ester (1j) in step 10 to obtain the title compound 42.

LC-MS: m/z 412.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.84 (br, 1H), 8.50-8.44 (m, 1H), 8.39-8.34 (m, 1H), 7.85 (d, 1H), 7.74 (s, 1H), 7.60-7.52 (m, 2H), 5.07-5.00 (m, 1H), 3.83-3.72 (m, 4H), 3.23-3.17 (m, 2H), 2.77 (d, 3H), 2.58-2.13 (m, 2H), 1.18 (t, 3H).

Example 43: Preparation of 5-((1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3-methylazetidin-3-yl)oxy)-N-methylpicolinamide (43)

Step 1: Preparation of 5-fluoro-N-methylpicolinamide (43a)

At room temperature, 5-fluoropicolinic acid (1.00 g, 7.09 mmol) was dissolved in DMF (10 mL), and DIEA (3.66 g, 28.4 mmol), methylamine hydrochloride (950 mg, 14.2 mmol) and HATU (4.04 g, 10.6 mmol) were added, and stirred at room temperature for 16 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (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=100/1-1/100) to obtain 900 mg of the title compound as a light yellow solid, with a yield of 81.8%.

LC-MS: m/z 155.1 [M+H] ⁺ .

Step 2: Preparation of tert-butyl 3-methyl-3-((6-(methylcarbamoyl)pyridin-3-yl)oxy)azetidine-1-carboxylate (43b)

At room temperature, tert-butyl 3-hydroxy-3-methylazetidine-1-carboxylate (100 mg, 0.642 mmol) was dissolved in DMF/ACN (1 mL/1 mL), and 5-fluoro-N-methylpicolinamide (43a) (100 mg, 0.534 mmol) and NaH (64.0 mg, 16.1 mmol) were added. Stir at 80 ° C for 16 hours under nitrogen atmosphere. Water (5 mL) was added, extracted with ethyl acetate (5 mL x 3), washed with saturated brine (20.0 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%). 60 mg of the title compound was obtained as a light yellow solid. Yield: 29.1%.

LC-MS: 322.2 [M+H] ⁺ .

The other steps were the same as the preparation method of Example 1, except that 3-methyl-3-((6-(methylcarbamoyl)pyridin-3-yl)oxy)azetidine-1-carboxylic acid tert-butyl ester (43b) was used instead of 3-(methyl(6-(methylcarbamoyl)pyridin-3-yl)amino)azetidine-1-carboxylic acid tert-butyl ester (1j) in step 10 to obtain the title compound 43.

LC-MS: m/z 408.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.83 (s, 1H), 8.53 (d, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.13 (d, J=2.8 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.76-7.71 (m, 1H), 7.60-7.55 (m, 1H), 7.28 (dd, J=8.7, 2.9 Hz, 1H), 3.77 (s, 2H), 3.61-3.54 (m, 2H), 2.79 (d, J=4.8 Hz, 3H), 2.55 (dd, J=7.5, 6.3 Hz, 4H), 1.64 (s, 3H), 1.18 (t, J=7.4 Hz, 3H).

Example 44: Preparation of 5-((3-ethyl-1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)azetidin-3-yl)oxy)-N-methylpicolinamide (44)

Step 1: Preparation of benzyl 3-ethyl-3-hydroxyazetidine-1-carboxylate (44a)

Benzyl 3-oxoazetidine-1-carboxylate (5.00 g, 24.4 mmol) was dissolved in tetrahydrofuran (30 mL). Ethyl magnesium bromide (36.5 mL, 2 M) was added at -78 °C under a nitrogen atmosphere and stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate (100 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 = 50%) to obtain 4.00 g of the title compound as a yellow solid, with a yield of 69.8%.

LC-MS: m/z 236.1 [M+H] ⁺ .

Step 2: Preparation of methyl 5-((1-((benzyloxy)carbonyl)-3-ethylazetidin-3-yl)oxy)picolinate (44b)

3-Ethyl-3-hydroxyazetidine-1-carboxylic acid benzyl ester (44a) (1.00 g, 4.26 mmol) was dissolved in 1,4-dioxane (15.0 mL), and 5-fluoropicolinic acid methyl ester (660 mg, 4.26 mmol) and carbonyl were added. Cesium ether (2.77 g, 8.51 mmol). Stir in microwave at 110°C for 10 hours. Filter and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: EA/PE=40%) to obtain 130 mg of the title compound as a yellow oil. Yield: 8.2%.

LC-MS: m/z 371.2 [M+H] ⁺ .

Step 3: Preparation of benzyl 3-ethyl-3-((6-(methylcarbamoyl)pyridin-3-yl)oxy)azetidine-1-carboxylate (44c)

Methyl 5-((1-((benzyloxy)carbonyl)-3-ethylazetidin-3-yl)oxy)picolinate (44b) (130 mg, 0.351 mmol) was dissolved in methanol (2.5 mL), and aqueous methylamine solution (2.5 mL, 30%) was added, and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: EA/PE = 95%) to obtain 130 mg of the title compound as a yellow oil, with a yield of 99.9%.

LC-MS: m/z 370.2 [M+H] ⁺ .

