TW202415658A - Nitrogen-containing heterocyclic compounds and their medical use - Google Patents

Abstract

The present invention relates to nitrogen-containing heterocyclic compounds and their medical use. Specifically, the present invention relates to a nitrogen-containing heterocyclic compound represented by general formula (I), their preparation method, pharmaceutical compositions containing them, and their use as polyADP ribose polymerase 1 (PARP1) inhibitors for treating diseases related to PARP1 activity. The definitions of each substituent in general formula (I) are the same as those in the specification.

Description

Nitrogen-containing heterocyclic compounds and their medical uses

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), their preparation methods, pharmaceutical compositions containing them, and their use as poly (ADP-ribose) polymerase 1 inhibitors for treating diseases related to PARP1 activity.

Poly (ADP-ribose) polymerases (PARPs) play an important role in processes such as DNA replication, recombination, chromatin remodeling, and DNA damage repair. The family includes 18 members with ADP-ribose transferase 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 and 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 the choice of substrates. PARP1 and PARP2 can repair DNA single-strand breaks (SSBs), and PARP1 can also repair DNA double-strand breaks (DSBs) and replication fork damage. PARP1, as a sensor of DNA breaks, is activated after DNA damage and recognizes and binds to the DNA break site through the zinc finger domain, reducing recombination and protecting the 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 cause the receptor protein and PARP1 itself to undergo "PARylation", forming a PARP-ADP-ribose branched chain, which can prevent nearby DNA molecules from recombining with damaged DNA, and on the other hand, it can attract DNA repair proteins to bind and reduce the affinity of PARP1 with DNA, causing PARP1 to dissociate from the DNA break, and then the DNA repair proteins bind to the DNA gap to repair the damaged site. The "PARylation" 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 there the formation of PAR chains, but also the degradation of PAR chains catalyzed by poly(ADP-ribose)glycohydrolase (PARG) and type 3 ADP-ribosylhydrolase (ARH3). Four enzymes, PARP1, PARP2, PARP5A and PARP5B, can catalyze the synthesis of PAR chains. Most 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 important steps in the tumor cell response to DNA damage caused by chemotherapy 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 tumor cells with harmful BRCA1 or BRCA2 mutations are sensitive to PARP inhibitors. Tumors generated by mutation carriers usually lose the wild-type allele, which leads to tumor-specific homologous recombination repair (HRR) dysfunction during double-strand breaks, 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 replication forks encountering unrepaired breaks can form double-strand 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 inhibitors are mainly used for cancer patients with BRCA mutations. However, 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-cell 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 resection, 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 deficient in XRCC1 and Polβ are highly sensitive to PARPis. The PARP-DNA complex is a barrier to replication. In response to replication damage and stress, ataxia telangiectasia and rad3-related protein kinase (ATR) and cycle checkpoint kinase 1 (CHK1) activate the S phase checkpoint, slowing down replication forks and preventing replication initiation, maintaining genome stability. Inhibition of ATR or CHK1 leads to loss of the S phase checkpoint, replication initiation, and double-bond breaks. Combination use with PARP inhibitors shows a synergistic effect. FANCI-FANCD2 can stabilize the RAD51-DNA complex, PALB2 binds to BRCA2 and promotes BRCA2 nuclear stability and accumulation, 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, RAD51), and show synergistic effects with PARPis in cells with normal BRCA.

PARP1/2 inhibitors currently on the market or in clinical trials have severe hematological toxicity as single therapeutic drugs, which limits chronic treatment plans or combination treatments. Therefore, it is necessary to develop compounds with high selectivity for PARP1 and less toxicity to meet clinical needs.

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 related to PARP1 activity.

Therefore, the purpose of the present invention is to provide a compound represented by the general formula (I) or its racemate, racemate, enantiomer, diastereomer, 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 );

Ring A is selected from bicyclic aryl, bicyclic heteroaryl, bicyclic heterocyclic group, and the bicyclic aryl, bicyclic heteroaryl, bicyclic heterocyclic group is optionally further substituted by one or more ^R2 ;

^R1 is selected from alkyl or halogen alkyl;

Each ^R2 is independently selected from hydrogen, halogen, amine, nitro, cyano, hydroxyl, oxirane, pendoxy, thio, alkyl ^, alkoxy, -C(O) ^Rc , -S(O) ^Rc , -S(O) _2Rc , -C(O) ^{NRaRb ,} -S(O)NRaRb ^, -S(O) ^{2NRaRb ,} -OC(O) ^Rc , _-N ( ^Ra )C(O) ^Rc , ^-N ( ^Ra )S(O) ^Rc , -N ^{( Ra} )S(O) _2Rc , cycloalkyl, heterocyclic group, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl is optionally further substituted by one or more groups selected from deuterium, halogen, amine, nitro, cyano, pendoxy, hydroxyl, alkoxy, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl;

or two adjacent ^R2 together with the atoms to which they are attached form a cycloalkyl, heterocyclic, aryl or heteroaryl group; the cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally further substituted by one or more groups selected from deuterium, halogen, amine, nitro, cyano, pendoxy, hydroxyl, alkyl, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

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

^Ra and ^Rb are each independently selected from hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl is optionally substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, carboxyl, ester, pendoxy, alkyl, alkoxy, halogenalkyl, halogenalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, 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 by one or more groups selected from halogen, amine, nitro, cyano, oxo, hydroxyl, alkyl, carboxyl, ester, alkyl, alkoxy, halogenalkyl, halogenalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

R ^c is selected from hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl group is optionally substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, carboxyl, ester, pendoxy, alkyl, alkoxy, halogenalkyl, halogenalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl.

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

Where m is an integer from 0 to 2;

Ring A, R ¹ and R ³ 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) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, wherein,

Ring A is selected from C ₈ -C ₁₀ bicyclic aryl, 8 to 10-membered bicyclic heteroaryl or 8 to 10-membered bicyclic heterocyclic group; preferably 8 to 10-membered bicyclic heteroaryl; the C ₈ -C ₁₀ bicyclic aryl, 8 to 10-membered bicyclic heteroaryl and 8 to 10-membered bicyclic heterocyclic group are optionally further substituted by one or more 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 the general formula (II) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, is the compound represented by the general formula (III) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt,

Wherein, Y is selected from N or C;

Ring _A1 is selected from 5- to 6-membered heterocyclic groups or 5- to 6-membered heteroaryl groups;

Each R ^2a is independently selected from hydrogen, halogen, amine, nitro, cyano, hydroxyl, oxirane, sulfhydryl, alkyl, alkoxy, -C(O)R ^c , -S(O)R ^c , -S(O) ₂ R ^c , -C(O)NR ^a R ^b , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OC(O)R ^c , -N(R ^a )C(O)R ^c , -N(R ^a )S(O)R ^c , -N(R ^a )S(O) ₂ R ^c , cycloalkyl, heterocyclic group, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl is optionally further substituted by one or more groups selected from deuterium, halogen, amine, nitro, cyano, pendoxy, hydroxyl, alkoxy, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl;

or two adjacent R ^2a together with the atoms to which they are attached form a cycloalkyl, heterocyclic, aryl or heteroaryl group; the cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally further substituted with one or more groups selected from deuterium, halogen, amine, nitro, cyano, oxo, hydroxyl, alkynyl, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

Each R ^2b is independently selected from hydrogen, halogen, amine, nitro, cyano, hydroxyl, oxirane, sulfhydryl, alkyl, alkoxy, -C(O)R ^c , -S(O)R ^c , -S(O) ₂ R ^c , -C(O)NR ^a R ^b , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OC(O)R ^c , -N(R ^a )C(O)R ^c , -N(R ^a )S(O)R ^c , -N(R ^a )S(O) ₂ R ^c , cycloalkyl, heterocyclic group, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl is optionally further substituted by one or more groups selected from deuterium, halogen, amine, nitro, cyano, pendoxy, hydroxyl, alkoxy, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl;

^Ra and ^Rb are each independently selected from hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl is optionally substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, carboxyl, ester, pendoxy, alkyl, alkoxy, halogenalkyl, halogenalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, 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 by one or more groups selected from halogen, amine, nitro, cyano, oxo, hydroxyl, alkyl, carboxyl, ester, alkyl, alkoxy, halogenalkyl, halogenalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

R ^c is selected from hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl is optionally substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, carboxyl, ester, pendoxy, alkyl, alkoxy, halogenalkyl, halogenalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl.

m is an integer from 0 to 2;

p is an integer from 0 to 4;

q is an integer from 0 to 2;

R ¹ and R ³ are as defined in the general formula (I).

In another embodiment of the present invention, the compound represented by the general formula (III) or its racemate, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (III) or its racemate, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein each R ^2a is independently selected from halogen, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl; p is an integer from 0 to 4.

In another embodiment of the present invention, the compound represented by general formula (III) or its racemate, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (III) or its racemate, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein each R ^2b is independently selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl; q is an integer from 0 to 2.

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

、

、

、

、

、 Ring A selected from

,

,

,

,

,

、

、

；較佳為

、

、

、

、

、

、

；更佳

,

,

; preferably

,

,

,

,

,

,

; better

；進一步佳

、

、

、

、

; Further improvement

,

,

,

,

Ring A is optionally further substituted by one or more R ² ; R ² is as defined in the general formula (I);

Preferably, R ² is selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, phenyl, -C(O)NR ^a R ^b ; wherein ^Ra and R ^b are each independently selected from hydrogen and C ₁ -C ₆ alkyl.

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

、

、

、

、

、

、

；進一步佳

、

、 Ring A selected from

,

,

,

,

,

,

; Further improvement

,

,

in,

R ²¹ , R ²² , and R ²³ are each independently selected from hydrogen and halogen;

R ²⁴ and R ²⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl;

R ²⁶ , R ²⁷ , and R ²⁸ are each independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl, and C ₁ -C ₆ halogenalkyl;

^R29 is selected from hydrogen, _C1-6 alkyl, ^-C (O) ^NRaRb ; wherein ^Ra and ^Rb are each independently selected from hydrogen and _C1 - _C6 alkyl;

R ²¹⁰ is selected from hydrogen and C ₁ -C ₆ alkyl, preferably hydrogen;

R ²¹¹ is selected from hydrogen and C ₁ -C ₆ alkyl, preferably C ₁ -C ₆ alkyl;

^R212 is selected from hydrogen and _C1 - _C6 alkyl, preferably _C1 - _C6 alkyl.

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

； Ring A selected from

;

in,

R ²¹ , R ²² , and R ²³ are each independently selected from hydrogen and halogen;

R ²⁴ and R ²⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl.

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

； Ring A selected from

;

in,

R ²⁶ , R ²⁷ , and R ²⁸ are each independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl, and C ₁ -C ₆ halogenalkyl;

^R29 is selected from hydrogen, _C1-6 alkyl, ^-C (O) ^NRaRb ; wherein ^Ra and ^Rb are each independently selected from hydrogen and _C1 - _C6 alkyl;

^R210 is selected from hydrogen and _C1 - _C6 alkyl, preferably hydrogen.

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

、

。 Ring A selected from

,

.

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

。 Ring A selected from

.

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

； Ring A selected from

;

Wherein, R ²¹¹ is selected from hydrogen and C ₁ -C ₆ alkyl, preferably C ₁ -C ₆ alkyl.

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

；其中，R²¹²選自氫和C₁-C₆烷基，較佳C₁-C₆烷基。 Ring A selected from

; wherein R ²¹² is selected from hydrogen and C ₁ -C ₆ alkyl, preferably C ₁ -C ₆ alkyl.

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

Wherein, ^R1 is selected from _C1-6 alkyl or _C1-6 halogenalkyl.

In another embodiment of the present invention, the compound represented by general formula (I), general formula (II) or general formula (III) or its racemate, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 halogenalkyl.

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

或其內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式，或其可藥用鹽。

or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt.

The present invention further provides a method for preparing the compound represented by the general formula (II) of the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, which comprises the following steps:

In the presence of a base, the compound of general formula IId undergoes a substitution reaction with the compound of general formula IIe to obtain the compound represented by general formula (II) or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein Ring A, R ¹ , R ³ , and m are as defined in the general formula (II).

The present invention further provides a pharmaceutical composition comprising the compound according to the present invention or its racemate, 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 racemate, 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 mesomorph, racemate, enantiomer, diastereoisomer, 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, 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 racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing 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 its pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, which is used to prevent and/or treat diseases related to 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 its pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, which is used as a drug for preventing and/or treating diseases related to the activity of poly ADP-ribose polymerase 1, 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 the compound according to the present invention or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

The present invention further relates to a method for preventing and/or treating diseases related to poly (ADP-ribose) polymerase 1 activity, which comprises administering to a patient in need thereof a preventive or therapeutically effective amount of the compound according to the present invention or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing 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 can be in a form suitable for oral administration, such as tablets, troches, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions can be prepared according to any known method for preparing pharmaceutical compositions in the art, and such compositions may contain one or more ingredients selected from the following: sweeteners, flavoring agents, coloring agents and preservatives to provide pleasing and palatable pharmaceutical preparations. Tablets contain the active ingredient and a non-toxic pharmaceutically acceptable excipient suitable for preparing tablets for mixing. 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, cross-linked sodium carboxymethyl cellulose, corn starch or alginic acid; binders such as starch, gelatin, polyvinyl pyrrolidone or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release over a longer period of time. For example, water-soluble taste-masking substances such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time-extending substances such as ethylcellulose, cellulose acetate butyrate may be used.

Oral preparations may also be provided in hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in soft gelatin capsules in which 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 a suitable excipient for mixing to prepare an aqueous suspension. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersing agents or wetting agents, which may be naturally occurring phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyethylene oxide sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene oxide dehydrated sorbitan monooleate. The aqueous suspension may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose, saccharin, or aspartame.

Oil suspensions may 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 wax. The oil suspension may contain a thickener such as beeswax, hard wax or cetyl alcohol. Sweeteners and flavoring agents as described above may be added to provide a palatable preparation. These compositions may be preserved by the addition of an antioxidant such as butylated hydroxyanisole or alpha-tocopherol.

The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may 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 may be naturally occurring phospholipids, such as soy 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 may also contain sweeteners, flavoring agents, preservatives and antioxidants. Syrups and elixirs may be formulated with sweeteners such as glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain demulcents, preservatives, coloring agents and antioxidants.

The pharmaceutical composition of the present invention may be in the form of a sterile injectable aqueous solution. Acceptable vehicles 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 the 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 injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compound of the present invention. To maintain this constant concentration, a continuous intravenous drug delivery device may be used.

The pharmaceutical composition of the present invention may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension may be prepared according to known techniques using appropriate dispersants or wetting agents and suspending agents as described above. Sterile injection preparations may also be sterile injection solutions or suspensions prepared in non-toxic parenterally acceptable diluents or solvents, such as solutions prepared in 1,3-butanediol. In addition, sterile fixed oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils including synthetic mono- or diglycerides may be used. In addition, fatty acids such as oleic acid may 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 melt there to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.

It is well known to those skilled in the art that the dosage of a drug depends on many 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 time of administration, the method of administration, the rate of excretion, the combination of drugs, etc. In addition, the best treatment method such as the mode of treatment, the daily dosage of the general formula compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment plans.

