Substituted nitrogen-containing bicyclic compounds and their use

Abstract

This invention relates to the field of medicine and to substituted nitrogen-containing bicyclic compounds and their use. Specifically, this invention relates to novel substituted nitrogen-containing bicyclic compounds and pharmaceutical compositions comprising these compounds, which can be used to inhibit PARP1 and exhibit higher selectivity for PARP1 than other PARP subtypes. This invention also relates to methods for preparing the compounds and pharmaceutical compositions, as well as to the use of the compounds and pharmaceutical compositions in the preparation of drugs for treating PARP1-mediated diseases, particularly cancer.

Description

[Technical Field]

[0001] This invention belongs to the field of pharmaceutical technology and more specifically to novel substituted nitrogen-containing bicyclic compounds, pharmaceutical compositions containing these compounds, and methods of use and application thereof. In particular, the novel substituted nitrogen-containing bicyclic compounds described in this invention can be used to inhibit PARP1 for the prevention, treatment, or mitigation of PARP1-mediated diseases, especially cancer. [Background technology]

[0002] Cancer refers to malignant tumors originating from epithelial tissue and is the most common type of malignant tumor. Generally, the term "cancer" is used to refer to all malignant tumors. Cancer is a group of diseases characterized by abnormal cell differentiation and proliferation. In its later stages, it may spread to other areas of the body, including bones and vital organs. Cancer is characterized by abnormal cell differentiation and proliferation, uncontrolled growth, metastasis, and invasiveness. Its development is a complex, multifactorial, multistage process, divided into three stages: carcinogenesis, tumorigenesis, and progression. The causes of malignant tumors are not fully understood, but they are closely associated with infection, smoking, occupational exposure, environmental pollution, genetic factors, and unhealthy diets.

[0003] Cancer is one of the leading diseases that endangers human health and disrupts family and social harmony. It is a major global health problem and remains a leading cause of death. Since 2010, cancer has ranked second among human causes of death, after cardiovascular and cerebrovascular diseases. The global cancer situation is becoming increasingly serious, with both incidence and mortality rates continuing to rise. According to relevant organizations, with population growth and aging, as well as social development and the emergence of unhealthy lifestyles, the number of new cancer cases worldwide could reach 22 million per year in the next 20 years, and cancer-related deaths could also rise to 13 million per year during the same period. Globally, approximately 60% of new cancer cases occur in developing countries, which account for 70% of annual cancer deaths worldwide.

[0004] Despite significant progress in the feasibility of various cancer treatment options, currently available chemotherapy remains unsatisfactory, and the prognosis for most patients diagnosed with cancer remains poor. Therefore, the development of new antitumor drugs (or anticancer drugs) is of paramount importance.

[0005] Poly(ADP)ribose polymerase (PARP) is a type of ribozyme widely found in eukaryotic cells that catalyzes the ribosylation of ADP. There are at least 18 subtypes, all of which contain highly conserved PARP catalytic sequences. Based on the degree of modification that catalyzes ADP-ribosylation, these can be divided into three categories: The first category catalyzes the formation of long, branched poly(ADP-ribose) chains (PARs) and includes PARP1, PARP2, Tank1, and Tank2; the second category catalyzes the formation of mono(ADP-ribosyl)transferases (MARs) and includes PARP3, 4, 6-8, 10-12, and 14-16; and the third category lacks enzymatic catalytic activity and includes PARP9 and PARP13. These subtypes share similar catalytic domains, but only the PARP1 and PARP2 subtypes contain a DNA-binding domain, enabling them to bind to damaged DNA and repair it via the base excision repair (BER) pathway. PARP1 was the first to be discovered and has the highest intracellular content, accounting for 85%–90% of total intracellular PARP activity. PARP1 is primarily involved in DNA damage repair and is the most important PARP enzyme. It is also the most widely studied and applied subtype, involved in the treatment of diseases such as cancer, stroke, inflammation, diabetes, myocardial ischemia, and neurodegenerative diseases.

[0006] PARP1 consists of 10¹⁴ amino acid residues and has a relative molecular weight of 116 kDa. Its main structure is highly conserved in eukaryotes (for example, the amino acid sequences of humans and mice share 92% homology) and comprises three domains: a C-terminal catalytic domain, an intermediate self-regulating domain (AD), and an N-terminal domain (DBD). The C-terminal catalytic domain contains two active catalytic sites: a donor domain and an acceptor domain. The intermediate self-regulating domain contains two closely linked nuclear localization signal sequences and has caspase-3 cleavage function. The N-terminal domain contains three zinc finger motifs.

[0007] PARP1 is structurally very similar to PARP2 and is an important protein-modifying enzyme involved in DNA damage repair, exhibiting high expression in various tumors. PARP1 subtypes play a crucial role in the DNA damage repair pathway, accounting for over 90% of the repair process. This pathway is abnormally activated in tumor cells, so inhibiting PARP1 activity can suppress tumor growth. In recent years, several PARP1 inhibitors have received marketing approval, and several others have entered clinical trials. This indicates that PARP1 inhibitors are a hot topic in the development of antitumor drugs.

[0008] The mechanisms of action of PARP1 inhibitors in tumors are complex and diverse, primarily involving hypotheses such as synthetic lethality, improved DNA damage repair in tumor cells, and improved regulation of nuclear factor-κB (NF-κB) and heat shock protein 70 (HSP70) in tumor cells. Although the mechanisms of action of PARP1 inhibitors are not fully understood, their tumor-suppressive effects offer new hope for cancer treatment.

[0009] Many chemotherapy drugs exert their antitumor effects by disrupting the DNA structure of tumor cells. Since tumor cells use PARP1 to repair damaged DNA, they can develop resistance to chemotherapy drugs. Therefore, PARP1 inhibitors can act as sensitizers, used in combination with other chemotherapy drugs to overcome resistance and improve efficacy. Furthermore, studies have found that using PARP1 inhibitors alone in tumor cells with BRCA1 / 2 (breast cancer 1 / 2) deletions or mutations can also yield good antitumor effects.

[0010] Compared to other clinically available PARP1 / 2 inhibitors, PARP inhibitors with high selectivity for PARP1 offer advantages in terms of improved efficacy and lower toxicity. Furthermore, potent selective inhibition of PARP1 leads to PARP1 capture in DNA, causing DNA double-strand breaks (DSBs) by disrupting the S-phase replication fork. PARP1-DNA capture is an effective mechanism for selectively killing tumor cells with homologous recombination repair deficiency (HRD).

[0011] Therefore, further investigation is needed to find better, more effective, and safer PARP inhibitors, particularly PARP1-selective PARP inhibitors.

[0012] Through continuous research, the inventors have obtained an unexpected new class of highly selective PARP1 inhibitors. The substituted nitrogen-containing bicyclic compounds described in the present invention have potent PARP1 inhibitory activity and can therefore be used to treat PARP1-mediated diseases, particularly cancer. Furthermore, the substituted nitrogen-containing bicyclic compounds described in the present invention exhibit significantly higher selectivity for PARP1 than other PARP subtypes (e.g., PARP2). [Prior art documents] [Patent Documents]

[0013] [Patent Document 1] U.S. Patent No. 4,328,245

Patent document 2

Patent document 3

Patent document 4

Patent document 5

Non-licensed literature

[0014] [Non-licensed document 1] Handbook of Chemistry and Physics, 75th edition, 1994 [Non-licensed document 2] "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, 1999 [Non-licensed document 3] Smith et al., "March's Advanced Organic Chemistry", John Wiley & Sons, New York: 2007

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

[0015] The present invention provides a novel type of substituted nitrogen-containing bicyclic compound that can be used to inhibit PARP1 as a highly selective PARP1 inhibitor, and therefore can be used to treat PARP1-mediated diseases, particularly cancer. Furthermore, the substituted nitrogen-containing bicyclic compound described in the present invention exhibits significantly higher selectivity for PARP1 than other PARP subtypes (e.g., PARP2). Moreover, experiments have shown that the substituted nitrogen-containing bicyclic compound of the present invention is stable, has a good safety profile, and possesses desirable pharmacodynamic and pharmacokinetic properties such as good brain-plasma ratio, good bioavailability, or good metabolic stability. Therefore, it has promising potential for clinical application.

[0016] The present invention also provides such compounds, methods for preparing pharmaceutical compositions containing such compounds, and the use of such compounds and pharmaceutical compositions containing such compounds in the preparation of pharmaceuticals.

[0017] In one embodiment, the present invention relates to a compound, the compound being a compound of formula (I), or its stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs.

[0018] [ka]

[0019] [In the formula, X is CR x or N;

[0020] [ka]

[0021] It is a 3-12 member heterocycline; R 1These are H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1~C6 alkyl), -C(=O)-(C1~C6 alkoxy), C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 haloalkyl, C1~C6 alkoxy, C1~C6 haloalkoxy, C1~C6 alkylthio, C1~C6 alkylamino, C1~C6 hydroxyalkyl, C3~C8 cycloalkyl, or 3~8 membered heterocyclyl; R 2a and R 2b Each of these is independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1~C6 alkyl), -C(=O)-(C1~C6 alkoxy), C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 haloalkyl, C1~C6 alkoxy, C1~C6 haloalkoxy, C1~C6 alkylthio, C1~C6 alkylamino, C1~C6 hydroxyalkyl, C1~C6 cyanoalkyl, C3~C8 cycloalkyl, 3~8 membered heterocyclyl, C6~C 10 It is an aryl or a 5- to 10-membered heteroaryl; R 2 -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1~C6 alkyl), -C(=O)-(C1~C6 alkoxy), C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, C1~C6 haloalkoxy, C1~C6 alkylthio, C1~C6 alkylamino, C1~C6 hydroxyalkyl, C1~C6 cyanoalkyl, C3~C8 cycloalkyl-L-, 3~8 membered heterocyclyl-L-, C6~C 10 It is an aryl-L- or a 5- to 10-membered heteroaryl-L-, which is either unsubstituted or substituted with 1, 2, 3, 4, or 5 Rw units; Each -L- is independent, combined, -NRn -, -O-, -S-, -C(=O)-, -C(=O)O-, -C(=O)N(R n1 )- or -(CR a R b ) m -; m is 1, 2, 3, 4, 5 or 6; R n and R n1 each independently is H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 member heterocyclyl, C6-C 10 aryl or 5-10 member heteroaryl; R a and R b each independently is H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkylamino or C1-C6 hydroxyalkyl; R 3 , R 3a and R 3b each independently is H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1-C6 alkyl), -C(=O)-(C1-C6 alkoxy), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkylamino or C1-C6 hydroxyalkyl; R 4 is H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C3-C8 cycloalkyl, 3-8 member heterocyclyl, C6-C 10It is an aryl or 5-10 member heteroaryl, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 member heterocyclyl, C6-C 10 Each of the aryl and 5-10 membered heteroaryls is independently and optionally substituted with 1, 2, 3, 4, or 5 groups selected from D, F, Cl, Br, I, -OH, -NH2, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; R x and R z Each of these is independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -COOH, -C(=O)NH2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C1-C6 hydroxyalkyl; Each R w These are independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1~C6 alkyl), -C(=O)-(C1~C6 alkoxy), C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 haloalkyl, C1~C6 alkoxy, C1~C6 haloalkoxy, C1~C6 alkylthio, C1~C6 alkylamino, C1~C6 hydroxyalkyl, C3~C8 cycloalkyl, 3~8 membered heterocyclyl, C6~C 10 It is an aryl or a 5- to 10-membered heteroaryl; n is 1, 2, 3, 4, 5, or 6. The compounds represented by formula (I) are the following compounds:

[0022] [ka]

[0023] [ka]

[0024] It does not include.

[0025] In another embodiment,

[0026] [ka]

[0027] teeth

[0028] [ka]

[0029] Here, * indicates a -CH2- connection on the left, and ** indicates a pyridinyl connection on the right.

[0030] One embodiment, each R 1 These are independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1~C4 alkyl), -C(=O)-(C1~C4 alkoxy), C1~C4 alkyl, C2~C4 alkenyl, C2~C4 alkynyl, C1~C4 haloalkyl, C1~C4 alkoxy, C1~C4 haloalkoxy, C1~C4 alkylthio, C1~C4 alkylamino, C1~C4 hydroxyalkyl, C3~C6 cycloalkyl, or 3~6 membered heterocyclyl; R 3 , R 3a and R 3b Each of these is independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1~C4 alkyl), -C(=O)-(C1~C4 alkoxy), C1~C4 alkyl, C2~C4 alkenyl, C2~C4 alkynyl, C1~C4 haloalkyl, C1~C4 alkoxy, C1~C4 haloalkoxy, C1~C4 alkylthio, C1~C4 alkylamino, or C1~C4 hydroxyalkyl; Rx and R z Each of these is independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -COOH, -C(=O)NH2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or C1-C4 hydroxyalkyl.

[0031] In another embodiment, R 1 H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-CH3, -C(=O)-OCH3, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n -Propyloxy, isopropyloxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidinyl, tetrahydrofuranil, piperidinyl, piperazinyl, or morpholinil; R 3 , R 3a and R 3bEach of these is independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-CH3, -C(=O)-OCH3, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, or 2-hydroxyethyl; R x and R z Each of these is independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -COOH, -C(=O)NH2, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, hydroxymethyl, or 2-hydroxyethyl.

[0032] In one embodiment, R 4 These are H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylamino, C3-C6 cycloalkyl, 3-6 member heterocyclyl, C6-C 10 It is an aryl or 5-6 member heteroaryl, C1-C4 alkyl, C3-C6 cycloalkyl, 3-6 member heterocyclyl, C6-C 10Aryl and 5-6 membered heteroaryls are optionally and independently substituted with 1, 2, 3, 4, or 5 groups selected from D, F, Cl, Br, I, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy.

[0033] In another embodiment, R 4H, D, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylthio, ethylthio, methylamino, dimethylamino, ethylamino, cy Clopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, phenyl, indole, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, and methyl, ethyl, n-propyl, isopropyl, cyclo Ropropyl, cyclobutyl, cyclopentyl, cyclohexyl, azacyclobutyl, oxacyclobutyl, pyrrolyl, tetrahydrofuranil, tetrahydropyranil, piperidinil, piperazine, morpholinil, phenyl, indole, naphthyl, pyrrolyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, furanil, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are each independently and optionally selected. The molecules are substituted with 1, 2, 3, 4, or 5 groups selected from D, F, Cl, Br, I, -OH, -NH2, -NO2, -CN, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, and -OCH2CF2CHF2.

[0034] In one embodiment, R 2a and R 2bEach of these is independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1~C4 alkyl), -C(=O)-(C1~C4 alkoxy), C1~C4 alkyl, C2~C4 alkenyl, C2~C4 alkynyl, C1~C4 haloalkyl, C1~C4 alkoxy, C1~C4 haloalkoxy, C1~C4 alkylthio, C1~C4 alkylamino, C1~C4 hydroxyalkyl, C1~C4 cyanoalkyl, C3~C6 cycloalkyl, 3~6 member heterocyclyl, C6~C 10 It is an aryl or 5-6 member heteroaryl.

[0035] In one embodiment, R n and R n1 Each of these is independently H, D, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 3-6 member heterocyclyl, C6-C 10 It is an aryl or a 5-6 member heteroaryl; R a and R b Each of these is independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylamino, or C1-C4 hydroxyalkyl.

[0036] In one embodiment, R 2 -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1~C4 alkyl), -C(=O)-(C1~C4 alkoxy), C1~C4 alkyl, C2~C4 alkenyl, C2~C4 alkynyl, C1~C4 alkoxy, C1~C4 haloalkoxy, C1~C4 alkylthio, C1~C4 alkylamino, C1~C4 hydroxyalkyl, C1~C4 cyanoalkyl, C3~C6 cycloalkyl-L-, 3~6 member heterocyclyl-L-, C6~C10 It is an aryl-L- or a 5-6 member heteroaryl-L-, and is either unsubstituted or has 1, 2, 3, 4, or 5 R units. w It is replaced by; R w These are independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1~C4 alkyl), -C(=O)-(C1~C4 alkoxy), C1~C4 alkyl, C2~C4 alkenyl, C2~C4 alkynyl, C1~C4 haloalkyl, C1~C4 alkoxy, C1~C4 haloalkoxy, C1~C4 alkylthio, C1~C4 alkylamino, C1~C4 hydroxyalkyl, C3~C6 cycloalkyl, 3~6 member heterocyclyl, C6~C 10 It is an aryl or a 5-6 member heteroaryl; L is as defined herein.

[0037] In one embodiment, R 2a and R 2bEach of these is independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1~C2 alkyl), -C(=O)-(C1~C2 alkoxy), methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCF3, -OCHFCH2F, -OC F2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyanomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazine, morpholinyl, phenyl, indole, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0038] In one embodiment, R n and R n1 Each of these is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazine, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; R a and R bEach of these is independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, or 2-hydroxyethyl.

[0039] In one embodiment, R 2 -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-CH3, -C(=O)-OCH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, allyl, propenyl, propargyl, propynyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyanomethyl, cyclopropyl-L-, cyclobutyl-L -, cyclopentyl-L-, cyclohexyl-L-, oxacyclopropyl-L-, azacyclopropyl-L-, oxacyclobutyl-L-, azacyclobutyl-L-, tetrahydrofuranyl-L-, pyrrolidinyl-L-, tetrahydropyranyl-L-, piperidinyl-L-, piperazinyl-L-, morpholinyl-L-, phenyl-L-, naphthyl-L-, pyrrolidinyl-L-, furanyl-L-, thiophenyl-L-, pyrazolyl-L-, imidazolyl-L-, thiazolyl-L-, oxazolyl-L-, triazolyl-L-, tetrazolyl-L-, pyridinyl-L-, pyrimidinyl-L-, pyrazinyl-L- or pyridazinyl-L-, and are unsubstituted or have 1, 2, 3, 4 or 5 R w It is replaced by; Each R w These are independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1~C3 alkyl), -C(=O)-(C1~C3 alkoxy), methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, allyl, propenyl, propargyl, propynyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazine, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; each L has the definition described in this invention.

[0040] In some embodiments, the present invention relates to a compound, which is a compound of formula (II) or formula (III), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (II) or formula (III).

[0041] [ka]

[0042] R 1 , R 2 , R 2a , R 2b , R 3 , R z , R 4and n are as defined herein.

[0043] In other embodiments, the present invention relates to a pharmaceutical composition comprising a compound of formula (I), (II), or (III) disclosed herein.

[0044] In one embodiment, the pharmaceutical composition of the present invention further comprises pharmaceutically acceptable additives, carriers, adjuvants, or any combination thereof.

[0045] In another aspect, the present invention relates to the use of compounds of formula (I), (II), or (III) disclosed herein, or pharmaceutical compositions thereof, in the manufacture of pharmaceuticals for the prevention, treatment, or mitigation of PARP1-mediated diseases.

[0046] In one embodiment, PARP1-mediated diseases include cancer, neurodegenerative diseases, cardiovascular diseases, ischemic diseases, diabetic neuropathy, reperfusion injury, osteoarthritis, osteoporosis, inflammatory diseases, and metabolic diseases.

[0047] In another embodiment, the cancer is laryngeal cancer, esophageal cancer, stomach cancer, intestinal cancer, liver cancer, kidney cancer, lung cancer, brain cancer, head and neck cancer, squamous cell carcinoma, lymphoid cancer, thyroid cancer, bladder cancer, ovarian cancer, cervical cancer, prostate cancer, genitourinary cancer, breast cancer, hematological malignancies, small cell lung cancer, lung adenocarcinoma, pancreatic cancer, colon cancer, glioblastoma, and / or monocytic leukemia.

[0048] In other embodiments, the present invention relates to the use of compounds of formula (I), (II), or (III) disclosed herein, or pharmaceutical compositions thereof, in the manufacture of a pharmacopoeia for inhibiting PARP1.

[0049] On the other hand, the present invention relates to methods for the preparation, isolation, and purification of compounds of formula (I), (II), or (III).

[0050] In biological assays, it has been shown that the compounds of the present invention can inhibit PARP1 and exhibit a selectivity for PARP1 that is significantly higher than other PARP subtypes (e.g., PARP2). Therefore, it can play the role of a highly selective PARP1 inhibitor.

[0051] Any of the embodiments disclosed herein can be combined with other embodiments as long as they do not conflict with each other, even when the embodiments are described under different aspects of the present invention. In addition, any technical feature in one embodiment can be applied to the corresponding technical features in other embodiments as long as they do not conflict with each other, even when the embodiments are described under different aspects of the present invention.

[0052] The foregoing merely summarizes certain specific aspects disclosed herein and is not intended to be limiting in nature. These aspects as well as other aspects and embodiments are described in more detail below. All cited references herein are incorporated herein by reference in their entirety. In the event of a conflict between the information disclosed herein and the cited references, the information disclosed herein shall prevail.

Mode for Carrying Out the Invention

[0053] Definitions and General Terms Here, specific embodiments of the present invention are referred to in detail, and these examples are shown in the accompanying structures and formulas. The present invention is intended to encompass all modifications, corrections, and equivalents that may be included within the scope of the present invention as defined in the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein and will be able to use them in the implementation of the present invention. The present invention is not limited to the methods and materials described herein. If one or more of the incorporated documents, patents, and similar materials are different from or conflict with the present application (including, but not limited to, defined terms, usage of terms, described techniques, etc.), the present application shall prevail.

[0054] To clarify, it is further understood that certain features of the invention that are described in the context of separate embodiments can also be provided in combination with a single embodiment. Conversely, for the sake of brevity, the various features of the invention that are described in the context of a single embodiment can also be provided separately or in any suitable partial combination.

[0055] As used herein, the following definitions apply unless otherwise indicated. For the purposes of the present invention, chemical components are identified according to the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th Edition, 1994. Further, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, 1999 and Smith et al., “March's Advanced Organic Chemistry”, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0056] As used herein, the grammatical articles “a”, “an” and “the” are intended to include “at least one” or “one or more” unless otherwise indicated herein or clearly contradicted by the context. Thus, the articles are used herein to refer to one or more than one (i.e., at least one) of the grammatical object of the article. By way of example, “a component” means one or more components, so in some cases two or more components are contemplated and can be utilized or used in the implementation of the described embodiments.

[0057] “Stereoisomer” refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric (cis / trans) isomers, atropisomers, and the like.

[0058] The term "chiral molecule" refers to a molecule that cannot be superimposed on its mirror image, while the term "achiral molecule" refers to a molecule that can be superimposed on its mirror image.

[0059] An "enantiomer" refers to two stereoisomers of a compound that are mirror images of each other and cannot be superimposed.

[0060] The term "racemic mixture" refers to an equimolar mixture of two enantiomers that lack optical activity.

[0061] A "diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectroscopic properties, or biological activity. Mixtures of diastereomers can be separated under high-resolution analytical procedures such as electrophoresis and chromatography such as HPLC.

[0062] The definitions and specifications of stereochemistry used herein generally follow SP. Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994, all of which are incorporated herein by reference. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate in the plane of polarized light. When describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule with respect to its chiral center. The prefixes d and l, or (+) and (-), are used to indicate the rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. Specific stereoisomers can be called enantiomers, and mixtures of such stereoisomers are called enantiomer mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, and this can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0063] Any chiral atom (e.g., carbon) of the compounds disclosed herein may exist in racemic or enantiomerically enriched configurations, such as (R), (S), or (R,S). In certain embodiments, each chiral atom has an enantiomer excess of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% in the (R) or (S) configuration.

[0064] Depending on the selection of starting materials and procedures, the compound may exist in one form or a mixture thereof of possible stereoisomers, such as racemates and diastereomer mixtures, depending on the number of chiral carbon atoms. Optically active (R) or (S) isomers are prepared using chiral synthons or chiral reagents, or separated using conventional techniques. If the compound contains a double bond, the substituent may be in an E or Z configuration, and if the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may be in a cis or trans configuration.

[0065] Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on the physicochemical differences of the components, for example by chromatography and / or fractional crystallization. Cis and trans isomers are diastereomers.

[0066] Any resulting racemic mixture of the final product or intermediate can be separated into optically charged enantiomers by methods known to those skilled in the art, for example, by separation of its diastereomer salts. The racemic product can also be separated by chiral chromatography, for example, high-performance liquid chromatography (HPLC) using a chiral adsorbent. Preferred enantiomers can also be prepared by asymmetric synthesis. For example, see Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Principles of Asymmetric Synthesis (2nd edition, Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions, p. 268 (EL Eliel, ed., Univ. of Notre Dame Press, Notre Dame, 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G., ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0067] The term "tautomer" or "tautomer" refers to structural isomers of different energies that can be interconverted across a low energy barrier. If tautomerization is possible (e.g., in solution), then chemical equilibrium of the tautomer can be achieved. For example, proton tautomers (also known as prototropic tautomers) involve interconversion via proton transfer, such as the isomerization of keto-enols and imino-enamines.

[0068] The term "pharmaceutically acceptable," as used herein, means a compound, material, composition, and / or dosage form that is suitable for use in contact with a patient's tissue without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio, and which is effective for its intended use, within the bounds of appropriate medical judgment.

[0069] The term "optionally substituted by ~" can be used interchangeably with the term "unsubstituted or substituted by ~", and means that the structure is either unsubstituted or substituted by one or more substituents described in the present invention, including but not limited to D, F, Cl, Br, I, N3, -CN, -NO2, -NH2, -OH, -SH, -COOH, -CONH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-alkyl, -C(=O)-alkoxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, hydroxyalkyl, cyanoalkyl, aminoalkyl, (alkoxy)-alkylene, (alkylamino)-alkylene, (cycloalkyl)-alkylene, (heterocyclyl)-alkylene, (aryl)-alkylene, (heteroaryl)-alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl, etc.

[0070] In general, the term "substitution" refers to the substitution of one or more hydrogen groups in a given structure or group having a particular substituent. Unless otherwise indicated, substituents may be substituted at any reasonable position on the group. If two or more positions in a given structural formula can be substituted by one or more specific substituents selected from the group, the substituents may be substituted at reasonable positions in the structural formula in the same or different ways.

[0071] Furthermore, it needs to be explained that the phrases "each ~ is independently ~" and "each of ~ is independently ~" should be understood broadly unless otherwise specified. Specific options represented by the same symbol are either independent of each other on different bases, or specific options represented by the same symbol are independent of each other on the same base.

[0072] As used herein, the term “subject” refers to an animal. Typically, an animal is a mammal. The subject may also refer to, for example, primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0073] As used herein, “patient” means a human being (including adults and children) or another animal. In one embodiment, “patient” means a human being.

[0074] The term "comprise" is an open expression meaning that it includes the content disclosed herein but does not exclude other content.

[0075] Throughout this specification, substituents of the compounds disclosed herein are disclosed in groups or ranges. It is specifically intended that the present invention encompasses any individual partial combination of members of such groups and ranges. For example, the term “C1-C6 alkyl” is specifically intended to disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl individually.

[0076] Linking substituents are described in various places in this specification. Where a structure clearly requires a linking group, the Markush variables listed in that group are understood to be linking groups. For example, if a structure requires a linking group and the definition of the Markush group for that variable lists "alkyl" or "aryl," it is understood that "alkyl" or "aryl" represents the linking alkylene group or arylene group, respectively.

[0077] The term "D" refers to a single deuterium atom.

[0078] The terms "halogen" and "halogenated" can be used interchangeably in the present invention and refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0079] The term "heteroatom" includes N, S, and P in any oxidation state, O, S, N, P, and Si, primary, secondary, tertiary amines, and quaternary ammonium salts, or a hydrogen atom on a nitrogen atom of a heterocyclic ring is replaced by, for example, N (such as N in 3,4-dihydro-2H-pyrrole), NH (such as NH in pyrrolidinyl), or NR' (such as NR' in N-substituted pyrrolidinyl, where R' is a substituent described in the present invention).

[0080] The term "alkyl" or "alkyl group" refers to a linear or branched monovalent saturated hydrocarbon group having 1 to 20 carbon atoms, and the alkyl group is optionally substituted by one or more substituents described herein. In one embodiment, the alkyl group contains 1 to 6 carbon atoms, in another embodiment, the alkyl group contains 1 to 4 carbon atoms, and in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), etc.

[0081] The term "alkylene" refers to a divalent saturated hydrocarbon group derived from a straight-chain or branched-chain saturated hydrocarbon by the removal of two hydrogen atoms. Unless otherwise specified, alkylene groups contain 1 to 12 carbon atoms. In some embodiments, alkylene groups contain 1 to 6 carbon atoms, in other embodiments, alkylene groups contain 1 to 4 carbon atoms, in other embodiments, alkylene groups contain 1 to 3 carbon atoms, and in other embodiments, alkylene groups contain 1 to 2 carbon atoms. Examples of alkylene groups include methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), etc. Alkylene groups are optionally substituted with one or more substituents described herein.