Step 4: Preparation of 5-((3-ethylazetidin-3-yl)oxy)-N-methylpicolinamide (44d)

At room temperature, benzyl 3-ethyl-3-((6-(methylcarbamoyl)pyridin-3-yl)oxy)azetidine-1-carboxylate (44c) (50.0 mg, 0.136 mmol) was dissolved in methanol (3 mL), and aqueous palladium carbon (50 mg) was added. The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 50 mg (crude) of the title compound as a colorless oil.

LC-MS: m/z 236.1 [M+H] ⁺ .

The other steps were the same as the preparation method of Example 1, except that 5-((3-ethylazetidin-3-yl)oxy)-N-methylpicolinamide (44d) was used instead of 5-(azetidin-3-yl(methyl)amino)-N-methylpicolinamide (1k) in step 11 to obtain the title compound 44.

LC-MS: m/z 422.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.83 (s, 1H), 8.54 (q, J = 4.8 Hz, 1H), 8.36 (d, J = 1.6 Hz, 1H), 8.15 (d, J = 2.8 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.73 (s, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.29 (dd, J = 8.8, 2.8 Hz, 1H ),3.78(s,2H),3.66-3.59(m,2H),3.31-3.24(m,2H),2.79(d,J＝4.8Hz,3H),2.55(td,J＝7.2,1.2Hz, 2H), 2.10-1.98 (m, 2H), 1.18 (t, J = 7.2 Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H).

Example 45: Preparation of 5-((1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-3-(trifluoromethyl)azetidin-3-yl)oxy)-N-methylpicolinamide (45)

Step 1: Preparation of tert-butyl 3-((6-(methylcarbamoyl)pyridin-3-yl)oxy)-3-(trifluoromethyl)azetidine-1-carboxylate (45a)

At room temperature, tert-butyl 3-hydroxy-3-(trifluoromethyl)azetidine-1-carboxylate (100 mg, 0.622 mmol) was dissolved in DMF (1 mL), and 5-fluoro-N-methylpicolinamide (43a) (100 mg, 0.534 mmol) and K ₂ CO ₃ (286 mg, 2.10 mmol) were added. The mixture was stirred at 110° C. for 16 hours under a nitrogen atmosphere. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (5 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 obtain 110 mg of the title compound as a light yellow solid. Yield: 47.2%.

LC-MS: m/z 376.1 [M+H] ⁺ .

The other steps were the same as the preparation method of Example 1, except that 3-((6-(methylcarbamoyl)pyridin-3-yl)oxy)-3-(trifluoromethyl)azetidine-1-carboxylic acid tert-butyl ester (45a) was used instead of 3-(methyl(6-(methylcarbamoyl)pyridin-3-yl)amino)azetidine-1-carboxylic acid tert-butyl ester (1j) in step 10 to obtain the title compound 45.

LC-MS: m/z 462.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.84 (s, 1H), 8.64 (d, J=4.9 Hz, 1H), 8.33 (dd, J=6.2, 2.3 Hz, 2H), 7.99 (d, J=8.7 Hz, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.58-7.49 (m, 2H), 3.96-3.87 (m, 2H), 3.80 (s, 2H), 3.58 (d, J=9.6 Hz, 2H), 2.80 (d, J=4.8 Hz, 3H), 2.55 (dd, J=7.9, 6.7 Hz, 2H), 1.18 (t, J=7.4 Hz, 3H).

Example 46: Preparation of 5-((1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperidin-4-yl)oxy)-N-methylpicolinamide (46)

Step 1: Preparation of methyl 5-((1-(tert-butyloxycarbonyl)piperidin-4-yl)oxy)picolinate (46a)

At room temperature, methyl 5-hydroxypicolinate (500 mg, 1.61 mmol) was dissolved in DMF (10 mL), and tert-butyl 4-iodopiperidine-1-carboxylate (291 mg, 1.93 mmol) and K ₂ CO ₃ (630 mg, 4.83 mmol) were added. The mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. Water (20 mL) was added, and the mixture was 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 to obtain 100 mg of the crude title compound as a light yellow solid.

LC-MS: m/z 337.2 [M+H] ⁺ .

The remaining steps were the same as those of Example 1, except that 5-((1-(tert-butyloxycarbonyl)piperidin-4-yl)oxy)picolinic acid methyl ester (46a) was used instead of 5-((1-(tert-butyloxycarbonyl)azetidin-3-yl) (methyl) in step 9. The title compound 46 was prepared by adding 1,2-dimethyl-1,2-diamino-1,2-picolinic acid methyl ester (1h).

LC-MS: m/z 422.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.83 (s, 1H), 8.53 (d, J=5.1 Hz, 1H), 8.38 (d, J=1.7 Hz, 1H), 8.27 (d, J=2.9 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.74 (s, 1H), 7.64-7.49 (m, 2H), 4.65-4.60 (m, 1H), 3.62 (s, 2H), 2.78 (d, J=4.9 Hz, 3H), 2.69 (s, 2H), 2.60-2.51 (m, 2H), 2.31 (t, J=9.7 Hz, 2H), 1.97 (s, 2H), 1.68 (d, J=9.2 Hz, 2H), 1.24-1.08 (m, 3H).