The present invention may contain the compound and its pharmaceutically acceptable salt, hydrate or solvate 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 can be used in combination with other active ingredients, as long as they do not produce other adverse effects, such as allergic reactions. The compound of the present invention can be used as the only active ingredient, or it can be used in combination with other drugs for treating diseases related to tyrosine kinase activity. Combination therapy is achieved by administering each treatment component simultaneously, separately or successively.

Terminology

Unless otherwise stated, the terms used in the specification and application 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, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-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, alkyl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, pendoxy, 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, alkyl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, 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, alkyl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, 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, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocyclic, fused-ring, and bridged-ring cycloalkyls.

The term "spirocycloalkyl" refers to a polycyclic group in which a carbon atom (called a spiro atom) is shared between single rings of 5 to 20 members, 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, it is 7 to 10 members. According to the number of spiro atoms shared between rings, spirocycloalkyl is divided into monospirocycloalkyl, dispirocycloalkyl or polyspirocycloalkyl, preferably monospirocycloalkyl and dispirocycloalkyl. More preferably, it is 4-member/4-member, 4-member/5-member, 4-member/6-member, 5-member/5-member or 5-member/6-member monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

The term "fused cycloalkyl" refers to a full-carbon polycyclic group with 5 to 20 members, each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, one or more of 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, it is 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, and more preferably 5-member/5-member or 5-member/6-member bicyclic alkyl. Non-limiting examples of fused cycloalkyl include:

The term "bridged cycloalkyl" refers to a 5-20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6-14 members, and more preferably 7-10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, and more preferably 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 connected to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl may be substituted or unsubstituted as desired, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, alkyl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, pendoxy, carboxyl or carboxylate.

The term "heterocyclic group" 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; most preferably, it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; and most preferably, it contains 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1,2,5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged heterocyclic groups.

The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between monocyclic rings of 5 to 20 members, 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. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between rings, the spiroheterocyclic group is divided into a single spiroheterocyclic group, a double spiroheterocyclic group or a multi-spiroheterocyclic group, preferably a single spiroheterocyclic group and a double spiroheterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclic group. Non-limiting examples of spiroheterocyclic groups include:

The term "fused heterocyclic group" refers to a polycyclic heterocyclic group with 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, 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 has 6 to 14 members, and more preferably, it has 8 to 10 members. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

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 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, and more preferably, it is 8 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 heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic ring, non-limiting examples of which include:

、

、

、

和

等。

,

,

,

and

wait.

The heterocyclic group may be substituted or unsubstituted as required. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, alkyl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, pendoxy, 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 carbon atom pairs) group with a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring can be fused to a heteroaryl, heterocyclic or cycloalkyl ring, i.e., a fused ring aryl, in which 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. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, alkyl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, 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 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, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, i.e. a fused heteroaryl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

The heteroaryl group may be substituted or unsubstituted as required. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, alkyl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be substituted or unsubstituted as desired, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, oxalyl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

”表示未指定構型，即如果化學結構中存在手性異構體，鍵“

”可以為“

”或“

”，或者同時包含“

”和“

”兩種構型。 In the chemical structure of the compound disclosed in the present invention, 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 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 groups, wherein alkyl is as defined above.

The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium groups, 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 the -OH group.

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

The term "amine" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "oxo" refers to =O.

The term "sulfhydryl" refers to =S.

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

The term "巰基" 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 radical, wherein R is alkyl, cycloalkyl, heterocyclo, aryl, or heteroaryl as defined above.

The term "alkylsulfonyl" refers to a -S(O) _2R radical, wherein R is alkyl, cycloalkyl, heterocyclo, aryl or heteroaryl as defined above.

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

The compounds of the present invention may be in deuterated form. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom. A person having ordinary knowledge in the art will be able to synthesize deuterated compounds with reference to the relevant literature. Commercially available deuterated starting materials may be used in the preparation of deuterated compounds, or they may be synthesized using conventional techniques using deuterated reagents.

"Optionally" 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 the 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 independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person with ordinary knowledge in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amine or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (such as olefinic) bond.

"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 the 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 represented by the general formula (II) of the present invention can be prepared by the following scheme.

plan 1

Step 1) In the presence of a catalyst, the compound of formula IIa undergoes a coupling reaction with compound IIb to obtain a compound of formula IIc;

Step 2) Under acidic conditions, the compound of general formula IIc undergoes a deprotection reaction to obtain a compound of general formula IId;

Step 3) In the presence of a base, the compound of general formula IId undergoes a substitution reaction with the compound of general formula IIe to obtain the compound represented by general formula (II) or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein Ring A, R ¹ , R ³ , and m are as defined in the general formula (II).

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 sodium hydroxide and lithium hydroxide.

The catalyst includes but is not limited to _Pd2 (dba) ₃ , RuPhosPdG3, Pd(t- _Bu3P ) ₂ and Pd(OAc) ₂ .

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

The compounds of the present invention and their preparation are further understood by means of the 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 present invention as described and claimed herein.

The compounds of the present invention are prepared using convenient starting materials and general 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 vary with the use of specific reactants or solvents, but under normal circumstances, the reaction optimization 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 with ordinary knowledge in the relevant technical field. For example, T.W.Greene and G.M.Wuts's "Protecting Groups in Organic Preparation" (3rd edition, Wiley, New York, 1999 and references cited in the book) describes in detail the protection or deprotection of a large number of protecting groups.

The separation and purification of compounds and intermediates adopt appropriate methods and steps according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin layer chromatography, preparative high performance liquid chromatography or a combination of the above methods. The specific method of use can refer to the examples described in the present invention. Of course, other similar separation and purification methods can also be used. It can be characterized using conventional methods (including physical constants and spectral data).

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

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

The preparative liquid chromatography method uses a 1c6000 high performance liquid chromatograph (manufacturer: Chuangxin Tongheng). The chromatographic column is Daisogel C18 10μm 100A (30mm×250mm), and the mobile phase is acetonitrile/water.

Thin layer chromatography (TLC) uses Qingdao Ocean Chemical GF254 silica plate. The silica plate used for reaction monitoring is 0.20mm~0.25mm in size, and the silica plate used for separation and purification is 0.5mm in size.

The silica column chromatography method uses Qingdao Marine Silica Gel 100~200 mesh, 200~300 mesh and 300~400 mesh 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 can be 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 volume of about 1L.

The reaction solvent, organic solvent or inert solvent is each described 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, N-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 under atmospheric pressure, and are completed within about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. Unless otherwise specified in the embodiments, the reaction temperature is room temperature, which is 20°C to 30°C.

The reaction process in the embodiment is monitored by thin layer chromatography (TLC). The developing agent systems used in the reaction are: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, C: acetone. The volume ratio of the solvent is adjusted according to the polarity of the compound.

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

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

Implementation example

Example 1: Preparation of 3-ethyl-7-(((4-(1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 1 )

Step 1: Preparation of 6-methyl-5-nitro-pyridine-3-carboxylic acid ethyl ester ( 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), stir at 110 ° C for 12 hours under nitrogen atmosphere, cool the reaction solution to room temperature, filter through diatomaceous earth, wash the filter cake with EA (10 mL x 2), reduce the pressure and concentrate the filtrate, separate and purify the residue by silica gel column chromatography (mobile phase PE/EA=3:1), and obtain 9.65 g of the light yellow solid title compound 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 (diethoxyphosphatyl)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 a THF solution (20 ml) of ethyl 6-methyl-5-nitro-pyridine-3-carboxylate ( 1a ) (9.50 g, 42.4 mmol) was slowly added at 0°C, and stirred at 0°C for 2 hours. The mixture was quenched with saturated _NH4Cl solution (100 mL), and extracted with EA (100 mL x 3). The product was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was separated and purified by silica gel column chromatography (mobile phase PE/EA=4:1) to obtain 9.40 g of the light yellow solid title compound with a yield of 69.1%.

LC-MS: m/z 323 [M+H] ⁺ .

Step 3: Preparation of 5-amino-6-(2-(ethoxycarbonyl)butyl)-pyridine-3-carboxylic acid ethyl ester ( 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 the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The mixture was filtered through diatomaceous earth, and the filter cake was washed with MeOH (50 mL x 1). 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)-pyridine-3-carboxylic acid ethyl ester (1.00g, 3.40mmol) in dioxane hydrochloride solution (10ml), and stir at room temperature overnight under nitrogen atmosphere. Add 30mL of PE and EA mixed solution (PE/EA=5:1), and stir at room temperature for 1 hour. Filter, and wash the filter cake with PE/EA=5:1 mixed solution (5mL x 3) to obtain 600mg (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 of 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 a nitrogen atmosphere. Add 50 mL of water, extract with EA (50 mL x 3), wash with saturated brine (40 mL x 2), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (mobile phase: PE/EA = 100:1-1:1) to obtain 2.8 g of the title compound as a light yellow solid, with a yield of 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 _LiAlH4 (12.5 mL, 1 mol/L) at 0°C, and stir at 0°C for 1 hour. Then 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, and 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 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h )

Dissolve 5-bromoisoindolin-1-one (500 mg, 2.37 mmol) in tetrahydrofuran (10 mL), add di-tert-butyl dicarbonate (775 mg, 3.56 mmol) and DMAP (580 mg, 4.74 mmol), and stir at room temperature for 2 hours. Add water (20 mL), 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: EA/PE=20%) to obtain 830 mg of the title compound as a light yellow solid, yield: 92.6%.

LC-MS: m/z 312.0 [M+H] ⁺ .

Step 9: Preparation of 5-(4-(tert-butyloxycarbonyl)piperazin-1-yl)-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1i )

5-Bromo-1-oxoisoindolin-2-carboxylic acid tert-butyl ester ( 1h ) (400 mg, 1.29 mmol) was dissolved in 1,4-dioxane (8 mL), and piperazine-1-carboxylic acid tert-butyl ester (263 mg, 1.41 mmol), cesium carbonate (836 mg, 2.57 mmol) and Ruphos pd G3 (37.7 mg, 0.0450 mmol) were added. The mixture was stirred at 110 °C for 16 hours under nitrogen atmosphere. Water (20 mL) was added, extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=100/1-1/1) to obtain 480 mg of the title compound as a light yellow solid. Yield: 89.2%.

LC-MS: m/z 418.2 [M+H] ⁺ .

Step 10: Preparation of 5-(piperazin-1-yl)isoindolin-1-one ( 1j )

At room temperature, tert-butyl 5-(4-(tert-butoxycarbonyl)piperazine-1-yl)-1-oxoisoindoline-2-carboxylate ( 1i ) (450 mg, 1.08 mmol) was dissolved in dichloromethane (10 mL), and a dioxane hydrochloride solution (3.3 mL, 4 mol/L) was added, and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to obtain 380 mg (crude) of the title compound as a pale yellow solid.

LC-MS: m/z 218.1 [M+H] ⁺ .

Step 11: Preparation of 3-ethyl-7-(((4-(1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 1 )

5-(Piperazin-1-yl)isoindolin-1-one ( 1j ) (180 mg, 0.225 mmol) and 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one ( 1g ) (61.2 mg, 0.225 mmol) were dissolved in acetonitrile (2 mL) at room temperature, and DIEA (145 mg, 1.13 mmol) and sodium iodide (6.80 mg, 0.0450 mmol) were added, and the mixture was 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 3.0 mg of the title compound as a white solid, with a yield of 8.6%.

LC-MS: m/z 404.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.85 (s, 1H), 8.48 (s, 1H), 8.41 (d, J =1.6 Hz, 1H), 8.11 (s, 1H), 7.75 (s, 1H), 7.63 (d, J =1.6 Hz, 1H), 7.46 (d, J =9.2 Hz, 1H), 7.02 (dd, J =6.0, 2.4 Hz, 1H), 4.25 (s, 2H), 3.65 (s, 2H), 3.27 (d, J =6.0 Hz, 4H), 2.58-2.52 (m, 6H), 1.18 (t, J =7.2 Hz, 3H).

Example 2: Preparation of 3-ethyl-7-((4-(2-methyl-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 2 )

The title compound 2 was prepared in the same manner as in Example 1, except that 5-bromo-2-methylisoindolin-1-one was used instead of 5-bromo-1-oxoisoindolin-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 .

LC-MS: m/z 418.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.82 (s, 1H), 8.40 (d, J =1.6 Hz, 1H), 7.75 (d, J =1.6 Hz, 1H), 7.63 (d, J =1.6 Hz, 1H), 7.45 (d, J =8.4 Hz, 1H), 7.05 (d, J =2.0 Hz, 1H), 7.00 (dd, J =8.4, 2.0 Hz, 1H), 4.33 (s, 2H), 3.65 (s, 2H), 3.29-3.24 (m, 4H), 3.00 (s, 3H), 2.59-2.51 (m, 6H), 1.18 (t, J =7.2 Hz, 3H).

Example 3: Preparation of 7-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-1,3-dimethylquinazoline-2,4(1H,3H)-dione ( 3 )

Step 1: Preparation of 2-amino-4-bromo- N -methylbenzamide ( 3a )

Dissolve 2-amino-4-bromobenzoic acid (1.00 g, 4.65 mmol) in DMF (10 mL), add methylamine hydrochloride (377 mg, 5.58 mmol), DIEA (1.80 g, 13.9 mmol), HATU (2.65 g, 6.97 mmol), and stir at room temperature for 2 hours. Add water (20 mL), extract with ethyl acetate (20.0 mL x 3), wash with saturated brine (20.0 mL), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 1.3 g (crude) of the title compound as a light yellow solid.

LC-MS: m/z 229.0 [M+H] ⁺ .

Step 2: Preparation of 7-bromo-3-methylquinazoline-2,4(1H,3H)-dione ( 3b )

2-Amino-4-bromo- N -methylbenzamide ( 3a ) (1.00 g, 4.38 mmol) was dissolved in THF (20 mL), and DIEA (1.7 g, 13.1 mmol) and triphosgene (1.43 g, 4.81 mmol) were added at 0°C. The mixture was stirred at room temperature for 16 hours 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 = 100/1-1/100) to obtain 550 mg of the title compound as a light yellow solid, with a yield of 47.4%.

LC-MS: m/z 255.0 [M+H] ⁺ .

Step 3: Preparation of 7-bromo-1,3-dimethylquinazoline-2,4(1H,3H)-dione ( 3c )

7-Bromo-3-methylquinazoline-2,4(1H,3H)-dione ( 3b ) (500 mg, 1.96 mmol) was dissolved in DMF (10 mL), and cesium carbonate (1.28 g, 3.92 mmol) and iodomethane (552 mg, 3.92 mmol) were added. The mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. Water (20 mL) was added, extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=100/1-1/100) to obtain 180 mg of the title compound as a light yellow solid. Yield: 33.6%.

LC-MS: m/z 269.0 [M+H] ⁺ .

The remaining steps were the same as those of Example 1, except that 7-bromo-1,3-dimethylquinazoline-2,4(1H,3H)-dione ( 3c ) was used instead of 5-bromo-1-oxoisoindoleline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 to obtain the title compound 3.