[0082] The term "alkenyl" refers to a molecule with at least one unsaturated site, i.e., carbon-carbon, sp. 2 Alkenyl refers to a linear or branched monovalent hydrocarbon group of 2 to 12 carbon atoms having a double bond. Alkenyl groups may be independently substituted by one or more substituents as described herein, and may include groups having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. In some embodiments, the alkenyl contains 2 to 8 carbon atoms. In other embodiments, the alkenyl contains 2 to 6 carbon atoms. In yet another embodiment, the alkenyl contains 2 to 4 carbon atoms. Some non-limiting examples of alkenyl groups include ethenyl or vinyl (-CH=CH2), allyl (-CH2CH=CH2), 1-propenyl (i.e., propenyl, -CH=CH-CH3), etc.

[0083] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group of 2 to 12 carbon atoms having at least one unsaturated site, i.e., a carbon-carbon, sp triple bond, and the alkynyl group may be independently substituted by one or more substituents as described herein, of optional choice. In some embodiments, the alkynyl contains 2 to 8 carbon atoms. In other embodiments, the alkynyl contains 2 to 6 carbon atoms. In yet another embodiment, the alkynyl contains 2 to 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), 1-propynyl (i.e., propynyl, -C≡C-CH3), etc.

[0084] The term "alkoxy," as already defined, refers to an alkyl group bonded to a portion of the parent molecule via an oxygen atom. Unless otherwise specified, an alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms. In another embodiment, the alkoxy group contains 1 to 4 carbon atoms. In yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.

[0085] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), and 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3).

[0086] The term "alkathio" indicates that an alkyl group is bonded to the rest of the molecule via a sulfur atom, and the alkyl group has the meaning described in this invention. Unless otherwise specified, the alkathio group contains 1 to 12 carbon atoms. In one embodiment, the alkathio group contains 1 to 6 carbon atoms, in another embodiment, the alkathio group contains 1 to 4 carbon atoms, and in yet another embodiment, the alkathio group contains 1 to 3 carbon atoms. The alkathio group may optionally be substituted with one or more substituents described in this invention.

[0087] Examples of alkylthio groups include, but are not limited to, methylthio (MeS, -SCH3), ethylthio (EtS, -SCH2CH3), 1-propanthio (n-PrS, n-propanthio, -SCH2CH2CH3), 2-propanthio (i-PrS, i-propanthio, -SCH(CH3)2), 1-butanthio (n-BuS, n-butanthio, -SCH2CH2CH2CH3), 2-methyl-1-propanthio (i-BuS, i-butanthio, -SCH2CH(CH3)2), 2-butanthio (s-BuS, s-butanthio, -SCH(CH3)CH2CH3), and 2-methyl-2-propanthio (t-BuS, t-butanthio, -SC(CH3)3).

[0088] The terms “alkamino” or “alkylamino” refer to “N-alkylamino” and “N,N-dialkylamino,” where the amino group is independently substituted with one or two alkyl groups, which are defined herein. Preferred alkylamino groups may be monoalkylaminos or dialkylaminos, examples of which include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N,N-dimethylamino (dimethylamino), and N,N-diethylamino (diethylamino). The alkylamino group is optionally substituted with one or more substituents as described herein.

[0089] The term "hydroxyalkyl" means that an alkyl group is substituted with one or more hydroxyl groups, and the alkyl group has the meaning described in this invention. Examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-1-propyl, 3-hydroxy-1-propyl, and 2,3-dihydroxypropyl.

[0090] The term "cyanoalkyl" means that an alkyl group is replaced with one or more cyano groups, and the alkyl group has the meaning described in this invention. Examples of cyanoalkyls include, but are not limited to, cyanomethyl, 2-cyanoethyl, 2-cyano-1-propyl, 3-cyano-1-propyl, and 2,3-dicyanopropyl.

[0091] The term "aminoalkyl" means that an alkyl group is substituted with one or more amino groups, and the alkyl group has the meaning described in this invention. Examples of aminoalkyl groups include, but are not limited to, aminomethyl, 2-aminoethyl, 2-amino-1-propyl, 3-amino-1-propyl, and 2,3-diaminopropyl.

[0092] The term "haloalkyl" means that an alkyl group is substituted with one or more halogen atoms, and the alkyl group has the meaning described in this invention. Examples of haloalkyls include, but are not limited to, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CHFCH3, -CH2CH2F, -CF2CH3, -CHCF2CHF2, etc. In one embodiment, C1-C6 haloalkyls include fluorinated C1-C6 alkyl groups, in another embodiment, C1-C4 haloalkyls include fluorinated C1-C4 alkyl groups, and in yet another embodiment, C1-C2 haloalkyls include fluorinated C1-C2 alkyl groups.

[0093] The term "haloalkoxy" indicates that an alkoxy group is substituted with one or more halogen atoms, and the alkoxy group has the meaning described in this invention. Examples of such alkoxy groups include, but are not limited to, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCHFCH3, -OCH2CH2F, -OCF2CH3, -OCH2CF2CHF2, etc. In one embodiment, the C1-C6 haloalkoxy group includes a fluorinated C1-C6 alkoxy group; in another embodiment, the C1-C4 haloalkoxy group includes a fluorinated C1-C4 alkoxy group; and in yet another embodiment, the C1-C2 haloalkoxy group includes a fluorinated C1-C2 alkoxy group.

[0094] The terms "consisting of j-k atoms" or "j-k elements" indicate that the cyclic group consists of j-k ring atoms, including carbon atoms and / or heteroatoms such as O, N, S, P, etc., where j and k are independently any non-zero natural numbers and k > j, and "j-k" includes j, k, and any natural numbers between them. For example, "consisting of 3-8 atoms" or "3-8 members", "consisting of 3-6 atoms" or "3-6 members", "consisting of 5-10 atoms" or "5-10 members", and "consisting of 5-6 atoms" or "5-6 members" indicate that the cyclic group consists of 3-8 (i.e., 3, 4, 5, 6, 7, or 8), 3-6 (i.e., 3, 4, 5, or 6), 5-10 (i.e., 5, 6, 7, 8, 9, or 10), or 5-6 (i.e., 5, or 6) ring atoms, including carbon atoms and / or heteroatoms such as O, N, S, P, etc. For example, piperidinyl is a heterocyclyl or a six-membered heterocyclyl consisting of six atoms, and pyridinyl is a heteroaryl group or a six-membered heteroaryl group consisting of six atoms.

[0095] The terms "(alkoxy)-alkylene," "(alcamino)-alkylene," "(cycloalkyl)-alkylene," "(heterocyclyl)-alkylene," "(aryl)-alkylene," and "(heteroaryl)-alkylene" indicate that each of the alkoxy, alcamino, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is independently linked to the remainder of the molecule via an alkylene group, and each of the alkoxy, alcamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, and alkylene groups has the meaning described in the present invention. For example, examples of (cycloalkyl)-alkylene include, but are not limited to, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, and cyclohexylmethylene. Another example, examples of (aryl)-alkylene include, but are not limited to, phenylmethylene, phenylethylene, and phenylpropylene. Each of (alkoxy)-alkylene, (alkylamino)-alkylene, (cycloalkyl)-alkylene, (heterocyclyl)-alkylene, (aryl)-alkylene, and (heteroaryl)-alkylene may be optionally and independently replaced with one or more substituents described in the present invention.

[0096] The term "carbobicyclyl" or "carbocyclic ring" refers to a monovalent or polyvalent non-aromatic saturated or partially unsaturated ring having 3 to 12 carbon atoms as a monocyclic, bicyclic, or tricyclic ring system. Carbocyclyl groups include spirocarbobicyclyl groups or condensed carbocyclyl groups. Preferred carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl groups. In one embodiment, the carbocyclic group contains 3 to 10 carbon atoms, for example, C3 to C 10A carbocyclic group is, in another embodiment, a carbocyclic group containing 3 to 8 carbon atoms, for example, a C3 to C8 carbocyclic group, and in yet another embodiment, a carbocyclic group containing 3 to 6 carbon atoms, for example, a C3 to C6 carbocyclic group. In yet another embodiment, a monocyclic carbocyclic group containing 4 to 8 carbon atoms, for example, a C4 to C8 monocyclic carbocyclic group, and in yet another embodiment, a monocyclic carbocyclic group containing 4 to 6 carbon atoms, for example, a C4 to C6 monocyclic carbocyclic group. Further examples of carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopenta-1-enyl, 1-cyclopenta-2-enyl, 1-cyclopenta-3-enyl, cyclohexyl, 1-cyclohexa-1-enyl, 1-cyclohexa-2-enyl, 1-cyclohexa-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc., and the carbocyclyl group is optionally substituted with one or more substituents described herein.

[0097] The term "cycloalkyl" refers to a monocyclic, bicyclic, or tricyclic saturated ring having 3 to 12 carbon atoms, whether monovalent or polyvalent. Bicyclic or tricyclic ring systems may include fused rings, bridging rings, and spiro rings. In one embodiment, the cycloalkyl group contains 3 to 10 carbon atoms, for example, C3 to C 10 The cycloalkyl group is a cycloalkyl group, and in another embodiment, the cycloalkyl group comprises 3 to 8 carbon atoms, for example, a C3-C8 cycloalkyl group, and in yet another embodiment, the cycloalkyl group comprises 3 to 6 carbon atoms, for example, a C3-C6 cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. As described herein, the C3-C8 cycloalkyl group includes the C3-C6 cycloalkyl group, and the C3-C6 cycloalkyl group includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl group is optionally substituted with one or more substituents as described herein.

[0098] The terms “heterocyclic group” and “heterocyclyl” are used interchangeably herein and refer to a non-aromatic saturated or partially unsaturated monocyclic, bicyclic, or tricyclic system containing 3 to 12 ring atoms, where bicyclic or tricyclic systems may include fused rings, bridging rings, and spirocyclic rings. One or more atoms of the ring are independently replaced with heteroatoms having the meanings set forth in this invention. In one embodiment, the heterocyclic group is a monocyclic heterocyclic group consisting of 3 to 8 ring atoms (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally replaced with one or more oxygen atoms to obtain groups such as SO, SO2, PO, PO2), and in another embodiment, the heterocyclic group is a monocyclic heterocyclic group consisting of 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally replaced with one or more oxygen atoms) In another embodiment, the heterocyclic group is a monocyclic heterocyclic group consisting of 7 to 12 ring atoms (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally replaced with one or more oxygen atoms to obtain groups such as SO, SO2, PO, PO2), and the carbocyclyl group is optionally substituted with one or more substituents as described herein.

[0099] The ring atoms of a heterocyclyl can be carbon groups or heteroatomic groups. The -CH2- group of the ring is replaced with -C(=O)-, the sulfur atom of the ring is optionally oxidized to an S-oxide, and the nitrogen atom of the ring is optionally oxidized to an N-oxygen compound. Some non-limiting examples of heterocyclyl groups include oxyranil, azetidinil, oxetanil, thietanil, pyrrolidinil, 2-pyrrolinil, 3-pyrrolinil, pyrazolinil, pyrazolidinil, imidazolinil, imidazolidinil, tetrahydrofuranil, dihydrofuranil, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolanil, dithiolanil, tetrahydropyranil, dihydropyranil, 2H-pyranil, 4H-pyranil, tetrahydrothiopyranil, piperidinil, morpholinil, thiomorpholinil, piperazinil, dioxanil, dithianil, thioxanil, homopiperazinil, homopiperidinil, oxepanil, thiepanil, oxazepinil, diazepinil, thiazepinil, 2-oxa-5-azabicyclo[2.2.1]hepta-5-yl, etc. Some non-limiting examples of heterocyclyl groups in which the -CH2- group is substituted by a -C(=O)- moiety include 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinol, 3,5-dioxopiperidinyl, pyrimidinedioneyl, etc. Some non-limiting examples of heterocyclyl groups in which the sulfur atom of the ring is oxidized include sulforanyl, 1,1-dioxo-thiomorpholinyl, etc. The heterocyclyl group is optionally substituted by one or more substituents described herein.

[0100] The term "aryl" refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems having a total of 6 to 14 ring members, or 6 to 12 ring members, or 6 to 10 ring members, where at least one ring in the system is aromatic, and each ring in the system contains 3 to 7 ring members and has one or more bonds to the rest of the molecule. Aryl groups are generally, but not necessarily, bonded to the parent molecule through the aromatic ring of the aryl group. The terms "aryl" and "aromatic ring" are interchangeable herein. Examples of aryl groups include phenyl, indenyl, naphthyl, and anthracene. Aryl groups are optionally substituted with one or more substituents as described herein.

[0101] The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems having a total of 5 to 12 ring members, or 5 to 10 ring members, or 5 to 6 ring members, wherein at least one ring in the system is aromatic, at least one ring member is selected from heteroatoms, and each ring in the system contains 5 to 7 ring members and has one or more bonding sites to the rest of the molecule. Heteroaryl groups are generally, but not necessarily, bonded to the parent molecule through the aromatic ring of the heteroaryl group. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "aromatic heterocyclic," or "heteroaromatic compound." Heteroaryl groups are optionally substituted with one or more substituents disclosed herein. In one embodiment, a 5 to 10-membered heteroaryl contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.

[0102] Examples of heteroaryl groups include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyrimidinyl), 2-thiazolyl, 4-thiazolyl, This includes, but is not limited to, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, and 1,3,5-triazinyl, as well as the following bicyclic compounds: This includes, but is not limited to, benzimidazolyl, benzofuranil, benzothiophenyl, indoleyl (e.g., 2-indoleyl), purineyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl) (e.g., 3-isoquinolinyl or 4-isoquinolinyl), imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, etc.

[0103] The term “protecting group” or “PG” refers to a substituent commonly used to block or protect specific functionalities in a compound during reaction with other functional groups. For example, an “amino protecting group” is a substituent attached to an amino group that blocks or protects amino functionalities in a compound. Preferred amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a “hydroxy protecting group” refers to a substituent of a hydroxyl group that blocks or protects hydroxy functionalities. Some non-limiting examples of preferred hydroxy protecting groups include trialkylsilyl, acetyl, benzoyl, and benzyl. A “carboxy protecting group” refers to a substituent of a carboxyl group that blocks or protects carboxyl functionalities. Common carboxyl protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2-(diphenylphosphinol)ethyl, and nitroethyl. For a general explanation of protecting groups and their use, see Greene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991, and Kocienski et al., Protecting Groups, Thieme, Stuttgart, 2005.

[0104] The term "prodrug" refers to a compound that is transformed in vivo into a compound of formula (I), (II), or (III). Such transformations may be affected by hydrolysis of the prodrug form to the parent form in blood or tissue, for example, in the transformation of blood or enzymes. Prodrugs of the compounds disclosed herein may be esters, for example. Some common esters used as prodrugs are phenyl esters, aliphatic (C) esters. 1~24These include esters, acyloxymethyl esters, carbonate esters, carbamic acid esters, and amino acid esters. For example, compounds disclosed herein that contain a hydroxyl group may be acylated at this position in their prodrug form. Other prodrug forms include phosphates, such as phosphate compounds derived from the phosphononation of the hydroxyl group of the parent compound.

[0105] A “metabolite” is a product produced in the body through the metabolism of a particular compound or a salt thereof. Metabolites of compounds can be identified using conventional techniques known in the art, and their activity can be determined using tests such as those described herein. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc., of the administered compound. Accordingly, the present invention includes metabolites of compounds disclosed herein, including metabolites produced by contacting mammals with the compounds disclosed herein for a sufficient period of time.

[0106] "Pharmacologically acceptable salts" means organic or inorganic salts of the compounds disclosed herein. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al., in J. Pharmaceutical Sciences, 1977, 66: pp. 1-19, describe pharmaceutically acceptable salts in detail, which are incorporated herein by reference. Some non-limiting examples of pharmaceutically acceptable, non-toxic salts include salts of amino groups formed with inorganic acids, e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids, e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-H. This includes droxyethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, malons, methanesulfons, 2-naphthalenesulfons, nicotinates, nitrates, oleates, palmitates, pamoates, pectins, peroxosulfates, 3-phenylpropionates, picrates, pivalates, propions, stearates, thiocyans, p-toluenesulfons, undecanoates, valersates, etc. Suitable base-derived salts include alkali metals, alkaline earth metals, ammonium and N + (C 1~4This invention also includes alkyl) tetrasalts. The present invention also envisions the quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Water-soluble or oil-soluble, or water-dispersible or oil-dispersible products can be obtained by such quaternization. Typical alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-C8 sulfonates, or aryl sulfonates. Other salts may be used, for example, in the separation or purification of the product, but non-toxic and physiologically acceptable salts are preferred.

[0107] These salts can be formed by conventional methods, for example, by reacting the free base form of the product with one or more equivalent acids in a solvent or culture medium (the salt is insoluble) or a solvent (e.g., a solvent from which water has been removed under vacuum), by freeze-drying, or by exchanging the anions of the existing salt with other anions using a suitable ion-exchange resin.

[0108] The term "solvate" refers to an association or complex of one or more solvent molecules and a compound disclosed herein. Some non-limiting examples of solvents that form solvates include water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0109] The term "hydrate" can be used when the solvent is water. In one embodiment, one solvent molecule associates with one molecule of the compound disclosed herein, such as a hydrate. In another embodiment, two or more solvent molecules may associate with one molecule of the compound disclosed herein, such as a dihydrate. In yet another embodiment, fewer than one solvent molecule may associate with one molecule of the compound disclosed herein, such as a hemihydrate. Furthermore, all solvates of the present invention retain the biological efficacy of the unhydrated form of the compound disclosed herein.

[0110] As used herein, the terms “to treat,” “to treat,” or “treatment” of any disease or disorder mean, in one embodiment, to alleviate the disease or disorder (i.e., to delay, cessate, or reduce the onset of the disease or at least one of its clinical symptoms). In another embodiment, “to treat,” “to treat,” or “treatment” means to alleviate or improve at least one physical parameter, including one that the patient may not perceive. In yet another embodiment, “to treat,” “to treat,” or “treatment” means to modulate the disease or disorder in any way, either physically (e.g., stabilization of perceived symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, “to treat,” “to treat,” or “treatment” means to prevent or delay the onset, development, or progression of the disease or disorder.

[0111] The term “prevention” or “prevention” means reducing the risk of developing a disease or disability (i.e., causing at least one clinical symptom of a disease that has not yet developed in an individual who is exposed to or susceptible to a disease but has not yet experienced or presented with any symptoms of the disease).

[0112] Unless otherwise stated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, salts, and pharmaceutically acceptable prodrugs of the compounds of the present invention are included within the scope of the present invention.

[0113] In structures disclosed herein, if the stereochemistry of any particular chiral atom is not specified, all stereoisomers of that structure are considered to be within the scope of the invention and are included in the invention as disclosed compounds. If the stereochemistry is indicated by a solid wedge or dotted line representing a particular configuration, the stereoisomers of that structure are therefore clearly defined.

[0114] The "N-oxides" of the compounds of the present invention are also included within the scope of the present invention. The N-oxides of the compounds of the present invention can be prepared by oxidizing the corresponding nitrogen-containing basic substance at high temperature using a common oxidizing agent (e.g., hydrogen peroxide) in the presence of an acid such as acetic acid, or by reacting it with a peracid in a suitable solvent, such as peracetic acid in dichloromethane, ethyl acetate, or methyl acetate, or 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

[0115] The compounds represented by formulas (I), (II), or (III) may exist in the form of salts. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other components of the formulation and / or the mammal being treated. In another embodiment, the salt is not necessarily a pharmaceutically acceptable salt and may be an intermediate used in the preparation and / or purification of the compounds represented by formulas (I), (II), or (III), and / or the isolation of the enantiomer compounds represented by formulas (I), (II), or (III).

[0116] The pharmaceutically acceptable salts of the present invention can be synthesized from basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (e.g., hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or an organic solvent, or a mixture of the two. Generally, when feasible, the use of a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable. A list of additional suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 20th Edition, Mack Publishing Company, Easton, Pa., (1985), as well as in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0117] Any formula shown herein is also intended to represent both the non-isotopically enriched and isotopically enriched forms of the compounds. Any formula shown herein is also intended to represent both the non-isotopically enriched and isotopically enriched forms of the compounds. Exemplary isotopes that can be introduced into the compounds of the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.

[0118] In another aspect, the present invention relates to intermediates for preparing compounds of formula (I), (II) or (III).

[0119] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention. In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, additive, adjuvant, solvent or combination thereof. In another embodiment, the pharmaceutical composition can be in the form of a liquid, solid, semi-solid, gel or spray formulation.

[0120] Description of the compounds of the present invention The present invention relates to substituted nitrogen-containing bicyclic compounds, pharmaceutically acceptable salts thereof, pharmaceutical preparations and compositions thereof, which can be used to inhibit PARP1 and have the potential for use in the treatment of PARP1-mediated diseases, particularly cancer. Furthermore, the substituted nitrogen-containing bicyclic compounds described in the present invention exhibit a significantly higher selectivity for PARP1 than other PARP subtypes (e.g., PARP2). The present invention further describes a method for synthesizing this compound. The compounds of the present invention exhibit good biological activity.

[0121] In one aspect, the present invention relates to a compound which is a compound of formula (I), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I).

[0122] [Chemical formula]

[0123] [Wherein, R 1 , R 2 , R 2a , R 2b , R 3 , R 3a , R 3b , R 4 , X,

[0124] [Chemical formula]

[0125] , R z Each of n is as defined herein.

[0126] In some embodiments, the compound of formula (I) of the present invention does not contain the following compounds:

[0127] [ka]

[0128] [ka]

[0129] [ka]

[0130] In some embodiments, X is CR x Or it is N.

[0131] In some embodiments,

[0132] [ka]

[0133] These are 3-12 member heterocyclines.

[0134] In some embodiments,

[0135] [ka]

[0136] These are 3- to 8-membered heterocyclines.

[0137] In another embodiment,

[0138] [ka]

[0139] teeth

[0140] [ka]

[0141] Here, * indicates the -CH2- link on the left, and ** indicates the pyridinyl group link on the right.

[0142] In one embodiment, R 1 These are H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1~C6 alkyl), -C(=O)-(C1~C6 alkoxy), C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 haloalkyl, C1~C6 alkoxy, C1~C6 haloalkoxy, C1~C6 alkylthio, C1~C6 alkylamino, C1~C6 hydroxyalkyl, C3~C8 cycloalkyl, or 3~8 membered heterocyclyl.

[0143] In one embodiment, R 1 These are H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1~C4 alkyl), -C(=O)-(C1~C4 alkoxy), C1~C4 alkyl, C2~C4 alkenyl, C2~C4 alkynyl, C1~C4 haloalkyl, C1~C4 alkoxy, C1~C4 haloalkoxy, C1~C4 alkylthio, C1~C4 alkylamino, C1~C4 hydroxyalkyl, C3~C6 cycloalkyl, or 3~6 membered heterocyclyl.

[0144] In one embodiment, R 1H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-CH3, -C(=O)-OCH3, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n -Propyloxy, isopropyloxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidinyl, tetrahydrofuranil, piperidinyl, piperazinyl, or morpholinil.

[0145] In one embodiment, R 2a and R 2b Each of these is independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1~C4 alkyl), -C(=O)-(C1~C6 alkoxy), C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 haloalkyl, C1~C6 alkoxy, C1~C6 haloalkoxy, C1~C6 alkylthio, C1~C6 alkylamino, C1~C6 hydroxyalkyl, C1~C6 cyanoalkyl, C3~C8 cycloalkyl, 3~8 membered heterocyclyl, C6~C 10 It is an aryl or 5-10 membered heteroaryl.

[0146] In one embodiment, R 2a and R 2bEach of these is independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1~C4 alkyl), -C(=O)-(C1~C4 alkoxy), C1~C4 alkyl, C2~C4 alkenyl, C2~C4 alkynyl, C1~C4 haloalkyl, C1~C4 alkoxy, C1~C4 haloalkoxy, C1~C4 alkylthio, C1~C4 alkylamino, C1~C4 hydroxyalkyl, C1~C4 cyanoalkyl, C3~C6 cycloalkyl, 3~6 member heterocyclyl, C6~C 10 It is an aryl or 5-6 member heteroaryl.

[0147] In another embodiment, R 2a and R 2b Each of these is independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1~C2 alkyl), -C(=O)-(C1~C2 alkoxy), methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCF3, -OCHFCH 2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyanomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazine, morpholinyl, phenyl, indole, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0148] In one embodiment, R 2-CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1~C6 alkyl), -C(=O)-(C1~C6 alkoxy), C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, C1~C6 haloalkoxy, C1~C6 alkylthio, C1~C6 alkylamino, C1~C6 hydroxyalkyl, C1~C6 cyanoalkyl, C3~C8 cycloalkyl-L-, 3~8 membered heterocyclyl-L-, C6~C 10 It is an aryl-L- or a 5- to 10-membered heteroaryl-L-, and is either unsubstituted or has 1, 2, 3, 4, or 5 R members. w It is replaced by L and R w This has the meaning described in the present invention.

[0149] In one embodiment, R 2 -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1~C4 alkyl), -C(=O)-(C1~C4 alkoxy), C1~C4 alkyl, C2~C4 alkenyl, C2~C4 alkynyl, C1~C4 alkoxy, C1~C4 haloalkoxy, C1~C4 alkylthio, C1~C4 alkylamino, C1~C4 hydroxyalkyl, C1~C4 cyanoalkyl, C3~C6 cycloalkyl-L-, 3~6 member heterocyclyl-L-, C6~C 10 It is an aryl-L- or a 5-6 member heteroaryl-L-, and is either unsubstituted or has 1, 2, 3, 4, or 5 R units. w It is replaced by L and R w This has the meaning described in the present invention.

[0150] In another embodiment, R 2-CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-CH3, -C(=O)-OCH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, allyl, propenyl, propynyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyanomethyl, cyclopropyl-L-, cyclobutyl-L-, cyclopentyl-L-, cyclohexyl-L- , oxacyclopropyl-L-, azacyclopropyl-L-(azircyclopropyl-L-), oxacyclobutyl-L-, azacyclobutyl-L-(azircyclobutyl-L-), tetrahydrofuranyl-L-, pyrrolidinyl-L-, tetrahydropyranyl-L-, piperidinyl-L-, piperazinyl-L-, morpholinyl-L-, phenyl-L-, naphthyl-L-, pyrrolidinyl-L-, furanyl-L-, thiophenyl-L-, pyrazolyl-L-, imidazolyl-L-, thiazolyl-L-, oxazolyl-L-, triazolyl-L-, tetrazolyl-L-, pyridinyl-L-, pyrimidinyl-L-, pyrazinyl-L- or pyridazinyl-L-, and are unsubstituted or have 1, 2, 3, 4 or 5 R w It is replaced by L and R w This has the meaning described in the present invention.

[0151] In one embodiment, each -L- is independently combined with -NR n -, -O-, -S-, -C(=O)-, -C(=O)O-, -C(=O)N(R n1 )- or -(CR a R b ) m - and R n , R n1 , R a , R b And m each have the meanings described in this invention.

[0152] In one embodiment, each -L- is independently bonded to -NH-, -O-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NH-, or -(CH2) m - and m has the meaning described in this invention.

[0153] In one embodiment, R n and R n1 Each is independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 member heterocyclyl, and C6-C 10 It is an aryl or 5-10 membered heteroaryl.

[0154] In one embodiment, R n and R n1 Each of these is independently H, D, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 3-6 member heterocyclyl, C6-C 10 It is an aryl or 5-6 member heteroaryl.

[0155] In another embodiment, R n and R n1 Each of these is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazine, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0156] In one embodiment, R 3 , R 3a and R 3bEach of these is independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1~C6 alkyl), -C(=O)-(C1~C6 alkoxy), C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 haloalkyl, C1~C6 alkoxy, C1~C6 haloalkoxy, C1~C6 alkylthio, C1~C6 alkylamino, or C1~C6 hydroxyalkyl.

[0157] In one embodiment, R 3 , R 3a and R 3b Each of these is independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1~C4 alkyl), -C(=O)-(C1~C4 alkoxy), C1~C4 alkyl, C2~C4 alkenyl, C2~C4 alkynyl, C1~C4 haloalkyl, C1~C4 alkoxy, C1~C4 haloalkoxy, C1~C4 alkylthio, C1~C4 alkylamino, or C1~C4 hydroxyalkyl.

[0158] In another embodiment, R 3 , R 3a and R 3bEach of these is independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-CH3, -C(=O)-OCH3, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, or 2-hydroxyethyl.

[0159] In one embodiment, R a and R b Each of these is independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkylamino, or C1-C6 hydroxyalkyl.