Example 47: Preparation of 5-((2-(((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-azaspiro[3.3]heptane-6-yl)oxy)-N-methylpicolinamide (47)

Step 1: Preparation of tert-butyl 6-(6-(methoxycarbonyl)pyridin-3-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (47a)

At room temperature, tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (330 mg, 1.55 mmol) was dissolved in DMF (4 mL), and methyl 5-fluoropicolinate (200 mg, 1.29 mmol) and potassium carbonate (534 mg, 3.87 mmol) were added. Stir at 80 ° C for 16 hours under nitrogen atmosphere. Water (10 mL) was added, extracted with ethyl acetate (10 mL x 3), washed with saturated brine (10 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 = 60%) to obtain 100 mg of the title compound as a white solid, yield: 22.3%.

LC-MS: m/z 349.2 [M+H] ⁺ .

The remaining steps were the same as the preparation method of Example 1, except that 6-(6-(methoxycarbonyl)pyridin-3-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (47a) was used instead of 5-((1-(tert-butyloxycarbonyl)azetidin-3-yl)(methyl)amino)picolinic acid methyl ester (1h) in step 9 to obtain the title compound 47.

LC-MS: m/z 434.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.81 (s, 1H), 8.53 (d, J = 4.9 Hz, 1H), 8.32 (d, J = 1.8 Hz, 1H), 8.18 (d, J = 2.8Hz,1H),7.94(d,J＝8.7Hz,1H),7.73(q,J＝1.0Hz,1H),7.55-7.51(m,1H),7.39(dd,J＝8.7,2.9Hz, 1H),4.78( t, J = 6.8 Hz, 1H), 3.62 (s, 2H), 3.26 (s, 2H), 3.17 (s, 2H), 2.78 (d, J = 4.8 Hz, 3H), 2.70 (ddd, J = 10.1 ,6.9,3.1Hz,2H),2.54(td,J＝7.4,1.2Hz,2H),2.24-2.15(m,2H),1.18(t,J＝7.4Hz,3H).

Example 48: Preparation of 5-(3-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperidin-4-yl)azetidin-1-yl)-N-methylpicolinamide (48)

The title compound 48 was prepared in the same manner as Example 39, except that tert-butyl 3-(piperidin-4-yl)azetidine-1-carboxylate was used instead of tert-butyl 3-(pyrrolidin-3-yl)azetidine-1-carboxylate in step 1.

LC-MS: m/z 461.3 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.81 (s, 1H), 8.38-8.29 (m, 2H), 8.22 (s, 1H), 7.85 (d, J＝2.8 Hz, 1H), 7.79 ( d, J = 8.7 Hz, 1H), 7.75-7.71 (m, 2H), 7.58 (d, J = 1.8 Hz, 1H), 6.84 (dd, J = 8.7, 2.9 Hz, 1H), 4 .02(t,2H),3.70-3.65(m,2H),3.56(s,2H),2.82(d,2H),2.77(d,J＝4.8Hz,3H),2.57-2.51(m,3H ),1.96(t,2H),1.64(d,2H),1.53-1.46(m,1H),1.18(t,J＝7.4Hz,3H).

Biological tests

Experimental Example 1: PARP1 capture experiment

Experimental materials: test compounds, PARP1 (BPS, 80501), NAD (Sigma, 10127965001), DSB DNA probe-1 (Kanglong Chemical), Mab anti GST-Tb cryptate (cisbio, 61GSTTLA).

Experimental steps:

(I) Reagent preparation

Prepare experimental buffer: 10 mM potassium phosphate (pH 7.9), 50 mM NaCl, 1 mM EDTA, 0.05% Brij-35, 1 mM DTT.

(II) Experimental methods

The buffer solution was prepared by the above method, the compound was dissolved in DMSO and diluted in a gradient manner, the compound was diluted to the test concentration using the experimental buffer, and the mixture was shaken on an oscillator for 15 min.

PARP1 enzyme was diluted 4X using assay buffer and GST-Tb was added simultaneously.

Add the prepared enzyme solution to the assay plate, 4 μL per well.

Dilute PARP1probe1 to 4X using assay buffer and add 4 μL per well to the assay plate.

The test compound was added to the experimental plate, 4 μL per well, and incubated in a room temperature incubator for 1 hour.

Dilute NAD to 4X using assay buffer, add 4 μL per well to the assay plate, and incubate in a room temperature incubator for 10 minutes.

The final values (Ex: 340nm, Em 665nm and 615nm) were read by Envision (2105).

data analysis:

The % inhibition rate was calculated as follows:
Suppression % = (Signal cmpd - Signal Ave_PC) / (Signal Ave_VC - Signal Ave_PC) × 100

Signal cmpd: Fluorescence signal value of different concentrations of compounds

SignalAve_PC: The average value of the maximum fluorescence signal of the system

SignalAve_VC: Average value of negative control fluorescence signal value

Calculate IC50 and draw compound effect dose curve:

IC50s were calculated by fitting percent inhibition values and logarithms of compound concentration to non-linear regression (dose response - variable slope) using Graphpad 5.0.
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))

X: logarithmic value of inhibitor concentration; Y: percentage of inhibition rate

Table 1 provides the in vitro activities (IC ₅₀ ) of the compounds of the present invention on PARP1 capture.

In Table 1, the PARP1 capture in vitro activity values of the compounds are: A refers to IC ₅₀ <10 nM; B refers to 10 nM<IC ₅₀ <100 nM; C refers to 100 nM<IC ₅₀ <1000 nM; D refers to IC ₅₀ >1000 nM.

Table 1 Activity of the compounds of the present invention on PARP1 capture

Results: The compounds of the present invention have good capture activity on PARP1-DNA complex.