LC-MS: m/z 461.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.86 (s, 1H), 8.41 (d, J =1.8 Hz, 1H), 7.82 (d, J =8.9 Hz, 1H), 7.75 (s, 1H), 7.63 (d, J =1.7 Hz, 1H), 6.89 (dd, J =9.0, 2.1 Hz, 1H), 6.61 (d, J =2.1 Hz, 1H), 3.66 (s, 2H), 3.49 (s, 2H), 3.44 (dd, J =6.4, 3.6 Hz, 3H), 2.55 (t, J =5.3 Hz, 6H), 1.25-1.12 (m, 3H).

Example 4: Preparation of 7-((4-(1H-indazol-5-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one ( 4 )

The title compound 4 was prepared in the same manner as in Example 1, except that 5-bromo-1H-indazole was used instead of 5-bromo-1-oxoisoindoleline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 .

LC-MS: m/z 389.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.79 (s, 1H), 11.85 (s, 1H), 8.41 (d, J =1.8 Hz, 1H), 7.89 (s, 1H), 7.75 (s, 1H), 7.64 (d, J =1.8 Hz, 1H), 7.40 (d, J =9.0 Hz, 1H), 7.17 (dd, J =9.1, 2.2 Hz, 1H), 7.08 (d, J =2.2 Hz, 1H), 3.66 (s, 2H), 3.09 (t, J =4.6 Hz, 4H), 2.59 (t, J =5.0 Hz, 3H), 2.54 (dd, J =7.4, 1.2 Hz, 3H), 1.18 (t, J =7.4 Hz, 3H).

Example 5: Preparation of 3-ethyl-7-((4-(imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 5 )

The title compound 5 was prepared in the same manner as in Example 1, except that 6-bromo-imidazo[1,2-a]pyridine was used instead of 5-bromo-1-oxoisoindoleline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 .

LC-MS: m/z 389.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d 6) δ 11.85 (s, 1H), 8.41 (d, 1H), 8.15 (s, 1H), 7.97 (d, 1H), 7.79 (d, 2H), 7.63 (s, 1H), 7.41 (dd, 1H), 7.21 (dd, 1H), 3.66 (s, 2H), 3.16 (s, 4H), 2.58-2.54 (m, 6H), 1.20 (t, 3H).

Example 6: Preparation of 7-((4-([1,2,4]triazolo[4,3-a]pyridin-6-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one ( 6 )

The title compound 6 was prepared in the same manner as in Example 1, except that 5-bromo-1-oxoisoindoleline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 was replaced by 6-bromo-triazolo[1,2-a]pyridine .

LC-MS: m/z 390.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.85 (s, 1H), 9.05 (d, J =0.8 Hz, 1H), 8.41 (d, J =2.0 Hz, 1H), 7.92 (d, J =2.0 Hz, 1H), 7.76 (d, J =1.2 Hz, 1H), 7.68-7.61 (m, 2H), 7.42 (dd, J =10.0, 2.0 Hz, 1H), 3.66 (s, 2H), 3.09 (t, J =4.8 Hz, 4H), 2.62-2.52 (m, 6H), 1.18 (t, J =7.6 Hz, 3H).

Example 7: Preparation of 3-ethyl-7-((4-(7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 7 )

Step 1: Preparation of 5-bromo-3-(bromomethyl)pyridinecarboxylic acid methyl ester ( 7a )

Dissolve 5-bromo-3-methylpyridinecarboxylic acid methyl ester (3.80 g, 16.6 mmol) in DCE (40 mL), add NBS (4.43 mg, 24.9 mmol) and AIBN (534 mg, 3.32 mmol), and stir at 80 ° C for 6 hours under nitrogen atmosphere. Concentrate under reduced pressure, and separate and purify the residue by silica gel column chromatography (mobile phase: PE/EA=100/1-1/2) to obtain 4.2 g of the title compound as a light yellow solid, with a yield of 82.3%.

LC-MS: m/z 307.9 [M+H] ⁺ .

Step 2: Preparation of 3-bromo-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one ( 7b )

5-Bromo-3-(bromomethyl)pyridinecarboxylic acid methyl ester ( 7a ) (3.70 g, 12.1 mmol) was dissolved in 1,4-dioxane (20 mL), and amine water (20 mL) was 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 (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=100/1-1/100) to obtain 2.1 g of the title compound as a light yellow solid, with a yield of 83.6%.

LC-MS: m/z 213.0 [M+H] ⁺ .

Step 3: Preparation of 3-bromo-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester ( 7c )

3-Bromo-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one ( 7b ) (750 mg, 3.83 mmol) was dissolved in THF (10 mL), and _Boc2O (1.25 mg, 5.74 mmol) and DMAP (934 g, 7.66 mmol) were added. The mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. Water (20 mL) was added, extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=100/1-1/100) to obtain 1.05 g of the title compound as a light yellow solid. Yield: 83.3%.

LC-MS: m/z 313.0 [M+H] ⁺ .

The remaining steps were the same as those of Example 1, except that 3-bromo-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester ( 7c ) was used instead of 5-bromo-1-oxoisoindoline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 to obtain the title compound 7 .

LC-MS: m/z 405.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.86 (s, 1H), 8.49 (s, 1H), 8.42 (dd, J =8.1, 2.3 Hz, 2H), 7.75 (s, 1H), 7.63 (d, J =1.8 Hz, 1H), 7.42 (d, J =2.7 Hz, 1H), 4.27 (s, 2H), 3.66 (s, 2H), 3.39-3.35 (m, 2H), 2.56 (ddd, J =8.6, 6.7, 2.4 Hz, 6H), 1.18 (t, J =7.4 Hz, 3H).

Example 8: Preparation of 3-ethyl-7-(4-(8-oxo-7,8-dihydro-1,7-naphthyridin-3-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 8 )

Step 1: Preparation of 5-bromo-3-methylpyridinamide ( 8a )

Dissolve 5-bromo-3-methylpyridinecarboxylic acid (5.00 g, 23.2 mmol) in DMF (50.0 mL), add ammonium chloride (3.77 mg, 69.7 mmol), DIEA (15.00 g, 11.5 mmol), HATU (13.0 g, 34.5 mmol), and stir at room temperature for 2 hours. Add water (100 mL), extract with ethyl acetate (100 mL x 3), wash with saturated brine (200 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 6 g crude product of the title compound as a light yellow solid.

LC-MS: m/z 215.0 [M+H] ⁺ .

Step 2: Preparation of (E )-5-bromo- N- (dimethylamino)methylene)-3-methylpyridinamide ( 8b )

5-Bromo-3-methylpyridinamide ( 8a ) (5.00 g, 23.3 mmol) was dissolved in toluene (100 mL), and DMF-DMA (4.17 g, 35.2 mol) was added, and the mixture was stirred at 80°C for 16 hours. The mixture was concentrated under reduced pressure to obtain 5.5 g of the crude title compound as a light yellow solid.

LC-MS: m/z 270.0 [M+H] ⁺ .

Step 3: Preparation of 3-bromo-1,7-naphthyridin-8(7H)-one ( 8c )

( E )-5-Bromo- N- (dimethylamino)methylene)-3-methylpyridinamide 8b ) (500 mg, 1.86 mmol) was dissolved in THF (10 mL), potassium tert-butoxide (312 mg, 2.78 mmol) was added, and the mixture was stirred at 70°C for 16 hours 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=100/1-1/100) to obtain 280 mg of the title compound as a light yellow solid, with a yield of 33.6%.

LC-MS: m/z 225 [M+H] ⁺ .

Step 4: Preparation of 3-bromo-8-oxo-1,7-naphthyridine-7(8H)-carboxylic acid tert-butyl ester ( 8d )

3-Bromo-1,7-naphthyridin-8(7H)-one ( 8c ) (1.10 g, 4.91 mmol) was dissolved in DCM (10 mL), and _Boc2O (1.60 g, 7.36 mmol) and DMAP (1.20 g, 9.82 mmol) were added. The mixture was stirred at room temperature for 16 hours under nitrogen 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: PE/EA = 100/1-1/100) to obtain 0.80 g of the title compound as a light yellow solid, with a yield of 50.3%.

LC-MS: m/z 325.0 [M+H] ⁺ .

The remaining steps were the same as those of Example 1, except that 3-bromo-8-oxo-1,7-naphthyridine-7(8H)-carboxylic acid tert-butyl ester ( 8d ) was used instead of 5-bromo-1-oxoisoindoleline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 to obtain the title compound 8 .

LC-MS: m/z 417.20 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.87 (s, 1H), 11.09 (d, J =5.6 Hz, 1H), 8.57 (d, J =2.8 Hz, 1H), 8.42 (d, J =1.8 Hz, 1H), 7.76 (s, 1H), 7.64 (d, J =1.8 Hz, 1H), 7.28 (d, J =2.9 Hz, 1H), 7.11 (t, J =6.3 Hz, 1H), 6.35 (d, J =7.0 Hz, 1H), 3.66 (s, 2H), 3.42-3.36 (m, 4H), 2.59-2.52 (m, 6H), 1.19 (t, J =7.4 Hz, 3H).

Example 9: Preparation of 3-ethyl-7-((4-(2-oxoindolin-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 9 )

Step 1: Preparation of 5-(piperazin-1-yl)indolin-2-one ( 9a )

5-Aminoindolin-2-one (100 mg, 0.680 mmol) was dissolved in 2 mL of EtOH, and bis(2-bromoethyl)amine (232 mg, 0.740 mmol) and Na ₂ CO ₃ (86.5 mg, 0.820 mmol) were added, and the mixture was stirred at 70°C for 5 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure and purified by preparative thin layer chromatography (mobile phase: DCM/MeOH=10/1) to obtain 86.7 mg of the title compound as a light yellow solid, with a yield of 59.1%.

LC-MS: m/z 218.1 [M+H] ⁺ .

The remaining steps were the same as those of Example 1, except that 5-(piperazin-1-yl)indolin-2-one ( 9a ) was used instead of 5-(piperazin-1-yl)isoindolin-1-one ( 1j ) in step 11 to obtain the title compound 9 .

LC-MS: m/z 404.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.80 (s, 1H), 10.11 (s, 1H), 8.39 (s, 1H), 7.75 (s, 1H), 7.62 (s, 1H), 6.89 (s, 1H), 6.70 (dd, 2H), 3.63 (s, 2H), 3.40 (s, 4H), 3.02 (s, 4H), 2.54 (d, 4H), 1.18 (t, 3H).

Example 10: Preparation of 3-ethyl-7-((4-(8-methylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 10 )

The title compound 10 was prepared in the same manner as in Example 1, except that 5-bromo-1-oxoisoindoleline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 was replaced by 6-bromo-8-methylimidazo[1,2-a]pyridine .

LC-MS: m/z 403.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.85 (s, 1H), 8.41 (d, J =2.0 Hz, 1H), 7.82 (d, J =2.0 Hz, 1H), 7.78-7.73 (m, 2H), 7.63 (d, J =1.6 Hz, 1H), 7.40 (d, J =1.2 Hz, 1H), 7.04 (dd, J =2.4, 1.2 Hz, 1H), 3.66 (s, 2H), 3.04 (t, J =4.8 Hz, 4H), 2.61-2.52 (m, 6H), 2.45-2.39 (m, 3H), 1.18 (t, J =7.2 Hz, 3H).

Example 11: Preparation of 3-ethyl-7-((4-(8-fluoroimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 11 )

Step 1: Preparation of 6-bromo-8-fluoroimidazo[1,2-a]pyridine ( 11a )

5-Bromo-3-fluoropyridin-2-amine (500 mg, 2.63 mmol) was dissolved in ethanol (10 mL), and 2-bromo-1,1-diethoxyethane (1.03 g, 5.26 mmol) and hydrobromic acid (2.5 mL, 48%) were added at 0°C. The mixture was stirred at 90°C for 16 hours under nitrogen atmosphere. Adjust the pH to 8-9 with saturated sodium bicarbonate, extract with ethyl acetate (30mL x 3), wash with saturated brine (50mL), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate and purify the residue by silica gel column chromatography (mobile phase: PE/EA=100/1-2/3) to obtain 580mg of the title compound as a yellow solid, yield: 89.6%.

LC-MS: m/z 215.0 [M+H] ⁺ .

The remaining steps were the same as those of Example 1, except that 6-bromo-8-fluoroimidazo[1,2-a]pyridine ( 11a ) was used instead of 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 to obtain the title compound 11 .

LC-MS: m/z 407.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.85 (s, 1H), 8.41 (d, J =2.0 Hz, 1H), 7.91 (dd, J =3.2, 1.2 Hz, 1H), 7.87 (d, J =2.0 Hz, 1H), 7.75 (s, 1H), 7.63 (d, J =2.0 Hz, 1H), 7.49 (d, J =1.2 Hz, 1H), 7.24 (dd, J =13.6, 2.0 Hz, 1H), 3.66 (s, 2H), 3.07 (t, J =5.2 Hz, 4H), 2.60-2.53 (m, 6H), 1.18 (t, J =7.2 Hz, 3H).

Example 12: Preparation of 3-ethyl-7-((4-(2-methylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 12 )

The title compound 12 was prepared in the same manner as in Example 1, except that 5-bromo-1-oxoisoindoleline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 was replaced by 6-bromo-2-methylimidazo[ 1,2- a]pyridine.

LC-MS: m/z 403.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.85 (s, 1H), 8.41 (d, J =1.9 Hz, 1H), 7.88 (d, J =2.3 Hz, 1H), 7.76 (d, J =1.5 Hz, 1H), 7.63 (d, J =1.8 Hz, 1H), 7.52 (s, 1H), 7.29 (d, J =9.7 Hz, 1H), 7.13 (dd, J =9.7, 2.3 Hz, 1H), 3.66 (s, 2H), 3.03 (t, J =4.8 Hz, 4H), 2.61-2.51 (m, 6H), 2.31-2.22 (m, 3H), 1.18 (t, J =7.4 Hz, 3H).

Example 13: Preparation of 3-ethyl-7-((4-(2-methylbenzo[d]oxazol-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 13 )

The title compound 13 was prepared in the same manner as in Example 1, except that 5-bromo-2-methylbenzo[d]oxazole was used instead of 5-bromo-1-oxoisoindoline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9.

LC-MS: m/z 404.20 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.83 (s, 1H), 8.41 (d, J =1.8 Hz, 1H), 7.75 (d, J =1.6 Hz, 1H), 7.63 (d, J =1.8 Hz, 1H), 7.46 (d, J =8.9 Hz, 1H), 7.13 (d, J =2.4 Hz, 1H), 6.99 (dd, J =9.0, 2.4 Hz, 1H), 3.65 (s, 2H), 3.39-3.32 (m, 4H), 3.14 (t, J =4.9 Hz, 3H), 2.56 (d, J =9.1 Hz, 6H), 1.18 (t, J =7.4 Hz, 3H).

Example 14: Preparation of 3-ethyl-7-((4-(2-methylbenzo[d]thiazol-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 14 )

The title compound 14 was prepared in the same manner as in Example 1, except that 5-bromo-2-methylbenzo[d]thiazole was used instead of 5-bromo-1-oxoisoindoline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9.

LC-MS: m/z 420.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.84 (s, 1H), 8.41 (d, J =2.0 Hz, 1H), 7.83-7.73 (m, 2H), 7.64 (d, J =2.0 Hz, 1H), 7.37 (d, J =2.4 Hz, 1H), 7.12 (dd, J =8.8, 2.4 Hz, 1H), 3.66 (s, 2H), 3.20 (t, J =4.8 Hz, 4H), 2.74 (s, 3H), 2.62-2.51 (m, 6H), 1.19 (t, J =7.2 Hz, 3H).