[0160] In one embodiment, R a and R b Each of these is independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylamino, or C1-C4 hydroxyalkyl.

[0161] In another embodiment, R a and R bEach of these is independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, or 2-hydroxyethyl.

[0162] In one embodiment, R 4 These are H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C3-C8 cycloalkyl, 3-8 member heterocyclyl, C6-C 10 It is an aryl or 5-10 member heteroaryl, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 member heterocyclyl, C6-C 10 Aryl and 5-10 membered heteroaryls are optionally and independently substituted with 1, 2, 3, 4, or 5 groups selected from D, F, Cl, Br, I, -OH, -NH2, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.

[0163] In one embodiment, R 4 These are H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylamino, C3-C6 cycloalkyl, 3-6 member heterocyclyl, C6-C 10 It is an aryl or 5-6 membered heteroaryl, C1-C4 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C 10Aryl and 5-6 membered heteroaryls are optionally and independently substituted with 1, 2, 3, 4, or 5 groups selected from D, F, Cl, Br, I, -OH, -NH2, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy.

[0164] In another embodiment, R 4H, D, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylthio, ethylthio, methylamino, dimethylamino, ethyl Mino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azacyclobutyl, oxacyclobutyl, pyrrolyl, tetrahydrofuranil, tetrahydropyranil, piperidinil, piperazinil, morpholinil, phenyl, indole, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanil, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinil, pyrazinyl, or pyridazinil, and methyl, ethyl, n-propyl Each of the following is independently and optionally selected: Substituted with 1, 2, 3, 4, or 5 groups selected from F, Cl, Br, I, -OH, -NH2, -NO2, -CN, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3 and -OCH2CF2CHF2.

[0165] In one embodiment, R x and R zEach of these is independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -COOH, -C(=O)NH2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C1-C6 hydroxyalkyl.

[0166] In one embodiment, R x and R z Each of these is independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -COOH, -C(=O)NH2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or C1-C4 hydroxyalkyl.

[0167] In another embodiment, R x and R z Each of these is independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -COOH, -C(=O)NH2, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, hydroxymethyl, or 2-hydroxyethyl.

[0168] One embodiment, each R w These are independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1~C6 alkyl), -C(=O)-(C1~C6 alkoxy), C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 haloalkyl, C1~C6 alkoxy, C1~C6 haloalkoxy, C1~C6 alkylthio, C1~C6 alkylamino or C1~C6 hydroxyalkyl, C3~C8 cycloalkyl, 3~8 membered heterocyclyl, C6~C 10 It is an aryl or 5-10 membered heteroaryl.

[0169] One embodiment, each R w These are independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1~C4 alkyl), -C(=O)-(C1~C4 alkoxy), C1~C4 alkyl, C2~C4 alkenyl, C2~C4 alkynyl, C1~C4 haloalkyl, C1~C4 alkoxy, C1~C4 haloalkoxy, C1~C4 alkylthio, C1~C4 alkylamino, C1~C4 hydroxyalkyl, C3~C6 cycloalkyl, 3~6 member heterocyclyl, C6~C 10 It is an aryl or 5-6 member heteroaryl.

[0170] In another embodiment, each R w These are independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1~C3 alkyl), -C(=O)-(C1~C3 alkoxy), methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, allyl, propenyl, propargyl, propynyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazine, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0171] In one embodiment, m is 1, 2, 3, 4, 5, or 6.

[0172] In one embodiment, n is 1, 2, 3, 4, 5, or 6.

[0173] In some embodiments, the present invention relates to a compound of formula (II), or its stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs.

[0174] [ka]

[0175] R 1 , R 2 , R 2a , R 2b , R 3 , R 4 , R z Each of n and n is as defined herein.

[0176] In other embodiments, the present invention relates to a compound of formula (III), or its stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs.

[0177] [ka]

[0178] R 1 , R 2 , R 2a , R 2b , R 3 , R 4 , R z Each of n and n is as defined herein.

[0179] In one embodiment, the compound of the present invention is a compound having one of the following structures, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof, but is not limited thereto:

[0180] [ka]

[0181] [ka]

[0182] [ka]

[0183] [ka]

[0184] [ka]

[0185] [ka]

[0186] [ka]

[0187] [ka]

[0188] [ka]

[0189] [ka]

[0190] [ka]

[0191] [ka]

[0192] In other embodiments, the present invention relates to a pharmaceutical composition comprising a compound of formula (I), (II), or (III) disclosed herein.

[0193] In one embodiment, the pharmaceutical composition of the present invention further comprises pharmaceutically acceptable additives, carriers, adjuvants, or any combination thereof.

[0194] In another aspect, the present invention relates to the use of compounds of formula (I), (II), or (III) disclosed herein, or pharmaceutical compositions thereof, in the manufacture of pharmaceuticals for the prevention, treatment, or mitigation of PARP1-mediated diseases.

[0195] In one embodiment, PARP1-mediated diseases include cancer, neurodegenerative diseases, cardiovascular diseases, ischemic diseases, diabetic neuropathy, reperfusion injury, osteoarthritis, osteoporosis, inflammatory diseases, and metabolic diseases.

[0196] In one embodiment, the cancers mentioned are laryngeal cancer, esophageal cancer, stomach cancer, intestinal cancer, liver cancer, kidney cancer, lung cancer, brain cancer, head and neck cancer, squamous cell carcinoma, lymphoid cancer, thyroid cancer, bladder cancer, ovarian cancer, cervical cancer, prostate cancer, genitourinary cancer, breast cancer, hematological cancer, small cell lung cancer, lung adenocarcinoma, pancreatic cancer, colon cancer, glioblastoma, and / or monocytic leukemia.

[0197] In another embodiment, the PARP1-mediated disease mentioned is cancer.

[0198] In other embodiments, the present invention relates to the use of compounds of formula (I), (II), or (III) disclosed herein, or pharmaceutical compositions thereof, in the manufacture of a pharmacopoeia for inhibiting PARP1.

[0199] On the other hand, the present invention relates to methods for the preparation, isolation, and purification of compounds of formula (I), (II), or (III).

[0200] Pharmaceutical compositions, formulations, and administration of the compounds of the present invention. The present invention provides pharmaceutical compositions comprising compounds of formula (I), (II), or (III), or stereoisomers thereof, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof. In one embodiment of the present invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, additive, or excipient, and optionally other therapeutic and / or prophylactic components.

[0201] The dosage form of the compound used in the method of the present invention can be determined by the specific compound selected, the pharmacokinetic distribution required by the route of administration, and the patient's condition.

[0202] Preparations suitable for oral, sublingual, intranasal, or injectable administration are prepared by methods known in the pharmaceutical industry and contain at least one active compound. See, for example, Remington's Pharmaceutical Sciences (16th edition, 1980).

[0203] Generally, the formulations of the present invention contain an active ingredient (a compound represented by formula (I), (II), or (III)) and are typically mixed with a carrier, diluted with a carrier, or encapsulated in a carrier, which may be in the form of a capsule, pouch, paper, or other container. When an excipient is used as an excipient, it may be a solid, semi-solid, or liquid material that acts as an additive, carrier, or medium to the active ingredient. Thus, the formulations may be tablets, pills, powders, lozenges, pouches, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in a solid or liquid medium), for example, ointments, soft capsules or hard capsules, gels, suppositories, sterile injections, and sterile encapsulated powders containing up to 10% by mass of the active compound.

[0204] During the preparation of a formulation, the active compound needs to be ground to a suitable particle size before being mixed with other components. If the active compound is substantially insoluble, it is typically ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, its particle size is adjusted by grinding to achieve a uniform particle size distribution in the formulation, for example, at about 40 mesh. In one embodiment of the present invention, the particle size is approximately 0.1 to 100 μm.

[0205] Suitable carriers, adjuvants, and additives are well known to those skilled in the art and are described in detail, for example, Ansel HC, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia, Gennaro AR, Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia, and Rowe RC, and Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.

[0206] "Pharmacopoeia-acceptable additive," as used herein, means a pharmaceutically acceptable material, composition, or vehicle that contributes to giving form or consistency to a pharmaceutical composition. Each additive, when mixed, must be compatible with the other components of the pharmaceutical composition so as to avoid interactions that substantially reduce the efficacy of the compounds of the present invention and / or result in a pharmaceutically unacceptable composition when administered to a patient. In addition, each additive must, of course, be of sufficiently high purity to be pharmaceutically acceptable.

[0207] Preferably pharmaceutically acceptable excipients vary depending on the specific dosage form chosen. In addition, preferred pharmaceutically acceptable excipients can be selected with respect to specific functions that may be useful in the composition. For example, a particular pharmaceutically acceptable excipient can be selected with respect to its ability to facilitate the production of a uniform dosage form. A particular pharmaceutically acceptable excipient can be selected with respect to its ability to facilitate the production of a stable dosage form. A particular pharmaceutically acceptable excipient can be selected with respect to its ability, when administered to a patient, to facilitate the loading or transport of the compound of the present invention from one organ or part of the body to another organ or part of the body. A particular pharmaceutically acceptable excipient can be selected with respect to its ability to enhance patient compliance.

[0208] Examples of suitable additives include lactose, glucose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. Suitable pharmaceutically acceptable additives also include the following types: excipients, fillers, binders, disintegrants, lubricants (e.g., talc, magnesium stearate, and mineral oil), flow promoters, granulators, coatings, wetting agents, solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavorings, masking agents, colorants, anticaking agents, wetting agents, chelating agents, plasticizers, thickeners, antioxidants, preservatives (e.g., methylparaben and propylparaben), stabilizers, surfactants, and buffers. Those skilled in the art will understand that a particular pharmaceutically acceptable excipient may perform two or more functions, or even substitute functions, depending on the extent to which the excipient is present in the formulation and which other components are present in the formulation. The compounds of the present invention can be formulated using methods known in the art to enable rapid, sustained, or delayed release of the active ingredient after administration to a patient.

[0209] Those skilled in the art possess the knowledge and skills in the art that will enable them to select suitable pharmaceutically acceptable additives in appropriate amounts for use in the present invention. In addition, there are several sources available to those skilled in the art that describe pharmaceutically acceptable additives and may be useful in selecting suitable pharmaceutically acceptable additives. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (American Pharmaceutical Association and Pharmaceutical Press).

[0210] For the preparation of pharmaceutical compositions using the compounds described in the present invention, pharmaceutically acceptable carriers may be solid or liquid carriers. Solid forms of formulations include powders, tablets, dispersible granules, capsules, pouches, and suppositories. Powders and tablets may contain about 5% to about 95% of the active ingredient. Suitable solid carriers are known in the art and include, for example, magnesium carbonate, magnesium stearate, talc, sugar, or lactose. Tablets, powders, pouches, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods for preparing various compositions can be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th edition, 1990, Mack Publishing Company Co., Easton, Pennsylvania.

[0211] Remington discloses various carriers for preparing pharmaceutically acceptable compositions and known techniques for their preparation (The Science and Practice of Pharmacy, 21st edition, 2005, edited by DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and JC Boylan, 1988–1999, Marcel Dekker, New York), the contents of which are incorporated herein by reference. The use of carriers is within the scope of the present invention, except for any commonly used carriers that are incompatible with the compounds of the present invention by producing any undesirable biological effects or by interacting in a harmful manner with any other components of the pharmaceutically acceptable composition.

[0212] The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0213] Accordingly, another aspect of the present invention relates to a method for preparing a pharmaceutical composition, wherein the pharmaceutical composition contains the compounds disclosed herein and pharmaceutically acceptable additives, carriers, adjuvants, vehicles or combinations thereof, and the method comprises mixing various components. Pharmaceutical compositions containing the compounds disclosed herein can be prepared, for example, at ambient temperature and atmospheric pressure.

[0214] The compounds of the present invention are typically formulated into dosage forms adjusted for administration to patients via a desired route of administration. For example, dosage forms include (1) for oral administration such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, pouches and cachets; (2) for parenteral administration such as sterile solutions, suspensions and powders for reconstitution; (3) for transdermal administration such as transdermal patches; (4) for rectal administration such as suppositories; (5) for inhalation such as aerosols, solutions and dry powders; and (6) for topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.

[0215] It will also be understood that some of the compounds of the present invention may exist in a form advantageous for treatment, or, where appropriate, as pharmaceutically acceptable derivatives or prodrugs thereof. According to the present invention, pharmaceutically acceptable derivatives or prodrugs include, but are not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adducts or derivatives that can directly or indirectly provide the compounds, metabolites or residues thereof, as otherwise described herein, to patients in need.

[0216] In one embodiment, the compounds disclosed herein can be prepared for oral administration. In another embodiment, the compounds disclosed herein can be prepared for inhalation. In yet another embodiment, the compounds disclosed herein can be prepared for nasal administration. In yet another embodiment, the compounds disclosed herein can be prepared for transdermal administration. In yet another embodiment, the compounds disclosed herein can be prepared for topical administration.

[0217] The pharmaceutical compositions provided herein may be provided as compressed tablets, wet tablets, chewable lozenges, fast-dissolving tablets, multilayer tablets, or enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that is resistant to the action of stomach acid but dissolves or disintegrates in the intestines, thus protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylates, waxes, shellac, ammonia-modified shellac, and cellulose phthalate acetate. Sugar-coated tablets are compressed tablets covered with a sugar coating, which may be beneficial in masking unpleasant flavors or odors and protecting the tablet from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose phthalate acetate. Film coatings impart the same general characteristics as sugar coatings. Multilayer tablets are compressed tablets produced by two or more compression cycles, including layered tablets and core tablets (press-coated tablets or dry-coated tablets).

[0218] Tablet dosage forms can be prepared from the active ingredient in powder, crystalline, or granular form, either alone or in combination with one or more other carriers or additives described herein, including binders, disintegrants, sustained-release polymers, lubricants, excipients, and / or colorants. Flavoring agents and sweeteners are particularly useful in the formation of chewable tablets and lozenges.

[0219] The pharmaceutical compositions provided herein may be provided as soft capsules or hard capsules, which may be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFCs), consist of two parts, one of which fits into the other, thus completely enclosing the active ingredient. Soft-elastic capsules (SECs) are soft, spherical shells, such as gelatin shells, which are plasticized by adding glycerin, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives that prevent microbial growth. Suitable preservatives are those described herein, including methylparaben, propylparaben, and sorbic acid. The liquid, semi-solid, and solid dosage forms provided herein can be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include solutions and suspensions of propylene carbonate, vegetable oil, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Patent Nos. 4,328,245, 4,409,239, and 4,410,545. Capsules can also be coated as is known to those skilled in the art to modify or maintain the dissolution of the active ingredient.

[0220] The pharmaceutical compositions provided herein may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems, in which one liquid is dispersed in the whole of another liquid in the form of small spheres, and may be oil-in-water or water-in-oil. Emulsions may contain pharmaceutically acceptable non-aqueous liquids or solvents, emulsifiers, and preservatives. Suspensions may contain pharmaceutically acceptable suspending agents and preservatives. Alcoholic aqueous solutions may contain pharmaceutically acceptable acetals, such as di(lower alkyl)acetals of lower alkylaldehydes, such as acetaldehyde diethyl acetal, and water-miscible solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened aqueous-alcohol solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose solutions, and may also contain preservatives. Regarding liquid dosage forms, for example, a polyethylene glycol solution can be diluted with a pharmaceutically acceptable liquid carrier, such as water, in an amount sufficient for convenient measurement at the time of administration.

[0221] In another embodiment, the pharmaceutical compositions of the present invention are prepared in dosage forms adjusted for administration to a patient by inhalation, such as dry powders, aerosols, suspensions, or solutions. In one embodiment, the present invention relates to a dosage form adjusted for administration to a patient by inhalation as a dry powder. In one embodiment, the present invention relates to a dosage form adjusted for administration to a patient by inhalation as a dry powder. A dry powder composition for delivery to the lungs by inhalation typically comprises one or more pharmaceutically acceptable additives as a finely divided powder, along with a compound disclosed herein or a pharmaceutically acceptable salt thereof. pharmaceutically acceptable additives particularly suitable for use in dry powders are known to those skilled in the art and include lactose, starch, mannitol, and monosaccharides, disaccharides, and polysaccharides. Finely divided powders can be prepared, for example, by micronization and grinding. Generally, the miniaturized (e.g., micronized) compounds are about 1 to about 10 microns. 50 It can be defined by a value (e.g., measured using laser diffraction).

[0222] Pharmaceutical compositions formulated for transdermal administration may exist as isolated patches intended to remain in close contact with the patient's epidermis for extended periods. For example, the active ingredient may be delivered from the patch by iontophoresis, as commonly described in Pharmaceutical Research, 3(6), page 318 (1986).

[0223] Pharmaceutical compositions prepared for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. For example, ointments, creams, and gels can be formulated with aqueous or oily bases by adding suitable thickeners and / or gelling agents. Thus, such bases may include, for example, water and / or oil, such as liquid paraffin or vegetable oil (e.g., peanut oil or castor oil), or a solvent, such as polyethylene glycol. Thickeners and gelling agents that can be used depending on the properties of the base include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carboxypolymethylene and cellulose derivatives, and / or glyceryl monostearate and / or nonionic emulsifiers.

[0224] The compounds disclosed herein can also be bonded to soluble polymers as target pharmaceutical carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamidophenol, polyhydroxyethyl aspartamidophenol, or polyethylene oxide polylysine substituted with palmitoyl groups. Furthermore, the compounds can be bonded to a type of biodegradable polymer suitable for achieving controlled release of pharmaceuticals, such as polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyran, polycyanoacrylates, and hydrogels, or amphiphilic block copolymers.

[0225] The pharmaceutical compositions provided herein may be administered parenterally by injection, infusion, or implantation for topical or systemic administration. Parenteral administration, as used herein, includes intravenous, intra-arterial, intraperitoneal, intrasacral, intraventricular, intra-ventricular, intramuscular, intra-synovial, intra-synovial, intra-sacral, intra-ventricular, and subcutaneous administration.

[0226] The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquids before injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the pharmaceutical field (see Remington: The Science and Practice of Pharmacy, above).

[0227] Pharmaceutical compositions intended for parenteral administration may include, but are not limited to, one or more pharmaceutically acceptable carriers and additives, including, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against microbial growth, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, metal ion sequestering or chelating agents, antifreeze agents, lyoprotectants, thickeners, pH adjusters, and inert gases.

[0228] The pharmaceutical compositions provided in this invention can be administered via rectal suppositories. The drug is mixed with a suitable non-irritating additive (e.g., a glyceride synthesized from cocoa butter or polyethylene glycol), which is solid at room temperature but liquefies or dissolves the drug in the rectal lumen, releasing it. Due to individual differences, the severity of symptoms varies considerably, and each drug has its own unique therapeutic properties. Therefore, the precise method of administration, dosage form, and treatment plan for each individual must be determined by a qualified physician.

[0229] The pharmaceutical compositions provided herein can be formulated as immediate-release or controlled-release dosage forms, including delayed-release, sustained-release, pulsed-release, controlled-release, targeted-release, and programmed-release forms.

[0230] The compounds of the present invention can be administered directly without formulation, but are typically taken in the form of pharmaceutical preparations containing pharmaceutically acceptable excipients and at least one active ingredient. These preparations can be administered via various routes, including oral, buccal, rectal, intranasal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal administration. Many of the compounds used in the methods of the present invention are effective as injectable and oral compositions.

[0231] For transdermal drug delivery, a transdermal delivery device ("patch") is required. Such a transdermal patch can be used to continuously or intermittently inject a controlled amount of the compound of the present invention. The structure and application of transdermal patches for drug delivery are well known in the art. See, for example, US 5,023,252. Such patches can be formulated to release the drug continuously, pulsatilely, or as needed.

[0232] Compounds having formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, are typically administered orally in pharmaceutically acceptable dosage forms as pharmaceutical preparations containing the active ingredient or a pharmaceutically acceptable salt thereof or a solvated form, or as a solvated form of a pharmaceutically acceptable salt. The form of administration depends on the disease being treated and the patient, and pharmaceutical compositions may be administered in different doses.

[0233] Pharmaceutical preparations having the compounds of formula (I), (II), or (III) described above can be prepared for oral administration, specifically in the form of tablets or capsules, and in particular, with regard to techniques aimed at releasing the drug into the colon (Patel, MM Expert Opin. Drug Deliv. [Expert Opinion on Drug Delivery] 2011, 8(10), pp. 1247-1258).

[0234] Pharmaceutical preparations containing compounds represented by formulas (I), (II), or (III) described above can be conveniently administered in unit dosage forms and can be prepared by any method well known in the pharmaceutical field, such as those described in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA. (1985). The term "unit dosage form" refers to a physically separated unit suitable for use as a unit dose in human patients and other mammals, each unit containing a predetermined amount of the active ingredient and the aforementioned suitable pharmaceutically acceptable excipients calculated to produce the desired therapeutic effect.

[0235] Pharmaceutical formulations suitable for oral administration may contain one or more physiologically compatible carriers and / or additives and may be in solid or liquid form. Tablets and capsules may be prepared using fillers, binders, lubricants, and / or surfactants (e.g., sodium lauryl sulfate). Liquid compositions may contain conventional additives such as emulsifiers, suspending agents, and / or preservatives. Liquid compositions may be encapsulated in gelatin, for example, to provide unit dosage forms. Solid oral dosage forms include tablets, two-stage hard-shell capsules, and soft-elastic gelatin (SEG) capsules. Such two-stage hard-shell capsules may be prepared, for example, by filling a shell of hydroxypropyl methylcellulose (HPMC) or gelatin with a compound having formula (I), (II), or (III).

[0236] Dry shell formulations typically contain about 40 w / w% to 60 w / w% gelatin, about 30% to 40% water, and about 20% to 30% plasticizers (e.g., glycerin, propylene glycol, or sorbitol). Other materials such as colorants, flavorings, preservatives, and opacifiers may also be present. Liquid filler materials include solid drugs that are dissolved, solubilized, or dispersed (using suspending agents, e.g., polyethylene glycol 4000, hydrogenated castor oil, or beeswax), or liquid drugs combined with one or more mediators (e.g., glycols, polyols, vegetable oils, mineral oils, triglycerides, and surfactants).

[0237] As used herein, the term “therapeutic dose” refers to the total amount of all active ingredients sufficient to produce a beneficial therapeutic effect. For example, when administered or equilibrated in the body, it refers to the amount sufficient to treat, cure, or alleviate the symptoms of a disease. The effective dose required for a particular treatment regimen depends on a variety of factors, including the disease being treated, the severity of the disease, the activity of the specific drug used, the route of administration, the clearance rate of the specific drug, the duration of treatment, concomitant medications, age, weight, sex, diet, and the patient’s overall health. For further explanation of other factors to consider in this field regarding “therapeutic dose,” see Gilman et al., Goodman and Gilman’s: The Pharmacological Bases of Therapeutics, 8th edition, Pergamon Press, 1990, and Remington’s Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1990.

[0238] Oral formulations are particularly preferred in the form of tablets or capsules, and can be formulated using methods known to those skilled in the art to provide a dose of the active compound in the range of 0.1 mg to 1000 mg.

[0239] When treating humans, the preferred daily dose of a compound having formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof is approximately 0.0001 to 100 mg / kg of body weight. However, it should be understood that the actual amount of compound administered will be determined by the attending physician based on the relevant circumstances, including the disease being treated, the chosen route of administration, one or more compounds administered, the specific patient's age, weight, and response, as well as the severity of the patient's symptoms. Therefore, the above dose range should not limit the scope of the present invention in any way. In some cases, dose levels below the lower limit of the above dose range may be more appropriate, but in other cases, a higher dose can be used without causing any side effects by initially administering a larger dose and then dividing it into smaller doses for administration throughout the day.

[0240] The term "drug administration" refers to providing an effective therapeutic dose of a drug to an individual. Routes of administration include oral, sublingual, intravenous, subcutaneous, transdermal, intramuscular, intradermal, intrasacral, epidural, intraocular, intracranial, inhalation, rectal, and vaginal administration. Dosage forms include ointments, lotions, tablets, capsules, pills, powders, granules, suppositories, lozenges, injections, sterile solutions or non-aqueous solutions, suspensions, emulsions, and patches. The active ingredient is formulated with a non-toxic, pharmaceutically acceptable carrier (e.g., glucose, lactose, acacia gum, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, silica gel, potato starch, urea, dextran, etc.).

[0241] The preferred route of administration varies depending on clinical characteristics, and dosage adjustments should be based on the individual patient's condition. The physician determines the appropriate dosage for each patient. The effective therapeutic dose per unit dose depends on body weight, physiological function, and the chosen vaccination regimen. Each unit dose of the compound refers to the mass of the compound at each administration, excluding the mass of the carrier (contained in the drug).

[0242] The pharmaceutical compositions provided herein can be formulated for single-dose or multi-dose administration. Single-dose formulations are packaged in ampoules, vials, or syringes. Multi-dose parenteral formulations must contain an antimicrobial agent at a bacteriostatic or fungal concentration. All parenteral formulations must be sterile as is known and practiced in the art.

[0243] The pharmaceutical compositions provided herein can be co-formulated with other active ingredients that do not affect the desired therapeutic effect, or with substances that complement the desired effect.

[0244] In one embodiment, the treatment disclosed herein comprises administering to a patient in need of treatment a safe and effective amount of the compound of the present invention or a pharmaceutical composition containing the compound of the present invention. Various embodiments of the present invention involve treating the diseases referred to in the present invention by administering to a patient in need a safe and effective amount of the compound of the present invention or a pharmaceutical composition containing the compound of the present invention.

[0245] In one embodiment, the compound of the present invention or its pharmaceutical composition may be administered by any preferred route of administration, including both systemic and topical administration. Systemic administration includes oral, parenteral, transdermal, and rectal administration. Parenteral administration refers to routes of administration other than enteral or transdermal, typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Topical administration includes application to the skin and administration by intraocular, ear, vaginal, inhalation, and nasal cavity. In one embodiment, the compound of the present invention or its pharmaceutical composition may be administered orally. In another embodiment, the compound of the present invention or its pharmaceutical composition may be administered by inhalation. In yet another embodiment, the compound of the present invention or a pharmaceutical composition containing the compound of the present invention may be administered intranasally.

[0246] In one embodiment, the compound of the present invention or its pharmaceutical composition may be administered in a single dose or according to a dosing regimen in which several doses are administered at different time intervals over a given period. For example, the dose may be administered once, twice, three times, or four times per day. In one embodiment, the dose is administered once per day. In a further embodiment, the dose is administered twice per day. The dose may be administered to achieve a desired therapeutic effect or to maintain a desired therapeutic effect indefinitely. A suitable dosing regimen for the compound of the present invention or its pharmaceutical composition may depend on the pharmacokinetic properties of the compound, such as absorption, distribution, and half-life, and can be determined by those skilled in the art. In addition, a suitable dosing regimen for the compound of the present invention or its pharmaceutical composition may depend on the duration for which such a regimen is administered, but also on the disorder being treated, the severity of the disorder being treated, the age and physical condition of the patient being treated, the patient's medical history, the nature of the combination therapy, the desired therapeutic effect, and similar factors within the knowledge and expertise of those skilled in the art. Those skilled in the art will further understand that a suitable medication regimen may require adjustment over time, taking into account the individual patient's response to the medication regimen or as individual patients require changes.

[0247] The compounds of the present invention may be administered simultaneously with one or more other therapeutic agents, or before or after other therapeutic agents. The compounds of the present invention may be administered separately, via the same or different routes of administration, or together in the same pharmaceutical composition as other agents. This is to be selected by those skilled in the art based on the patient's health, age, weight, and physical condition. When formulated in fixed doses, such combination products may use the compounds of the present invention (within the dosage ranges specified herein) and other pharmaceutically active agents (within their respective dosage ranges).

[0248] Accordingly, in one embodiment, the present invention comprises a combination of drugs comprising a certain amount of at least one compound of the present invention or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, and an effective amount of one or more of the aforementioned additional therapeutic agents.

[0249] Furthermore, the compounds of the present invention can be administered as prodrugs. As used herein, a “prodrug” of a compound of the present invention is a functional derivative of a compound that, upon administration to a patient, ultimately releases the compound of the present invention in vivo. By administering a compound of the present invention as a prodrug, one or more of the following can be achieved: (a) altering the onset of action of the compound in vivo; (b) altering the duration of action of the compound in vivo; (c) altering the transport or distribution of the compound in vivo; (d) altering the solubility of the compound in vivo; and (e) overcoming side effects or other difficulties faced by the compound. Typical functional derivatives used to prepare prodrugs include modifications of compounds that are chemically or enzymatically cleaved in vivo. Such modifications include phosphates, amides, esters, thioesters, carbonates, and carbamates, which are well known to those skilled in the art.