Experimental Example 2: PARP2 capture experiment

Experimental materials: Test compounds, PARP2 (BPS, 80502), NAD (Sigma, 10127965001), DSB DNA probe-2 (Kanglong Chemical), Mab anti GST-Tb cryptate (cisbio, 61GSTTLA)

Experimental steps:

(I) Reagent preparation

(II) Experimental methods:

The reagents were prepared by the above method. The compounds were dissolved in DMSO and serially diluted, and the compounds were diluted to the test concentration using the assay buffer and shaken on a shaker for 15 min.

PARP2 enzyme was diluted 4X using assay buffer and GST-Tb was added simultaneously.

Add the prepared enzyme solution to the assay plate, 4 μL per well.

Dilute PARP2probe2 to 4X using assay buffer and add 4 μL per well to the assay plate.

The final values (Ex: 340nm, Em 665nm and 615nm) were read by Envision (2105).

data analysis:

Signal cmpd: Fluorescence signal value of different concentrations of compounds

SignalAve_VC: Average value of negative control fluorescence signal value

Calculate IC ₅₀ and draw compound effect dose curve:

_{IC50 values} were calculated by fitting the percent inhibition values and logarithms of compound concentration to non-linear regression (dose response - variable slope) using Graphpad 5.0.
Y＝Bottom+(Top-Bottom)/(1+10^(( _LogIC50 -X)*HillSlope))

X: logarithmic value of inhibitor concentration; Y: percentage of inhibition rate.

Table 2 provides the in vitro activities ( _IC50 ) of the compounds of the invention on PARP2 capture.

In Table 2, the PARP2 capture in vitro activity values of the compounds are: A refers to IC ₅₀ <10 nM; B refers to 10 nM<IC ₅₀ <100 nM; C refers to 100 nM<IC ₅₀ <1000 nM; D refers to IC ₅₀ >1000 nM.

Table 2 Activity of the compounds of the present invention on PARP2 capture

Results: The compounds of the present invention have low capture activity on PARP2-DNA complex.

Experimental Example 3: Antiproliferation experiment of DLD-1 wild type (WT) and DLD-1BRCA2 (-/-) cells

Experimental materials: test compounds, RPMI1640 medium (Corning, 10-040-CV), fetal bovine serum (Aus GeneX, FBS500-S), penicillin/streptomycin antibiotics (Gibco, 15140-122), CelltiterGlo analysis kit (CTG) (Promega, G7573), DLD-1WT (Punosai, CL-0074) and DLD-1BRCA2(-/-) (Horizon, HD 105-007) cell lines.

The experimental method is as follows:

On the first day, Echo transferred 40 nl of the test compound (10 mM, dissolved in DMSO) into a 384-well plate, seeded DLD-1WT and DLD-1BRCA2(-/-) cells in a white 384-well plate, added 40 ul of cell suspension to each well, containing 600 DLD-1WT or DLD-1BRCA2(-/-) cells, and cultured the cell plate in a 37°C, 5% carbon dioxide incubator for 7 days.

Promega CellTiter-Glo assay was then performed. The cell plate was removed and equilibrated at room temperature for 30 minutes. 20 μL CTG was added to each well and mixed by vortexing. The cells were incubated at room temperature for 30 minutes and luminescence was read using Envision (2105) multi-label analyzer.

data analysis:

The inhibition rate was calculated as follows:
Suppression % = (Signal cmpd - Signal Ave_PC) / (Signal Ave_VC - Signal Ave_PC) × 100

Signal cmpd: Chemiluminescence values of compounds at different concentrations

SignalAve_PC: The average value of the maximum chemiluminescence value of the system

SignalAve_VC: Average value of negative control chemiluminescence value

Calculate IC ₅₀ and draw compound effect dose curve:
Y＝Bottom+(Top-Bottom)/(1+10^(( _LogIC50 -X)*HillSlope))

X: logarithmic value of compound concentration; Y: percentage of inhibition rate.

Table 3 provides the inhibitory activity of the compounds of the present invention on the proliferation of DLD-1WT and DLD-1BRCA2(-/-) cells.

In Table 3, the inhibitory activity values of the compounds on the proliferation of DLD-1WT and DLD-1BRCA2(-/-) cells are as follows: A refers to IC ₅₀ <100 nM; B refers to 100 nM<IC ₅₀ <1000 nM; C refers to 1000 nM<IC ₅₀ <10000 nM; and D refers to IC ₅₀ >10000 nM.

Table 3 Inhibitory activity of the compounds of the present invention on proliferation of DLD-1WT and BRCA2(-/-) cells

Results: The compounds of the present invention have good antiproliferative activity against BRCA2 mutated DLD-1 cells, but poor inhibitory activity against wild-type DLD-1 cells, indicating that the compounds of the present invention have good selectivity against BRCA2 mutated DLD-1 cells.

Test Example 4: Determination of the inhibitory effect of the compounds of the present invention on the proliferation activity of triple-negative breast cancer MDA-MB-436 cells

Experimental purpose: To determine the inhibitory effect of compounds on the proliferation activity of MDA-MB-436 cells.

Experimental materials: MDA-MB-436 cells (Wuhan Prosai Biotechnology Co., Ltd., CL-0383A), Leibovitz's L-15 cell culture medium (Wuhan Prosai Biotechnology Co., Ltd., CM-0383A), PBS (Gibco, 8121763), CellTiter Glo assay kit (Promega, G7572), 384-well plate (Thermo, 164610), microplate reader (Biotek, Cytation 3).