Example 15: Preparation of 3-ethyl-7-((4-(1-methyl-1H-indazol-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 15 )

The title compound 15 was prepared in the same manner as in Example 1, except that 5-bromo-1-methyl-1H-indazole was used instead of 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h ) in step 9.

LC-MS: m/z 403.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.85 (s, 1H), 8.41 (d, J =1.8 Hz, 1H), 7.84 (d, J =0.9 Hz, 1H), 7.75 (s, 1H), 7.64 (d, J =1.8 Hz, 1H), 7.49 (d, J =9.2 Hz, 1H), 7.23 (dd, J =9.2, 2.2 Hz, 1H), 7.06 (d, J =2.1 Hz, 1H), 3.98 (s, 3H), 3.66 (s, 2H), 3.10 (t, J =4.9 Hz, 4H), 2.63-2.54 (m, 6H), 1.18 (t, J =7.4 Hz, 3H).

Example 16: Preparation of 3-ethyl-7-((4-(quinazolin-7-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 16 )

The title compound 16 was prepared in the same manner as in Example 1, except that 7-bromoquinazoline was used instead of 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h ) in step 9.

LC-MS: m/z 401.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.86 (s, 1H), 9.19 (s, 1H), 9.00 (s, 1H), 8.42 (d, J =1.8 Hz, 1H), 7.90 (d, J =9.2 Hz, 1H), 7.76 (s, 1H), 7.64 (d, J =1.8 Hz, 1H), 7.57 (dd, J =9.2, 2.5 Hz, 1H), 7.09 (d, J =2.4 Hz, 1H), 3.67 (s, 2H), 3.48 (t, J =5.1 Hz, 4H), 2.56 (ddd, J =12.5, 6.9, 2.8 Hz, 6H), 1.19 (t, J =7.4 Hz, 3H).

Example 17: Preparation of 3-ethyl-7-((4-(7-methyl-1H-indazol-5-yl)piperazin-1-yl)methyl)-1,5-naphthalen-2(1H)-one ( 17 )

The title compound 17 was prepared in the same manner as in Example 1, except that 5-bromo-7-methyl-1H-indazole was used instead of 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h ) in step 9.

LC-MS: m/z 403.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.87 (s, 1H), 11.84 (s, 1H), 8.41 (d, J =1.8 Hz, 1H), 7.87 (s, 1H), 7.75 (s, 1H), 7.64 (d, J =1.8 Hz, 1H), 6.97 (d, J =2.0 Hz, 1H), 6.89 (d, J =2.1 Hz, 1H), 3.65 (s, 2H), 3.07 (t, J =4.7 Hz, 4H), 2.61-2.53 (m, 6H), 2.45 (s, 3H), 1.18 (t, J =7.4 Hz, 3H).

Example 18: Preparation of 3-ethyl-7-((4-(6-fluoro-1H-indazol-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 18 )

The title compound 18 was prepared in the same manner as in Example 1, except that 5-bromo-6-fluoro-1H-indazole was used instead of 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h ) in step 9.

LC-MS: m/z 407.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.93 (s, 1H), 11.85 (s, 1H), 8.41 (d, J =1.9 Hz, 1H), 7.96 (s, 1H), 7.75 (s, 1H), 7.63 (d, J =1.8 Hz, 1H), 7.37-7.27 (m, 2H), 3.66 (s, 2H), 2.99 (s, 4H), 2.62-2.52 (m, 6H), 1.18 (t, J =7.4 Hz, 3H).

Example 19: Preparation of 3-ethyl-7-((4-(4-fluoro-1H-indazol-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 19 )

The title compound 19 was prepared in the same manner as in Example 1, except that 5-bromo-4-fluoro-1H-indazole was used instead of 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h ) in step 9.

LC-MS: m/z 407.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.17 (s, 1H), 11.85 (s, 1H), 8.41 (d, J =1.6 Hz, 1H), 8.07 (s, 1H), 7.75 (s, 1H), 7.63 (d, J =1.6 Hz, 1H), 7.30 (d, J =8.8 Hz, 1H), 7.27-7.20 (m, 1H), 3.66 (s, 2H), 3.03 (t, J =4.8 Hz, 4H), 2.59 (t, J =5.2 Hz, 4H), 2.54 (d, J =7.2 Hz, 2H), 1.18 (t, J =7.2 Hz, 3H).

Example 20: Preparation of 3-ethyl-7-((4-(5-methylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 20 )

20

Step 1: Preparation of 6-bromo-5-methylimidazo[1,2-a]pyridine ( 20a )

Dissolve 5-bromo-6-methylpyridin-2-amine (1.00g, 5.38mmol) in ethanol (10mL), add chloroacetaldehyde (1.26g, 6.45mmol) and sodium bicarbonate (542mg, 6.45mmol), and stir at 60℃ for 2 hours. Add 30mL of water, extract with ethyl acetate (20mL x 3), wash with saturated brine (20mL x 1), dry over 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=100/1-1/9) to obtain 750mg of the title compound as a yellow solid, yield: 66.4%.

LC-MS: m/z 211.0 [M+H] ⁺ .

The remaining steps were the same as those of Example 1, except that 6-bromo-5-methylimidazo[1,2-a]pyridine ( 20a ) was used instead of 5-bromo-1-oxoisoindoleline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 to obtain the title compound 20 .

LC-MS: m/z 403.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.97 (s, 1H), 8.47 (d, J =1.6 Hz, 1H), 8.08 (d, J =1.6 Hz, 1H), 7.98 (d, J =1.6 Hz, 1H), 7.77 (s, 1H), 7.68 (d, J =5.6 Hz, 3H), 3.94 (s, 2H), 2.98 (t, J =4.8 Hz, 4H), 2.85 (s, 4H), 2.66 (s, 3H), 2.58-2.53 (m, 2H), 1.19 (t, J =7.2 Hz, 3H).

Example 21: Preparation of 3-ethyl-7-((4-(3-methylimidazo[1,5-a]pyridin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 21 )

Step 1: Preparation of 6-bromo-3-methylimidazo[1,5-a]pyridine ( 21a )

Dissolve 5-bromo-6-methylpyridin-2-amine (970 mg, 5.19 mmol) and p-toluenesulfonic acid (892 mg, 5.19 mmol) in acetic anhydride (10 mL) and stir at 100°C for 3 hours. Pour the reaction solution into ice water (20 mL), adjust the pH to 9 with 2 mol/L sodium hydroxide solution, extract with ethyl acetate (20 mL x 3), wash with saturated brine (20 mL), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 1.2 g (crude) of the title compound as a brown oil.

LC-MS: m/z 211.0 [M+H] ⁺ .

The remaining steps were the same as those of Example 1, except that 6-bromo-3-methylimidazo[1,5-a]pyridine ( 21a ) was used instead of 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 to obtain the title compound 21 .

LC-MS: m/z 403.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.97 (s, 1H), 8.48 (s, 1H), 7.77 (s, 1H), 7.68 (d, J =5.6 Hz, 1H), 7.59-7.50 (m, 2H), 7.38 (s, 1H), 7.07-6.99 (m, 1H), 3.89 (br, 2H), 3.25-3.12 (m, 4H), 2.94-2.70 (m, 4H), 2.67 (s, 3H), 2.60-2.54 (m, 2H), 1.19 (t, J =7.2 Hz, 3H).

Example 22: Preparation of 3-ethyl-7-((4-(8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 22 )

Step 1: Preparation of 6-bromo-8-(trifluoromethyl)imidazo[1,2-a]pyridine ( 22a )

Dissolve 5-bromo-3-(trifluoromethyl)pyridin-2-amine (1.50 g, 6.22 mmol), sodium acetate (765 mg, 9.33 mmol) and chloroacetaldehyde (970 mg, 12.4 mmol) in 60% ethanol aqueous solution (15 mL). Stir at 100 °C for 16 hours under nitrogen atmosphere. Concentrate under reduced pressure, and separate the residue by high pressure preparative liquid phase separation (mobile phase: acetonitrile/water, gradient: 30%-60%, pure water) for 30 minutes to obtain 700 mg of the title compound as a brown solid with a yield of 42.6%.

LC-MS: m/z 265.0 [M+H] ⁺ .

The remaining steps were the same as those of Example 1, except that 6-bromo-8-(trifluoromethyl)imidazo[1,2-a]pyridine ( 22a ) was used instead of 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 to obtain the title compound 22 .

LC-MS: m/z 457.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.86 (s, 1H), 8.41 (d, J =1.9 Hz, 1H), 8.31-8.23 (m, 1H), 7.97 (d, J =1.2 Hz, 1H), 7.75 (d, J =1.7 Hz, 1H), 7.64 (dd, J =10.4, 2.1 Hz, 2H), 7.57 (d, J =1.1 Hz, 1H), 3.67 (s, 2H), 3.11 (t, J =4.8 Hz, 4H), 2.59 (t, J =4.9 Hz, 4H), 2.55 (dd, J =7.4, 1.2 Hz, 2H), 1.19 (t, J =7.4 Hz, 3H).

Example 23: Preparation of 3-ethyl-7-((4-(1-methyl-1H-benzo[d]imidazol-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 23 )

The title compound 23 was prepared in the same manner as in Example 1, except that 5-bromo-1-methyl-1H-benzo[d]imidazole was used instead of 5-bromo-1-oxoisoindoline-2-carboxylic acid tert-butyl ester ( 1h ) in step 8.

LC-MS: m/z 403.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.8 (s, 1H), 8.41 (d, 1H), 8.03 (s, 1H), 7.64 (d, 2H), 7.39 (d, 1H), 7.10 (s, 1H), 7.04 (d, 1H), 3.77 (s, 3H), 3.65 (s, 2H), 3.11 (t, 4H), 2.59 (t, 4H), 2.55-2.51 (m, 2H), 1.18 (t, 3H).

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

The title compound 24 was prepared in the same manner as in Example 1, except that 6-bromo-1-methyl-1H-benzo[d]imidazole was used instead of 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h ) in step 9.

LC-MS: m/z 403.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.85 (s, 1H), 8.41 (d, 1H), 7.97 (s, 1H), 7.76 (d, 1H), 7.64 (d, 1H), 7.46 (d, 1H), 6.99-6.92 (m, 2H), 3.76 (s, 3H), 3.66 (s, 2H), 3.18 (t, 4H), 2.60 (t, 4H), 2.56-2.51 (m, 2H), 1.19 (t, 3H).

Example 25: Preparation of 3-ethyl-7-((4-(5-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 25 )

Step 1: Preparation of 6-bromo-5-(trifluoromethyl)imidazo[1,2-a]pyridine ( 25a )

Dissolve 5-bromo-6-(trifluoromethyl)pyridin-2-amine (1.50 g, 6.22 mmol), sodium acetate (765 mg, 9.33 mmol) and chloroacetaldehyde (970 mg, 12.4 mmol) in 60% ethanol aqueous solution (15 mL). Stir at 100 °C for 16 hours under nitrogen atmosphere. Concentrate under reduced pressure, and separate the residue by high pressure preparative liquid phase separation (mobile phase: acetonitrile/water, gradient: 30%-60%, pure water) for 30 minutes to obtain 330 mg of the title compound as a brown solid with a yield of 20.0%.

LC-MS: m/z 265.0 [M+H] ⁺ .

The other steps were the same as those of Example 1, except that 6-bromo-5-(trifluoromethyl)imidazo[1,2-a]pyridine ( 25a ) was used instead of 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 to obtain the title compound 25 .

LC-MS: m/z 457.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.86 (s, 1H), 8.42 (d, J =1.8 Hz, 1H), 8.00-7.95 (m, 1H), 7.88 (d, J =9.7 Hz, 1H), 7.77-7.70 (m, 2H), 7.62 (d, J =1.8 Hz, 1H), 7.51 (d, J =9.7 Hz, 1H), 3.66 (s, 2H), 2.98 (d, J =5.0 Hz, 4H), 2.55 (td, J =7.4, 1.2 Hz, 6H), 1.18 (t, J =7.4 Hz, 3H).

Example 26: Preparation of 7-((4-(1H-benzo[d]imidazol-5-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one ( 26 )

The title compound 26 was prepared in the same manner as in Example 1, except that 5-bromo-1H-benzo[d]imidazole was used instead of 5-bromo-1-oxoisoindoline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9.

LC-MS: m/z 389.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.12 (s, 1H), 11.85 (s, 1H), 8.41 (d, 1H), 8.01 (s, 1H), 7.64 (d, 2H), 7.45 (s, 1H), 6.93 (s, 2H), 3.65 (s, 2H), 3.12 (d, 4H), 2.59-2.54 (m, 6H), 1.18 (t, 3H).

Example 27: Preparation of 3-ethyl-7-((4-(7-fluoroimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 27 )

Step 1: Preparation of 5-bromo-4-fluoro-2-nitropyridine ( 27a )

Dissolve 5-bromo-4-fluoropyridin-2-amine (2.00 g, 10.5 mmol) in concentrated sulfuric acid (13.2 mL) for later use. At -20°C, slowly drop 40% hydrogen peroxide (7.62 g, 224 mmol) into concentrated sulfuric acid (24.1 g, 246 mmol). At -20°C, slowly add the above-prepared solution into the mixture of concentrated sulfuric acid and hydrogen peroxide. Stir at 0°C for 0.5 hours, raise the temperature to 30°C and stir for 2 hours. Slowly pour the reaction solution into ice water (400 mL), filter, wash the filter cake with a large amount of ice water, collect the filter cake, and dry to obtain 1.8 g (crude) of the title compound as a white solid.

LC-MS: m/z 220.9 [M+H] ⁺ .

Step 2: Preparation of 4-(4-fluoro-6-nitropyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester ( 27b )

5-Bromo-4-fluoro-2-nitropyridine ( 27a ) (730 mg, 3.32 mmol) was dissolved in dioxane (18 mL), and piperazine-1-carboxylic acid tert-butyl ester (926 mg, 4.98 mmol), cesium carbonate (1.62 g, 4.98 mmol) and Ruphos-Pd-G3 (222 mg, 0.265 mmol) were added. The mixture was stirred at 110°C for 16 hours under nitrogen atmosphere. Water (50 mL) was added, extracted with ethyl acetate (50 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: EA/PE = 1/100-1/1) to obtain 500 mg of the title compound as a yellow solid. Yield: 46.2%.

LC-MS: m/z 327.1 [M+H] ⁺ .

Step 3: Preparation of 4-(6-amino-4-fluoropyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester ( 27c )

Dissolve tert-butyl 4-(4-fluoro-6-nitropyridin-3-yl)piperazine-1-carboxylate ( 27b ) (380 mg, 1.17 mmol) in methanol (10 mL), add aqueous Pd/C (80 mg). Stir at room temperature for 2 hours under hydrogen atmosphere. Filter, and concentrate the filtrate under reduced pressure to obtain 400 mg (crude) of the title compound as a yellow solid.

LC-MS: m/z 297.2 [M+H] ⁺ .