[0250] Use of compounds and pharmaceutical compositions The compounds and pharmaceutical compositions provided in this invention can be used to inhibit PARP1 and / or PARP2, and to prepare pharmaceuticals for the prevention, treatment, or mitigation of PARP-mediated diseases, particularly cancer.

[0251] Specifically, the amount of the compound or pharmaceutical composition of the present invention can effectively and selectively inhibit PARP1 and / or PARP2 to a detectable degree.

[0252] The compounds of the present invention can be used to administer to a patient an amount of the compounds or pharmaceutical compositions of the present invention that is effective in preventing, treating, or relieving PARP-mediated diseases. These PARP-mediated diseases include, but are not limited to, cancer, neurodegenerative diseases, cardiovascular diseases, ischemic diseases, diabetic neuropathy, reperfusion injury, osteoarthritis, osteoporosis, inflammatory diseases, and metabolic diseases.

[0253] The compounds of the present invention can be used to administer to a patient an amount of the compounds or pharmaceutical compositions of the present invention that is effective in preventing, treating, or mitigating cancer, but are not limited to these. Cancers further include, but are not limited to, laryngeal cancer, esophageal cancer, gastric cancer, intestinal cancer, liver cancer, kidney cancer, lung cancer, brain cancer, head and neck cancer, squamous cell carcinoma, lymphatic cancer, thyroid cancer, bladder cancer, ovarian cancer, cervical cancer, prostate cancer, genitourinary cancer, breast cancer, hematological malignancies, small cell lung cancer, lung adenocarcinoma, pancreatic cancer, colon cancer, glioblastoma, and / or monocytic leukemia.

[0254] The compounds of the present invention can be used to administer to a patient an amount of the compounds or pharmaceutical compositions of the present invention that is effective in preventing, treating, or alleviating neurodegenerative diseases, but are not limited to those listed above. Neurodegenerative diseases include, but are not limited to, stroke, epilepsy, Parkinson's disease, Huntington's disease, schizophrenia, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), neuropathic pain, chronic or acute pain, ischemic brain injury, neuronal loss after hypoxia, trauma, and nerve injury.

[0255] The compounds of the present invention can be applied to administer to a patient an amount of the compounds or pharmaceutical compositions of the present invention that is effective in preventing, treating, or alleviating cardiovascular diseases. These cardiovascular diseases include, but are not limited to, angina pectoris, myocardial infarction, cardiac shock, arteriosclerosis, coronary artery disease, cardiovascular tissue injury, and hyperlipidemia.

[0256] In addition to their therapeutic benefits in humans, the compounds and pharmaceutical compositions of the present invention can also be used in veterinary treatments for mammals, including pets, introduced breeds of animals, and livestock. In other embodiments, the animals disclosed herein include horses, dogs, and cats. When used herein, the compounds disclosed herein include pharmaceutically acceptable derivatives thereof.

[0257] Typical synthesis steps: Examples are listed below to illustrate the present invention. However, it should be understood that the present invention is not limited to these examples, but merely provides methods for carrying out the present invention.

[0258] Generally, the compounds disclosed herein can be prepared by the methods described herein, and the substituents are as defined by formulas (I), (II), or (III) above, unless otherwise specified. The following non-limiting schemes and examples are provided to further illustrate the invention.

[0259] Those skilled in the art will recognize that the chemical reactions described can be readily modified to prepare several other compounds disclosed herein, and that alternative methods for preparing the compounds disclosed herein can be considered to fall within the scope of disclosure herein. For example, the synthesis of non-exemplary compounds according to the present invention can be successfully carried out by modifications obvious to those skilled in the art, for example, by appropriately protecting interfering groups, by using other suitable reagents known in the art other than those described, and / or by making conventional modifications to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered suitable for the preparation of other compounds disclosed herein.

[0260] In the examples described below, all temperatures are given in degrees Celsius unless otherwise specified. Reagents were purchased from commercially available suppliers such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company, and were used without further purification unless otherwise specified. Common solvents were purchased from commercially available suppliers such as Shantou XiLong Chemical Factory, Guangdong Guanghua Reagent Chemical Factory Co. Ltd., Guangzhou Reagent Chemical Factory, Tianjin YuYu Fine Chemical Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Reagent Chemical Ltd., and Qingdao Ocean Chemical Factory.

[0261] Anhydrous THF, dioxane, toluene, and ether were obtained by refluxing the solvent with sodium. Anhydrous dichloromethane and chloroform were obtained by refluxing the solvent with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were used after drying with anhydrous sodium sulfate.

[0262] The reactions described below were generally carried out under positive pressure of nitrogen or argon or in an anhydrous solvent with a drying tube (unless otherwise specified), and the reaction flask was typically fitted with a rubber septum for introducing the substrate and reagent via syringe. Glassware was oven-dried and / or heat-dried.

[0263] Column chromatography was performed using a silica gel column. The silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory.

[0264] 1 ¹H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz NMR spectrometer. 1 ¹H NMR spectra were obtained using TMS (0 ppm) or chloroform (7.26 ppm) as a standard, and CDCl3, DMSO-d6, CD3OD, or acetone-d6 as the solvent (ppm). Multiple peaks were observed and the following abbreviations were used: s (singular), d (double), t (tripular), q (quadrupular), m (multiple lines), br (broad line), brs (broad single), dd (double line of double), ddd (double line of double), dt (double line of triple), td (triple line of double), tt (triple line of triple). The coupling constant J was expressed in Hertz (Hz).

[0265] The conditions for determining the low-resolution mass spectrometry (MS) data were as follows: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1 × 30 min, 3.5 μm, 6 min, flow rate 0.6 mL / min, mobile phase: 5% to 95% (CH3CN containing 0.1% formic acid) in (H2O containing 0.1% formic acid), electrospray ionization (ESI) at 210 nm / 254 nm, detected by UV).

[0266] The pure compound was detected using UV at 210 nm / 254 nm with either an Agilent 1260 pre-HPLC or a Calesep pump 250 pre-HPLC (column model: NOVASEP 50 / 80 mm DAC).

[0267] The following abbreviations will be used throughout this specification.

[0268] [Table 1A]

[0269] [Table 1B]

[0270] The following synthesis scheme describes the steps for preparing the compounds disclosed in this invention, and R 1 , R 2 , R 3 and R 4 Each of these has the definitions described herein unless otherwise stated.

[0271] Synthesis Scheme 1

[0272] [ka]

[0273] M is a leaving group, for example -I, -Br, -Cl, -OH, -OMs, -OTs,

[0274] [ka]

[0275] It represents things like this.

[0276] The compound shown in formula (8) can be prepared by the following synthesis scheme 1: coupling the compound shown in formula (1) and the compound shown in formula (2) to obtain the compound shown in formula (3); adding an oxidizing agent to the compound shown in formula (3) to obtain the compound shown in formula (4); reducing the ester group of the compound shown in formula (4) to obtain the compound shown in formula (5); brominating the hydroxyl group of the compound shown in formula (5) to obtain the compound shown in formula (6); and substituting the compound shown in formula (6) and the compound shown in formula (7) to obtain the compound shown in formula (8).

[0277] Synthesis Scheme 2

[0278] [ka]

[0279] M is a leaving group, for example -I, -Br, -Cl, -OH, -OMs, -OTs,

[0280] [ka]

[0281] It represents things like this.

[0282] The compound shown in formula (8) can be prepared by the following synthesis scheme 2: coupling the compound shown in formula (1a) and the compound shown in formula (2) to obtain the compound shown in formula (3a); reacting the compound shown in formula (3a) with an oxidizing agent to obtain the compound shown in formula (4a); reducing the ester group of the compound shown in formula (4a) to obtain the compound shown in formula (5); brominating the hydroxyl group of the compound shown in formula (5) to obtain the compound shown in formula (6); and substituting the compound shown in formula (6) and the compound shown in formula (7) to obtain the compound shown in formula (8).

[0283] Synthesis scheme 3

[0284] [ka]

[0285] R 2n This is the R of the present invention. 2 It has the definition described above, and is, for example, a C1-C6 alkyl group.

[0286] The compound shown in formula (8b) can be prepared by the following synthesis scheme 3: by substitution reaction of the compound shown in formula (1b) and the compound shown in formula (2b) to obtain the compound shown in formula (3b); by coupling reaction of the compound shown in formula (3b) and the compound shown in formula (4b) to obtain the compound shown in formula (5b); by bromination reaction of the hydroxyl group of the compound shown in formula (5b) to obtain the compound shown in formula (6b); and by substitution reaction of the compound shown in formula (6b) and the compound shown in formula (7) to obtain the compound shown in formula (8b).

[0287] Synthesis scheme 4

[0288] [ka]

[0289] The compound shown in formula (8c) can be prepared by the following synthesis scheme 4: by substitution reaction of the compound shown in formula (1c) and the compound shown in formula (7c) to obtain the compound shown in formula (9c), and by coupling reaction of the compound shown in formula (9c) and the compound shown in formula (10) to obtain the compound shown in formula (8c).

[0290] The compound shown in formula (8d) can be prepared by the following synthesis scheme 4: by substitution reaction of the compound shown in formula (1c) and the compound shown in formula (7) to obtain the compound shown in formula (9), and by coupling reaction of the compound shown in formula (9) and the compound shown in formula (10) to obtain the compound shown in formula (8d).

[0291] The following examples further illustrate the compounds, pharmaceutical compositions, and applications provided in the present invention.

[0292] Intermediate 1: 6-Fluoro-N-methyl-5-(piperazine-1-yl)picolinamide hydrochloride

[0293] [ka]

[0294] It was prepared using the synthesis method of intermediate 23 in Example 7 of patent application WO2021013735. [Examples]

[0295] (Example 1) Synthesis of 5-(4-((8-cyclopropyl-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide

[0296] [ka]

[0297] Step 1) Synthesis of ethyl 8-cyclopropyl-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate Ethyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.80 g, 2.55 mmol) and potassium cyclopropyltrifluoroborate (0.75 g, 5.1 mmol) were sequentially added to a flask and stirred to dissolve in 1,4-dioxane (20 mL). Next, an aqueous solution of potassium phosphate (1.62 g, 7.65 mmol) (4 mL) was added and stirred until homogeneous. Finally, Pd(dppf)Cl2 (0.19 g, 0.26 mmol) was added, the mixture was purged with nitrogen, and the reaction was heated at 105 °C for 12 hours. The mixture was cooled to room temperature, quenched with water (15 mL), extracted with ₹ (15 mL x 3), combined with the organic phase, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 3 / 2) to obtain a pale yellow oily product (0.655 g, 93.46%). MS (ESI, pos. ion) m / z: 275.20 [M+H] + .

[0298] Step 2) Synthesis of ethyl 8-cyclopropyl-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate Ethyl 8-cyclopropyl-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.45 g, 1.64 mmol) was added to a flask and dissolved in DCM (9 mL) with stirring. After cooling, DDQ (0.41 g, 1.80 mmol) was added under ice bath conditions, and the mixture was reacted overnight at room temperature. The solvent was removed by concentration under reduced pressure, and the solvent was quenched by adding saturated sodium bicarbonate aqueous solution (18 mL). The solid was precipitated. The mixture was stirred for 30 minutes, filtered, and the filtered cake was collected. The cake was washed with saturated sodium bicarbonate aqueous solution and dried under vacuum to obtain a grayish-white solid (0.345 g, 77.24%). MS (ESI, pos. ion) m / z: 273.20 [M+H] + .

[0299] Step 3) Synthesis of 5-cyclopropyl-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one Ethyl 8-cyclopropyl-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (0.341 g, 1.25 mmol) and THF (12.5 mL) were sequentially added to a 100 mL flask. After cooling, LAH (0.098 g, 2.5 mmol) was added gradually under ice bath conditions. The mixture was stirred until no further exothermic reaction occurred, and the reaction was continued at room temperature for 4 hours. After cooling, the mixture was quenched with water (2.5 mL) under ice bath conditions, the pH was adjusted to 3-4 with dilute hydrochloric acid (1 M), extracted with THF (10 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH(V / V) = 9 / 1) to obtain a white solid (0.18 g, 62.42%). MS (ESI, pos. ion) m / z: 231.2 [M+H] + .

[0300] Step 4) Synthesis of 7-(bromomethyl)-5-cyclopropyl-3-methylquinoxaline-2(1H)-one 5-Cyclopropyl-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one (0.179 g, 0.78 mmol) and DCM (10 mL) were added to a flask. The mixture was cooled, and phosphorus tribromide (0.1 mL, 1.06 mmol) was added dropwise under ice bath conditions. The mixture was stirred until no further exothermic reaction occurred, and the reaction was continued at room temperature for 4 hours. The solvent was removed by concentration under reduced pressure. The residue was washed with MTBE (10 mL x 2) to obtain a yellow solid (0.22 g, 99%), which was used directly in the next reaction.

[0301] Step 5) Synthesis of 5-(4-((8-cyclopropyl-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide 7-(bromomethyl)-5-cyclopropyl-3-methylquinoxaline-2(1H)-one (0.22 g, 0.75 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide hydrochloride (0.29 g, 0.83 mmol), and potassium iodide (0.025 g, 0.15 mmol) were added to a flask and stirred until dissolved in ACN (5 mL). The mixture was cooled, and DIPEA (0.91 mL, 5.25 mmol) was slowly added dropwise under ice bath conditions. The mixture was heated to 80°C and reacted for 2 hours. After cooling to room temperature, stirring was continued to precipitate the solid. The filtered cake was collected by filtration, washed with MTBE (5 mL x 3), washed with water (5 mL x 3), and dried under vacuum to obtain a white solid (0.184 g, 54.42%). MS (ESI, pos. ion) m / z: 451.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 12.20 (br, 1H), 8.41 (s, 1H), 7.84 (d, J = 6.8 Hz, 1H), 7.57 (t, J = 9.3 Hz, 1H), 7.05 (s, 1H), 6.66 (s, 1H), 3.54 (s, 2H), 3.20 - 3.12 (m, 4H), 2.95 (br, 1H), 2.77 (d, J = 3.1 Hz, 3H), 2.61 - 2.53 (m, 4H), 2.43 (s, 3H), 1.08 - 0.78 (m, 4H).

[0302] (Example 2) Synthesis of 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-phenyl-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)picolinamide

[0303] [ka]

[0304] Step 1) Synthesis of ethyl 4-((1-methoxy-1-oxopropan-2-yl)amino)-3-nitrobenzoate Ethyl 4-fluoro-3-nitrobenzoate (3.0 g, 14.07 mmol) and DL-alanine methyl hydrochloride (2.36 g, 16.88 mmol) were added to a flask and dissolved with stirring in acetonitrile (30 mL). After cooling, potassium carbonate (4.67 g, 33.77 mmol) was added under ice bath conditions, and the mixture was heated to 70 °C and reacted overnight. After cooling to room temperature, water (60 mL) was added with stirring to quench the reaction. The solid was precipitated, the filtered cake was collected, and dried under vacuum to obtain a bright yellow solid (3.86 g, 92.57%). MS (ESI, pos. ion) m / z: 297.20 [M+H] + .

[0305] Step 2) Synthesis of ethyl 2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaloline-6-carboxylate Ethyl 4-((1-methoxy-1-oxopropan-2-yl)amino)-3-nitrobenzoate (2.0 g, 6.75 mmol), AcOH (15 mL), and iron powder (1.51 g, 27 mmol) were added to a flask and heated to 70°C for 1 hour. The mixture was cooled to room temperature, quenched with 15 mL of water, and extracted with dimethyl phosphate (20 mL x 2). The organic phases were combined, washed with water (10 mL), washed with saturated brine (10 mL), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid (1.58 g, 99.92%). MS (ESI, pos. ion) m / z: 235.20 [M+H] + .

[0306] Step 3) Synthesis of ethyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate Ethyl 2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (1.46 g, 6.23 mmol) was added to a flask and dissolved in 1,4-dioxane (30 mL). The mixture was cooled, and NBS (1.13 g, 6.35 mmol) was added under ice bath conditions. The mixture was gradually brought to room temperature and stirred overnight. The solution was quenched with saturated sodium thiosulfate, extracted with toluene (40 mL x 2), and the organic phases were combined. The mixture was washed with saturated brine (30 mL), dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / toluene (V / V) = 2 / 1) to obtain a milky white solid (1.56 g, 79.93%). 1H NMR (599 MHz, DMSO-d6) δ (ppm) 10.59 (s, 1H), 7.62 (s, 1H), 7.35 (s, 1H), 6.39 (s, 1H), 4.24 (dd, J = 13.7, 6.7 Hz, 2H), 4.06 (dd, J = 12.4, 6.3 Hz, 1H), 1.35 - 1.25 (m, 6H); MS (ESI, pos. ion) m / z: 313.20 [M+H] + .

[0307] Step 4) Synthesis of ethyl 2-methyl-3-oxo-8-phenyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylate Ethyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.60 g, 1.92 mmol), phenylboronic acid (0.30 g, 2.50 mmol), Pd(dppf)Cl2 (0.070 g, 0.096 mmol), and sodium carbonate (0.41 g, 3.84 mmol) were sequentially added to a flask. The mixture was stirred and dissolved in 1,4-dioxane (12 mL) and water (3 mL). The mixture was heated to 105 °C and reacted overnight. After cooling to room temperature, water (25 mL) was added to quench the reaction. The mixture was extracted with RINKAN (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / Â(V / V) = 3 / 2) to obtain a brown solid (0.54 g, 90.81%). MS (ESI, pos. ion) m / z: 311.20 [M+H] + .

[0308] Step 5) Synthesis of ethyl 2-methyl-3-oxo-8-phenyl-3,4-dihydroquinoxaline-6-carboxylate Ethyl 2-methyl-3-oxo-8-phenyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.54 g, 1.74 mmol) was sequentially added to a flask and dissolved with stirring in DCM (19 mL). After cooling, DDQ (0.43 g, 1.91 mmol) was added under ice bath conditions, and the reaction was allowed to proceed to room temperature for 8 hours. The reaction product was quenched with saturated sodium bicarbonate aqueous solution (38 mL), stirred for 2 hours, extracted with DCM (25 mL x 3), and the organic phases were combined. The mixture was washed with saturated sodium bicarbonate aqueous solution, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an orange-yellow solid (0.517 g, 96.37%). MS (ESI, pos. ion) m / z: 309.20 [M+H] + .

[0309] Step 6) Synthesis of 7-(hydroxymethyl)-3-methyl-5-phenylquinoxaline-2(1H)-one Ethyl 2-methyl-3-oxo-8-phenyl-3,4-dihydroquinoxaline-6-carboxylate (0.51 g, 1.64 mmol) was sequentially added to the flask and dissolved with stirring in THF (16.4 mL). After cooling, LAH (0.196 g, 5.01 mmol) was added little by little under ice bath conditions. The mixture was stirred until no further exothermic reaction occurred, and the reaction was continued at room temperature for 4 hours. After cooling, water (5 mL) was added under ice bath conditions to quench the reaction product. Then, dilute hydrochloric acid (1 M) was added dropwise to adjust the pH to 3-4. The mixture was extracted with THF (25 mL x 2). The combined organic phase was washed with saturated brine (30 mL), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH(V / V) = 10 / 1) to obtain a white solid (0.28 g, 63.57%). MS (ESI, pos. ion) m / z: 267.40 [M+H] + .

[0310] Step 7) Synthesis of 7-(bromomethyl)-3-methyl-5-phenylquinoxaline-2(1H)-one 7-(hydroxymethyl)-3-methyl-5-phenylquinoxaline-2(1H)-one (0.15 g, 0.56 mmol) and DCM (10 mL) were added to a flask. After cooling in an ice bath, phosphorus tribromide (0.08 mL, 0.85 mmol) was added dropwise, and the mixture was stirred until no further exothermic reaction was observed. The reaction was then allowed to proceed at room temperature for 4 hours. The solvent was removed by concentration under reduced pressure, and the residue was washed with MTBE (10 mL × 2) to obtain 0.185 g of yellow solid, which was used directly in the next step.

[0311] Step 8) Synthesis of 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-phenyl-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)picolinamide 7-(bromomethyl)-3-methyl-5-phenylquinoxaline-2(1H)-one (0.185 g, 0.56 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide hydrochloride (0.21 g, 0.62 mmol), and potassium iodide (0.019 g, 0.11 mmol) were added to a flask. The mixture was dissolved in ACN (4 mL) with stirring, cooled in an ice bath, and DIPEA (0.68 mL, 3.92 mmol) was added dropwise. The reaction mixture was then heated to 80 °C and stirred for 2 hours. After cooling to room temperature, stirring was continued to precipitate the solid. The solid was collected by filtration, and the filtration cake was sequentially washed with MTBE (4 mL × 3) and water (4 mL × 3), and then dried under vacuum to obtain a white solid (0.177 g, 64.73%). MS (ESI, pos. ion) m / z: 487.20 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 12.32 (br, 1H), 8.38 (d, J = 4.2 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.57 - 7.52 (m, 3H), 7.44 (t, J = 7.2 Hz, 2H), 7.41 - 7.35 (m, 1H), 7.25 (d, J = 15.5 Hz, 2H), 3.64 (s, 2H), 3.22 - 3.14 (m, 4H), 2.75 (d, J = 4.2 Hz, 3H), 2.63 - 2.55 (m, 4H), 2.32 (s, 3H).

[0312] (Example 3) Synthesis of 6-fluoro-5-(4-((8-isopropoxy-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-N-methylpicolinamide

[0313] [ka]

[0314] Step 1) Synthesis of methyl(4-bromo-2-fluoro-6-nitrophenyl)aminopropionate 5-Bromo-1,2-difluoro-3-nitrobenzene (10 g, 42.02 mmol), DL-alanine methyl hydrochloride (6.16 g, 44.12 mmol), and DIPEA (16.29 g, 126.06 mmol) were added to MeCN (120 mL) and reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, diluted with DCM (120 mL), washed with water (80 mL) and saturated NaCl solution (80 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a yellow liquid (13 g, 96%). MS (ESI, pos. ion) m / z: 321.1 [M+H] + .

[0315] Step 2) Synthesis of 7-bromo-5-fluoro-3-methyl-3,4-dihydroquinoxaline-2(1H)-one Methyl(4-bromo-2-fluoro-6-nitrophenyl)aminopropionate (13.00 g, 40.49 mmol), iron powder (13.57 g, 242.94 mmol), and ammonium chloride (12.99 g, 242.94 mmol) were added to MeOH (120 mL) and water (40 mL) and reacted at 60°C for 16 hours. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, water (100 mL) was added, and the mixture was stirred for 1 hour. After filtration, the solid was dried at 50°C for 12 hours to obtain a pale yellow solid (10.49 g, 90%). MS (ESI, pos. ion) m / z: 259.0 [M+H] + .

[0316] Step 3) Synthesis of 7-bromo-5-fluoro-3-methylquinoxaline-2(1H)-one DDQ (9.16 g, 40.34 mmol) was added to a solution of 7-bromo-5-fluoro-3-methyl-3,4-dihydroquinoxaline-2(1H)-one (9.5 g, 36.67 mmol) in DCM (150 mL) and reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and a solution of NaHCO3 (400 mL) was added and stirred. The mixture was filtered to obtain a solid, which was dried under vacuum at 50°C for 12 hours to obtain a pale yellow solid (9.0 g, 95%). MS (ESI, pos. ion) m / z: 257.0 [M+H] + .

[0317] Step 4) Synthesis of 7-bromo-5-isopropoxy-3-methylquinoxaline-2(1H)-one At 0°C, NaH (390 mg, 9.75 mmol, 60%) was added to a solution of 7-bromo-5-fluoro-3-methylquinoxaline-2(1H)-one (500 mg, 1.95 mmol) and isopropanol (586 mg, 9.75 mmol) in DMF (10 mL). After the addition was complete, the reaction was carried out at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / Â(V / V) = 4 / 1) to obtain a pale yellow solid (400 mg, 69%). MS (ESI, pos. ion) m / z: 297.1 [M+H] + .

[0318] Step 5) Synthesis of 7-(hydroxymethyl)-5-isopropoxy-3-methylquinoxaline-2(1H)-one 7-Bromo-5-isopropoxy-3-methylquinoxaline-2(1H)-one (1.20 g, 4.04 mmol), (tributyltin)methanol (1.43 mg, 4.44 mmol), and Xphos-Pd-G2 (318 mg, 0.40 mmol) were added to 1,4-dioxane (40 mL). The reaction was carried out at 80°C for 14 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH(V / V) = 20 / 1) to obtain a pale yellow solid (910 mg, 90%). MS (ESI, pos. ion) m / z: 249.2 [M+H] + .

[0319] Step 6) Synthesis of 7-(bromomethyl)-5-isopropoxy-3-methylquinoxaline-2(1H)-one CBr4 (602 mg, 1.81 mmol) was added to 8 mL of DCM containing 7-(hydroxymethyl)-5-isopropoxy-3-methylquinoxaline-2(1H)-one (300 mg, 1.21 mmol) and PPh3 (476 mg, 1.81 mmol), and the mixture was reacted at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / Â(V / V) = 1 / 1) to obtain a yellow solid (300 mg, 80%). MS (ESI, pos. ion) m / z: 311.1 [M+H] + .

[0320] Step 7) Synthesis of 6-fluoro-5-(4-((8-isopropoxy-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-N-methylpicolinamide 7-(bromomethyl)-5-isopropoxy-3-methylquinoxaline-2(1H)-one (300 mg, 0.96 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (297 mg, 1.25 mmol), and DIPEA (496 mg, 3.84 mmol) were sequentially added to MeCN (8 mL), and the reaction was carried out at 70°C for 4 hours. The reaction solution was concentrated under reduced pressure, diluted with DCM (50 mL), washed with water (30 mL) and saturated NaCl solution (30 mL), dehydrated with anhydrous Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH(V / V) = 20 / 1) to obtain a pale yellow solid (130 mg, 29%). MS (ESI, pos. ion) m / z: 469.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 12.15 (s, 1H), 8.39 (d, J = 4.7 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.62 - 7.51 (m, 1H), 6.81 (s, 2H), 4.79 - 4.73 (m, 1H), 3.57 (s, 2H), 3.23 - 3.10 (m, 4H), 2.76 (d, J = 4.6 Hz, 3H), 2.61 - 2.53 (m, 4H), 2.37 (s, 3H), 1.34 (d, J = 6.0Hz, 6H).

[0321] (Example 4) Synthesis of 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-phenoxy-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)picolinamide

[0322] [ka]

[0323] Step 1) Synthesis of 7-bromo-3-methyl-5-phenoxyquinoxaline-2(1H)-one 7-Bromo-5-fluoro-3-methylquinoxaline-2(1H)-one (1.0 g, 3.89 mmol), phenol (730 mg, 7.78 mmol), and K2CO3 (1.61 g, 11.67 mmol) were added to DMF (12 mL). After addition, the mixture was microwaved at 120 °C for 18 hours. The reaction solution was diluted with water (50 mL) and the solid was precipitated. The solid was filtered, dissolved in MeOH (5 mL) and DCM (50 mL), dehydrated with anhydrous Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / siRNA(V / V) = 4 / 1) to obtain a pale yellow solid (300 mg, 23%). MS (ESI, pos. ion) m / z: 331.1 [M+H] + .

[0324] Step 2) Synthesis of 7-(hydroxymethyl)-3-methyl-5-phenoxyquinoxaline-2(1H)-one 7-Bromo-3-methyl-5-phenoxyquinoxaline-2(1H)-one (300 g, 0.91 mmol), (tributyltin)methanol (321 mg, 1.00 mmol), and Xphos-Pd-G2 (71 mg, 0.09 mmol) were added to 1,4-dioxane (16 mL) under nitrogen protection and reacted at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH(v / v) = 20 / 1) to obtain a pale yellow solid (200 mg, 78%). MS (ESI, pos. ion) m / z: 283.2 [M+H] + .

[0325] Step 3) Synthesis of 7-(bromomethyl)-3-methyl-5-phenoxyquinoxaline-2(1H)-one CBr4 (114 mg, 0.35 mmol) was added to 6 mL of DCM containing 7-(hydroxymethyl)-3-methyl-5-phenoxyquinoxaline-2(1H)-one (65 mg, 0.23 mmol) and PPh3 (90 mg, 0.35 mmol), and the reaction was carried out at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a yellow solid (75 mg, 94%). MS (ESI, pos. ion) m / z: 345.1 [M+H] + .