Experimental method: MDA-MB-436 cells were cultured in a dedicated Leibovitz's L-15 medium. After the cells were revived, they were passaged 1-3 times, and the cells were collected and centrifuged at 1000rpm for 5 minutes to prepare a cell suspension. The cells were counted and the cell density was adjusted to 1.33×10 ⁴ /mL. The cell suspension was added to a 384-well plate, 45μL per well, i.e. 600 viable cells/well. Compound solutions of different concentrations were prepared using DMSO and culture medium, and solvent control wells and blank control wells were set up at the same time. 5μL of compound solution was added to 45μL of cells in a 384-well plate, 2 replicates, and the final DMSO concentration in the 50μL reaction system was 0.1%. The final concentrations of the compounds were: 10000nM, 2500nM, 625nM, 156.25nM, 39.06nM, 9.77nM, 2.44nM, 0.61nM, 0.15nM, 0nM. The cell culture plate was placed in a 37°C, 5% CO ₂ incubator for 7 days, then taken out and equilibrated at room temperature for 30 minutes. 20 μL CTG was added to each well, vortexed and mixed, and the luminescence value was read with a microplate reader after incubation at room temperature for 10 minutes.

The cell proliferation activity inhibition rate was calculated as follows:
Suppression % = 100 - (Signalcmpd - SignalAve_PC) / (SignalAve_VC - SignalAve_PC) × 100

Among them, Signalcmpd: the chemiluminescence value of each concentration of the compound, SignalAve_VC: the average chemiluminescence value of the solvent control, SignalAve_PC: the average chemiluminescence value of the blank control.

The concentration and inhibition rate were fitted with nonlinear regression curve using Graphpad Prism software to obtain the IC ₅₀ value.
Y＝Bottom+(Top-Bottom)/(1+10^(( _LogIC50 -X)*HillSlope))

Where, X: logarithmic value of compound concentration; Y: percentage of inhibition rate

Table 4 provides the inhibitory activity of the compounds of the present invention on the proliferation of MDA-MB-436 cells.

In Table 4, the inhibitory activity values of the compounds on MDA-MB-436 cell proliferation are as follows: A refers to IC ₅₀ <100 nM; B refers to 100 nM<IC ₅₀ <1000 nM; C refers to 1000 nM<IC ₅₀ <10000 nM; and D refers to IC ₅₀ >10000 nM.

Table 4 IC ₅₀ of the compounds of the present invention on the proliferation activity of MDA-MB-436 cells

Results: The compounds of the present invention have good antiproliferative activity against MDA-MB-436 cells.

Test Example 5: Pharmacokinetic evaluation of the compounds of the present invention in Wistar rats

Male 6-8 week old Wistar rats (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) were orally administered with the compound of the present invention, the compound preparation solvent contained 5% DMSO and 20% hydroxypropyl-β-cyclodextrin, and the administration volume was 10 mL/kg. Blood was collected from the canthal venous plexus before administration and at 0.25, 0.50, 1.00, 2.00, 4.00, 6.00, 8.00 and 24.00 hours after administration, respectively. The blood was anticoagulated with sodium heparin and incubated at 4°C, 3500 rpm. Centrifuge for 10 minutes, obtain plasma and store at -20°C until testing. Take 20 μL of the plasma sample to be tested and add it to a 96-well plate, add 200 μL of acetonitrile working solution containing 5 ng/mL verapamil hydrochloride (internal standard) (100223-200102, China Pharmaceutical and Biological Products Testing Institute), vortex for 5 minutes to mix thoroughly, and centrifuge at 4000rpm for 10 minutes. Take 50 μL of the supernatant, add 150 μL of acetonitrile to mix, centrifuge at 4000rpm for 10min, take the supernatant, place it in a 96-well sample tray, and analyze it by LC/MS (Waters UPLC I Class/LC 30AD, Waters) to obtain the blood drug concentration. MassLynx V4.2 SCN977 data processing software is used to analyze the pharmacokinetic parameters. The main pharmacokinetic parameters of the compounds of the present invention are shown in the table below.

Table 5 Pharmacokinetic parameters of the compounds of the present invention after single oral administration to male Wistar rats

Results: The compounds of the present invention have good pharmacokinetic properties in rats.

Claims

A compound represented by general formula (I) or its meso form, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

in:

X 1 , X 2 , X 3 , and X 4 are each independently selected from N or C(R 3 );

Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from N or C(R 4 );

Ring A is selected from heterocyclic groups, which are optionally substituted by R 2 ;

R1 is selected from alkyl or haloalkyl;

R2 is selected from hydrogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, deuterated alkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano;

Each R 3 is independently selected from hydrogen, alkyl, haloalkyl, halogen;

Each R 4 is independently selected from hydrogen, alkyl, halogen, amino, nitro, cyano, hydroxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)NR a R b , -C(O)R c , -S(O)NR a R b , -S(O) 2 NR a R b , -S(O)R c , -S(O) 2 R c , the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, thiol, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

L is selected from a bond , -C( R5R6 )-, N( R7 )-, -O-, -S-, -C(O)-, -S(O)-, -S(O) 2- , -C(O)NH-, -S(O)NH-, -S(O) 2 NH-, cycloalkylene, heterocyclylene, arylene, heteroarylene, wherein the cycloalkylene, heterocyclylene, arylene, heteroarylene are optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