Step 4: Preparation of 4-(7-fluoroimidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylic acid tert-butyl ester ( 27d )

4-(6-amino-4-fluoropyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester ( 27c ) (370 mg, 1.25 mmol), sodium acetate (154 mg, 1.88 mmol) and chloroacetaldehyde (731 mg, 3.75 mmol) were dissolved in 60% aqueous ethanol solution (5 mL). The mixture was stirred at 100 °C for 16 hours under nitrogen atmosphere. The mixture was concentrated under reduced pressure and the residue was separated by high pressure preparative liquid chromatography (mobile phase: acetonitrile/water, gradient: 30%-60%, pure water, 30 min) to obtain 300 mg of the title compound as a white solid with a yield of 75.0%.

LC-MS: m/z 321.2 [M+H] ⁺ .

The other steps were the same as those of Example 1, except that 4-(7-fluoroimidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylic acid tert-butyl ester ( 27d ) was used instead of 5-(4-(tert-butoxycarbonyl)piperazine-1-yl)-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1i ) in step 10 to obtain the title compound 27 .

LC-MS: m/z 407.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.94 (s, 1H), 8.45 (d, J =1.8 Hz, 1H), 8.37 (d, J =7.9 Hz, 1H), 7.90 (d, J =1.4 Hz, 1H), 7.77 (s, 1H), 7.66 (d, J =1.8 Hz, 1H), 7.62 (d, J =1.4 Hz, 1H), 7.55 (d, J =12.3 Hz, 1H), 3.86 (s, 2H), 3.07 (s, 4H), 2.78 (s, 4H), 2.55 (dd, J =7.3, 1.2 Hz, 2H), 1.19 (t, J =7.4 Hz, 3H).

Example 28: Preparation of 3-ethyl-7-((4-(7-methylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 28 )

Step 1: Preparation of 5-bromo-4-methyl-2-nitropyridine ( 28a )

Dissolve 5-bromo-4-methylpyridin-2-amine (1.00g, 4.17mmol) in concentrated sulfuric acid (13.2mL) for later use. At -20℃, slowly drop 40% hydrogen peroxide (8.0g, 229mmol) into concentrated sulfuric acid (24.0g, 251mmol). At -20℃, slowly add the above-prepared solution into the mixture of hydrogen peroxide and concentrated sulfuric acid. Stir at 0℃ for 0.5 hours, raise the temperature to 30℃ and stir for 2 hours. Pour the reaction solution into ice water (400mL), filter, wash the filter cake with a large amount of ice water, collect the filter cake, and dry to obtain 1.9g of the title compound as a yellow solid, with a yield of 81.8%.

LC-MS: m/z 217.0 [M+H] ⁺ .

Step 2: Preparation of 4-(4-methyl-6-nitropyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester ( 28b )

5-Bromo-4-methyl-2-nitropyridine ( 28a ) (1.90 g, 8.79 mmol) was dissolved in dioxane (30 mL), and piperazine-1-carboxylic acid tert-butyl ester (2.45 g, 13.2 mmol), cesium carbonate (4.29 g, 13.2 mmol), BINAP (1.09 g, 1.76 mmol) and _Pd2 (dba) ₃ (806 mg, 0.879 mmol) were added. The mixture was stirred at 110°C for 16 hours under nitrogen atmosphere. Water (50 mL) was added, extracted with ethyl acetate (50 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=100/1-1/1) to obtain 1.35 g of the title compound as a yellow solid. Yield: 47.7%.

LC-MS: m/z 323.2 [M+H] ⁺ .

Step 3: Preparation of 4-(6-amino-4-methylpyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester ( 28c )

Dissolve tert-butyl 4-(4-methyl-6-nitropyridin-3-yl)piperazine-1-carboxylate ( 28b ) (1.30 g, 4.04 mmol) in methanol (40 mL) and add aqueous Pd/C (500 mg). Stir at room temperature for 2 hours under hydrogen atmosphere. Filter and concentrate the filtrate under reduced pressure to obtain 1.10 g of the title compound as a yellow solid. Yield: 93.3%.

LC-MS: m/z 293.2 [M+H] ⁺ .

Step 4: Preparation of 4-(7-methylimidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylic acid tert-butyl ester ( 28d )

4-(6-amino-4-methylpyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester ( 28c ) (300 mg, 1.03 mmol), sodium acetate (126 mg, 1.54 mmol) and chloroacetaldehyde (601 mg, 3.08 mmol) were dissolved in 60% ethanol aqueous solution (5 mL). The mixture was stirred at 100°C for 16 hours under nitrogen atmosphere, concentrated under reduced pressure, and the residue was separated by high pressure preparative liquid chromatography (mobile phase: acetonitrile/water, gradient: 30%-60%, pure water) for 30 minutes to obtain 150 mg of the title compound as a brown solid with a yield of 46.2%.

LC-MS: m/z 317.2 [M+H] ⁺ .

The other steps were the same as those of Example 1, except that 4-(7-methylimidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylic acid tert-butyl ester ( 28d ) was used instead of 5-(4-(tert-butoxycarbonyl)piperazine-1-yl)-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1i ) in step 10 to obtain the title compound 28 .

LC-MS: m/z 403.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.86 (s, 1H), 8.42 (d, J =1.9 Hz, 1H), 8.20 (s, 1H), 7.75 (s, 2H), 7.63 (d, J =2.1 Hz, 1H), 7.41 (d, J =1.2 Hz, 1H), 7.36-7.31 (m, 1H), 3.67 (s, 2H), 2.89 (d, J =6.0 Hz, 4H), 2.64-2.52 (m, 6H), 2.29 (d, J =1.0 Hz, 3H), 1.18 (t, J =7.4 Hz, 3H).

Example 29: Preparation of 3-ethyl-7-((4-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 29 )

The title compound 29 was prepared in the same manner as in Example 1, except that 6-bromo-3-methyl-[1,2,4]triazolo[4,3-a]pyridine was used instead of 5-bromo-1-oxoisoindoleline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 .

LC-MS: m/z 404.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.86 (s, 1H), 8.41 (s, 1H), 7.77 (s, 1H), 7.63 (d, J =5.6 Hz, 1H), 7.61-7.57 (m, 1H), 7.49 (s, 1H), 7.40-7.36 (m, 1H), 3.67 (s, 2H), 3.17- 3.06 (m, 4H), 2.63 (s, 3H), 2.60-2.57 (m, 4H), 2.56-2.52 (m, 2H), 1.19 (t, J =7.2 Hz, 3H).

Example 30: Preparation of 3-ethyl-7-((4-(5-methoxyimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 30 )

Step 1: Preparation of 6-bromo-5-chloroimidazo[1,2-a]pyridine ( 30a )

5-Bromo-6-chloropyridin-2-amine (1.00 g, 4.85 mmol), sodium bicarbonate (489 mg, 5.83 mmol) and chloroacetaldehyde (454 mg, 5.83 mmol) were dissolved in 60% ethanol aqueous solution (15 mL). Stir at 100 °C for 16 hours under nitrogen atmosphere, reduce pressure and concentrate, and the residue was separated by high pressure preparative liquid chromatography (mobile phase: acetonitrile/water, gradient: 30%-60%, pure water, 30 min) to obtain 320 mg of the title compound as a brown solid, with a yield of 28.7%.

LC-MS: m/z 230.9 [M+H] ⁺ .

Step 2: Preparation of 6-bromo-5-methoxyimidazo[1,2-a]pyridine ( 30b )

6-Bromo-5-chloroimidazo[1,2-a]pyridine ( 30a ) (280 mg, 1.22 mmol), methanol (58.4 mg, 1.83 mmol), and sodium hydride (73.0 mg, 1.83 mmol) were dissolved in THF (5 mL). The mixture was stirred at 60 °C for 16 hours under a nitrogen atmosphere. The mixture was quenched with water, extracted with ethyl acetate (10 mL x 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH = 100/1-10/1) to obtain 120 mg of the title compound as a white solid, with a yield of 43.6%.

LC-MS: m/z 227.0 [M+H] ⁺ .

The other steps were the same as those of Example 1, except that 6-bromo-5-methoxyimidazo[1,2-a]pyridine ( 30b ) was used instead of 5-bromo-1-oxoisoindoleline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 to obtain the title compound 30 .

LC-MS: m/z 419.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.84 (s, 1H), 8.40 (d, J =1.8 Hz, 1H), 7.75 (q, J =1.0 Hz, 1H), 7.65-7.58 (m, 2H), 7.49 (d, J =2.3 Hz, 1H), 7.15 (d, J =8.5 Hz, 1H), 6.08 (dd, J =8.5, 0.7 Hz, 1H), 3.63 (d, J =1.7 Hz, 5H), 2.99 (s, 4H), 2.55 (qd, J =5.7, 4.0, 2.0 Hz, 6H), 1.18 (t, J =7.4 Hz, 3H).

Example 31: Preparation of 6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl) -N ,7-dimethylimidazo[1,2-a]pyridine-2-carboxamide ( 31 )

Step 1: Preparation of ethyl 6-bromo-7-methylimidazo[1,2-a]pyridine-2-carboxylate ( 31a )

Dissolve 5-bromo-4-methylpyridin-2-amine (1.50 g, 8.06 mmol) and ethyl 3-bromo-2-hydroxypropionate (3.13 g, 16.1 mmol) in ethylene glycol dimethyl ether solution (45 mL). Stir at room temperature for 3 hours under nitrogen atmosphere. Filter, dissolve the filter cake in ethanol solution (45 mL), and stir at 85°C for 3 hours. Concentrate under reduced pressure, add water (30 mL), extract with ethyl acetate (30mL x 3), wash with saturated brine (30mL), 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=100/1-1/4) to obtain 400 mg of the title compound as a white solid, yield: 17.6%.

LC-MS: m/z 283.0 [M+H] ⁺ .

Step 2: Preparation of ethyl 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-7-methylimidazo[1,2-a]pyridine-2-carboxylate ( 31b )

Ethyl 6-bromo-7-methylimidazo[1,2-a]pyridine-2-carboxylate ( 31a ) (400 mg, 1.42 mmol) was dissolved in 1,4-dioxane (10 mL), and tert-butyl piperazine-1-carboxylate (396 mg, 2.13 mmol), cesium carbonate (691 mg, 2.13 mmol), BINAP (176 mg, 0.284 mmol) and _Pd2 (dba) ₃ (130 mg, 0.142 mmol) were added, and the mixture was stirred at 110°C for 16 hours under nitrogen atmosphere. Water (20 mL) was added, extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and 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 yellow solid. Yield: 18.2%.

LC-MS: m/z 389.2 [M+H] ⁺ .

Step 3: Preparation of 4-(7-methyl-2-(methylaminoformyl)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylic acid tert-butyl ester ( 31c )

Ethyl 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-7-methylimidazo[1,2-a]pyridine-2-carboxylate ( 31b ) (100 mg, 0.355 mmol) was dissolved in methanol (1 mL), and a 30% aqueous methylamine solution (0.6 mL) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to obtain 70 mg (crude) of the title compound as a white solid.

LC-MS: m/z 374.2 [M+H] ⁺ .

The other steps were the same as those of Example 1, except that 4-(7-methyl-2-(methylaminocarbonyl)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylic acid tert-butyl ester ( 31c ) was used instead of 5-(4-(tert-butoxycarbonyl)piperazine-1-yl)-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1i ) in step 10 to obtain the title compound 31 .

LC-MS: m/z 460.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.86 (s, 1H), 8.42 (d, J =1.8 Hz, 1H), 8.24 (d, J =3.9 Hz, 2H), 8.15 (s, 1H), 7.76 (s, 1H), 7.63 (d, J =1.8 Hz, 1H), 7.35 (s, 1H), 3.68 (s, 2H), 2.90 (s, 4H), 2.76 (d, J =4.8 Hz, 3H), 2.68-2.52 (m, 6H), 2.35-2.29 (m, 3H), 1.19 (t, J =7.4 Hz, 3H).

Example 32: Preparation of 6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl) -N ,5-dimethylimidazo[1,2-a]pyridine-2-carboxamide ( 32 )

Step 1: Preparation of ethyl 6-bromo-5-methylimidazo[1,2-a]pyridine-2-carboxylate ( 32a )

Dissolve 5-bromo-6-methylpyridin-2-amine (1.50 g, 8.06 mmol) and ethyl 3-bromo-2-oxopropionate (3.13 g, 16.1 mmol) in ethylene glycol dimethyl ether solution (45 mL), stir at room temperature for 3 hours under nitrogen atmosphere. Filter, dissolve the filter cake in ethanol solution (45 mL), and stir at 85°C for 3 hours. Concentrate under reduced pressure, add water (30mL), extract with ethyl acetate (30mL x 3), wash with saturated brine (30mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate and purify the residue by silica gel column chromatography (mobile phase: EA/PE/EA=100/1-1/4) to obtain 520mg of the title compound as a white solid, yield: 22.9%.

LC-MS: m/z 283.0 [M+H] ⁺ .

Step 2: Preparation of ethyl 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-methylimidazo[1,2-a]pyridine-2-carboxylate ( 32b )

Ethyl 6-bromo-5-methylimidazo[1,2-a]pyridine-2-carboxylate ( 32a ) (450 mg, 1.59 mmol) was dissolved in 1,4-dioxane (10 mL), and piperazine-1-carboxylic acid tert-butyl ester (445 mg, 2.39 mmol), cesium carbonate (778 mg, 2.39 mmol) and Ruphos-Pd- _G3 (107 mg, 0.128 mmol) were added. The mixture was stirred at 110°C for 16 hours under nitrogen atmosphere. Water (20 mL) was added, extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=100/1-2/3) to obtain 50 mg of the title compound as a white solid. Yield: 8.1%.

LC-MS: m/z 389.2 [M+H] ⁺ .

Step 3: Preparation of 4-(5-methyl-2-(methylaminoformyl)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylic acid tert-butyl ester ( 32c )

Ethyl 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-methylimidazo[1,2-a]pyridine-2-carboxylate ( 32b ) (50.0 mg, 0.129 mmol) was dissolved in methanol (1 mL), and a 30% aqueous methylamine solution (0.6 mL) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to obtain 25 mg (crude) of the title compound as a white solid.

LC-MS: m/z 374.2 [M+H] ⁺ .

The other steps were the same as those of Example 1, except that 4-(5-methyl-2-(methylaminocarbonyl)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylic acid tert-butyl ester ( 32c ) was used instead of 5-(4-(tert-butoxycarbonyl)piperazine-1-yl)-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1i ) in step 10 to obtain the title compound 32 .

LC-MS: m/z 460.3 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.86 (s, 1H), 8.42 (d, J =1.9 Hz, 1H), 8.33 (d, J =4.9 Hz, 1H), 8.15 (s, 1H), 7.76 (d, J =1.5 Hz, 1H), 7.63 (d, J =1.8 Hz, 1H), 7.47 (d, J =2.0 Hz, 2H), 3.67 (s, 2H), 2.89 (t, J =4.8 Hz, 4H), 2.79 (d, J =4.7 Hz, 3H), 2.65-2.53 (m, 9H), 1.18 (t, J =7.4 Hz, 3H).