[0326] Step 4) Synthesis of 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-phenoxy-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)picolinamide 7-(bromomethyl)-3-methyl-5-phenoxyquinoxaline-2(1H)-one (50 mg, 0.14 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (43 mg, 0.18 mmol), and DIPEA (72 mg, 0.56 mmol) were sequentially added to MeCN (4 mL), and the reaction was carried out at 70°C for 4 hours. The reaction solution was concentrated under reduced pressure, diluted with DCM (50 mL), washed with water (30 mL) and saturated NaCl solution (30 mL), dehydrated with anhydrous Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH(V / V) = 20 / 1) to obtain a pale yellow solid (25 mg, 34%). MS (ESI, pos. ion) m / z: 503.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 12.37 (s, 1H), 8.40 (d, J = 4.7 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.56 (dd, J = 10.5, 8.2 Hz, 1H), 7.40 (t, J = 7.9 Hz, 2H), 7.15 (dd, J = 15.8, 8.4 Hz, 1H), 7.09 - 7.01 (m, 3H), 6.75 (s, 1H), 3.55 (s, 2H), 3.17 - 3.09 (m, 4H), 2.77 (d, J = 4.7Hz, 3H), 2.59 - 2.53 (m, 4H), 2.36 (s, 3H).

[0327] (Example 5) Synthesis of 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-(phenylamino)-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)picolinamide

[0328] [ka]

[0329] Step 1) Synthesis of ethyl 4-((1-methoxy-1-oxopropyl-2-yl)amino)-3-nitrobenzoate Ethyl 4-fluoro-3-nitrobenzoate (6.42 g, 30.13 mmol) was dissolved in N,N-dimethylformamide (100 mL), and potassium carbonate (12.49 g, 90.36 mmol) and DL-alanine methyl hydrochloride (4.63 g, 33.13 mmol) were added. The mixture was heated to 100 °C and reacted for 3 hours. The reaction was then stopped, the mixture was cooled to room temperature, and water (500 mL) was added. The mixture was extracted with ethyl acetate (400 mL x 3). The organic phase was washed with saturated brine, dehydrated with anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 4 / 1) to obtain a yellow solid (1.6 g, 17.9%). MS (ESI, pos. ion) m / z: 297.4 [M+H] + .

[0330] Step 2) Synthesis of ethyl 2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate Ethyl 4-((1-methoxy-1-oxopropyl-2-yl)amino)-3-nitrobenzoate (1.5 g, 5.06 mmol), acetic acid (10 mL), and iron powder (1.41 g, 25.30 mmol) were added to a reaction flask and heated to 80°C, where the mixture was reacted for 5 hours. The reaction was then stopped, the mixture was cooled to room temperature, and water (500 mL) was added. The mixture was extracted with dichloromethane (150 mL x 2). The organic phase was washed with saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a pale yellow solid (1.10 g, 92.7%). MS (ESI, pos. ion) m / z: 235.2 [M+H] + .

[0331] Step 3) Synthesis of ethyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate Ethyl 2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.53 g, 2.27 mmol) was dissolved in 1,4-dioxane (10 mL), and N-bromosuccinimide (0.42 g, 2.37 mmol) was added while stirring at room temperature. After the reaction was carried out for 16 hours, water (150 mL) was added. The mixture was extracted with dichloromethane (200 mL), the organic phase was washed with saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow solid (0.52 g, 73.3%). MS (ESI, pos. ion) m / z: 313.3 [M+H] + .

[0332] Step 4) Synthesis of ethyl 8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate Ethyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.1 g, 0.32 mmol) was dissolved in dichloromethane (4 mL). Activated manganese dioxide (0.2 g, 1.96 mmol, 85%) was added while stirring at room temperature. The mixture was stirred and reacted at room temperature for 2.5 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 4 / 1) to obtain a pale yellow solid (0.078 g, 78.5%). MS (ESI, pos. ion) m / z: 311.2 [M+H] + .

[0333] Step 5) Synthesis of ethyl 2-methyl-3-oxo-8-(phenylamino)-3,4-dihydroquinoxaline-6-carboxylate Ethyl 8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (0.084 g, 0.27 mmol), aniline (0.038 g, 0.41 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.021 g, 0.027 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.026 g, 0.054 mmol), sodium tert-butoxide (0.052 g, 0.54 mmol), and toluene (toluene) (5 mL) were added. The reaction was added to a reaction flask, the nitrogen was replaced, and the mixture was heated to 100°C under nitrogen protection and reacted for 18 hours. The reaction was then stopped, the mixture was cooled to room temperature, and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 3 / 1) to obtain a yellow solid (0.04 g, 45.8%). MS (ESI, pos. ion) m / z: 324.2 [M+H] + .

[0334] Step 6) Synthesis of 7-(hydroxymethyl)-3-methyl-5-(phenylamino)quinoxaline-2(1H)-one Ethyl 2-methyl-3-oxo-8-(phenylamino)-3,4-dihydroquinoxaline-6-carboxylate (0.16 g, 0.49 mmol) was dissolved in tetrahydrofuran (5 mL). Lithium aluminum hydride (0.07 g, 1.85 mmol) was added at 0°C. After the addition was complete, the reaction was maintained at this temperature for 22 hours. The temperature was then raised to 65°C and the reaction was continued for a further 4.5 hours. The reaction was then stopped, cooled to room temperature, and the reaction product was quenched by adding water (500 mL) dropwise. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to obtain a yellow solid (0.05 g, 35.92%). MS (ESI, pos. ion) m / z: 282.2 [M+H] + .

[0335] Step 7) Synthesis of 2-methyl-3-oxo-8-(phenylamino)-3,4-dihydroquinoxaline-6-carboxyaldehyde 7-(hydroxymethyl)-3-methyl-5-(phenylamino)quinoxaline-2(1H)-one (0.04 g, 0.14 mmol) was dissolved in a mixture of tetrahydrofuran (2 mL) and dichloromethane (2 mL). Dess-Martin periodinane (0.12 g, 0.28 mmol) was added at 0°C, and the reaction was allowed to proceed to room temperature for 16 hours. The reaction was then stopped, filtered, and the filtrate was washed with dichloromethane (10 mL). The filtrate was concentrated to obtain a yellow oily substance (0.038 g, 95.6%). MS (ESI, pos. ion) m / z: 280.2 [M+H] + .

[0336] Step 8) Synthesis of 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-(phenylamino)-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)picolinamide 6-Fluoro-N-methyl-5-(piperazin-1-yl)pyridineamide (0.05 g, 0.21 mmol) was dissolved in a mixed solution of dichloromethane (2 mL) and methanol (2 mL). Triethylamine (0.028 g, 0.28 mmol), 2-methyl-3-oxo-8-(phenylamino)-3,4-dihydroquinoxaline-6-carboxyaldehyde (0.038 g, 0.14 mmol), acetic acid (0.0017 g, 0.028 mmol), and sodium borocyanohydride (0.026 g, 0.42 mmol) were added. The mixture was reacted at room temperature for 20 hours, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 15 / 1) to obtain a yellow solid (0.014 g, 20.5%). MS (ESI, pos. ion) m / z: 502.3 [M+H] + ; HRMS: C 27 H 28FN7O2[M+H] + Calculated value: 502.2361, Measured value: 502.2368; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 12.19 (s, 1H), 8.40 (d, J = 4.9 Hz, 1H), 8.21 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.68 - 7.51 (m, 1H), 7.34 (d, J = 4.2 Hz, 4H), 7.05 (s, 1H), 7.03 - 6.92 (m, 1H), 6.65 (s, 1H), 3.51 (s, 2H), 3.19 - 3.12 (m, 4H), 2.77 (d, J = 4.7 Hz, 3H), 2.59 - 2.52 (m, 4H), 2.44 (s, 3H).

[0337] (Example 6) Synthesis of 6-fluoro-5-(4-((8-(4-fluorophenoxy)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-N-methylpicolinamide

[0338] [ka]

[0339] Step 1) Synthesis of 7-bromo-5-(4-fluorophenoxy)-3-methylquinoxaline-2(1H)-one 7-Bromo-5-fluoro-3-methylquinoxaline-2(1H)-one (0.8 g, 3.11 mmol, see step 3 of Example 3), 4-fluorophenol (1.05 g, 9.33 mmol), and K2CO3 (1.29 g, 9.33 mmol) were added to a DMSO (12 mL) solution. After addition, the mixture was microwaved at 130°C for 16 hours. The reaction solution was diluted with water (60 mL) and the solid was precipitated. The solid was filtered, dissolved in methanol (5 mL) and dichloromethane (50 mL), dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a pale yellow solid (0.6 g, 55%). MS (ESI, pos. ion) m / z: 349.2 [M+H] + .

[0340] Step 2) Synthesis of 5-(4-fluorophenoxy)-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one 7-Bromo-5-(4-fluorophenoxy)-3-methylquinoxaline-2(1H)-one (600 mg, 1.72 mmol), (tributyltin)methanol (607 mg, 1.89 mmol), and Xphos-Pd-G2 (135 mg, 0.17 mmol) were added to 1,4-dioxane (16 mL), and the mixture was reacted at 80°C for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 20 / 1) to obtain a pale yellow solid (350 mg, 68%). MS (ESI, pos. ion) m / z: 301.2 [M+H] + .

[0341] Step 3) Synthesis of 7-(bromomethyl)-5-(4-fluorophenoxy)-3-methylquinoxaline-2(1H)-one At 0°C, CBr4 (776 mg, 2.34 mmol) was added to dichloromethane (20 mL) containing 5-(4-fluorophenoxy)-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one (350 mg, 1.17 mmol) and PPh3 (613 mg, 2.34 mmol). After 1 hour, the reaction was carried out at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to obtain a yellow solid (300 mg, 71%). MS (ESI, pos. ion) m / z: 363.1 [M+H] + .

[0342] Step 4) Synthesis of 6-fluoro-5-(4-((8-(4-fluorophenoxy)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-N-methylpicolinamide 7-(bromomethyl)-5-(4-fluorophenoxy)-3-methylquinoxaline-2(1H)-one (300 mg, 0.83 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridineamide (198 mg, 0.83 mmol), and N,N-diisopropylethylamine (429 mg, 3.32 mmol) were sequentially added to acetonitrile (8 mL), and the reaction was carried out at 70°C for 3 hours. The reaction solution was concentrated under reduced pressure, diluted with dichloromethane (50 mL), washed with water (30 mL) and saturated NaCl solution (30 mL), dehydrated with anhydrous Na2SO4, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to obtain a pale yellow solid (260 mg, 60%). MS (ESI, pos. ion) m / z: 521.3 [M+H] + ; HRMS: C 27 H 26 F2N6O3[M+H] + Calculated value: 521.2034, Measured value: 521.2111; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 12.34 (s, 1H), 8.37 (d, J = 4.7 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.58 - 7.51 (m, 1H), 7.22 (t, J = 8.7 Hz, 2H), 7.12 - 7.05 (m, 2H), 7.04 (s, 1H), 6.71 (s, 1H), 3.54 (s, 2H), 3.17 - 3.09 (m, 4H), 2.76 (d, J = 4.7 Hz, 3H), 2.56 - 2.51 (m, 4H), 2.36 (s, 3H).

[0343] (Example 7) Synthesis of 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-(propa-1-in-1-yl)-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)picolinamide

[0344] [ka]

[0345] Step 1) Synthesis of methyl 8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate Methyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.31 g, 1.04 mmol; see step 3 of Example 8) was added to a 100 mL reaction flask and dissolved with stirring in dichloromethane (12 mL). After cooling, 2,3-dichloro-5,6-dicyanobenzoquinone (0.26 g, 1.14 mmol) was added gradually under an ice bath, and the mixture was stirred until homogeneous, and the reaction was carried out at room temperature for 4 hours. The solvent was removed by concentration under reduced pressure, the mixture was cooled, and the mixture was quenched under an ice bath by adding saturated sodium bicarbonate aqueous solution (24 mL). A solid was precipitated. The mixture was stirred for 30 minutes, filtered, and the filtered cake was collected. The filtered cake was washed with saturated sodium bicarbonate aqueous solution and dried under vacuum to obtain a brownish-red solid (0.18 g, 58.46%). MS (ESI, pos. ion) m / z: 297.10, 299.05 [M+H] + .

[0346] Step 2) Synthesis of 5-bromo-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one Methyl 8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (0.18 g, 0.61 mmol) was added to a 50 mL reaction flask and dissolved by stirring in tetrahydrofuran (9 mL). After cooling, lithium aluminum hydride (0.070 g, 1.79 mmol) was added under ice bath conditions, and the reaction was continued at 0°C for 2 hours. The mixture was quenched with water (1.79 mL) under ice bath conditions. The pH was adjusted to 3-4 by adding 1 M dilute hydrochloric acid. The mixture was extracted with tetrahydrofuran (10 mL x 2). The organic phases were combined, washed with saturated brine, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 95 / 5) to obtain a brick-red solid (0.112 g, 68.70%). MS (ESI, pos. ion) m / z: 269.20, 271.15 [M+H] + .

[0347] Step 3) Synthesis of 5-bromo-7-(bromomethyl)-3-methylquinoxaline-2(1H)-one 5-Bromo-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one (0.11 g, 0.41 mmol) and dichloromethane (10 mL) were added to a 100 mL reaction flask. The mixture was cooled, and phosphorus tribromide (0.060 mL, 0.64 mmol) was added dropwise under ice bath conditions. The mixture was stirred until no further exothermic reaction occurred, and then the reaction was allowed to proceed overnight at room temperature. The solvent was removed by concentration under reduced pressure to obtain a yellow solid product (0.135 g, 99.5%), which was then used directly in the next reaction.

[0348] Step 4) Synthesis of 5-(4-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpyridineamide 5-bromo-7-(bromomethyl)-3-methylquinoxaline-2(1H)-one (0.135 g, 0.41 mmol) was added to a 100 mL reaction flask, followed by 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide hydrochloride (0.12 g, 0.45 mmol) and potassium iodide (0.014 g, 0.082 mmol). The mixture was dissolved in acetonitrile (2.5 mL) with stirring. After cooling, N,N-diisopropylethylamine (0.50 mL, 2.87 mmol) was slowly added dropwise under ice bath. After stirring the mixture homogeneously, it was heated to 80°C and reacted for 2 hours. After cooling to room temperature, the solid was precipitated. The resulting solid was collected by filtration, washed with methyl tert-butyl ether (2.5 mL x 2), then washed with water (2.5 mL x 2), and dried under vacuum to obtain an off-white solid (145 mg, 72.87%). MS (ESI, pos. ion) m / z: 489.15, 490.10 [M+H] + .

[0349] Step 5) Synthesis of 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-(propa-1-in-1-yl)-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)picolinamide 5-(4-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridineamide (0.10 g, 0.20 mmol) and tributyl(propa-1-in-1-yl) stannan (0.12 g, 0.36 mmol) were sequentially added to a 100 mL reaction flask and dissolved by stirring in 1,4-dioxane (8 mL). Then, Xphos-Pd-G2 (0.024 g, 0.031 mmol) was added, the mixture was purged with nitrogen, and the reaction product was heated overnight at 90°C. After cooling to room temperature, the solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 97 / 3) to obtain a white solid (0.030 g, 32.73%). MS (ESI, pos. ion) m / z: 449.40 [M+H] + ; HRMS: C 24 H 25 FN6O2[M+H] + Calculated value: 449.2096, Measured value: 449.2128; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 12.32 (s, 1H), 8.37 (s, 1H), 7.85 (s, 1H), 7.59 (s, 1H), 7.31 - 7.22 (m, 2H), 3.59 (s, 2H), 3.21 - 3.13 (m, 4H), 2.77 (s, 3H), 2.59 - 2.53 (m, 4H), 2.43 (s, 3H), 2.14 (s, 3H).

[0350] (Example 8) Synthesis of 6-fluoro-5-(4-((8-(2-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-N-methylpicolinamide

[0351] [ka]

[0352] Step 1) Synthesis of methyl 4-((1-methoxy-1-oxopropyl-2-yl)amino)-3-nitrobenzoate At room temperature, DL-alanine methyl hydrochloride (9.81 g, 70.31 mmol) and K2CO3 (17.35 g, 125.55 mmol) were added to a solution of methyl 4-fluoro-3-nitrobenzoate (10 g, 50.22 mmol) in acetonitrile (100 mL), and the mixture was heated to 70°C for 12 hours. After cooling, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 3 / 1) to obtain a yellow solid product (14 g, 98.78%). MS (ESI, pos. ion) m / z: 283.1 [M+H] + .

[0353] Step 2) Synthesis of methyl 2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate At room temperature, iron powder (13.85 g, 248 mmol) was added to a solution of methyl 4-((1-methoxy-1-oxopropyl-2-yl)amino)-3-nitrobenzene (14 g, 49.60 mmol) in acetic acid (200 mL). The mixture was heated to 80 °C and stirred for 5 hours. After cooling the reaction solution, water (500 mL) was added, the mixture was filtered, and the solid was dried to obtain a yellow solid product (8.5 g, 77.82%). MS (ESI, pos. ion) m / z: 221.3 [M+H] + .

[0354] Step 3) Synthesis of methyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate At room temperature, NBS (4.00 g, 22.47 mmol) was added to a solution of methyl 2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (4.5 g, 20.43 mmol) in 1,4-dioxane (50 mL), and the reaction mixture was stirred at room temperature for 8 hours. Water (150 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (150 mL). The organic phase was washed with saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 3 / 1) to obtain a yellow solid product (4.5 g, 73.62%). MS (ESI, pos. ion) m / z: 299.1, 301.1 [M+H] + .

[0355] Step 4) Synthesis of methyl 8-(2-fluorophenyl)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate At room temperature, methyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.6 g, 2.01 mmol) was mixed with 1,4-dioxane (12 mL) and water (3 mL). Then, 2-fluorophenylboronic acid pinacol ester (0.37 g, 2.61 mmol), Pd(dppf)Cl2 (0.074 g, 0.10 mmol), and sodium carbonate (0.43 g, 4.02 mmol) were added. After replacing with N2, the mixture was heated to 105°C and reacted for 12 hours. The reaction solution was cooled to room temperature, quenched with water (25 mL), extracted with ethyl acetate (50 mL x 3), combined the organic phases, washed with saturated brine, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 3 / 1) to obtain a yellow solid product (0.4 g, 63.44%). MS (ESI, pos. ion) m / z: 315.2 [M+H] + .

[0356] Step 5) Synthesis of methyl 8-(2-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate Under ice bath conditions, 2,3-dichloro-5,6-dicyanobenzoquinone (0.32 g, 1.40 mmol) was added to a solution of methyl 8-(2-fluorophenyl)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.40 g, 1.27 mmol) in dichloromethane (12 mL). The mixture was then slowly brought to room temperature and stirred for 3 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (38 mL), stirred for 2 hours, extracted with dichloromethane (25 mL x 3), and the organic phases were combined. The mixture was then washed with saturated sodium bicarbonate solution, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an orange-yellow solid product (0.21 g, 52.84%). MS (ESI, pos. ion) m / z: 313.1 [M+H] + .

[0357] Step 6) Synthesis of 5-(2-fluorophenyl)-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one Under ice bath conditions, lithium aluminum hydride (0.080 g, 2.04 mmol) was gradually added to a solution of methyl 8-(2-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (0.21 g, 0.67 mmol) in tetrahydrofuran (16.4 mL). The mixture was stirred until no further exothermic reaction occurred, and the reaction was allowed to proceed at room temperature for 4 hours. The mixture was cooled, and the reaction products were quenched by adding water (5 mL) under ice bath conditions. Then, 1 M dilute hydrochloric acid was added dropwise to adjust the pH to 3-4. The mixture was extracted with tetrahydrofuran (25 mL x 2) and the organic phases were combined. The combined organic phases were washed with saturated brine and dehydrated with anhydrous sodium sulfate. After filtration, the solvent was removed from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to obtain a white solid (0.11 g, 57.54%). MS (ESI, pos. ion) m / z: 285.2 [M+H] + .

[0358] Step 7) Synthesis of 7-(bromomethyl)-5-(2-fluorophenyl)-3-methylquinoxaline-2(1H)-one Under ice bath conditions, 5-(2-fluorophenyl)-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one (0.16 g, 0.56 mmol), dichloromethane (10 mL), and then phosphorus tribromide (0.056 mL, 0.59 mmol) were added dropwise. The mixture was stirred for 5 minutes, then transferred to room temperature and reacted for a further 2 hours. The reaction solution was concentrated under reduced pressure to remove the solvent. The residue was washed with methyl tert-butyl ether (10 mL x 2) and dried to obtain a yellow solid crude product (0.13 g, 96.77%), which was used directly in the next reaction. MS (ESI, pos. ion) m / z: 347.1, 349.1 [M+H] + .

[0359] Step 7) Synthesis of 6-fluoro-5-(4-((8-(2-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-N-methylpicolinamide At room temperature, 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridineamide (0.13 g, 0.55 mmol) and N,N-diisopropylethylamine (0.36 g, 2.75 mmol) were added to a solution of 7-(bromomethyl)-5-(2-fluorophenyl)-3-methylquinoxaline-2(1H)-one (0.19 g, 0.55 mmol) in acetonitrile (20 mL). The mixture was heated to 70 °C and stirred for 3 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 10 / 1) to obtain a yellow solid product (0.029 g, 10.50%). MS (ESI, pos. ion) m / z: 505.4 [M+H] + ; HRMS: C 27 H 26 F2N6O2[M+H] + Calculated value: 505.2085, Measured value: 505.2186; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 12.34 (s, 1H), 8.36 (d, J = 5.7 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 9.3 Hz, 1H), 7.48 - 7.39 (m, 2H), 7.34 (s, 1H), 7.32 - 7.24 (m, 2H), 7.21 (s, 1H), 3.67 (s, 2H), 3.21 - 3.16 (m, 4H), 2.77 (d, J = 4.7 Hz, 3H), 2.63 - 2.58 (m, 4H), 2.29 (s, 3H).

[0360] (Example 9) Synthesis of 6-fluoro-5-(4-((8-(3-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-N-methylpicolinamide

[0361] [ka]

[0362] Step 1) Synthesis of methyl 8-(3-fluorophenyl)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate At room temperature, (3-fluorophenyl)boronic acid (0.45 g, 7.43 mmol), Pd(dppf)Cl2 (0.18 g, 0.25 mmol), and sodium carbonate (1.06 g, 10.02 mmol) were added to a solution of methyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (1.5 g, 5.01 mmol) in 1,4-dioxane (20 mL) and water (5 mL). The mixture was then purged with nitrogen and reacted at 105 °C for 10 hours. The reaction solution was diluted with dichloromethane, filtered through diatomaceous earth, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate (V / V) = 90 / 10) to obtain a yellow solid product (0.65 g, 41.24%). MS (ESI, pos. ion) m / z: 315.1, 316.2 [M+H] + .

[0363] Step 2) Methyl 8-(3-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate At 0°C, 2,3-dichloro-5,6-dicyanobenzoquinone (0.56 g, 2.48 mmol) was added to a solution of methyl 8-(3-fluorophenyl)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.65 g, 2.07 mmol) in dichloromethane (50 mL). The reaction was monitored by TLC at room temperature for 5 hours. The reaction product was quenched by adding saturated sodium bicarbonate aqueous solution (10 mL), extracted with dichloromethane (50 mL x 3), dehydrated with anhydrous sodium sulfate, filtered, concentrated under reduced pressure in the organic phase, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate (V / V) = 9 / 1) to obtain a white solid product (0.55 g, 85.16%). MS (ESI, pos. ion) m / z: 313.15 [M+H] + .

[0364] Step 3) Synthesis of 5-(3-fluorophenyl)-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one At 0°C and under N2, lithium aluminum hydride (0.2 g, 5.28 mmol) was slowly added to a solution of methyl 8-(3-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (0.55 g, 1.76 mmol) in tetrahydrofuran (20 mL). The mixture was stirred at 0°C for 5 minutes, then allowed to rise to room temperature and stirred for 3 hours. After the reaction was complete, water (0.2 mL), aqueous NaOH solution (0.2 mL, 15%), and water (0.6 mL) were added sequentially at 0°C, and the mixture was stirred for 10 minutes. The mixture was filtered through diatomaceous earth, and the filtration cake was dissolved in water and dilute hydrochloric acid (14 mL, 1 M) to dissolve the solid. The solution was then extracted with dichloromethane (50 mL x 3). The product was dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 97 / 3) to obtain a gray solid product (0.3 g, 59.92%). MS (ESI, pos. ion) m / z: 285.2 [M+H] + .

[0365] Step 4) Synthesis of 7-(bromomethyl)-5-(3-fluorophenyl)-3-methylquinoxaline-2(1H)-one Under ice bath conditions, phosphorus tribromide (0.15 mL, 1.59 mmol) was added dropwise to a solution of 5-(3-fluorophenyl)-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one (0.3 g, 1.06 mmol) in dichloromethane (8 mL). The mixture was stirred for 5-10 minutes, and then reacted at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 98 / 2) to obtain a white solid powder (0.27 g, 73.70%). MS (ESI, pos. ion) m / z: 347.15, 349.15 [M+H] + .

[0366] Step 5) Synthesis of 6-fluoro-5-(4-((5-(3-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-N-methylpicolinamide At room temperature, potassium iodide (6.5 mg, 0.0039 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (0.2 g, 0.86 mmol), and N,N-diisopropylethylamine (1.03 mL, 6.24 mmol) were added to a solution of 7-(bromomethyl)-5-(3-fluorophenyl)-3-methylquinoxaline-2(1H)-one (0.27 g, 0.78 mmol) in acetonitrile (15 mL). The mixture was stirred for 5-10 minutes, and the reaction was allowed to stand at room temperature for 5 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 97 / 3) to obtain a white solid powder (0.15 g, 38.23%). MS (ESI, pos. ion) m / z: 505.25 [M+H] + ; HRMS: C 27 H 26 F2N6O2[M+H] + Calculated value: 505.2158, Measured value: 505.2191; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 12.34 (s, 1H), 8.40 - 8.32 (m, 1H), 7.87 - 7.80 (m, 1H), 7.60 - 7.46 (m, 2H), 7.44 - 7.38 (m, 2H), 7.33 - 7.26 (m, 2H), 7.26 - 7.19 (m, 1H), 3.66 (s, 2H), 3.22 - 3.14 (m, 4H), 2.76 (d, J = 4.8 Hz, 3H), 2.64 - 2.56 (m, 4H), 2.34 (s, 3H).

[0367] (Example 10) Synthesis of 6-fluoro-5-(4-((8-(4-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-N-methylpicolinamide

[0368] [ka]

[0369] Step 1) Synthesis of methyl 8-(4-fluorophenyl)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate Methyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.60 g, 2.01 mmol), 4-fluorophenylboronic acid (0.37 g, 2.61 mmol), Pd(dppf)Cl2 (0.074 g, 0.10 mmol), and sodium carbonate (0.43 g, 4.02 mmol) were added sequentially to a 100 mL reaction flask. The mixture was stirred and dissolved in 1,4-dioxane (12 mL) and water (3 mL). The mixture was then purged with nitrogen and heated overnight at 105 °C. The mixture was cooled to room temperature, filtered to remove insoluble substances, and the organic phase was collected. Water was added to separate the layers, and the mixture was extracted with ethyl acetate (25 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 97 / 3) to obtain a white solid (0.383 g, 60.75%). MS (ESI, pos. ion) m / z: 315.15 [M+H] + .

[0370] Step 2) Synthesis of methyl 8-(4-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate Methyl 8-(4-fluorophenyl)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.38 g, 1.22 mmol) was added to a 100 mL reaction flask and stirred until dissolved in 12 mL of dichloromethane. After cooling, 2,3-dichloro-5,6-dicyanobenzoquinone (0.30 g, 1.33 mmol) was added under ice bath conditions, and the reaction was allowed to proceed at room temperature for 6 hours. The solvent was removed by concentration under reduced pressure, and the solvent was quenched by adding 24 mL of saturated sodium bicarbonate aqueous solution. The mixture was stirred for 30 minutes to precipitate the solid. The precipitate was collected by filtration, washed with saturated sodium bicarbonate aqueous solution, and dried under vacuum to obtain a brownish-yellow solid (0.30 g, 79.46%). MS (ESI, pos. ion) m / z: 313.20 [M+H] + .

[0371] Step 3) Synthesis of 5-(4-fluorophenyl)-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one Methyl 8-(4-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (0.30 g, 0.96 mmol) was added to a 100 mL reaction flask and dissolved by stirring in tetrahydrofuran (11 mL). After cooling, lithium aluminum hydride (0.106 g, 2.71 mmol) was added under ice bath conditions, and the mixture was gradually brought to room temperature and reacted overnight. After cooling, water (2.7 mL) was added under ice bath conditions to quench the reaction product, and then 1 M dilute hydrochloric acid was added dropwise to adjust the pH to 3-4. The mixture was extracted with tetrahydrofuran (10 mL x 2), the organic phases were combined, washed with saturated brine, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 95 / 5) to obtain a white solid (0.186 g, 68.11%). MS (ESI, pos. ion) m / z: 285.20 [M+H] + .