R 5 and R 6 are each independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, amino, mercapto, nitro, Hydroxy, cyano, oxo, thio, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, thiol, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

R is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

Ra and Rb are each independently selected from hydrogen, halogen, hydroxyl, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or,

Ra and Rb together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

R c is selected from hydrogen, halogen, hydroxyl, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The compound represented by the general formula (I) according to claim 1, or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a 4-10 membered heterocyclic group, preferably a 4-8 membered monocyclic heterocyclic group, a 6-10 membered bridged heterocyclic group, a 7-11 membered spiro heterocyclic group, or an 8-10 membered fused heterocyclic group; ring A is optionally substituted by R 2 ; R 2 is as defined in claim 1.
The compound represented by the general formula (I) according to claim 1 or 2, or its meso form, racemate, enantiomer, diastereoisomer, or mixture form, or pharmaceutically acceptable salt thereof, which is represented by the general formula (II) The compound or its meso form, racemate, enantiomer, diastereomer, or mixture form, or a pharmaceutically acceptable salt thereof,

in,

R2 is selected from hydrogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, deuterated alkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano;

m and n are integers from 0 to 3 respectively;

X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , R 1 , and L are as defined in claim 1.
A compound represented by the general 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 represented by the general formula (IIA) or (IIB), or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

in,

p is an integer from 0 to 2;

R 1 , R 2 , R 3 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , L, m and n are as defined in claim 2.
The compound represented by the general formula (I) according to any one of claims 1 to 4, or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are independently selected from N or C(R 4 );

R 1 is selected from C 1-6 alkyl or C 1-6 haloalkyl, preferably C 1-6 alkyl or C 1-6 fluoroalkyl, more preferably C 1-4 alkyl;

R 2 is selected from hydrogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, deuterated alkoxy, halogen, amino, mercapto , nitro, hydroxyl, cyano; preferably hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, hydroxyl, cyano;

Each R 3 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, halogen;

Each R4 is independently selected from hydrogen, alkyl, halogen, amino, nitro, cyano, hydroxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl , heteroaryl , -C(O) NRaRb , -C (O) Rc , -S ( O)NRaRb, -S(O)2NRaRb, -S(O) Rc , -S(O) 2Rc ; preferably hydrogen, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl , -C(O) NRaRb , -S (O) NRaRb , -S(O) 2NRaRb , C3-8 cycloalkyl , 4 to 10 membered heterocyclyl, C 6-10 membered aryl, 5 to 10 membered heteroaryl; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl may be further selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, thiol, substituted or unsubstituted alkenyl, substituted The alkyl radical is substituted with one or more substituents selected from deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylsulfonyl, alkylamino, halogen, amino, nitro, cyano, hydroxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

L is selected from a bond, -C( R5R6 )- , -N( R7 )-, -O-, -S-, -C(O)-, -S(O)-, -S(O)2-, -C(O)NH-, -S(O)NH-, -S(O) 2NH- , cycloalkylene, heterocyclylene, arylene, heteroarylene, preferably a bond, -C(R5R6)-, -N( R7 )-, -O-, -S-, -C(O)-, -S(O)-, -S(O)2-, -C(O)NH-, -S (O)NH- , -S(O)2NH-, cycloalkylene, heterocyclylene , arylene, heteroarylene. wherein the cycloalkylene, heterocyclylene, arylene, heteroarylene is optionally further selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, thiol, substituted or unsubstituted The alkyl radical is substituted with one or more substituents selected from alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When substituted, the substituents are selected from one or more of deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylsulfonyl, alkylamino, halogen, amino, nitro, cyano, hydroxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R 5 and R 6 are each independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, oxo, thio, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, preferably hydrogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuterated alkoxy , halogen, C 3-8 cycloalkyl, 4 to 10 membered heterocyclyl, C 6-10 aryl , 5 to 10 membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from deuterium, substituted with one or more of substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituent is selected from one or more of deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylsulfonyl, alkylamino, halogen, amino, nitro, cyano, hydroxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R7 is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, preferably hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, 4 to 10 membered heterocyclyl, C 6-10 membered aryl, 5 to 10 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, thiol, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituents are selected from one or more of deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylsulfonyl, alkylamino, halogen, amino, nitro, cyano, hydroxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

Ra and Rb are each independently selected from hydrogen, halogen, hydroxyl, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or,

Ra and Rb together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

R c is selected from hydrogen, halogen, hydroxyl, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

p is an integer from 0 to 2;

m and n are integers from 0 to 3 respectively.
A compound represented by the general formula (I) according to any one of claims 1 to 5, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IIIA) or (IIIB) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

in,

p is an integer from 0 to 2;

Y 4 and Y 5 are each independently selected from N or CH;

R4a and R4b are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, -C(O) NRaRb , -S (O) NRaRb , -S(O)2NRaRb, C3-8 cycloalkyl, 4 to 10 membered heterocyclyl, C6-10 aryl , 5 to 10 membered heteroaryl; preferably halogen, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl , -C(O) NRaRb , -S(O) NRaRb , -S(O) 2NRaRb , C3-8 cycloalkyl, 4 to 10 membered heterocyclyl, C6-10 aryl, 5 to 10 membered heteroaryl; preferably halogen, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, -C(O) NRaRb , -S ( O)NRaRb , -S(O)2NRaRb, C 3-8 cycloalkyl; the alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally further substituted by one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, thiol, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituents are selected from one or more of deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylsulfonyl, alkylamino, halogen, amino, nitro, cyano, hydroxyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl;