Example 33: Preparation of 6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl) -N -methylimidazo[1,2-a]pyridine-2-carboxamide ( 33 )

Step 1: Preparation of 6-bromo- N -methylimidazo[1,2-a]pyridine-2-carboxamide ( 33a )

6-Bromoimidazo[1,2-a]pyridine-2-carboxylic acid (1.00 g, 4.17 mmol), methylamine hydrochloride (419 mg, 6.25 mmol) and HATU (2.37 g, 6.25 mmol) were dissolved in DMF (15 mL), DIEA (1.61 g, 12.5 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Add water (20mL), extract with ethyl acetate (20mL x 3), wash with saturated brine (20mL), 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=100/1-7/3) to obtain 800mg of the title compound as a white solid, yield: 75.9%.

LC-MS: m/z 254.0 [M+H] ⁺ .

The other steps were the same as those of Example 1, except that 6-bromo- N -methylimidazo[1,2-a]pyridine-2-carboxamide ( 33a ) was used instead of 5-bromo-1-oxoisoindoline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 to obtain the title compound 33 .

LC-MS: m/z 446.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.86 (s, 1H), 8.41 (d, J =1.8 Hz, 1H), 8.23 (q, J =4.7 Hz, 1H), 8.16 (s, 1H), 8.00 (d, J =2.1 Hz, 1H), 7.76 (s, 1H), 7.63 (d, J =1.8 Hz, 1H), 7.43 (d, J =9.9 Hz, 1H), 7.34 (dd, J =9.9, 2.2 Hz, 1H), 3.67 (s, 2H), 3.08 (t, J =4.8 Hz, 4H), 2.77 (d, J =4.8 Hz, 3H), 2.59 (t, J =5.1 Hz, 4H), 2.56 (dd, J =7.4, 1.2 Hz, 2H), 1.18 (t, J = =7.4Hz,3H).

Example 34: Preparation of 3-ethyl-7-((4-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 34 )

Step 1: Preparation of 6-bromo-2-(trifluoromethyl)imidazo[1,2-a]pyridine ( 34a )

Dissolve 5-bromopyridin-2-amine (1.00g, 5.78mmol) and 3-bromo-1,1,1-trifluoropropane-2-one (2.21g, 11.6mmol) in ethanol (25mL), add potassium carbonate (1.20g, 8.67mmol), and stir at 90°C overnight. Concentrate under reduced pressure, add dilute sodium bicarbonate solution (50mL), extract with dichloromethane (30mL x 3), wash with saturated brine (50mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, slurry the residue with petroleum ether, filter, collect the filter cake, and dry to obtain 1.3g of the light yellow solid title compound, yield: 84.8%.

LC-MS: m/z 265.1 [M+H] ⁺ .

The other steps were the same as those of Example 1, except that 6-bromo-2-(trifluoromethyl)imidazo[1,2-a]pyridine ( 34a ) was used instead of 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 to obtain the title compound 34 .

LC-MS: m/z 457.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.84 (s, 1H), 8.42 (d, 1H), 8.33 (s, 1H), 7.99 (s, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.59-7.50 (m, 1H), 7.48-7.43 (m, 1H), 3.66 (s, 2H), 3.13-3.04 (m, 4H), 2.64-2.54 (m, 6H), 1.19 (t, J =7.2 Hz, 3H).

Example 35: Preparation of 3-ethyl-7-((4-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 35 )

Step 1: Preparation of 6-bromo-8-fluoro-2-methylimidazo[1,2-a]pyridine ( 35a )

Dissolve 5-bromo-3-fluoropyridin-2-amine (500 mg, 2.63 mmol) in isopropanol (10 mL), add 1-bromo-2,2-dimethoxypropane (530 mg, 2.89 mmol) and PPTS (66.1 mg, 0.263 mmol), and stir at 110°C for 16 hours. Extract with ethyl acetate (30 mL x 3), wash with saturated brine (50 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 420 mg of the title compound as a light yellow solid, yield: 70.0%.

LC-MS: m/z 229.0 [M+H] ⁺ .

The other steps were the same as those of Example 1, except that 6-bromo-8-fluoro-2-methylimidazo[1,2-a]pyridine ( 35a ) was used instead of 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 to obtain the title compound 35 .

LC-MS: m/z 421.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.85 (s, 1H), 8.40 (d, J =1.6 Hz, 1H), 7.77 (dd, J =10.4, 1.2 Hz, 2H), 7.66-7.60 (m, 2H), 7.15 (dd, J =13.6, 2.0 Hz, 1H), 3.65 (s, 2H), 3.04 (t, J =4.8 Hz, 4H), 2.60-2.51 (m, 6H), 2.29 (d, J =0.8 Hz, 3H), 1.18 (t, J =7.2 Hz, 3H).

Example 36: Preparation of 3-ethyl-7-((4-(6-fluoro-1-methyl-1H-indazol-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 36 )

Step 1: Preparation of 5-bromo-6-fluoro-1-methyl- 1H -indazole ( 36a )

5-Bromo-6-fluoro- 1H -indazole (860 mg, 4.00 mmol) was dissolved in dry tetrahydrofuran (10 mL) at room temperature. Sodium hydride (192 mg, 4.80 mmol) was added at 0°C and stirred at 0°C for 10 minutes. Iodomethane (680 mg, 4.8 mmol) was added and stirred at room temperature for 12 hours under nitrogen atmosphere. Saturated sodium bicarbonate solution (50 mL) was added, extracted with ethyl acetate (50 mL x 3), washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=100/1-4/1) to obtain 440 mg of the title compound as a light yellow solid. Yield: 48.0%.

LC-MS: m/z 229.0 [M+H] ⁺ .

The other steps were the same as those of Example 1, except that 5-bromo-6-fluoro-1-methyl- 1H -indazole ( 36a ) was used instead of 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 to obtain the title compound 36 .

LC-MS: m/z 421.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.89 (s, 1H), 8.42 (s, 1H), 7.93 (s, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.54 (d, J =12.0 Hz, 1H), 7.32 (d, J =8.0 Hz, 1H), 3.97 (s, 3H), 3.67 (s, 2H), 2.99 (br, 4H), 2.63-2.55 (m, 4H), 2.08-1.99 (m, 2H), 1.19 (t, J =7.2 Hz, 3H).

Example 37: Preparation of 3-ethyl-7-((4-(1-ethyl-1H-indazol-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 37 )

Step 1: Preparation of 5-bromo-1-ethyl- 1H -indazole ( 37a )

5-Bromo- 1H -indazole (2.96 g, 15.0 mmol) was dissolved in tetrahydrofuran (90 mL), sodium hydride (960 mg, 24.0 mmol) was added portionwise at 0°C, and the mixture was stirred at 0°C for 0.5 h. Ethyl iodide (5.15 g, 33.0 mmol) was added dropwise, and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction solution was poured into ice water (100 mL) for quenching, extracted with ethyl acetate (100 mL x 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 100/1-4/1) to obtain 1.76 g of the title compound as a yellow oil. Yield: 52.1%.

LC-MS: m/z 225.0 [M+H] ⁺ .

The other steps were the same as those of Example 1, except that 5-bromo-1-ethyl- 1H -indazole ( 37a ) was used instead of 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 to obtain the title compound 37 .

LC-MS: m/z 417.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.87 (s, 1H), 8.41 (s, 1H), 7.86 (s, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.53 (d, J =9.1 Hz, 1H), 7.21 (dd, J =9.2, 2.2 Hz, 1H), 7.07 (s, 1H), 4.36 (q, J =7.1 Hz, 2H), 3.65 (s, 2H), 3.09 (s, 4H), 2.61-2.52 (m, 6H), 1.35 (t, J =7.1 Hz, 3H), 1.18 (t, J =7.4 Hz, 3H).

Example 38: Preparation of 3-ethyl-7-((4-(2-phenylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 38 )

The title compound 38 was prepared in the same manner as in Example 1, except that 6-bromo-2-phenylimidazo[1,2-a]pyridine was used instead of 5-bromo-1-oxoisoindoleline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9.

LC-MS: m/z 465.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.86 (s, 1H), 8.42 (d, 1H), 8.23 (s, 1H), 7.91-7.89 (m, 3H), 7.76 (s, 1H), 7.64 (s, 1H), 7.46-7.39 (m, 3H), 7.30-7.23 (m, 2H), 3.67 (s, 2H), 3.08 (s, 4H), 2.60-2.54 (m, 6H), 1.19 (t, 3H).

Example 39: Preparation of 3-ethyl-7-((4-(imidazo[1,5-a]pyridin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 39 )

The title compound 39 was prepared in the same manner as in Example 1, except that 6-bromo-imidazo[1,5-a]pyridine was used instead of 5-bromo-1-oxoisoindoleline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9.

LC-MS: m/z 389.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.85 (s, 1H), 8.41 (d, 1H), 8.19 (s, 1H), 7.75 (s, 1H), 7.72 (s, 1H), 7.63 (s, 1H), 7.41 (d, 1H), 7.22 (s, 1H), 6.80 (dd, 1H), 3.66 (s, 2H), 3.03 (s, 4H), 2.57-2.54 (m, 6H), 1.18 (t, 3H).

Example 40: Preparation of 3-ethyl-7-((4-(2-methyl-2H-indazol-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 40 )

The title compound 40 was prepared in the same manner as in Example 1, except that 5-bromo-2-methyl- 2H -indazole was used instead of 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h ) in step 9.

LC-MS: m/z 403.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.85 (s, 1H), 8.41 (d, 1H), 8.19 (s, 1H), 7.75 (s, 1H), 7.72 (s, 1H), 7.63 (s, 1H), 7.41 (d, 1H), 7.22 (s, 1H), 6.80 (dd, 1H), 3.66 (s, 2H), 3.03 (s, 4H), 2.57-2.54 (m, 6H), 1.18 (t, 3H).

Example 41: Preparation of 7-((4-(2,4-dimethyl-2H-indazol-5-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one ( 41 )

The title compound 41 was prepared in the same manner as in Example 1, except that 5-bromo-2,4-dimethyl-2H-indazole was used instead of 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h ) in step 9.

LC-MS: m/z 417.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.85 (s, 1H), 8.41 (d, J =1.8 Hz, 1H), 8.25 (d, J =0.9 Hz, 1H), 7.75 (q, J =1.1 Hz, 1H), 7.67-7.61 (m, 1H), 7.38 (dt, J =9.2, 0.9 Hz, 1H), 7.17 (d, J =9.1 Hz, 1H), 4.12 (s, 3H), 3.66 (s, 2H), 2.85 (t, J =4.7 Hz, 4H), 2.58 (s, 2H), 2.58-2.52 (m, 4H), 2.39 (s, 3H), 1.18 (t, J =7.5 Hz, 3H).

Example 42: Preparation of 3-ethyl-7-((4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 42 )

The title compound 42 was prepared in the same manner as in Example 1, except that 5-bromo-1-methyl-1H-pyrazolo[3,4-b]pyridine was used instead of 5-bromo-1-oxoisoindoleline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 .

LC-MS: m/z 404.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.85 (s, 1H), 8.49 (d, J =2.7 Hz, 1H), 8.41 (d, J =1.8 Hz, 1H), 7.95 (s, 1H), 7.76 (q, J =1.0 Hz, 1H), 7.66-7.55 (m, 2H), 4.00 (s, 3H), 3.67 (s, 2H), 3.15 (t, J =4.9 Hz, 4H), 2.65-2.52 (m, 6H), 1.18 (t, J =7.4 Hz, 3H).

Example 43: Preparation of 7-((4-(1,3-dimethyl-1H-indazol-5-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one ( 43 )

The title compound 43 was prepared in the same manner as in Example 1, except that 5-bromo-1,3-dimethyl-3a,7a-dihydro- 1H -indazole was used instead of 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 .

LC-MS: m/z 417.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.85 (s, 1H), 8.41 (d, 1H), 7.75 (s, 1H), 7.54 (d, 1H), 7.41 (d, 1H), 7.20 (dd, 1H), 7.00 (d, 1H), 3.88 (s, 3H), 3.66 (s, 2H), 3.11 (s, 4H), 2.60 (t, 4H), 2.59-2.51 (m, 2H), 2.40 (s, 3H), 1.19 (t, 3H).

Example 44: Preparation of 3-ethyl-7-((4-(1-isopropyl-1H-indazol-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 44 )

The title compound 44 was prepared in the same manner as in Example 1, except that 5-bromo-1-isopropyl-1H-indazole was used instead of 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h ) in step 9.

LC-MS: m/z 431.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.78 (s, 1H), 8.34 (d, J =1.6 Hz, 1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.57 (d, J =1.6 Hz, 1H), 7.48 (d, J =9.2 Hz, 1H), 7.13 (dd, J =9.2, 2.2 Hz, 1H), 7.00 (d, J =2.0 Hz, 1H), 4.81 (h, J =6.4 Hz, 1H), 3.59 (s, 2H), 3.02 (t, J =4.8 Hz, 4H), 2.58-2.46 (m, 6H), 1.37 (d, J =6.4 Hz, 6H), 1.12 (t, J =7.2 Hz, 3H).

Example 45: Preparation of 7-((4-(1,6-dimethyl-1H-indazol-5-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one ( 45 )

The title compound 45 was prepared in the same manner as in Example 1, except that 5-bromo-1,6-dimethyl-1H-indazole was used instead of 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h ) in step 9.

LC-MS: m/z 417.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.83 (s, 1H), 8.42 (d, J =1.8 Hz, 1H), 7.86 (d, J =1.0 Hz, 1H), 7.75 (q, J =1.1 Hz, 1H), 7.67-7.61 (m, 1H), 7.42 (s, 1H), 7.33 (s, 1H), 3.96 (s, 3H), 3.67 (s, 2H), 2.86 (s, 4H), 2.59 (s, 2H), 2.55 (td, J =7.5, 1.2 Hz, 4H), 2.39 (d, J =0.9 Hz, 3H), 1.18 (t, J =7.4 Hz, 3H).

Example 46: Preparation of 3-ethyl-7-((4-(4-methoxy-1-methyl-1H-indazol-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 46 )

Step 1: Preparation of 3-bromo-6-fluoro-2-methoxybenzaldehyde ( 46a )

1-Bromo-4-fluoro-2-methoxybenzene (4.00 g, 19.5 mmol) was dissolved in tetrahydrofuran (10 mL). Under nitrogen atmosphere, LDA (19.5 mL, 2 M) was added at -78°C, and the mixture was stirred at -78°C for 1 hour. DMF (2.14 g, 29.3 mmol) was added and stirred for 1 hour. Quench with saturated ammonium chloride, extract with ethyl acetate (30mL x 3), wash with saturated brine (50mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, separate and purify the residue by silica gel column chromatography (mobile phase: PE/EA=100/1-96/4), and obtain 2.2g of the title compound as a yellow solid, yield: 48.6%.

LC-MS: m/z 233.0 [M+H] ⁺ .

Step 2: Preparation of 5-bromo-4-methoxy-1H-indazole ( 46b )

3-Bromo-6-fluoro-2-methoxybenzaldehyde ( 46a ) (1.80 g, 7.74 mmol) was dissolved in DMSO (54 mL), hydrazine hydrate (2.52 mL) was added, and the mixture was stirred at 130°C for 16 hours. The mixture was extracted with ethyl acetate (50 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA = 100/1-71/29) to obtain 1.60 g of the title compound as a yellow solid, with a yield of 91.5%.

LC-MS: m/z 227.0 [M+H] ⁺ .