[0372] Step 4) Synthesis of 7-(bromomethyl)-8-fluoro-5-(4-fluorophenyl)-3-methylquinoxaline-2(1H)-one 8-Fluoro-5-(4-fluorophenyl)-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one (0.186 g, 0.65 mmol) and dichloromethane (8.5 mL) were added to a 100 mL reaction flask. The mixture was cooled, and phosphorus tribromide (0.079 mL, 0.85 mmol) was added dropwise under ice bath conditions. The mixture was stirred until no further exothermic reaction occurred, and the reaction was allowed to proceed to room temperature for 4 hours. The solvent was removed by concentration under reduced pressure to obtain a crude yellow solid, which was then used directly in the next reaction.

[0373] Step 5) Synthesis of 6-fluoro-5-(4-((8-(4-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-N-methylpicolinamide 7-(bromomethyl)-8-fluoro-5-(4-fluorophenyl)-3-methylquinoxaline-2(1H)-one (0.22 g, 0.63 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridineamide hydrochloride (0.19 g, 0.69 mmol), and potassium iodide (0.021 g, 0.13 mmol) were added to a 100 mL reaction flask and dissolved with stirring in acetonitrile (4 mL). After cooling, N,N-diisopropylethylamine (0.77 mL, 4.41 mmol) was added dropwise under ice bath conditions. The mixture was heated to 80 °C and reacted for 2 hours. After cooling to room temperature, the solid was precipitated. The filtered cake was collected by filtration, washed with methyl tert-butyl ether (4 mL x 3), washed with water (4 mL x 3), and dried under vacuum to obtain a white solid (0.19 g, 59.43%). MS (ESI, pos. ion) m / z: 505.30 [M+H] + ; HRMS: C 27 H 26 F2N6O2[M+H] + Calculated value: 505.2158, Measured value: 505.2160; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 12.36 (s, 1H), 8.40 (d, J = 4.8 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.66 - 7.53 (m, 3H), 7.31 - 7.25 (m, 4H), 3.66 (s, 2H), 3.22 - 3.13 (m, 4H), 2.77 (d, J = 4.6 Hz, 3H), 2.63 - 2.55 (m, 4H), 2.34 (s, 3H).

[0374] (Example 11) Synthesis of 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-(pyridine-3-yl)-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)picolinamide

[0375] [ka]

[0376] Step 1) Synthesis of methyl 2-methyl-3-oxo-8-(pyridine-3-yl)-1,2,3,4-tetrahydroquinoxaline-6-carboxylate At room temperature, methyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (1 g, 3.34 mmol) was mixed with 1,4-dioxane (20 mL) and water (5 mL). This mixture was then combined with 3-pyridineboronic acid pinacol ester (0.89 g, 4.34 mmol), Pd(PPh3)4 (0.19 g, 0.17 mmol), and K2CO3 (0.92 g, 6.68 mmol). The mixture was purged with nitrogen, and the reaction was carried out at 110°C for 8 hours. The reaction solution was diluted with dichloromethane, filtered through diatomaceous earth, concentrated under reduced pressure in the organic phase, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 97 / 3) to obtain a pale red solid product (0.55 g, 55.33%). MS (ESI, pos. ion) m / z: 298.25 [M+H] + .

[0377] Step 2) Synthesis of methyl 2-methyl-3-oxo-8-(pyridine-3-yl)-3,4-dihydroquinoxaline-6-carboxylate 2,3-Dichloro-5,6-dicyanobenzoquinone (0.63 g, 2.78 mmol) was added to a solution of methyl 2-methyl-3-oxo-8-(pyridine-3-yl)-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.55 g, 1.85 mmol) in dichloromethane (30 mL) at 0°C. The reaction was monitored by TLC at room temperature for 5 hours. The reaction product was quenched by adding saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (50 ml x 3), dehydrated with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate (V / V) = 9 / 1) to obtain a white solid product (0.44 g, 80.55%). MS (ESI, pos. ion) m / z: 296.15 [M+H] + .

[0378] Step 3) Synthesis of 7-(hydroxymethyl)-3-methyl-5-(pyridine-3-yl)quinoxaline-2(1H)-one At 0°C and under N2, lithium aluminum hydride (0.17 g, 4.47 mmol) was slowly added to a solution of methyl 2-methyl-3-oxo-8-(pyridine-3-yl)-3,4-dihydroquinoxaline-6-carboxylate (0.44 g, 1.49 mmol) in tetrahydrofuran (20 mL). The mixture was stirred at 0°C for 5 minutes, then allowed to rise to room temperature and stirred for 3 hours. After the reaction was complete, water (0.2 mL), 15% aqueous NaOH solution (0.2 mL), and water (0.6 mL) were added at 0°C, and the mixture was stirred for 10 minutes. The mixture was filtered through diatomaceous earth and washed with dichloromethane (50 mL) and tetrahydrofuran (50 mL). After drying on anhydrous sodium sulfate, the mixture was evaporated to dryness. The residue was subjected to silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = The product was purified using 97 / 3) to obtain a gray solid product (0.19 g, 47.71%). MS (ESI, neg. ion) m / z: 266.15 [MH] - .

[0379] Step 4) Synthesis of 7-(bromomethyl)-3-methyl-5-(pyridine-3-yl)quinoxaline-2(1H)-one Under ice bath conditions, phosphorus tribromide (0.1 mL, 1.06 mmol) was added dropwise to a solution of 7-(hydroxymethyl)-3-methyl-5-(pyridine-3-yl)quinoxaline-2(1H)-one (0.19 g, 0.71 mmol) in dichloromethane (20 mL), and the mixture was stirred for 5-10 minutes. The mixture was then allowed to react at room temperature for 3.5 hours. The solution was then evaporated under vacuum and added directly in the following reaction.

[0380] Step 4) Synthesis of 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-(pyridine-3-yl)-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)picolinamide At room temperature, potassium iodide (4.8 mg, 0.029 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (0.17 g, 0.70 mmol), and N,N-diisopropylethylamine (0.96 mL, 5.8 mmol) were added to a solution of 7-(bromomethyl)-3-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (0.17 g, 0.70 mmol) in acetonitrile (10 mL). The mixture was stirred for 5-10 minutes, and then reacted at room temperature for 5 hours. The mixture was evaporated to dryness under vacuum, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 97 / 3) to obtain a white solid powder (0.034 g, 12.12%). MS (ESI, pos. ion) m / z: 488.20 [M+H] + ; HRMS: C 26 H 26 FN7O2[M+H] + Calculated value: 488.5469, Measured value: 488.2227; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 12.36 (s, 1H), 8.77 (dd, J = 2.1, 1.0 Hz, 1H), 8.57 (dd, J = 4.8, 1.6 Hz, 1H), 8.38 (q, J = 4.9 Hz, 1H), 8.02 - 7.95 (m, 1H), 7.85 - 7.80 (m, 1H), 7.56 (dd, J = 10.6, 8.1 Hz, 1H), 7.49 (dd, J = 7.9, 4.8 Hz, 1H), 7.36 - 7.28 (m, 2H), 3.67 (s, 2H), 3.21 - 3.15 (m, 4H), 2.75 (d, J = 4.8 Hz, 3H), 2.63 - 2.56 (m, 4H), 2.33 (s, 3H).

[0381] (Example 12) Synthesis of 2-fluoro-N-methyl-1'-((2-methyl-3-oxo-8-(propa-1-in-1-yl)-3,4-dihydroquinoxaline-6-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0382] [ka]

[0383] Step 1) Synthesis of methyl 5-bromo-6-fluoropicolinate Methyl 5-bromopyridine-2-carboxylate (2.00 g, 9.26 mmol), AgF2 (4.73 g, 32.41 mmol), and acetonitrile (30 mL) were sequentially added to a sealed tube and reacted at room temperature for 48 hours. The mixture was filtered, and the filtration cake was washed with EA (20 mL). The mixture was concentrated under reduced pressure, and the concentrated residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 4 / 1) to obtain a white solid (0.57 g, 26%). MS (ESI, pos. ion) m / z: 234.0, 236.0 [M+H] + .

[0384] Step 2) Synthesis of 1'-tert-butyl-6-methyl-2-fluoro-5',6'-dihydro-[3,4'-bipyridine]-1',6(2'H)-dicarboxylate Methyl 5-bromo-6-fluoropyridine-2-carboxylate (0.5 g, 2.14 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxobolonyl-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.79 g, 2.57 mmol), sodium carbonate (0.91 g, 8.56 mmol), bis(triphenylphosphine)palladium(II) chloride (0.15 g, 0.21 mmol), and H2O (2 mL) were sequentially added to 1,4-dioxane (20 mL). Under nitrogen protection, the mixture was heated to 85 °C and reacted for 16 hours. The reaction solution was concentrated under reduced pressure, and water (50 mL) and EA (80 mL) were added. The mixture was extracted and separated. The organic phase was washed with saturated brine, dehydrated with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 4 / 1) to obtain a pale yellow solid (0.48 g, 66.8%). MS (ESI, pos. ion) m / z: 337.4 [M+H] + .

[0385] Step 3) Synthesis of tert-butyl-2-fluoro-6-(methylcarbamoyl)-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate Methyl 5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-yl)-6-fluoropyridine-2-carboxylate (0.54 g, 1.61 mmol) and methanol (5 mL) were added to a methanol solution of methylamine (10 mL, 2 M), and the reaction was carried out in a sealed tube at 50°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 4 / 1) to obtain a colorless liquid (0.38 g, 70.6%). MS (ESI, pos. ion) m / z: 336.2 [M+H] + .

[0386] Step 4) Synthesis of 2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide tert-butyl 4-(2-fluoro-6-(methylcarbamoyl)pyridine-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (0.35 g, 1.04 mmol) was added to 10 mL of toluene (1 mL, 4 M) and then ethyl acetate solution (1 mL, 4 M) was added dropwise. The reaction mixture was allowed to react at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure to obtain a brown oily product (0.21 g, 85.5%). MS (ESI, pos. ion) m / z: 236.3 [M+H] + .

[0387] Step 5) Synthesis of 1'-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide At room temperature, 2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (0.53 g, 2.22 mmol), N,N-diisopropylethylamine (3.06 g, 23.68 mmol), and potassium iodide (0.012 g, 0.074 mmol) were added to a solution of 5-bromo-7-(bromomethyl)-3-methylquinoxaline-2(1H)-one (0.49 g, 1.48 mmol; see step 3 of Example 7) in acetonitrile (20 mL). The reaction mixture was heated at 80°C for 3 hours. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to obtain a yellow solid product (0.32 g, 44.58%). MS (ESI, pos. ion) m / z: 486.30, 488.3 [M+H] + .

[0388] Step 6) Synthesis of 2-fluoro-N-methyl-1'-((2-methyl-3-oxo-8-(propa-1-in-1-yl)-3,4-dihydroquinoxaline-6-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide At room temperature, tributyl(propa-1-in-1-yl) stannan (0.18 g, 0.56 mmol) and Xphos-Pd-G2 (0.037 g, 0.046 mmol) were added to a solution of 1'-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (0.15 g, 0.31 mmol) in 1,4-dioxane (20 mL). After purging the system with N2, it was heated to 90°C and stirred for 12 hours. Upon completion, the reaction mixture was cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to obtain a yellow solid product (0.075 g, 54.58%). MS (ESI, pos. ion) m / z: 446.5 [M+H] + ; HRMS: C 25 H 24 FN5O2[M+H] + Calculated value: 446.1914, Measured value: 446.2001; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 12.31 (s, 1H), 8.67 - 8.61 (m, 1H), 8.09 (t, J = 8.7 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.31 (s, 1H), 7.24 (s, 1H), 6.26 (s, 1H), 3.64 (s, 2H), 3.31 - 3.25 (m, 2H), 3.16 - 3.12 (m, 2H), 2.80 (d, J = 4.8 Hz, 3H), 2.70 - 2.66 (m, 2H), 2.42 (s, 3H), 2.14 (s, 3H).

[0389] (Example 13) Synthesis of 5-(4-((8-(difluoromethoxy)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide

[0390] [ka]

[0391] Step 1) Synthesis of 7-bromo-5-hydroxy-3-methylquinoxaline-2(1H)-one 2,3-diamino-5-bromophenol (100 mg, 0.49 mmol), methyl 2-oxopropionate (75 mg, 0.73 mmol), and acetic acid (29 mg, 0.49 mmol) were added to an ethanol solution (6 mL). After addition, the reaction mixture was reacted at 50°C for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate (V / V) = 3 / 1) to obtain a yellow solid (50 mg, 40%). MS (ESI, pos. ion) m / z: 255.1 [M+H] + .

[0392] Step 2) Synthesis of 7-bromo-5-(difluoromethoxy)-3-methylquinoxaline-2(1H)-one At 0°C, a solution of KOH (881 mg, 15.70 mmol) in water (6 mL) was added to a solution of 7-bromo-5-hydroxy-3-methylquinoxaline-2(1H)-one (400 mg, 1.57 mmol) in acetonitrile (16 mL), and then added to diethyl (bromodifluoromethyl)phosphonate (2.10 g, 7.85 mmol). The reaction mixture was allowed to react at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate (30 mL) and water (20 mL), extracted, and separated. The upper organic phase was dehydrated with anhydrous Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 2 / 1) to obtain a white solid (100 mg, 21%). MS (ESI, pos. ion) m / z: 305.0 [M+H] + .

[0393] Step 3) Synthesis of 5-(difluoromethoxy)-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one 7-Bromo-5-(difluoromethoxy)-3-methylquinoxaline-2(1H)-one (100 mg, 0.33 mmol), (tributyltin)methanol (127 mg, 0.40 mmol), and Xphos-Pd-G2 (26 mg, 0.03 mmol) were added to 1,4-dioxane (4 mL) under nitrogen protection and reacted at 80°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to obtain a pale yellow solid (50 mg, 60%). MS (ESI, pos. ion) m / z: 257.1 [M+H] + .

[0394] Step 4) Synthesis of 7-(bromomethyl)-5-(difluoromethoxy)-3-methylquinoxaline-2(1H)-one At 0°C, CBr4 (133 mg, 0.40 mmol) was added to 5-(difluoromethoxy)-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one (50 mg, 0.20 mmol) and PPh3 (105 mg, 0.40 mmol) in dichloromethane (3 mL). After addition, the reaction mixture was allowed to react at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to obtain a white solid (40 mg, 64%). MS (ESI, pos. ion) m / z: 319.1 [M+H] + .

[0395] Step 5) Synthesis of 5-(4-((8-(difluoromethoxy)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide 7-(bromomethyl)-5-(difluoromethoxy)-3-methylquinoxaline-2(1H)-one (40 mg, 0.13 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridineamide (40 mg, 0.17 mmol), and N,N-diisopropylethylamine (67 mg, 0.52 mmol) were sequentially added to acetonitrile (3 mL), and the reaction was carried out at 70°C for 3 hours. The reaction solution was concentrated under reduced pressure, diluted with dichloromethane (50 mL), washed with water (30 mL) and saturated NaCl solution (30 mL), dehydrated with anhydrous Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to obtain a pale yellow solid (40 mg, 67%). MS (ESI, pos. ion) m / z: 477.4 [M+H] + ; HRMS: C 22 H 23 F3N6O3[M+H] + Calculated value: 477.1784, Measured value: 477.1880; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.57 (s, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 4.4 Hz, 1H), 7.34 - 7.28 (m, 1H), 7.19 (s, 1H), 7.11 (s, 1H), 6.99 (t, J = 74.7 Hz, 1H), 3.65 (s, 2H), 3.29 - 3.19 (m, 4H), 3.00 (d, J = 4.9 Hz, 3H), 2.72 - 2.64 (m, 4H), 2.63 (s, 3H).

[0396] (Example 14) 5-(4-((8-(difluoromethoxy)-5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide

[0397] [ka]

[0398] Step 1) Synthesis of methyl 5-(difluoromethoxy)-2-fluoro-4-nitrobenzoate Methyl 2-fluoro-5-hydroxy-4-nitrobenzoate (10 g, 46.48 mmol), sodium 2-chloro-2,2-difluoroacetate (9.21 g, 60.42 mmol), and K2CO3 (7.07 mg, 51.13 mmol) were added to a 100 mL solution of DMF and reacted at 80°C for 22 hours. The reaction solution was diluted with siRNA (400 mL), washed with water (200 mL x 3), washed with saturated NaCl solution (200 mL), dehydrated with anhydrous Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / siRNA (v / v) = 6 / 1) to obtain a pale yellow solid (4.0 g, 32%). MS (ESI, pos. ion) m / z: 266.1 [M+H] + .

[0399] Step 2) Synthesis of methyl 4-amino-5-(difluoromethoxy)-2-fluorobenzoate Pd / C (600 mg, wt 10%) was added to a solution of methyl 5-(difluoromethoxy)-2-fluoro-4-nitrobenzoate (6.0 g, 22.63 mmol) in MeOH (40 mL), replacing H2, and the reaction was carried out at room temperature for 22 hours. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / siRNA(v / v) = 4 / 1) to obtain a pale yellow solid (4.6 g, 86%). MS (ESI, pos. ion) m / z: 236.1 [M+H] + .

[0400] Step 3) Synthesis of methyl 4-amino-5-(difluoromethoxy)-2-fluoro-3-nitrobenzene Methyl 4-amino-5-(difluoromethoxy)-2-fluorobenzoate (2.0 g, 8.50 mmol) and Fe(NO3)3·9H2O (3.43 g, 8.50 mmol) were added to hexafluoroisopropanol (17 mL) and reacted at 60°C for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / Â(v / v) = 3 / 1) to obtain a yellow solid (900 mg, 38%). MS (ESI, pos. ion) m / z: 281.0 [M+H] + .

[0401] Step 4) Synthesis of methyl 4-((1-ethoxy-1-oxopropyl-2-yl)amino)-2-fluoro-3-nitro-5-(trifluoromethoxy)benzoate 4-amino-5-(difluoromethoxy)-2-fluoro-3-nitrobenzoic acid (400 mg, 1.43 mmol), ethyl 2-bromopropionate (777 mg, 4.29 mmol), and K2CO3 (395 mg, 2.86 mmol) were added to ACN (10 mL) and reacted at 85°C for 16 hours. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / Â(v / v) = 4 / 1) to obtain a yellow liquid (150 mg, 27%). MS (ESI, pos. ion) m / z: 399.1 [M+H] + ;

[0402] Step 5) Synthesis of methyl 8-(difluoromethoxy)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid 4-((1-ethoxy-1-oxopropyl-2-yl)amino)-2-fluoro-3-nitro-5-(trifluoromethoxy)benzoate (150 mg, 0.41 mmol), Fe (137 mg, 2.46 mmol), and NH4Cl (132 mg, 2.46 mmol) were added to a mixture of MeOH (4 mL) and water (1 mL) and reacted at 70°C for 4 hours. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and siRNA (40 mL) and water (20 mL) were added for extraction and separation. The organic phase was washed with saturated NaCl solution (20 mL), dehydrated with anhydrous Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / siRNA(v / v) = 4 / 1) to obtain a white solid (84 mg, 67%). MS (ESI, pos. ion) m / z: 305.1 [M+H] + ;

[0403] Step 6) Synthesis of methyl 8-(difluoromethoxy)-5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate DDQ (117 mg, 0.52 mmol) was added to a solution of methyl 8-(difluoromethoxy)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (130 mg, 0.43 mmol) in DCM (6 mL). After addition, the reaction mixture was allowed to react at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, diluted with water (20 mL), and then saturated NaHCO3 solution (20 mL) was added. The mixture was filtered to obtain a pale yellow solid (100 mg, 77%). MS (ESI, pos. ion) m / z: 303.1 [M+H] + ;

[0404] Step 7) Synthesis of 5-(difluoromethoxy)-8-fluoro-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one At 0°C, LiAlH4 (28 mg, 0.66 mmol) was added to a solution of methyl 8-(difluoromethoxy)-5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (100 mg, 0.33 mmol) in THF (4 mL). After addition, the reaction was allowed to proceed at room temperature for 3 hours. The reaction product was quenched with MeOH (10 mL), diluted with DCM (50 mL), filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The reaction solution was also concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to obtain a white solid (40 mg, 44%). MS (ESI, pos. ion) m / z: 275.1 [M+H] + ;

[0405] Step 8) Synthesis of 7-(bromomethyl)-5-(difluoromethoxy)-8-fluoro-3-methylquinoxaline-2(1H)-one At 0°C, CBr4 (99 mg, 0.30 mmol) was added to DCM (4 mL) containing 5-(difluoromethoxy)-8-fluoro-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one (40 mg, 0.15 mmol) and PPh3 (79 mg, 0.30 mmol), and the reaction was carried out at 0°C for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / Â(v / v) = 1 / 1) to obtain a white solid (30 mg, 61%). MS (ESI, pos. ion) m / z: 337.0 [M+H] + ;

[0406] Step 9) Synthesis of 5-(4-((8-(difluoromethoxy)-5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide 7-(bromomethyl)-5-(difluoromethoxy)-8-fluoro-3-methylquinoxaline-2(1H)-one (30 mg, 0.09 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (32 mg, 0.13 mmol), and DIPEA (35 mg, 0.28 mmol) were sequentially added to ACN (4 mL), and the reaction was carried out at 70°C for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with DCM (50 mL), washed with water (30 mL) and saturated NaCl solution (30 mL), dehydrated with anhydrous Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH(v / v) = 20 / 1) to obtain a pale white solid (35 mg, 80%). MS (ESI, pos. ion) m / z: 495.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.40 (d, J = 4.9 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.56 (dd, J = 10.4, 8.3 Hz, 1H), 7.29 (t, J = 74.4 Hz, 1H), 7.13 (d, J = 5.4 Hz, 1H), 3.70 (s, 2H), 3.17 (s, 4H), 2.76 (d, J = 4.7 Hz, 3H), 2.60 (s, 4H), 2.44 (s, 3H).

[0407] (Example 15) 1'-((8-(difluoromethoxy)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0408] [ka]

[0409] 7-(bromomethyl)-5-(difluoromethoxy)-3-methylquinoxaline-2(1H)-one (160 mg, 0.50 mmol), 2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (153 mg, 0.65 mmol), and DIPEA (323 mg, 0.65 mmol) were sequentially added to MeCN (8 mL), and the reaction was carried out at 70°C for 3 hours. The reaction solution was concentrated under reduced pressure, diluted with DCM (60 mL), washed with water (30 mL) and saturated NaCl solution (30 mL), dehydrated with anhydrous Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH(v / v) = 20 / 1) to obtain a pale yellow solid (140 mg, 59%). MS (ESI, pos. ion) m / z: 474.1 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.66 (dd, J = 9.3, 4.5 Hz, 1H), 8.09 (dd, J = 9.8, 7.8 Hz, 1H), 7.92 (dd, J = 7.9, 1.5 Hz, 1H), 7.38 (t, J = 74.4 Hz, 1H), 7.17 (s, 1H), 7.06 (s, 1H), 6.27 (s, 1H), 3.68 (s, 2H), 3.16 (s, 2H), 2.79 (d, J = 4.8 Hz, 3H), 2.67 (t, J = 5.1 Hz, 2H), 2.52 (s, 2H), 2.41 (s, 3H).

[0410] (Example 16) 1'-((8-(difluoromethoxy)-5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0411] [ka]

[0412] Step 1) Synthesis of 1'-((8-(difluoromethoxy)-5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide 7-(bromomethyl)-5-(difluoromethoxy)-8-fluoro-3-methylquinoxaline-2(1H)-one (80 mg, 0.24 mmol), 2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (85 mg, 0.36 mmol), and DIPEA (124 mg, 0.96 mmol) were sequentially added to ACN (8 mL), and the reaction was carried out at 70°C for 3 hours. The reaction solution was concentrated under reduced pressure, diluted with DCM (50 mL), washed with water (30 mL) and saturated NaCl solution (30 mL), dehydrated with anhydrous Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH(v / v) = 20 / 1) to obtain a pale white solid (95 mg, 81%). MS (ESI, pos. ion) m / z: 492.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 8.64 (q, J = 4.7 Hz, 1H), 8.09 (dd, J = 9.8, 7.8 Hz, 1H), 7.92 (dd, J = 7.7, 1.3 Hz, 1H), 7.31 (d, J = 74.4 Hz, 1H), 7.15 (d, J = 5.4 Hz, 1H), 6.26 (s, 1H), 3.76 (s, 2H), 3.20 (d, J = 2.7 Hz, 2H), 2.80 (d, J = 4.8 Hz, 3H), 2.71 (t, J = 5.5 Hz, 2H), 2.53 (s, 2H), 2.45 (s, 3H).

[0413] (Example 17) 6-Fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-(trifluoromethoxy)-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)picolinamide

[0414] [ka]

[0415] Step 1) Synthesis of methyl 4-amino-3-nitro-5-(trifluoromethoxy)benzoate Methyl 4-amino-3-(trifluorofluoromethoxy)benzoate (4.0 g, 17.01 mmol) and Fe(NO3)3·9H2O (7.56 g, 18.71 mmol) were added to hexafluoroisopropanol (35 mL) and reacted at 60°C for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / siRNA(v / v) = 9 / 1) to obtain a yellow solid (3.5 g, 73%). MS (ESI, pos. ion) m / z: 281.0 [M+H] + .

[0416] Step 2) Synthesis of methyl 4-((1-methoxy-1-oxopropyl-2-yl)amino)-3-nitro-5-(trifluoromethoxy)benzoate Methyl 4-amino-3-nitro-5-(trifluoromethoxy)benzoate (3.5 g, 12.49 mmol), methyl 2-bromopropionate (6.26 g, 37.47 mmol), and K2CO3 (3.45 mg, 24.98 mmol) were added to ACN (40 mL) and reacted at 85°C for 24 hours. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / siRNA(v / v) = 9 / 1) to obtain a yellow liquid (1.5 g, 33%). MS (ESI, pos. ion) m / z: 367.1 [M+H] + ;

[0417] Step 3) Synthesis of methyl 2-methyl-3-oxo-8-(trifluoromethoxy)-1,2,3,4-tetrahydroquinoxaline-6-carboxylate Methyl 4-((1-methoxy-1-oxopropyl-2-yl)amino)-3-nitro-5-(trifluoromethoxy)benzoate (1.0 g, 2.73 mmol), Fe (0.91 g, 16.38 mmol), and NH4Cl (0.88 g, 16.88 mmol) were added to a mixture of MeOH (20 mL) and water (4 mL) and reacted at 70°C for 4 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. Extraction was performed by adding siRNA (60 mL) and water (30 mL). The organic phase was washed with saturated NaCl solution (30 mL), dehydrated with anhydrous Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / siRNA(v / v) = 4 / 1) to obtain a white solid (580 mg, 70%). MS (ESI, pos. ion) m / z: 305.1 [M+H] + ;

[0418] Step 4) Synthesis of methyl 2-methyl-3-oxo-8-(trifluoromethoxy)-3,4-dihydroquinoxaloline-6-carboxylic acid DDQ (520 mg, 2.29 mmol) was added to a solution of methyl 2-methyl-3-oxo-8-(trifluoromethoxy)-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid (580 mg, 1.91 mmol) in DCM (16 mL). After addition, the reaction mixture was allowed to react at room temperature for 11 hours. The reaction solution was concentrated under reduced pressure, diluted with water (30 mL), and alkalized with saturated NaHCO3 solution (30 mL) while stirring. The mixture was filtered to obtain a pale yellow solid (530 mg, 92%). MS (ESI, pos. ion) m / z: 303.1 [M+H] + ;

[0419] Step 5) Synthesis of 7-(hydroxymethyl)-3-methyl-5-(trifluoromethoxy)quinoxaline-2(1H)-one At 0°C, LiAlH4 (87 mg, 2.06 mmol) was added to a solution of methyl 2-methyl-3-oxo-8-(trifluoromethoxy)-3,4-dihydroquinoxaline-6-carboxylic acid ester (520 mg, 1.72 mmol) in THF (15 mL). After the addition was complete, the reaction was allowed to proceed at room temperature for 3 hours. The reaction solution was quenched with MeOH (2 mL), concentrated under reduced pressure, and the residue was diluted with DCM (100 mL) and MeOH (10 mL). The mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to obtain a white solid (260 mg, 55%). MS (ESI, pos. ion) m / z: 275.0 [M+H] + ;

[0420] Step 6) Synthesis of 7-(bromomethyl)-8-fluoro-3-methyl-5-(trifluoromethoxy)quinoxaline-2(1H)-one At 0°C, CBr4 (630 mg, 1.90 mmol) was added to 10 mL of DCM containing 7-(hydroxymethyl)-3-methyl-5-(trifluoromethoxy)quinoxaline-2(1H)-one (260 mg, 0.95 mmol) and PPh3 (498 mg, 1.90 mmol). The reaction was carried out at 0°C for 15 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / Â(v / v) = 1 / 1) to obtain a white solid (280 mg, 88%). MS (ESI, pos. ion) m / z: 337.0 [M+H] + ;

[0421] Step 7) Synthesis of 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-(trifluoromethoxy)-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)picolinamide 7-(bromomethyl)-8-fluoro-3-methyl-5-(trifluoromethoxy)quinoxaline-2(1H)-one (90 mg, 0.27 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (97 mg, 0.41 mmol), and DIPEA (105 mg, 0.81 mmol) were sequentially added to ACN (6 mL), and the reaction was carried out at 70°C for 3 hours. The reaction solution was concentrated under reduced pressure, diluted with DCM (50 mL), washed with water (30 mL) and saturated NaCl solution (30 mL), dehydrated with anhydrous Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH(v / v) = 20 / 1) to obtain a pale white solid (100 mg, 76%). MS (ESI, pos. ion) m / z: 495.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 8.40 (dd, J = 9.1, 4.3 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.57 (dd, J = 10.2, 8.5 Hz, 1H), 7.28 (s, 1H), 7.26 (s, 1H), 3.66 (s, 2H), 3.18 (s, 4H), 2.76 (d, J = 4.7 Hz, 3H), 2.58 (s, 4H), 2.42 (s, 3H).