R 1 , R 2 , R 3 , Ra , R b , L, m and n are as defined in claim 2.
The compound represented by the general formula (I) according to any one of claims 1 to 6, or its meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R 4a is selected from -C(O)NR a R b , -S(O)NR a R b , -S(O) 2 NR a R b , preferably -C(O)NR a R b ; Ra and R b are as defined in claim 1 .
A compound represented by the general formula (I) according to any one of claims 1 to 6, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IVA) or (IVB) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

in,

p is an integer from 0 to 2;

Y 4 and Y 5 are each independently selected from N or CH;

R 4b is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl , -C(O)NR a R b , -S(O)NR a R b , -S(O) 2 NR a R b , C 3-8 cycloalkyl, 4 to 10 membered heterocyclyl, C 6-10 aryl, 5 to 10 membered heteroaryl; preferably halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, -C(O)NR a R b , -S(O)NR a R b , -S(O) 2 NR a R b , C 3-8 cycloalkyl, 4 to 10 membered heterocyclyl, C 6-10 aryl, 5 to 10 membered heteroaryl; preferably halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, -C(O)NR a R b , -S(O)NR a R b , -S(O) 2 NR a R b , C 3-8 cycloalkyl; the alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally further substituted by one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, thiol, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituents are selected from one or more of deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylsulfonyl, alkylamino, halogen, amino, nitro, cyano, hydroxyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl;

Ra and Rb are each independently selected from hydrogen, halogen, hydroxy, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, Heterocyclic group, aryl group, heteroaryl group, the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group are optionally substituted by one or more groups selected from halogen, amino group, nitro group, cyano group, hydroxyl group, thiol group, carboxyl group, ester group, oxo group, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group; or,

Ra and Rb together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

R 1 , R 2 , R 3 , L, m and n are as defined in claim 2.
The 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, wherein:

L is selected from a bond , -C( R5R6 )-, -N( R7 )-, -O-, -S-, a C3-8 cycloalkylene group, a 4- to 10-membered heterocyclylene group, a C6-10 arylene group, and a 5- to 10-membered heteroarylene group, preferably a bond, -C( R5R6 )-, -N( R7 )-, -O-, 4 to 10 membered heterocyclylene, wherein the 4 to 10 membered heterocyclylene is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituent is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , halogen, cyano, hydroxyl;

R 5 and R 6 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuterated alkoxy, halogen, C 3-8 cycloalkyl, 4 to 10 membered heterocyclyl, C 6-10 aryl, 5 to 10 membered heteroaryl , preferably hydrogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl , halogen , C 3-8 cycloalkyl, 4 to 10 membered heterocyclyl, wherein the C 3-8 cycloalkyl, 4- to 10-membered heterocyclyl are optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, and when substituted, the substituents are selected from deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxyalkyl, alkylsulfonyl, halogen, cyano, hydroxyl;

R is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 4 to 10 membered heterocyclyl, preferably hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, wherein the C 3-8 cycloalkyl is optionally further selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituent is selected from deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxyalkyl , alkylsulfonyl, alkylamino, halogen, amino, nitro, cyano, hydroxyl, alkenyl, alkynyl, C 3-8 cycloalkyl, 4 to 10 membered heterocyclyl, C 6-10 aryl, 5 to 10 membered heteroaryl.
A compound represented by the general formula (I) according to any one of claims 1 to 9, or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (VA) or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein R 1 , Y 4 , Y 5 , R 2 , R 3 , R 4b , L, m, n, and p are as defined in claim 7;

R b is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 4 to 10 membered heterocyclyl, C 6-10 aryl, 5 to 10 membered heteroaryl, wherein the C 3-8 cycloalkyl, 4 to 10 membered heterocyclyl, C The 6-10 membered aryl, 5 to 10 membered heteroaryl is further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituents are selected from deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen; preferably R b is selected from C 1-6 alkyl and C 3-6 cycloalkyl.
A compound represented by the general formula (I) according to any one of claims 1 to 10, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y4 is N and Y5 is CH; or Y4 is CH and Y5 is N.
A compound represented by the general formula (I) according to any one of claims 1 to 11, or its meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in:

L is selected from a bond, -C( R5R6 )-, -N( R7 )-, -O-, a 4 to 10 membered heterocyclylene, wherein the 4 to 10 membered heterocyclylene is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituents are selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, halogen, further preferably C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, halogen, further preferably C1-6 alkyl, C1-6 1-6 alkoxy, halogen;

R 5 and R 6 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, halogen, C 3-8 cycloalkyl, and 4 to 10 membered heterocyclic groups, and are further preferably selected from hydrogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, halogen, and C 3-8 cycloalkyl, wherein the C 3-8 cycloalkyl is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, and when substituted, the substituent is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , halogen;

R is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, further preferably hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, wherein the C 3-8 cycloalkyl is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituent is selected from deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 1-6 haloalkoxy, halogen;