Step 3: Preparation of 5-bromo-4-methoxy-1-methyl-1H-indazole ( 46c )

5-Bromo-4-methoxy-1H-indazole ( 46b ) (1.50 g, 6.64 mmol) was dissolved in tetrahydrofuran (4 mL), sodium hydroxide (796 mg, 19.9 mmol) was added, and the mixture was stirred at 0°C for 0.5 h. Methyl iodide (3.19 g, 22.5 mmol) was added, and the mixture was stirred at room temperature for 2 h. The mixture was extracted with ethyl acetate (30 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA = 100/1-7/3) to obtain 290 mg of the title compound as a yellow solid, with a yield of 18.2%.

LC-MS: m/z 241.0 [M+H] ⁺ .

The other steps were the same as those of Example 1, except that 5-bromo-4-methoxy-1-methyl-1H-indazole ( 46c ) was used instead of 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 to obtain the title compound 46 .

LC-MS: m/z 433.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.85 (s, 1H), 8.41 (d, J =2.0 Hz, 1H), 8.07 (s, 1H), 7.75 (d, J =1.2 Hz, 1H), 7.63 (d, J =2.0 Hz, 1H), 7.19 (s, 2H), 4.06 (s, 3H), 3.96 (s, 3H), 3.65 (s, 2H), 2.98 (d, J =4.8 Hz, 4H), 2.63-2.53 (m, 6H), 1.18 (t, J =7.2 Hz, 3H).

Example 47: Preparation of 7-((4-(2-cyclopropylbenzo[d]oxazol-5-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one ( 47 )

Step 1: Preparation of 4-bromo-2-(cyclopropanecarboxamido)phenylcyclopropanecarboxylate ( 47a )

At room temperature, 2-amino-4-bromophenol (500 mg, 2.67 mmol) was dissolved in DCM (5 mL), DIEA (1.03 mg, 8.01 mmol) and cyclopropane acyl chloride (333 mg, 3.21 mmol) were added, and the mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. Water (10 mL) was added, and the mixture was extracted with DCM (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 600 mg (crude) of the title compound as a light yellow solid.

LC-MS: m/z 324.0 [M+H] ⁺ .

Step 2: Preparation of N- (5-bromo-2-hydroxyphenyl)cyclopropanecarboxamide ( 47b )

4-Bromo-2-(cyclopropanecarboxamido)phenylcyclopropanecarboxylate ( 47a ) (600 mg, 1.85 mmol) was dissolved in 1,4-dioxane (10 mL) and water (2 mL) at room temperature, and LiOH (51.0 mg, 1.85 mmol) was added. The mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. Water (5 mL) was added, extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=100/1-1/100) to obtain 360 mg of the title compound as a light yellow solid. Yield: 77.2%.

LC-MS: m/z 256.0 [M+H] ⁺ .

Step 3: Preparation of 5-bromo-2-cyclopropylbenzo[d]oxazole ( 47c )

At room temperature, N- (5-bromo-2-hydroxyphenyl)cyclopropanecarboxamide (350 mg, 1.36 mmol) was dissolved in 1,4-dioxane (5 mL), p-toluenesulfonic acid (470 mg, 2.72 mmol) was added, and 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: PE/EA=100/1-1/1) to obtain 50 mg of the title compound as a light yellow solid, with a yield of 15.5%.

LC-MS: m/z 238.0 [M+H] ⁺ .

The other steps were the same as those of Example 1, except that 5-bromo-2-cyclopropylbenzo[d]oxazole ( 47c ) was used instead of 5-bromo-1-oxoisoindoline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 to obtain the title compound 47 .

LC-MS: m/z 430.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.84 (s, 1H), 8.40 (d, J =1.8 Hz, 1H), 7.75 (s, 1H), 7.63 (d, J =1.8 Hz, 1H), 7.42 (d, J =8.9 Hz, 1H), 7.09 (d, J =2.4 Hz, 1H), 6.95 (dd, J =9.0, 2.4 Hz, 1H), 3.65 (s, 2H), 3.12 (t, J =4.9 Hz, 4H), 2.56 (ddd, J =8.8, 6.3, 2.2 Hz, 6H), 2.21 (tt, J =8.2, 4.9 Hz, 1H), 1.22-1.04 (m, 7H).

Example 48: Preparation of 3-ethyl-7-((4-(2-methylbenzo[d]oxazol-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 48 )

The title compound 48 was prepared in the same manner as in Example 1, except that 6-bromo-2-methylbenzo[d]oxazole was used instead of 5-bromo-1-oxoisoindoline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9.

LC-MS: m/z 404.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.84 (s, 1H), 8.41 (d, J =1.6 Hz, 1H), 7.75 (q, J =1.2 Hz, 1H), 7.63 (d, J =1.6 Hz, 1H), 7.44 (d, J =8.8 Hz, 1H), 7.16 (d, J =2.0 Hz, 1H), 6.97 (dd, J =8.8, 2.4 Hz, 1H), 3.65 (s, 2H), 3.17 (t, J =4.8 Hz, 4H), 2.60-2.51 (m, 9H), 1.18 (t, J =7.2 Hz, 3H).

Example 49: Preparation of 3-ethyl-7-((4-(2-methylbenzo[d]thiazol-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 49 )

The title compound 49 was prepared in the same manner as in Example 1, except that 6-bromo-2-methylbenzo[d]thiazole was used instead of 5-bromo-1-oxoisoindoline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9.

LC-MS: m/z 420.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.84 (s, 1H), 8.41 (d, J =1.8 Hz, 1H), 7.78-7.67 (m, 2H), 7.63 (d, J =1.8 Hz, 1H), 7.47 (d, J =2.5 Hz, 1H), 7.14 (dd, J =9.0, 2.5 Hz, 1H), 3.65 (s, 2H), 3.20 (t, J =5.0 Hz, 4H), 2.71 (s, 3H), 2.60-2.52 (m, 6H), 1.18 (t, J =7.4 Hz, 3H).

Example 50: Preparation of 3-ethyl-7-((4-(isoquinolin-7-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 50 )

The title compound 50 was prepared in the same manner as in Example 1, except that 7-bromoisoquinoline was used instead of 5-bromo-1-oxoisoindoline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9.

LC-MS: m/z 400.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.86 (s, 1H), 9.09 (s, 1H), 8.42 (d, J =1.8 Hz, 1H), 8.26 (d, J =5.6 Hz, 1H), 7.84-7.73 (m, 2H), 7.68-7.60 (m, 3H), 7.32 (d, J =2.4 Hz, 1H), 3.68 (s, 2H), 3.33 (d, J =3.0 Hz, 4H), 2.61 (t, J =4.9 Hz, 4H), 2.58-2.52 (m, 2H), 1.19 (t, J =7.4 Hz, 3H).

Example 51: Preparation of 3-ethyl-7-((4-(isoquinolin-6-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 51 )

The title compound 51 was prepared in the same manner as in Example 1, except that 6-bromoquinoline was used instead of 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h ) in step 9.

LC-MS: m/z 400.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.84 (s, 1H), 9.00 (s, 1H), 8.42 (d, 1H), 8.28 (d, 1H), 7.90 (s, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.57-7.48 (m, 2H), 7.11 (d, 1H), 3.66 (s, 2H), 3.44-3.35 (m, 4H), 2.64-2.54 (m, 6H), 1.19 (t, J =7.2 Hz, 3H).

Example 52: Preparation of 7-((4-(2,2-difluorobenzo[d][1,3]dihydroxy-5-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one ( 52 )

The title compound 52 was prepared in the same manner as in Example 1, except that 5-bromo-2,2-difluorobenzo[d][ 1,3 ]dioxolane was used instead of 5-bromo-1-oxoisoindoleline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9.

LC-MS: m/z 429.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.84 (s, 1H), 8.40 (d, J =1.6 Hz, 1H), 7.75 (q, J =1.2 Hz, 1H), 7.62 (d, J =1.6 Hz, 1H), 7.21 (d, J =8.8 Hz, 1H), 7.08 (d, J =2.4 Hz, 1H), 6.68 (dd, J =8.8, 2.4 Hz, 1H), 3.64 (s, 2H), 3.12 (dd, J =6.4, 3.6 Hz, 4H), 2.58-2.52 (m, 6H), 1.18 (t, J =7.2 Hz, 3H).

Example 53: Preparation of 7-((4-(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one ( 53 )

The title compound 53 was prepared in the same manner as in Example 1, except that 6-bromo-2,3-dihydrobenzo[b][1,4]dioxane was used instead of 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 .

LC-MS: m/z 407.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.84 (s, 1H), 8.39 (d, 1H), 7.75 (s, 1H), 7.62 (s, 1H), 6.70 (d, 1H), 6.44-6.40 (m, 2H), 4.16 (dd, 4H), 3.52 (s, 2H), 2.99 (d, 4H), 2.57-2.51 (m, 6H), 1.18 (t, 3H).

Example 54: Preparation of 7-((4-(benzo[d][1,3]dioxolan-5-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one ( 54 )

The title compound 54 was prepared in the same manner as in Example 1, except that 5-bromobenzo[ d ][1,3]dioxolane was used instead of 5-bromo-1-oxoisoindoleline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9.

LC-MS: m/z 393.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.84 (s, 1H), 8.39 (d, 1H), 7.75 (s, 1H), 7.52 (d, 1H), 6.75 (d, 1H), 6.66 (d, 1H), 6.32 (dd, 1H), 5.90 (s, 2H), 3.62 (s, 2H), 3.01 (d, 2H), 2.55-2.50 (m, 8H), 1.18 (t, 3H).

Example 55: Preparation of 3-ethyl-7-((4-(2-ethyl-2H-indazol-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 55 )

Step 1: Preparation of 5-bromo-2-ethyl- 2H -indazole ( 55a )

5-Bromo-1H-indazole (2.96 g, 15.0 mmol) was dissolved in tetrahydrofuran (90 mL), sodium hydride (960 mg, 24.0 mmol) was added portionwise, and the mixture was stirred at 0°C for 0.5 h. Ethyl iodide (5.15 g, 33.0 mmol) was added dropwise, and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction solution was poured into ice water (100 mL) for quenching, extracted with ethyl acetate (100 mL x 3), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 100/1-2/1) to obtain 1.81 g of the title compound as a yellow oil with a yield of 53.6%.

LC-MS: m/z 225.0 [M+H] ⁺ .

The other steps were the same as those of Example 1, except that 5-bromo-2-ethyl- 2H -indazole ( 55a ) was used instead of 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h ) in step 9 to obtain the title compound 55 .

LC-MS: m/z 209.1 [1/2M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.87 (s, 1H), 8.41 (d, J =1.8 Hz, 1H), 8.11 (s, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.45 (d, J =9.4 Hz, 1H), 7.11 (dd, J =9.3, 2.2 Hz, 1H), 6.87 (d, J =2.2 Hz, 1H), 4.36 (q, J =7.3 Hz, 2H), 3.65 (s, 2H), 3.06 (s, 4H), 2.60-2.52 (m, 6H), 1.46 (t, J =7.3 Hz, 3H), 1.18 (t, J =7.4 Hz, 3H).

Example 56: Preparation of 3-ethyl-7-((4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 56 )

The title compound 56 was prepared in the same manner as in Example 1, except that 5-bromo-1,3-dihydro-2H-benzo[d]imidazol-2-one was used instead of 5-bromo-1-oxoisoindoleline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9.

LC-MS: m/z 405.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.84 (s, 1H), 10.27 (s, 1H), 10.39 (s, 1H), 8.40 (d, J =1.8 Hz, 1H), 7.75 (q, J =1.1 Hz, 1H), 7.62 (d, J =1.8 Hz, 1H), 6.76 (d, J =8.4 Hz, 1H), 6.58-6.48 (m, 2H), 3.63 (s, 2H), 3.02 (t, J =4.8 Hz, 4H), 2.59-2.52 (m, 6H), 1.18 (t, J =7.4 Hz, 3H).

Example 57: Preparation of 3-ethyl-7-((4-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 57 )

The title compound 57 was prepared in the same manner as in Example 1, except that 5-bromo-1-methyl- 1,3- dihydro-2H-benzo[d]imidazol-2-one was used instead of 5-bromo-1-oxoisoindoleline-2-carboxylic acid tert-butyl ester ( 1h ) in step 9.

LC-MS: m/z 419.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.84 (s, 1H), 10.62 (s, 1H), 8.40 (d, J =1.9 Hz, 1H), 7.75 (d, J =1.7 Hz, 1H), 7.62 (d, J =1.8 Hz, 1H), 6.92 (d, J =8.5 Hz, 1H), 6.63 (dd, J =8.5, 2.3 Hz, 1H), 6.56 (d, J =2.2 Hz, 1H), 3.64 (s, 2H), 3.21 (s, 3H), 3.10-2.97 (m, 4H), 2.59-2.52 (m, 6H), 1.18 (t, J =7.4 Hz, 3H).

Example 58: Preparation of 3-ethyl-7-((4-(4-methoxy-2-methyl-2H-indazol-5-yl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one ( 58 )

The title compound 58 was prepared in the same manner as in Example 1, except that 5-bromo-4-methoxy-2-methyl-2H-indazole was used instead of 5-bromo-1-oxoisoindole-2-carboxylic acid tert-butyl ester ( 1h ) in step 9.

LC-MS: m/z 433.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.84 (s, 1H), 8.41 (d, J =1.6 Hz, 1H), 8.35 (s, 1H), 7.75 (d, J =1.2 Hz, 1H), 7.64 (d, J =1.6 Hz, 1H), 7.23 (dd, J =9.2, 1.2 Hz, 1H), 7.09 (d, J =9.2 Hz, 1H), 4.11 (s, 3H), 3.98 (s, 3H), 3.65 (s, 2H), 3.00 (t, J =4.8 Hz, 4H), 2.62-2.51 (m, 6H), 1.18 (t, J =7.2 Hz, 3H).

Biological tests

Experimental Example 1: PARP1 capture experiment

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

Experimental steps:

(I) Preparation of reagents

Prepare the experimental buffer: 10mM potassium phosphate (pH7.9), 50mM NaCl, 1mM EDTA, 0.05% Brij-35, 1mM DTT.

(II) Experimental methods

Prepare the buffer solution by the above method, dissolve the compound in DMSO and dilute it in a gradient manner, dilute the compound to the test concentration using the experimental buffer, and shake on an oscillator for 15 minutes.

Dilute the PARP1 enzyme 4X using assay buffer and add GST-Tb.

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

Dilute PARP1 probe 1 to 4X using assay buffer and add 4μL per well to the assay plate.

Add the test compound to the experimental plate, 4 μL per well, and place 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 were read by Envision (2105) (Ex: 340nm, Em 665nm and 615nm).

Data analysis:

The % inhibition rate is calculated as follows:

Suppression%=(Signal cmpd-Signal Ave_PC)/(Signal Ave_VC-Signal Ave_PC)×100

Signal cmpd: Fluorescence signal values of compounds at different concentrations

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

SignalAve_VC: Average value of negative contrast fluorescent signal value

Calculate IC ₅₀ and plot compound effect dose curve:

IC50 was calculated by fitting the percent inhibition values and logarithm of compound concentration to a nonlinear regression (dose response - variable slope) using Graphpad 5.0.

Y=Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -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 against PARP1 capture.