[0422] (Example 18) 5-(4-((8-(3,3-difluorocyclobutoxy)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide

[0423] [ka]

[0424] Step 1) Synthesis of methyl 4-chloro-3-(3,3-difluorocyclobutoxy)-5-nitrobenzene Methyl 4-chloro-3-hydroxy-5-nitrobenzene (2.0 g, 8.64 mmol), 3,3-difluorocyclobutyl-1-ol (1.21 g, 11.23 mmol), and PPh3 (3.40 g, 12.96 mmol) were added to THF (20 mL) at 0°C under nitrogen protection. DEAD (2.26 g, 12.96 mmol) was added, and the reaction was allowed to proceed at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / siRNA(v / v) = 9 / 1) to obtain a white solid (1.8 g, 65%). MS (ESI, pos. ion) m / z: 322.9 [M+H] + .

[0425] Step 2) Synthesis of methyl 3-(3,3-difluorocyclobutyloxy)-4-((1-methoxy-1-oxopropyl-2-yl)amino)-5-nitrobenzoate Methyl 4-chloro-3-(3,3-difluorocyclobutyloxy)-5-nitrobenzoate (600 mg, 1.87 mmol), methyl DL-2-aminopropionate hydrochloride (391 mg, 2.81 mmol), and DIPEA (725 mg, 5.61 mmol) were added to 1,4-dioxane (8 mL), and the reaction was carried out at 100 °C for 16 hours. The reaction product was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / siRNA(v / v) = 3 / 2) to obtain a yellow oily liquid (410 mg, 57%). MS (ESI, pos. ion) m / z: 389.2 [M+H] + .

[0426] Step 3) Synthesis of methyl 8-(3,3-difluorocyclobutoxy)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid Iron powder (519 mg, 9.30 mmol), NH4Cl (497 mg, 9.30 mmol), and methyl 3-(3,3-difluorocyclobutoxy)-4-((1-methoxy-1-oxopropyl-2-yl)amino)-5-nitrobenzene (600 mg, 1.55 mmol) were added to MeOH (8 mL) and water (4 mL), and the reaction was carried out at 70°C for 8 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was added to water (30 mL) and extracted with siRNA (60 mL × 3). The organic phase was washed with saturated aqueous NaCl (30 mL), dehydrated with anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / siRNA (v / v) = 3 / 2) to obtain a white solid product (400 mg, 79%). MS (ESI, pos. ion) m / z: 327.0 [M+H] + .

[0427] Step 4) Synthesis of methyl 8-(3,3-difluorocyclobutyloxy)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylic acid ester DDQ (459 mg, 2.02 mmol) was added to a 12 mL solution of methyl 8-(3,3-difluorocyclobutyloxy)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid ester (600 mg, 1.84 mmol) in DCM, and the reaction was carried out at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was neutralized by stirring with a 40 mL solution of saturated NaHCO3. The solid was precipitated and filtered to obtain the solid. The solid was dried under vacuum at 50°C for 12 hours to obtain a yellow solid (400 mg, 67%). MS (ESI, pos. ion) m / z: 325.1 [M+H] + .

[0428] Step 5) Synthesis of 5-(3,3-difluorocyclobutoxy)-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one LiAlH4 (103 mg, 2.46 mmol) was added to a solution of methyl 8-(3,3-difluorocyclobutoxy)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylic acid ester (400 mg, 1.23 mmol) in THF (8 mL), and the reaction was carried out at room temperature for 6 hours. The reaction product was quenched with MeOH (5 mL), diluted with DCM (20 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10 / 1) to obtain a white solid (110 mg, 30%). MS (ESI, pos. ion) m / z: 297.0 [M+H] + .

[0429] Step 6) Synthesis of 7-(bromomethyl)-5-(3,3-difluorocyclobutoxy)-3-methylquinoxaline-2(1H)-one At 0°C, CBr4 (184 mg, 0.55 mmol) was added to a solution of 5-(3,3-difluorocyclobutoxy)-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one (110 mg, 0.37 mmol) and PPh3 (146 mg, 0.55 mmol) in DCM (6 mL). After addition, the reaction was carried out at room temperature for 10 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / Â(v / v) = 1 / 1) to obtain a white solid (80 mg, 60%). MS (ESI, pos. ion) m / z: 359.0 [M+H] + .

[0430] Step 7) Synthesis of 5-(4-((8-(3,3-difluorocyclobutoxy)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide 7-(bromomethyl)-5-(3,3-difluorocyclobutyloxy)-3-methylquinoxaline-2(1H)-one (80 mg, 0.22 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (68 mg, 0.29 mmol), and DIPEA (85 mg, 0.66 mmol) were sequentially added to MeCN (5 mL), and the reaction was carried out at 70°C for 3 hours. The reaction solution was concentrated under reduced pressure, diluted with DCM (50 mL), washed with water (30 mL) and saturated NaCl solution (30 mL), dehydrated with anhydrous Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH(v / v) = 20 / 1) to obtain a white solid (60 mg, 52%). MS (ESI, pos. ion) m / z: 517.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ (ppm) 10.30 (s, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 4.6 Hz, 1H), 7.32 (dd, J = 9.9, 8.1 Hz, 1H), 6.84 (s, 1H), 6.67 (s, 1H), 4.87 - 4.80 (m, 1H), 3.62 (s, 2H), 3.25 (s, 4H), 3.21 - 3.14 (m, 2H), 3.04 - 2.96 (m, 5H), 2.66 (s, 4H), 2.63 (s, 3H).

[0431] (Example 19) 5-(4-((8-cyclopropyl-5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide

[0432] [ka]

[0433] Step 1) Synthesis of methyl(6-bromo-3-fluoro-2-nitrophenyl)aminopropionate 1-Bromo-2,4-difluoro-3-nitrobenzene (6.05 g, 25.42 mmol) and methyl 2-aminopropionate hydrochloride (3.58 g, 25.67 mmol) were added to a 250 mL flask and dissolved by stirring in DMF (30 mL). The mixture was cooled, and DIPEA (13.28 mL, 76.26 mmol) was added dropwise under ice bath conditions, and the temperature was gradually increased overnight until the reaction was complete. The reaction product was quenched with 30 mL of water, extracted with siRNA (30 mL x 3), the organic phases were combined, washed with water and saturated brine, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / siRNA (v / v) = 4 / 1) to obtain a yellow solid (2.78 g, 34.06%). MS (ESI, pos. ion) m / z: 321.10 [M+H] + .

[0434] Step 2) Synthesis of 5-bromo-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxarin-2-one Methyl (6-bromo-3-fluoro-2-nitrophenyl)aminopropionate (2.78 g, 8.66 mmol) was added to a 100 mL flask and dissolved in AcOH (19 mL). Then, iron powder (1.93 g, 34.64 mmol) was added, and the mixture was heated at 70 °C for 2 hours. After cooling to room temperature, the mixture was quenched with 38 mL of water, and the solid precipitated. The filtered cake was collected by filtration, dried under vacuum, and purified by silica gel column chromatography (PE / siRNA (v / v) = 1 / 1) to obtain a white solid (1.6 g, yield 71.33%). MS (ESI, pos. ion) m / z: 259.10 [M+H] + .

[0435] Step 3) Synthesis of 5-cyclopropyl-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxaline-2-one In a 100 mL flask, 5-bromo-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxalin-2-one (0.80 g, 3.09 mmol) and potassium cyclopropyltrifluoroborate (0.91 g, 6.18 mmol) were sequentially added and dissolved in 1,4-dioxane (25 mL). Next, an aqueous solution of potassium phosphate (1.97 g, 9.27 mmol) (4 mL) was added, and the mixture was stirred until homogeneous. Finally, Pd(dppf)Cl2 (0.23 g, 0.31 mmol) was added, the mixture was purged with nitrogen, and the mixture was heated to 105 °C and allowed to react overnight. The solution was cooled to room temperature, quenched with 20 mL of water, extracted with ₹ (30 mL x 2), combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH(v / v) = 30 / 1) to obtain a pale yellow solid (0.31 g, 45.58%). MS (ESI, pos. ion) m / z: 221.20 [M+H] + .

[0436] Step 4) Synthesis of 7-bromo-5-cyclopropyl-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxaline-2-one 5-Cyclopropyl-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxaline-2-one (0.304 g, 1.38 mmol) was added to a 100 mL flask and dissolved by stirring in 1,4-dioxane (14 mL). After cooling, NBS (0.279 g, 1.57 mmol) was added under ice bath conditions. The mixture was stirred until homogenized, then transferred to room temperature and stirred overnight under nitrogen protection. The mixture was quenched with saturated sodium thiosulfate and extracted with siRNA (15 mL x 2) to combine the organic phases. The mixture was washed with saturated brine, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH(v / v) = 30 / 1) to obtain (0.20 g, 48.44%). MS (ESI, pos. ion) m / z: 299.20 [M+H] + .

[0437] Step 5) Synthesis of 7-bromo-5-cyclopropyl-8-fluoro-3-methyl-1,2-dihydroquinoxarin-2-one 7-Bromo-5-cyclopropyl-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxaline-2-one (0.197 g, 0.66 mmol) was added to a 100 mL flask and dissolved in DCM (6 mL) with stirring. After cooling, DDQ (0.16 g, 0.73 mmol) was gradually added under ice bath conditions, and the mixture was stirred until homogenized. The mixture was then transferred to room temperature and stirred for a further 5 hours. The mixture was concentrated under reduced pressure, cooled, and quenched with saturated sodium bicarbonate (12 mL) under ice bath conditions. A solid was precipitated. The mixture was stirred for 1 hour, filtered, and the filtration cake was collected. It was washed with saturated sodium bicarbonate and dried under vacuum to obtain a brownish-pink solid (0.13 g, yield 66.44%). MS (ESI, pos. ion) m / z: 297.10 [M+H] + ;

[0438] Step 6) Synthesis of 5-cyclopropyl-8-fluoro-7-(hydroxymethyl)-3-methyl-1,2-dihydroquinoxarin-2-one 7-Bromo-5-cyclopropyl-8-fluoro-3-methyl-1,2-dihydroquinoxalin-2-one (0.13 g, 0.44 mmol) and (tributyltin)methanol (0.20 g, 0.59 mmol, 95% purity) were sequentially added to a 50 mL flask and dissolved by stirring in 1,4-dioxane (4 mL). Then, Xphos Pd G2 (0.021 g, 0.027 mmol) was added, the mixture was purged with nitrogen, and the reaction was heated at 80°C for 7 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH(v / v) = 30 / 1) to obtain a white solid (0.060 g, yield 55.24%). MS (ESI, pos. ion) m / z: 249.20 [M+H] + ;

[0439] Step 7) Synthesis of 7-(bromomethyl)-5-cyclopropyl-8-fluoro-3-methyl-1,2-dihydroquinoxaline-2-one 5-Cyclopropyl-8-fluoro-7-(hydroxymethyl)-3-methyl-1,2-dihydroquinoxalin-2-one (0.20 g, 0.81 mmol) and DCM (10 mL) were added to a 100 mL flask. The mixture was cooled, and phosphorus tribromide (0.1 mL, 1.06 mmol) was added dropwise under ice bath conditions. The mixture was stirred until no further exothermic reaction occurred, and the reaction was continued at room temperature for 4 hours. The mixture was concentrated under reduced pressure, the residue was washed with MTBE (5 mL × 2), and then purified by silica gel column chromatography (DCM / MeOH (v / v) = 30 / 1) to obtain a white solid (0.072 g, 28.72%).

[0440] Step 8) Synthesis of 5-(4-((8-cyclopropyl-5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide 7-(bromomethyl)-5-cyclopropyl-8-fluoro-3-methyl-1,2-dihydroquinoxalin-2-one (0.072 g, 0.23 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide dihydrochloride (0.085 g, 0.27 mmol), and potassium iodide (0.0076 g, 0.046 mmol) were added to a 50 mL flask and stirred until dissolved in ACN (2.5 mL). The mixture was cooled, and DIPEA (0.18 mL, 1.03 mmol) was slowly added dropwise under ice bath conditions. The mixture was stirred until homogenized and heated to 80°C for 2 hours. After cooling to room temperature, the solid was allowed to precipitate with stirring. The precipitate was collected by filtration and dried under vacuum to obtain a white solid (0.058 g, yield 53.50%). MS (ESI, pos. ion) m / z: 469.26 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.39 (dd, J = 9.6, 4.9 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.57 - 7.52 (m, 1H), 6.70 (d, J = 6.6 Hz, 1H), 3.64 (s, 2H), 3.15 (br, 4H), 2.90 - 2.82 (m, 1H), 2.76 (d, J = 4.5 Hz, 3H), 2.55 (br, 4H), 2.45 (s, 3H), 1.06 (q, J = 5.7 Hz, 2H), 0.76 (q, J = 6.2 Hz, 2H). 19 F NMR (376 MHz, DMSO-d6) δ -72.55 (s), -139.71 (s).

[0441] (Example 20) 5-(4-((8-ethynyl-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide

[0442] [ka]

[0443] 5-(4-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpyridine-2-carboxamide (0.127 g, 0.26 mmol) and (tributyltin)acetylene (0.15 g, 0.47 mmol) were sequentially added to a 100 mL flask and dissolved in 1,4-dioxane (5 mL). Then, Xphos Pd G2 (0.016 g, 0.021 mmol) was added. The mixture was purged with nitrogen and heated overnight at 90°C. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to obtain a yellow solid (0.014 g, yield 12.4%). MS (ESI, pos. ion) m / z: 435.30 [M+H] + ;

[0444] (Example 21) 6-Fluoro-5-(4-((5-Fluoro-2-methyl-3-oxo-8-(propa-1-in-1-yl)-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-N-methylpicolinamide

[0445] [ka]

[0446] Step 1) Synthesis of methyl 2-((6-bromo-3-fluoro-2-nitrophenyl)amino)propanoate 1-bromo-2,4-difluoro-3-nitrobenzene (6.05 g, 25.42 mmol) and methyl 2-aminopropanoate hydrochloride (3.58 g, 25.67 mmol) were added to a 250 mL flask, stirred, and dissolved in DMF (30 mL). The mixture was cooled, and DIPEA (13.28 mL, 76.26 mmol) was added dropwise under ice bath. The reaction mixture was then gradually warmed to room temperature and stirred overnight. The reaction mixture was quenched with water (30 mL) and extracted with siRNA (30 mL × 3). The combined organic phase was washed with water (20 mL) and brine (20 mL), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate (v / v) = 20 / 1) to obtain a yellow solid (2.78 g, 34.06%). MS (ESI, pos. ion) m / z: 321.10 [M+H] + .

[0447] Step 2) Synthesis of 7-bromo-8-fluoro-3-methyl-3,4-dihydroquinoxaline-2(1H)-one Methyl 2-((4-bromo-3-fluoro-2-nitrophenyl)amino)propionate (1.5 g, 4.67 mmol) was added to a 250 mL flask and dissolved with stirring in AcOH (18 mL). Iron powder (1.04 g, 18.68 mmol) was added, and the mixture was heated at 70 °C for 2 hours. After cooling to room temperature, toluene (40 mL) was added, and the mixture was stirred for 15 minutes. The mixture was filtered, the filtrate was collected, washed successively with water and saturated brine, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.25 g of a brownish-red solid, which was then directly carried over to the next step. MS (ESI, pos. ion) m / z: 259.1 [M+H] + .

[0448] Step 3) Synthesis of 7-(((tert-butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxaline-2-one 7-Bromo-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxalin-2-one (1.25 g, 4.82 mmol) and tert-butyldimethyl(tributylmethoxy)silane (3.78 g, 8.68 mmol) were sequentially added to a 250 mL flask and dissolved by stirring in 1,4-dioxane (30 mL). Then, Xphos Pd G2 (0.30 g, 0.39 mmol) was added, the mixture was purged with nitrogen, and the mixture was heated to 90°C and reacted overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (PE / siRNA(v / v) = 4 / 1) to obtain a pale yellow solid (1.02 g, 65.16%). MS (ESI, pos. ion) m / z: 325.20 [M+H] + .

[0449] Step 4) Synthesis of 5-bromo-7-(((tert-butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxaline-2-one 7-(((tert-butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxaline-2-one (0.61 g, 1.88 mmol) and sodium bicarbonate (0.24 g, 2.82 mmol) were added to a 250 mL flask and dissolved in 1,4-dioxane (10 mL) with stirring. After cooling, NBS (0.35 g, 1.97 mmol) was added under ice bath conditions, the mixture was purged with nitrogen, and stirred at room temperature for 2 hours. After quenching with saturated sodium thiosulfate (20 mL), the mixture was extracted with siRNA (25 mL x 3). The organic phases were combined, washed with saturated brine, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to obtain a white solid (0.66 g, 87.04%). MS (ESI, pos. ion) m / z: 403.2 [M+H] + ;

[0450] Step 5) Synthesis of 7-(((tert-butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-5-(propa-1-in-1-yl)-1,2,3,4-tetrahydroquinoxaline-2-one In a 100 mL flask, 5-bromo-7-(((tert-butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxaline-2-one (0.65 g, 1.61 mmol) and tributyl(propa-1-in-1-yl)tin (0.79 g, 2.42 mmol) were sequentially added and dissolved with stirring in 1,4-dioxane (13 mL). Then, Xphos Pd G2 (0.10 g, 0.13 mmol) was added, the mixture was purged with nitrogen, and the mixture was heated to 90°C and reacted overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5 / 1) to obtain a pale yellow solid (0.57 g, 97.04%). MS (ESI, pos. ion) m / z: 363.35 [M+H] + ;

[0451] Step 6) Synthesis of 7-(((tert-butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-5-(propa-1-in-1-yl)-1,2-dihydroquinoxalin-2-one 7-(((tert-butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-5-(propa-1-in-1-yl)-1,2,3,4-tetrahydroquinoxaline-2-one (0.56 g, 1.54 mmol) was added to a 100 mL flask and stirred, then dissolved in DCM (16 mL). The mixture was cooled, and DDQ (0.38 g, 1.69 mmol) was added under ice bath conditions. The reaction mixture was then warmed to room temperature and stirred for 4 hours. The mixture was concentrated under reduced pressure, cooled, and quenched under ice bath conditions by adding saturated sodium bicarbonate (32 mL). After stirring for 30 minutes, the solid precipitated. The solid was collected by filtration, washed with saturated sodium bicarbonate, and dried under vacuum to obtain a brownish-yellow solid (0.77 g), which was used directly in the next step. MS (ESI, pos. ion) m / z: 361.05 [M+H] + ;

[0452] Step 7) Synthesis of 8-fluoro-7-(hydroxymethyl)-3-methyl-5-(propa-1-in-1-yl)-1,2-dihydroquinoxalin-2-one 7-(((tert-butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-5-(propa-1-in-1-yl)-1,2-dihydroquinoxarin-2-one (0.56 g, 1.55 mmol) was added to a 100 mL flask and dissolved by stirring in THF (12 mL). Then, TBAF tetrahydrofuran solution was added dropwise, and the mixture was stirred at room temperature for 6 hours. After quenching with saturated brine (25 mL), the mixture was extracted with siRNA (25 mL x 2). The organic phases were combined, washed with water, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to obtain a brown solid (0.204 g, 53.33%). MS (ESI, pos. ion) m / z: 247.00 [M+H] + ;

[0453] Step 8) Synthesis of 7-(bromomethyl)-8-fluoro-3-methyl-5-(propa-1-in-1-yl)-1,2-dihydroquinoxalin-2-one 8-Fluoro-7-(hydroxymethyl)-3-methyl-5-(propa-1-in-1-yl)-1,2-dihydroquinoxalin-2-one (0.12 g, 0.49 mmol) and triphenylphosphine (0.19 g, 0.73 mmol) were added to a 100 mL flask and dissolved by stirring in DCM (5 mL). The mixture was cooled and carbon tetrabromide (0.24 g, 0.73 mmol) was added under ice bath conditions. The mixture was stirred at 0°C for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to obtain a white solid (0.052 g, 34.52%). MS (ESI, pos. ion) m / z: 309.1 [M+H] + ;

[0454] Step 9) Synthesis of 6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-8-(propa-1-in-1-yl)-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-N-methylpicolinamide 7-(bromomethyl)-8-fluoro-3-methyl-5-(propa-1-in-1-yl)-1,2-dihydroquinoxalin-2-one (0.051 g, 0.16 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide dihydrochloride (0.055 g, 0.18 mmol), and potassium iodide (0.0053 g, 0.032 mmol) were added to a 50 mL flask and dissolved by stirring in ACN (1.5 mL). The mixture was cooled, and DIPEA (0.11 mL, 0.64 mmol) was slowly added dropwise under an ice bath. The mixture was stirred until homogenized, and then heated to 80°C for 2 hours. The mixture was cooled to room temperature, and the solid was allowed to precipitate with stirring. The filtered cake was collected by filtration, washed with MTBE (1.5 mL x 3), followed by water (1.5 mL x 3), and dried under vacuum to obtain a white solid (0.031 g, 40.28%). MS (ESI, pos. ion) m / z: 467.05 [M+H] + ; 1 H NMR (599 MHz, DMSO-d6) δ 12.51 (s, 1H), 8.42 - 8.37 (m, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.55 (dd, J = 10.6, 8.0 Hz, 1H), 7.33 (d, J = 6.7 Hz, 1H), 3.66 (s, 2H), 3.18 - 3.14 (m, 4H), 2.76 (d, J = 4.8 Hz, 3H), 2.60 - 2.55 (m, 4H), 2.43 (s, 3H), 2.11 (s, 3H).

[0455] (Example 22) 5-(4-((8-(Cyclopropylethynyl)-5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide

[0456] [ka]

[0457] Step 1) Synthesis of 7-(((tert-butyldimethylsilyl)oxy)methyl)-5-(2-cyclopropylethynyl)-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxaline-2-one 5-Bromo-7-(((tert-butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxaline-2-one (1.0 g, 2.48 mmol) and tributyl(2-cyclopropylethynyl)tin (1.15 g, 3.22 mmol) were sequentially added to a 100 mL flask and dissolved in 1,4-dioxane (15 mL), after which Xphos Pd G2 (0.16 g, 0.20 mmol) was added. The mixture was purged with nitrogen and heated at 90°C for 6 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5 / 1) to obtain a yellow solid (0.895 g, 92.91%). MS (ESI, pos. ion) m / z: 389.10 [M+H] + .

[0458] Step 2) Synthesis of 7-(((tert-butyldimethylsilyl)oxy)methyl)-5-(2-cyclopropylethynyl)-8-fluoro-3-methyl-1,2-dihydroquinoxaline-2-one 7-(((tert-butyldimethylsilyl)oxy)methyl)-5-(2-cyclopropylethynyl)-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxalin-2-one (0.89 g, 2.29 mmol) was added to a 250 mL flask and dissolved in DCM (16 mL). After cooling in an ice bath, DDQ (0.57 g, 2.52 mmol) was added. The mixture was warmed to room temperature and stirred overnight. The mixture was then concentrated under reduced pressure, cooled again, quenched by adding saturated sodium bicarbonate solution (32 mL) under ice bath conditions, and stirred for 30 minutes. The solid was precipitated and the mixture was filtered. The filtered cake was collected, washed with saturated sodium bicarbonate, and dried under vacuum to obtain a brown solid (0.81 g, 91.48%). MS (ESI, pos. ion) m / z: 387.10 [M+H] + .

[0459] Step 3) Synthesis of 5-(2-cyclopropylethynyl)-8-fluoro-7-(hydroxymethyl)-3-methyl-1,2-dihydroquinoxaline-2-one 7-(((tert-butyldimethylsilyl)oxy)methyl)-5-(2-cyclopropylethynyl)-8-fluoro-3-methyl-1,2-dihydroquinoxarin-2-one (0.80 g, 2.07 mmol) was added to a 100 mL flask and dissolved in THF (16 mL) with stirring. Then, TBAF solution in THF (4.14 mL, 4.14 mmol) was added dropwise, and the mixture was stirred overnight at room temperature. The reaction was quenched by adding saturated brine (30 mL), and extracted with siRNA (25 mL × 2). The organic phases were combined, washed with water, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to obtain a brownish-yellow solid (0.32 g, 56.79%). MS (ESI, pos. ion) m / z: 273.15 [M+H] + .

[0460] Step 4) Synthesis of 7-(bromomethyl)-5-(2-cyclopropylethynyl)-8-fluoro-3-methyl-1,2-dihydroquinoxarin-2-one 5-(2-cyclopropylethynyl)-8-fluoro-7-(hydroxymethyl)-3-methyl-1,2-dihydroquinoxalin-2-one (0.318 g, 1.17 mmol) and triphenylphosphine (0.46 g, 1.75 mmol) were added to a 250 mL flask and dissolved by stirring in DCM (9 mL). After cooling, carbon tetrabromide (0.58 g, 1.75 mmol) was added gradually under ice bath conditions, and the mixture was stirred at 0°C for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to obtain a yellow solid (0.396 g, 101.16%). MS (ESI, pos. ion) m / z: 335.05 [M+H] + ;

[0461] Step 5) Synthesis of 5-(4-((8-(2-cyclopropylethynyl)-5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpyridine-2-carboxamide 7-(bromomethyl)-5-(2-cyclopropylethynyl)-8-fluoro-3-methyl-1,2-dihydroquinoxalin-2-one (0.14 g, 0.42 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide dihydrochloride (0.144 g, 0.46 mmol), and potassium iodide (0.014 g, 0.084 mmol) were added to a 50 mL flask and dissolved by stirring in ACN (3 mL). After cooling, DIPEA (0.29 mL, 1.68 mmol) was slowly added dropwise under an ice bath. The mixture was thoroughly stirred and heated at 80°C for 2 hours. After cooling to room temperature, the solid was precipitated while stirring. The filtered cake was collected by filtration, washed with MTBE (3 mL x 3) and water (3 mL x 3), dried under vacuum, and then purified by slurrying with methanol (1.5 mL) to obtain a white solid (0.030 g, 14.58%). MS (ESI, pos. ion) m / z: 493.15 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (q, J = 4.8 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.56 (dd, J = 10.5, 8.2 Hz, 1H), 7.31 (d, J = 6.9 Hz, 1H), 3.65 (s, 2H), 3.19 - 3.13 (m, 4H), 2.76 (d, J = 4.8 Hz, 3H), 2.61 - 2.54 (m, 4H), 2.44 (s, 3H), 0.97 - 0.90 (m, 2H), 0.85 (t, J = 6.7 Hz, 1H), 0.81 - 0.75 (m, 2H).

[0462] (Example 23) 2-Fluoro-1'-((5-Fluoro-2-methyl-3-oxo-8-(propa-1-in-1-yl)-3,4-dihydroquinoxaline-6-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0463] [ka]

[0464] In a 50 mL flask, 7-(bromomethyl)-8-fluoro-3-methyl-5-(propa-1-in-1-yl)-1,2-dihydroquinoxalin-2-one (0.21 g, 0.68 mmol), 6-fluoro-N-methyl-5-(1,2,3,6-tetrahydropyridine-4-yl)pyridine-2-carboxamide hydrochloride (0.268 g, 0.99 mmol), and potassium iodide (0.023 g, 0.14 mmol) were added and dissolved in ACN (3 mL) with stirring. After cooling in an ice bath, DIPEA (0.36 mL, 2.04 mmol) was slowly added dropwise, and the mixture was thoroughly stirred. Next, this was heated to 80°C and reacted for 2 hours. After cooling to room temperature, the solid was allowed to precipitate with stirring, and the mixture was filtered. The filtered cake was collected, washed with MTBE (1.5 mL x 3) and water (1.5 mL x 3), and dried under vacuum to obtain a yellow solid (0.025 g, 7.94%). MS (ESI, pos. ion) m / z: 464.15 [M+H] + .