R is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 4 to 10 membered heterocyclyl, C 6-10 aryl, 5 to 10 membered heteroaryl, preferably C 1-6 alkyl, C 3-8 cycloalkyl, 4 to 10 membered heterocyclyl, C 6-10 aryl, 5 to 10 membered heteroaryl, wherein the C 3-8 cycloalkyl, 4 to 10 membered heterocyclyl, C 6-10 aryl, 5 to 10 membered heteroaryl is selected from The 6-10 membered aryl and the 5 to 10 membered heteroaryl are further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituents are selected from deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and halogen.
The compound represented by the general formula (I) according to any one of claims 1 to 12, or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

L is selected from a bond, -C( R5R6 )-, -N( R7 )-, -O-, a 4- to 10-membered heterocyclyl, preferably a bond, -N( R7 )-, -O-, a 4- to 10-membered heterocyclyl, wherein the 4- to 10-membered heterocyclyl is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituents are selected from C1-6 alkyl, C1-6 alkoxy, halogen;

R5 and R6 are each independently selected from hydrogen, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl , halogen, C3-8 cycloalkyl, wherein the C3-8 cycloalkyl is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, thiol, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituent is selected from C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-8 1-6 haloalkoxy, halogen;

R is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, wherein the C 3-8 cycloalkyl is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituent is selected from deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen;

R is selected from C 1-6 alkyl, C 3-8 cycloalkyl, 4 to 10 membered heterocyclyl, C 6-10 aryl, 5 to 10 membered heteroaryl, preferably C 1-6 alkyl, C 3-8 cycloalkyl, 4 to 10 membered heterocyclyl, wherein the C 3-8 cycloalkyl, 4 to 10 membered heterocyclyl, C The 6-10 membered aryl, 5- to 10-membered heteroaryl is further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituents are selected from deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, preferably selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogen.
A compound represented by the general formula (I) according to any one of claims 1 to 13, or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

L is selected from a bond, -N(R 7 )-, O, a 4 to 10 membered heterocyclyl, wherein the 4 to 10 membered heterocyclyl is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituents are selected from C 1-6 alkyl, C 1-6 alkoxy, halogen;

R is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, preferably hydrogen, C 1-6 alkyl, wherein the C 3-8 cycloalkyl is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituent is selected from deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen;

R is selected from C1-6 alkyl, C3-8 cycloalkyl, 4 to 10 membered heterocyclyl, wherein the C3-8 cycloalkyl, 4 to 10 membered heterocyclyl is further substituted by one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituent is selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogen.
The compound represented by the general formula (I) according to any one of claims 1 to 14, or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

L is selected from a bond, -N(R 7 )-, -O-, a 4- to 10-membered heterocyclic group, wherein the 4- to 10-membered heterocyclic group is optionally further selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituent is selected from C 1-6 alkyl, C 1-6 alkoxy, halogen;

R7 is selected from hydrogen, C1-6 alkyl.
A compound represented by the general formula (I) according to any one of claims 1 to 15, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is -O-.
A compound represented by the general formula (I) according to any one of claims 1 to 16, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R2 is selected from hydrogen, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl , C1-6 alkoxy, C1-6 haloalkoxy, C1-6 deuterated alkoxy, halogen, amino, thiol, hydroxyl, cyano.
A compound represented by the general formula (I) according to any one of claims 1 to 17, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R 3 is selected from hydrogen or halogen, and p is 0 or 1.
The compound represented by the general formula (I) according to any one of claims 6 to 18, or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R 4b is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl , C 3-8 cycloalkyl, 4 to 10 membered heterocyclyl, C 6-10 aryl, 5 to 10 membered heteroaryl; preferably selected from halogen, C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl, 4 to 10 membered heterocyclyl; the alkyl, cycloalkyl, heterocyclyl is optionally further substituted by one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted aminoacyl, substituted or unsubstituted alkylacyl, oxo, halogen, nitro, cyano, hydroxyl, thiol, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; when substituted, the substituent is selected from one or more of deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylsulfonyl, alkylamino, halogen, amino, nitro, cyano, hydroxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably, R 4b is selected from hydrogen, halogen, and C 1-6 alkyl.
A compound represented by the general formula (I) according to any one of claims 1 to 18, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: m is 1 or 2, n is 1 or 2, preferably m is 1, n is 1 or 2.
A compound represented by the general formula (I) according to any one of claims 1 to 20, or its meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
A method for preparing a compound represented by general formula (IVA) or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

Under alkaline conditions, compound IVe and compound IVf undergo a substitution reaction to obtain a compound represented by general formula (IVA) or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

Wherein, Y 4 , Y 5 , R 1 , R 2 , R 3 , R 4b , Ra , R b , L, m, n, and p are as defined in claim 8 righteous.
A pharmaceutical composition comprising a compound represented by the general formula (I) according to any one of claims 1 to 21 or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
Use of a compound represented by general formula (I) according to any one of claims 1 to 21 or its mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23 in the preparation of a poly (ADP-ribose) polymerase 1 (PARP1) inhibitor.
Use of the compound represented by general formula (I) according to any one of claims 1 to 21 or its mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 23 in the preparation of a medicament for preventing and/or treating a disease associated with poly (ADP-ribose) polymerase 1 activity, wherein the disease is preferably a tumor disease, such as ovarian cancer, breast cancer, and prostate cancer.