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

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

結果：本發明化合物對PARP1-DNA複合物具有很好的捕獲活性。

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) Preparation of reagents

Prepare the experimental buffer: 10mM potassium phosphate (pH7.9), 50mM NaCl, 1mM EDTA, 0.05% Brij-35, 1mM DTT.

(II) Experimental methods:

Prepare the reagents by the above method. Dissolve the compound in DMSO and dilute it in a gradient, dilute the compound to the test concentration using the experimental buffer, and shake on a shaker for 15 minutes.

Dilute the PARP2 enzyme 4X using assay buffer and add GST-Tb.

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

Dilute PARP2 probe-2 to 4X using assay buffer and add 4μL per well to the assay plate.

Add the test compound to the experimental plate, 4 μL per well, and place 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 were read by Envision (2105) (Ex: 340nm, Em 665nm and 615nm).

Data analysis:

The % inhibition rate is calculated as follows:

Suppression%=(Signal cmpd-Signal Ave_PC)/(Signal Ave_VC-Signal Ave_PC)×100

Signal cmpd: Fluorescence signal values of compounds at different concentrations

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

SignalAve_VC: Average value of negative contrast fluorescent signal value

Calculate IC ₅₀ and plot compound effect dose curve:

_{IC50 values} were calculated by fitting the percent inhibition values and logarithm of compound concentration to a nonlinear regression (dose response - variable slope) using Graphpad 5.0.

Y=Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)*HillSlope))

X: Logarithmic value of inhibitor concentration; Y: Percentage of inhibition rate

Table 2 provides the in vitro activities (IC ₅₀ ) of the compounds of the present 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.

結果：本發明化合物對PARP2-DNA複合物的捕獲活性較低。 Table 2 Activity of the compounds of the present application on PARP2 capture

Results: The compounds of the present invention have low activity in capturing PARP2-DNA complexes.

Experimental Example 3: DLD-1 wild-type (WT) and DLD-1 BRCA2 (-/-) cell anti-proliferation experiment

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

The experimental method is as follows:

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

Then, the Promega CellTiter-Glo assay was performed. The cell plate was removed and equilibrated at room temperature for 30 minutes. 20 μL CTG was added to each well, vortexed to mix, and incubated at room temperature for 30 minutes. The luminescence was read by the Envision (2105) multi-label analyzer.

Data analysis:

The inhibition rate is calculated as follows:

Suppression%=(Signalcmpd-SignalAve_PC)/(SignalAve_VC-SignalAve_PC)×100

Signal cmpd: chemiluminescence values of compounds at different concentrations

SignalAve_PC: Average value of the maximum value of system chemiluminescence

SignalAve_VC: Average value of negative control chemiluminescence value

Calculate IC ₅₀ and plot compound effect dose curve:

Y=Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -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-1 WT and DLD-1 BRCA2(-/-) cells.

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

結果：本發明化合物對BRCA2突變的DLD-1細胞具有良好的抗增殖活性，對野生型的DLD-1細胞幾乎沒有抑制活性，說明本發明化合物具有良好的細胞選擇性。 Table 3 Inhibitory activity of the compounds of the present invention on proliferation of DLD-1 WT and DLD-1 BRCA2(-/-) cells

Results: The compound of the present invention has good anti-proliferation activity against BRCA2 mutant DLD-1 cells, and has almost no inhibitory activity against wild-type DLD-1 cells, indicating that the compound of the present invention has good cell selectivity.

Experimental Example 4: Determination of the inhibitory effect of the compound 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 the compound 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-specific culture medium (Wuhan Prosai Biotechnology Co., Ltd., CM-0383A), PBS (Gibco, 8121763), CellTiter Glo assay kit (Promega, G7572), 384-well plate (Thermo, 164610), enzyme labeler (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. 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 live cells/well. Compound solutions of different concentrations were prepared using DMSO and 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 replicate wells, 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 plates were placed in a 37°C, 5% CO ₂ incubator for 7 days, then taken out and equilibrated at room temperature for 30 minutes. 20μL CTG was added to each well, vortexed to mix, and incubated at room temperature for 10 minutes before reading the luminescence value using an enzyme marker.

The cell proliferation activity inhibition rate is calculated as follows:

Suppression%=100-(Signalcmpd-SignalAve_PC)/(SignalAve_VC-SignalAve_PC)×100

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

The concentration and inhibition rate were fitted with a nonlinear regression curve using Graphpad Prism software to obtain the IC ₅₀ value.

Y=Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -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 MDA-MB-436 cell proliferation.

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.

結果：本發明化合物對MDA-MB-436細胞具有良好的抗增殖活性。 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 anti-proliferation activity against MDA-MB-436 cells.

Experimental Example 5: Evaluation of drug metabolism kinetics 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 centrifuged at 3500 rpm for 10 minutes at 4°C to 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 Institute for the Control of Pharmaceutical and Biological Products), vortex for 5 minutes to mix thoroughly, and centrifuge at 4000 rpm for 10 minutes. Take 50 μL of the supernatant, add 150 μL of acetonitrile to mix, centrifuge at 4000 rpm for 10 minutes, take the supernatant, place it in a 96-well injection plate, and analyze the blood drug concentration by LC/MS (Waters UPLC I Class/LC 30AD, Waters). MassLynx V4.2SCN977 data processing software was used to analyze the drug metabolism kinetic parameters. The main drug metabolism kinetic parameters of the compounds of the present invention are shown in the table below.

結果：本發明化合物在大鼠體內具有較好的藥物代謝動力學性質。 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 (21)

A compound represented by the general formula (I) or its racemate, racemate, enantiomer, diastereomer, 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 ); Ring A is selected from bicyclic aryl, bicyclic heteroaryl, bicyclic heterocyclic group, and the bicyclic aryl, bicyclic heteroaryl, bicyclic heterocyclic group is optionally further substituted by one or more ^R2 ; ^R1 is selected from alkyl or halogen alkyl; Each ^R2 is independently selected from hydrogen, halogen, amine, nitro, cyano, hydroxyl, oxirane, pendoxy, thio, alkyl ^, alkoxy, -C(O) ^Rc , -S(O) ^Rc , -S(O) _2Rc , -C(O) ^{NRaRb ,} -S(O)NRaRb ^, -S(O) ^{2NRaRb ,} -OC(O) ^Rc , _-N ( ^Ra )C(O) ^Rc , ^-N ( ^Ra )S(O) ^Rc , -N ^{( Ra} )S(O) _2Rc , cycloalkyl, heterocyclic group, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl is optionally further substituted by one or more groups selected from deuterium, halogen, amine, nitro, cyano, pendoxy, hydroxyl, alkoxy, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; or two adjacent ^R2 together with the atoms to which they are attached form a cycloalkyl, heterocyclic, aryl or heteroaryl group; the cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally further substituted by one or more groups selected from deuterium, halogen, amine, nitro, cyano, pendoxy, hydroxyl, alkyl, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; Each R ³ is independently selected from hydrogen, alkyl, halogen, and halogen; ^Ra and ^Rb are each independently selected from hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl is optionally substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, carboxyl, ester, pendoxy, alkyl, alkoxy, halogenalkyl, halogenalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, 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 by one or more groups selected from halogen, amine, nitro, cyano, oxo, hydroxyl, alkyl, carboxyl, ester, alkyl, alkoxy, halogenalkyl, halogenalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R ^c is selected from hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl group is optionally substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, carboxyl, ester, pendoxy, alkyl, alkoxy, halogenalkyl, halogenalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl. The compound represented by the general formula (I) as described in claim 1, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, which is the compound represented by the general formula (II) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt,

Where m is an integer from 0 to 2; Ring A, R ¹ and R ³ are as defined in claim 1. The compound represented by the general formula (I) as described in claim 1 or 2, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, wherein, Ring A is selected from C ₈ -C ₁₀ bicyclic aryl, 8 to 10-membered bicyclic heteroaryl or 8 to 10-membered bicyclic heterocyclic group; preferably 8 to 10-membered bicyclic heteroaryl; the C ₈ -C ₁₀ bicyclic aryl, 8 to 10-membered bicyclic heteroaryl and 8 to 10-membered bicyclic heterocyclic group are optionally further substituted by one or more R ² ; The bicyclic aryl group, bicyclic heteroaryl group or bicyclic heterocyclic group is preferably a bifused-ring aryl group, bifused-ring heteroaryl group or bifused heterocyclic group; ^R2 is as defined in claim 1. The compound represented by the general formula (I) as described in any one of claims 1 to 3, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, which is the compound represented by the general formula (III) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt,

Wherein, Y is selected from N or C; Ring _A1 is selected from 5- to 6-membered heterocyclic groups or 5- to 6-membered heteroaryl groups; Each R ^2a is independently selected from hydrogen, halogen, amine, nitro, cyano, hydroxyl, oxirane, sulfhydryl, alkyl, alkoxy, -C(O)R ^c , -S(O)R ^c , -S(O) ₂ R ^c , -C(O)NR ^a R ^b , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OC(O)R ^c , -N(R ^a )C(O)R ^c , -N(R ^a )S(O)R ^c , -N(R ^a )S(O) ₂ R ^c , cycloalkyl, heterocyclic group, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl is optionally further substituted by one or more groups selected from deuterium, halogen, amine, nitro, cyano, pendoxy, hydroxyl, alkoxy, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; or two adjacent R ^2a together with the atoms to which they are attached form a cycloalkyl, heterocyclic, aryl or heteroaryl group; the cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally further substituted with one or more groups selected from deuterium, halogen, amine, nitro, cyano, oxo, hydroxyl, alkynyl, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; Each R ^2b is independently selected from hydrogen, halogen, amine, nitro, cyano, hydroxyl, oxirane, sulfhydryl, alkyl, alkoxy, -C(O)R ^c , -S(O)R ^c , -S(O) ₂ R ^c , -C(O)NR ^a R ^b , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OC(O)R ^c , -N(R ^a )C(O)R ^c , -N(R ^a )S(O)R ^c , -N(R ^a )S(O) ₂ R ^c , cycloalkyl, heterocyclic group, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl is optionally further substituted by one or more groups selected from deuterium, halogen, amine, nitro, cyano, pendoxy, hydroxyl, alkoxy, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; ^Ra and ^Rb are each independently selected from hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl group is optionally substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, carboxyl, ester, pendoxy, alkyl, alkoxy, halogenalkyl, halogenalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, 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 by one or more groups selected from halogen, amine, nitro, cyano, oxo, hydroxyl, alkyl, carboxyl, ester, alkyl, alkoxy, halogenalkyl, halogenalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R ^c is selected from hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl is optionally substituted with one or more groups selected from halogen, amine, nitro, cyano, hydroxyl, alkyl, carboxyl, ester, pendoxy, alkyl, alkoxy, halogenalkyl, halogenalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl. m is an integer from 0 to 2; p is an integer from 0 to 4; q is an integer from 0 to 2; R ¹ and R ³ are as defined in claim 1. The compound represented by the general formula (I) as described in claim 4, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, which is the compound represented by the general formula (III) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, wherein each R ^2a is independently selected from halogen, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl; p is an integer from 0 to 4. The compound represented by the general formula (I) as described in claim 4, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is the compound represented by the general formula (III) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R ^2b is independently selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl; q is an integer from 0 to 2. A compound represented by the general formula (I) as described in any one of claims 1 to 3, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A selected from

,

,

,

,

,

,

,

; preferably

,

,

,

,

,

,

; better

; Further improvement

,

,

,

,

Ring A is optionally further substituted by one or more ^R2 ; ^R2 is as defined in claim 1; Preferably, R ² is selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, phenyl, -C(O)NR ^a R ^b ; wherein ^Ra and R ^b are each independently selected from hydrogen and C ₁ -C ₆ alkyl. A compound represented by the general formula (I) as described in any one of claims 1 to 3, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A selected from

,

,

,

,

,

,

; Further improvement

,

,

in, R ²¹ , R ²² , and R ²³ are each independently selected from hydrogen and halogen; R ²⁴ and R ²⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl; R ²⁶ , R ²⁷ , and R ²⁸ are each independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl, and C ₁ -C ₆ halogenalkyl; ^R29 is selected from hydrogen, _C1-6 alkyl, ^-C (O) ^NRaRb ; wherein ^Ra and ^Rb are each independently selected from hydrogen and _C1 - _C6 alkyl; R ²¹⁰ is selected from hydrogen and C ₁ -C ₆ alkyl, preferably hydrogen; R ²¹¹ is selected from hydrogen and C ₁ -C ₆ alkyl, preferably C ₁ -C ₆ alkyl; ^R212 is selected from hydrogen and _C1 - _C6 alkyl, preferably _C1 - _C6 alkyl. A compound represented by the general formula (I) as described in any one of claims 1 to 3, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A selected from

; in, R ²¹ , R ²² , and R ²³ are each independently selected from hydrogen and halogen; R ²⁴ and R ²⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl. A compound represented by the general formula (I) as described in any one of claims 1 to 3, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A selected from

; in, R ²⁶ , R ²⁷ , and R ²⁸ are each independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl, and C ₁ -C ₆ halogenalkyl; ^R29 is selected from hydrogen, _C1-6 alkyl, ^-C (O) ^NRaRb ; wherein ^Ra and ^Rb are each independently selected from hydrogen and _C1 - _C6 alkyl; ^R210 is selected from hydrogen and _C1 - _C6 alkyl, preferably hydrogen. The compound represented by the general formula (I) as described in any one of claims 1 to 3, or its racemate, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from

,

. The compound represented by the general formula (I) as described in any one of claims 1 to 3, or its racemate, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from

. The compound represented by the general formula (I) as described in any one of claims 1 to 3, or its meso form, racemic form, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from

; Wherein, R ²¹¹ is selected from hydrogen and C ₁ -C ₆ alkyl, preferably C ₁ -C ₆ alkyl. The compound represented by the general formula (I) as described in any one of claims 1 to 3, or its racemate, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from

; wherein R ²¹² is selected from hydrogen and C ₁ -C ₆ alkyl, preferably C ₁ -C ₆ alkyl. A compound represented by the general formula (I) as described in any one of claims 1 to 14, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, Wherein, ^R1 is selected from _C1-6 alkyl or _C1-6 halogenalkyl. A compound represented by the general formula (I) as described in any one of claims 1 to 15, or its racemate, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 halogenalkyl. A compound represented by the general formula (I) as described in any one of claims 1 to 16, or its racemate, 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 (II) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

In the presence of a base, the compound of general formula IId undergoes a substitution reaction with the compound of general formula IIe to obtain the compound represented by general formula (II) or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof; wherein ring A, R ¹ , R ³ , and m are as defined in claim 2. A pharmaceutical composition comprising a compound represented by the general formula (I) as described in any one of claims 1 to 17 or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. A compound represented by the general formula (I) as described in any one of claims 1 to 17, or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or its pharmaceutically acceptable salt, or the pharmaceutical composition as described in claim 19, for use in the preparation of a poly ADP-ribose polymerase 1 (PARP1) inhibitor. A compound represented by the general formula (I) as described in any one of claims 1 to 17, or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or its pharmaceutically acceptable salt, or the pharmaceutical composition as described in claim 19, in the preparation of a drug for preventing or/and treating a disease associated with the activity of poly (ADP-ribose) polymerase 1, preferably a tumor disease, such as ovarian cancer, breast cancer, prostate cancer.