[0465] (Example 24) 1'-((8-(cyclopropylethynyl)-5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0466] [ka]

[0467] In a 50 mL flask, 7-(bromomethyl)-5-(2-cyclopropylethynyl)-8-fluoro-3-methyl-1,2-dihydroquinoxalin-2-one (0.15 g, 0.45 mmol), 6-fluoro-N-methyl-5-(1,2,3,6-tetrahydropyridine-4-yl)pyridine-2-carboxamide hydrochloride (0.12 g, 0.45 mmol), and potassium iodide (0.015 g, 0.090 mmol) were added and dissolved in ACN (4 mL) with stirring. After cooling in an ice bath, DIPEA (0.24 mL, 1.35 mmol) was slowly added dropwise, and the mixture was thoroughly stirred. Next, this was heated to 80 °C and reacted for 2 hours. After cooling to room temperature, the mixture was diluted with DCM (20 mL), washed with water (15 mL x 2), and then washed with saturated brine. The organic phase was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin-layer silica gel chromatography to obtain a white solid (0.018 g, 8.22%). MS (ESI, pos. ion) m / z: 489.80 [M+H] + .

[0468] (Example 25) Synthesis of 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-vinyl-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)picolinamide

[0469] [ka]

[0470] At room temperature, potassium ethylene trifluoroborate (0.11 g, 0.82 mmol), Pd(dppf)Cl2 (0.030 g, 0.041 mmol), and K3PO4 (0.17 g, 0.82 mmol) were added to a solution of 5-(4-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (0.2 g, 0.41 mmol) in 1,4-dioxane (8 mL) and water (2 mL). After purging with nitrogen, the mixture was heated to 110 °C and stirred for 12 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 20 / 1) to obtain a yellow solid product (0.1 g, 56.06%). MS (ESI, pos. ion) m / z: 437.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 12.26 (s, 1H), 8.44 - 8.35 (m, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.73 - 7.61 (m, 1H), 7.61 - 7.53 (m, 1H), 7.53 - 7.48 (m, 1H), 7.23 - 7.19 (m, 1H), 6.00 (d, J = 17.9 Hz, 1H), 5.46 (d, J = 11.3 Hz, 1H), 3.62 (s, 2H), 3.22 - 3.15 (m, 4H), 2.76 (d, J = 4.8 Hz, 3H), 2.61 - 2.54 (m, 4H), 2.42 (s, 3H).

[0471] (Example 26) 5-(4-((8-ethoxy-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide

[0472] [ka]

[0473] Step 1) Synthesis of 7-bromo-5-ethoxy-3-methylquinoxaline-2(1H)-one Under nitrogen protection at 0°C, NaH (466 mg, 11.65 mmol, wt 60%) was added to a solution of 7-bromo-5-fluoro-3-methylquinoxaline-2(1H)-one (600 mg, 2.33 mmol) and ethanol (537 mg, 11.65 mmol) in DMF (10 mL). After addition, the reaction was carried out at room temperature for 10 hours. The reaction solution was concentrated under reduced pressure, and saturated NaCl solution (50 mL) and DCM (100 mL) were added. The mixture was extracted and separated. The organic phase was dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a pale yellow solid (550 mg, 83%). MS (ESI, pos. ion) m / z: 283.0 [M+H] + .

[0474] Step 2) Synthesis of 5-ethoxy-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one 7-Bromo-5-ethoxy-3-methylquinoxaline-2(1H)-one (550 mg, 1.94 mmol), (tributyltin)methanol (685 mg, 2.13 mmol), and Xphos-Pd-G2 (153 mg, 0.19 mmol) were added to 1,4-dioxane (12 mL) under nitrogen protection and reacted at 80°C for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH(v / v) = 20 / 1) to obtain a pale yellow solid (231 mg, 51%). MS (ESI, pos. ion) m / z: 235.3 [M+H] + .

[0475] Step 3) Synthesis of 7-(bromomethyl)-5-ethoxy-3-methylquinoxaline-2(1H)-one CBr4 (478 mg, 1.44 mmol) was added to DCM (8 mL) containing 5-ethoxy-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one (210 mg, 0.90 mmol) and PPh3 (378 mg, 1.44 mmol), and the reaction was carried out at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / siRNA(v / v) = 1 / 1) to obtain a white solid (130 mg, 49%). MS (ESI, pos. ion) m / z: 297.1 [M+H] + ;

[0476] Step 4) Synthesis of 5-(4-((8-ethoxy-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide 7-(bromomethyl)-5-ethoxy-3-methylquinoxaline-2(1H)-one (107 mg, 0.36 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (94 mg, 0.40 mmol), and DIPEA (186 mg, 1.44 mmol) were sequentially added to MeCN (8 mL), and the reaction was carried out at 70°C for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with DCM (50 mL), washed with water (30 mL) and saturated NaCl solution (30 mL), dehydrated with anhydrous Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH(v / v) = 20 / 1) to obtain a pale yellow solid (100 mg, 61%). MS (ESI, pos. ion) m / z: 455.4 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.62 (s, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 4.6 Hz, 1H), 7.33 - 7.28 (m, 1H), 6.82 (d, J = 13.1 Hz, 2H), 4.30 (q, J = 6.9 Hz, 2H), 3.62 (s, 2H), 3.24 (s, 4H), 2.99 (d, J = 5.0 Hz, 3H), 2.66 (s, 4H), 2.63 (s, 3H), 1.57 (t, J = 7.0 Hz, 3H).

[0477] (Example 27) 6-Fluoro-5-(4-((8-(2-fluorophenoxy)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-N-methylpicolinamide

[0478] [ka]

[0479] Step 1) Synthesis of 7-bromo-5-(2-fluorophenoxy)-3-methylquinoxaline-2(1H)-one 7-Bromo-5-fluoro-3-methylquinoxaline-2(1H)-one (600 mg, 2.33 mmol), 2-fluorophenol (780 mg, 6.99 mmol), and K2CO3 (970 mg, 6.99 mmol) were added to DMSO (12 mL) solution. After addition, the reaction mixture was allowed to react at 160 °C for 24 hours. The reaction solution was diluted with water (60 mL), and the solid was precipitated. The solid was filtered to obtain a solid, which was dissolved in MeOH (5 mL) and DCM (50 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a yellow solid (500 mg, 61%). MS (ESI, pos. ion) m / z: 349.1 [M+H] + .

[0480] Step 2) Synthesis of 5-(2-fluorophenoxy)-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one 7-Bromo-5-(2-fluorophenoxy)-3-methylquinoxaline-2(1H)-one (500 mg, 1.43 mmol), (tributyltin)methanol (505 mg, 1.57 mmol), and Xphos-Pd-G2 (113 mg, 0.14 mmol) were added to 1,4-dioxane (10 mL) under nitrogen protection and reacted at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH(v / v) = 20 / 1) to obtain a pale yellow solid (250 mg, 58%). MS (ESI, pos. ion) m / z: 301.1 [M+H] + .

[0481] Step 3) Synthesis of 7-(bromomethyl)-5-(2-fluorophenoxy)-3-methylquinoxaline-2(1H)-one At 0°C, CBr4 (444 mg, 1.34 mmol) was added to 15 mL of DCM containing 5-(2-fluorophenoxy)-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one (200 mg, 0.67 mmol) and PPh3 (351 mg, 1.34 mmol). After 1 hour, the reaction was carried out at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / Â(v / v) = 1 / 1) to obtain a pale yellow solid (150 mg, 62%). MS (ESI, pos. ion) m / z: 363.1 [M+H] + ;

[0482] Step 4) Synthesis of 6-fluoro-5-(4-((8-(2-fluorophenoxy)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-N-methylpicolinamide 7-(bromomethyl)-5-(2-fluorophenoxy)-3-methylquinoxaline-2(1H)-one (150 mg, 0.41 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (107 mg, 0.45 mmol), and DIPEA (212 mg, 1.64 mmol) were sequentially added to MeCN (8 mL) and reacted at 70°C for 3 hours. The reaction solution was concentrated under reduced pressure, diluted with DCM (60 mL), washed with water (30 mL) and saturated NaCl solution (30 mL), dehydrated with anhydrous Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH(v / v) = 20 / 1) to obtain a pale yellow solid (120 mg, 56%). MS (ESI, pos. ion) m / z: 521.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 10.93 (s, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.50 (dd, J = 10.0, 5.1 Hz, 1H), 7.32 - 7.27 (m, 1H), 7.25 - 7.13 (m, 4H), 6.98 (s, 1H), 6.63 (s, 1H), 3.55 (s, 2H), 3.17 (s, 4H), 2.99 (d, J = 5.0 Hz, 3H), 2.66 (s, 3H), 2.59 (s, 4H).

[0483] (Example 28) 6-Fluoro-5-(4-((8-(3-fluorophenoxy)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-N-methylpicolinamide

[0484] [ka]

[0485] Step 1) Synthesis of 7-bromo-5-(3-fluorophenoxy)-3-methylquinoxaline-2(1H)one At room temperature, 7-bromo-5-fluoro-3-methyl-1,2-dihydroquinoxalin-2-one (600 mg, 2.33 mmol), potassium carbonate (970 mg, 7.02 mmol), and 3-fluorophenol (780 mg, 6.96 mmol) were added to a solution of N-methylpyrrolidone (20 mL). The mixture was heated to 160 °C and stirred for 12 hours. The reaction mixture was quenched with water (20 mL) and saturated NaCl solution (10 mL) was added. The mixture was stirred for 1 hour, filtered, and the filtered cake was dissolved in a mixed solvent (dichloromethane / methanol (v / v) = 10 / 1, 20 mL). The solution was concentrated under reduced pressure to obtain a black solid (620 mg, 76%). MS (ESI, pos. ion) m / z: 349.1 [M+H] + .

[0486] Step 2) Synthesis of 5-(3-fluorophenoxy)-7-hydroxymethyl-3-methylquinoxaline-2(1H)one At room temperature, 7-bromo-5-(3-fluorophenoxy)-3-methyl-1,2-dihydroquinoxalin-2-one (500 mg, 1.43 mmol), (tributyltin)methanol (505.07 mg, 1.57 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (112.51 mg, 0.14 mmol) catalyst were added to 1,4-dioxane (15 mL), and the reaction was carried out at 80°C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (dichloromethane / methanol (V / V) = 20 / 1) to obtain a yellow solid product (220 mg, 51.16%). MS (ESI, pos. ion) m / z: 301.2 [M+H] + .

[0487] Step 3) Synthesis of 7-(bromomethyl)-5-(3-fluorophenoxy)-3-methylquinoxaline-2(1H)-one At 0°C, tetrabromomethane (444.38 mg, 1.34 mmol) was added to a solution of 5-(3-fluorophenoxy)-7-hydroxymethyl-3-methylquinoxaline-2(1H)one (200 mg, 0.67 mmol) and triphenylphosphine (351.47 mg, 1.34 mmol) in dichloromethane (12 ml). After the reaction solution became clear, the mixture was transferred to room temperature and reacted for 22 hours. The reaction solution was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 1) to obtain a gray solid product (120 mg, 49.61%). MS (ESI, pos. ion) m / z: 363.1 [M+H] + .

[0488] Step 4) Synthesis of 6-fluoro-5-(4-((8-(3-fluorophenoxy)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-N-methylpicolinamide At room temperature, ethyldiisopropylamine was added to a solution of 7-(bromomethyl)-5-(3-fluorophenoxy)-3-methylquinoxaline-2(1H)-one (213.25 mg, 1.65 mmol) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (120 mg, 0.33 mmol) in acetonitrile (10 ml). The temperature was then raised to 70°C and the reaction mixture was stirred for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to obtain a white solid product (134 mg, 77.91%). MS (ESI, pos. ion) m / z: 521.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 4.8 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.59 - 7.50 (m, 1H), 7.38 (q, J = 8.0 Hz, 1H), 7.10 (s, 1H), 6.93 (t, J = 8.5 Hz, 1H), 6.85 (d, J = 10.1 Hz, 2H), 6.81 (d, J = 8.3 Hz, 1H), 3.14 (s, 4H), 2.76 (d, J = 4.7 Hz, 3H), 2.54 (s, 4H), 2.32 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 163.82, 163.56, 162.20, 159.14, 159.06, 158.49, 155.22, 153.68, 152.08, 150.99, 141.12, 138.58, 138.51, 137.38, 137.23, 133.85, 131.40, 131.33, 128.43, 128.40, 123.57, 121.31, 113.95, 113.86, 113.85, 111.25, 110.02, 109.88, 105.56, 105.39, 61.32, 52.31, 49.36, 49.33, 26.18, 20.83.

[0489] (Example 29) 6-Fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-(pyridine-4-yloxy)-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)picolinamide

[0490] [ka]

[0491] Step 1) Synthesis of 7-bromo-3-methyl-5-(pyridine-4-yloxy)quinoxaline-2(1H)-one 7-Bromo-5-fluoro-3-methylquinoxaline-2(1H)-one (1.00 g, 3.89 mmol), pyridine-4-ol (1.11 g, 11.67 mmol), and K2CO3 (1.61 g, 11.67 mmol) were added to DMF (16 mL). After addition, the mixture was microwaved at 120°C for 14 hours. The reaction solution was diluted with water (60 mL) and the pH was adjusted to 5 with HCl solution (4 M). The solid was precipitated and filtered to obtain the solid. The solid was dried under vacuum at 50°C for 8 hours to obtain a pale yellow solid (900 mg, 70%). MS (ESI, pos. ion) m / z: 332.0 [M+H] + .

[0492] Step 2) Synthesis of 7-(hydroxymethyl)-3-methyl-5-(pyridine-4-yloxy)quinoxaline-2(1H)-one 7-Bromo-3-methyl-5-(pyridine-4-yloxy)quinoxaline-2(1H)-one (500 mg, 1.51 mmol), (tributyltin)methanol (970 mg, 3.02 mmol), and Xphos-Pd-G2 (475 mg, 0.60 mmol) were added to 1,4-dioxane (12 mL) under nitrogen protection and reacted at 80°C for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH(v / v) = 4 / 1) to obtain a pale yellow solid (140 mg, 33%). MS (ESI, pos. ion) m / z: 284.2 [M+H] + .

[0493] Step 3) Synthesis of 7-(bromomethyl)-3-methyl-5-(pyridine-4-yloxy)quinoxaline-2(1H)-one At 0°C, CBr4 (325 mg, 0.98 mmol) was added to DCM (10 mL) containing 7-(hydroxymethyl)-3-methyl-5-(pyridine-4-yloxy)quinoxaline-2(1H)-one (138 mg, 0.49 mmol) and PPh3 (257 mg, 0.98 mmol). After 1 hour, the reaction was carried out at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH(v / v) = 10 / 1) to obtain a yellow solid (100 mg, 59%). MS (ESI, pos. ion) m / z: 346.1 [M+H] + ;

[0494] Step 4) Synthesis of 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-(pyridine-4-yloxy)-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)picolinamide 7-(bromomethyl)-3-methyl-5-(pyridine-4-yloxy)quinoxaline-2(1H)-one (100 mg, 0.29 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (76 mg, 0.32 mmol), and DIPEA (150 mg, 1.16 mmol) were sequentially added to MeCN (8 mL), and the reaction was carried out at 70°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH(v / v) = 10 / 1) to obtain a pale yellow solid (60 mg, 41%). MS (ESI, pos. ion) m / z: 504.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 12.62 (s, 1H), 9.72 (s, 1H), 8.40 (d, J = 4.7 Hz, 1H), 7.85 (t, J = 8.2 Hz, 3H), 7.64 - 7.53 (m, 1H), 7.41 (s, 1H), 6.25 (d, J = 7.5 Hz, 2H), 3.36 (s, 4H), 3.22 (s, 2H), 3.06 (d, J = 6.7 Hz, 4H), 2.76 (d, J = 4.6 Hz, 3H), 2.37 (s, 3H).

[0495] (Example 30) 5-(4-((8-(cyclopenta-1-en-1-yl)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide

[0496] [ka]

[0497] 5-(4-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (0.060 g, 0.12 mmol) and 1-cyclopentenboronic acid pinacol ester (0.054 g, 0.28 mmol) were added sequentially to a 100 mL flask. The mixture was dissolved in 1,4-dioxane (2.5 mL) while stirring. Then, an aqueous solution of potassium phosphate (0.054 g, 0.25 mmol) (0.5 mL) was added, and the mixture was stirred until homogenized. Finally, Pd(dppf)Cl2 (0.0092 g, 0.013 mmol) was added. After purging the system with nitrogen, it was heated to 105 °C for the reaction. After cooling to room temperature, the mixture was diluted with dimethyl sulfate (15 mL), washed with saturated brine (10 mL x 2), and dehydrated with anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH(v / v) = 20 / 1) to obtain a white solid (0.032 g, yield 54.76%). MS (ESI, pos. ion) m / z: 477.40 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.39 (s, 1H), 7.83 (s, 1H), 7.56 (s, 1H), 7.16 (s, 2H), 6.62 (s, 1H), 3.59 (s, 2H), 3.18 (br, 4H), 2.86 (s, 3H), 2.76 (br, 4H), 2.40 (s, 3H), 1.95 (br, 4H), 1.33 (br, 2H).

[0498] (Example 31) 5-(4-((8-cyclopentyl-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide

[0499] [ka]

[0500] Step 1) Synthesis of methyl 8-(cyclopenta-1-en-1-yl)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate Methyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.60 g, 2.01 mmol) and 2-(cyclopenta-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (0.70 g, 3.62 mmol) were sequentially added to a 100 mL flask and stirred until dissolved in 1,4-dioxane (12 mL). Next, an aqueous solution of potassium phosphate (0.85 g, 4.02 mmol) was added and stirred until homogeneous. Finally, Pd(dppf)Cl2 (0.15 g, 0.20 mmol) was added. The mixture was heated to 105 °C overnight under nitrogen purging. After cooling to room temperature, 15 mL of water was added to quench the reaction. The mixture was extracted with toluene (15 mL x 3), the organic phase was combined, washed with saturated brine, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / toluene (v / v) = 3 / 1) to obtain a pale yellow oily substance (0.253 g, 44.05%). MS (ESI, pos. ion) m / z: 287.30 [M+H] + .

[0501] Step 2) Synthesis of methyl 8-cyclopentyl-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate Methyl 8-(cyclopenta-1-en-1-yl)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.253 g, 0.88 mmol) was added to a 100 mL reaction flask and dissolved in methanol (4 mL) and tetrahydrofuran (4 mL). Then, 10% palladium-supported carbon (0.051 g, 0.048 mmol) was added, the flask was purged with hydrogen, and the mixture was stirred overnight at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 0.26 g of a colorless oil, which was then used directly in the next reaction. MS (ESI, pos. ion) m / z: 289.30 [M+H] + .

[0502] Step 3) Synthesis of methyl 8-cyclopentyl-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate Methyl 8-cyclopentyl-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.255 g, 0.88 mmol) was added to a 100 mL flask and dissolved in DCM (10 mL). After cooling, DDQ (0.22 g, 0.97 mmol) was added under ice bath conditions, and the mixture was reacted overnight at room temperature. The solution was concentrated under reduced pressure, cooled, and quenched with saturated sodium bicarbonate (20 mL) under ice bath conditions. After stirring for 30 minutes, the solid precipitated. The precipitate was collected by filtration, washed with saturated sodium bicarbonate (30 mL), and dried under vacuum to obtain a brownish-yellow solid (0.212 g, 83.72%). MS (ESI, pos. ion) m / z: 287.30 [M+H] + ;

[0503] Step 4) Synthesis of 5-cyclopentyl-7-(hydroxymethyl)-3-methyl-1,2-dihydroquinoxarin-2-one Methyl 8-cyclopentyl-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (0.212 g, 0.74 mmol) was added to a 100 mL reaction flask and dissolved with stirring in THF (8 mL). After cooling, LAH (0.077 g, 1.97 mmol, 97% purity) was added under ice bath conditions, and the reaction was continued at room temperature for 4 hours. The mixture was cooled, and the reaction product was quenched by adding water (2 mL) under ice bath conditions. Then, 1 M dilute hydrochloric acid was added dropwise to adjust the pH to 3-4. The mixture was extracted with THF (8 mL × 2). The organic phases were combined, washed with saturated brine, and dehydrated with anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to obtain a white solid (0.090 g, yield 47.06%). MS (ESI, pos. ion) m / z: 259.20 [M+H] + ;

[0504] Step 5) Synthesis of 7-(bromomethyl)-5-cyclopentyl-3-methylquinoxaline-2(1H)-one 5-cyclopentyl-7-(hydroxymethyl)-3-methyl-1,2-dihydroquinoxalin-2-one (0.090 g, 0.35 mmol) and DCM (4.5 mL) were added to a 100 mL flask. The mixture was cooled, and phosphorus tribromide (0.043 mL, 0.45 mmol) was added dropwise under ice bath. The mixture was stirred until no further exothermic reaction was observed, then the mixture was warmed to room temperature and stirred for a further 4 hours. The mixture was concentrated under reduced pressure, and the residue was washed with MTBE (4.5 mL × 2). The resulting crude product was used directly in the next step.

[0505] Step 6) Synthesis of 5-(4-((8-cyclopentyl-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide In a 100 mL flask, 7-(bromomethyl)-5-cyclopentyl-3-methylquinoxaline-2(1H)-one (0.11 g, 0.34 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide dihydrochloride (0.12 g, 0.37 mmol), and potassium iodide (0.011 g, 0.068 mmol) were added. The mixture was dissolved in acetonitrile (3.5 mL), cooled, and while stirring, DIPEA (0.41 mL, 2.38 mmol) was slowly added dropwise under an ice bath to ensure homogeneity. The mixture was heated to 80 °C and reacted for 2 hours. After cooling to room temperature, toluene (15 mL) was added for dilution, and then washed with water (10 mL) and saturated brine. The organic phase was dehydrated with anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH(v / v) = 20 / 1) to obtain a white solid (0.075 g, yield 45.76%). MS (ESI, pos. ion) m / z: 479.30 [M+H] + ; 1H NMR (599 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.40 (d, J = 4.0 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.61 - 7.54 (m, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 4.02 - 3.96 (m, 1H), 3.59 (s, 2H), 3.18 (br, 4H), 2.77 (d, J = 4.2 Hz, 3H), 2.56 (br, 4H), 2.41 (br, 3H), 2.03 (br, 2H), 1.83 (br, 2H), 1.70 (br, 2H), 1.61 (br, 2H).

[0506] (Example 32) 5-(4-((8-(4-cyanophenoxy)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide

[0507] [ka]

[0508] Step 1) Synthesis of 4-((7-bromo-3-methyl-2-oxo-1,2-dihydroquinoxaline-5-yl)oxy)benzonitrile 7-Bromo-5-fluoro-3-methylquinoxaline-2(1H)-one (800 mg, 3.11 mmol), 4-hydroxybenzonitrile (1.11 g, 9.33 mmol), and K2CO3 (1.29 g, 9.33 mmol) were added to DMSO (16 mL). After addition, the mixture was microwaved at 130 °C for 15 hours. The reaction solution was diluted with water (60 mL), and HCl solution (4 M) was added to adjust the pH to 5. The solid was precipitated and filtered to obtain the solid. The solid was dried under vacuum at 50 °C for 8 hours to obtain a pale yellow solid (600 mg, 54%). MS (ESI, pos. ion) m / z: 356.2 [M+H] + .

[0509] Step 2) Synthesis of 4-((7-(hydroxymethyl)-3-methyl-2-oxo-1,2-dihydroquinoxaline-5-yl)oxy)benzonitrile 4-((7-bromo-3-methyl-2-oxo-1,2-dihydroquinoxaline-5-yl)oxy)benzonitrile (300 mg, 0.84 mmol), (tributyltin)methanol (297 mg, 0.92 mmol), and Xphos-Pd-G2 (66 mg, 0.08 mmol) were added to 1,4-dioxane (8 mL). The reaction was carried out at 80°C for 10 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH(v / v) = 20 / 1) to obtain a pale yellow solid (150 mg, 58%). MS (ESI, pos. ion) m / z: 308.2 [M+H] + .

[0510] Step 3) Synthesis of 4-((7-(bromomethyl)-3-methyl-2-oxo-1,2-dihydroquinoxaline-5-yl)oxy)benzonitrile At 0°C, CBr4 (259 mg, 0.78 mmol) was added to DCM (8 mL) containing 4-((7-(hydroxymethyl)-3-methyl-2-oxo-1,2-dihydroquinoxaline-5-yl)oxy)benzonitrile (120 mg, 0.39 mmol) and PPh3 (205 mg, 0.78 mmol). After 1 hour, the reaction was carried out at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / Â(v / v) = 1 / 1) to obtain a yellow solid (50 mg, 35%). MS (ESI, pos. ion) m / z: 370.1 [M+H] + ;

[0511] Step 4) Synthesis of 5-(4-((8-(4-cyanophenoxy)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide 4-((7-(bromomethyl)-3-methyl-2-oxo-1,2-dihydroquinoxaline-5-yl)oxy)benzonitrile (50 mg, 0.14 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (40 mg, 0.17 mmol), and DIPEA (72 mg, 0.56 mmol) were sequentially added to MeCN (4 mL), and the reaction was carried out at 70°C for 3 hours. The reaction solution was concentrated under reduced pressure, diluted with DCM (60 mL), washed sequentially with water (30 mL) and saturated NaCl solution (30 mL), dehydrated with anhydrous Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH(v / v) = 20 / 1) to obtain a pale yellow solid (40 mg, 56%). MS (ESI, pos. ion) m / z: 528.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.58 (s, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.50 (dd, J = 10.1, 4.9 Hz, 1H), 7.28 (dd, J = 9.2, 1.8 Hz, 1H), 7.11 (s, 1H), 7.06 (d, J = 8.8 Hz, 2H), 6.99 (s, 1H), 3.63 (s, 2H), 3.22 (s, 4H), 3.00 (d, J = 5.0 Hz, 3H), 2.65 (s, 4H), 2.53 (s, 3H).

[0512] (Example 33) 6-Fluoro-5-(4-((8-((4-fluorophenyl)amino)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-N-methylpicolinamide

[0513] [ka]

[0514] Step 1) Synthesis of methyl 8-((4-fluorophenyl)amino)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate Methyl 8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (1.4 g, 4.71 mmol), 4-fluoroaniline (0.68 g, 6.12 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2-(2'-amino-1,1'-biphenyl))palladium(II) (0.26 g, 0.33 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (0.28 g, 0.66 mmol), sodium tert-butoxide (0.63 g, 6.59 mmol), and toluene (10 mL) were added to the reaction flask. The mixture was protected under nitrogen and heated to 110°C and reacted for 8 hours. Next, the reaction mixture was quenched and water (100 mL) was added. The mixture was extracted with  (300 mL). The organic phases were sequentially washed with water (100 mL) and saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM /  (v / v) = 2 / 1) to obtain the product as a yellow solid (0.58 g, 36%). MS (ESI, pos. ion) m / z: 328.3 [M+H] + .

[0515] Step 2) Synthesis of 5-((4-fluorophenyl)amino)-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one Methyl 8-((4-fluorophenyl)amino)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (0.57 g, 1.74 mmol) and tetrahydrofuran (20 mL) were added to the reaction flask. Lithium aluminum hydride (0.17 g, 4.52 mmol) was added while stirring at 0°C. After the addition was complete, the reaction was allowed to proceed at room temperature for 4.5 hours. The reaction products were quenched by adding water (0.2 mL), and then 15% sodium hydroxide solution (0.2 mL) was added. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH(v / v) = 20 / 1) to obtain a yellow solid (85 mg, 16%). MS (ESI, pos. ion) m / z: 300.2 [M+H] + .

[0516] Step 3) Synthesis of 8-((4-fluorophenyl)amino)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxyaldehyde 5-((4-fluorophenyl)amino)-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one (0.12 g, 0.40 mmol) was dissolved in a mixture of tetrahydrofuran (2 mL) and dichloromethane (2 mL). Dess-Martin periodinane (0.34 g, 0.80 mmol) was added at room temperature. After the addition was complete, the reaction was continued at room temperature for 4 hours. The reaction was then stopped, water (140 mL) was added, and the mixture was extracted with DCM (40 mL). The organic phase was successively washed with saturated sodium bicarbonate (60 mL) and brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow solid (0.09 g, 75%). MS (ESI, pos. ion) m / z: 298.3 [M+H] + .

[0517] Step 4) Synthesis of 6-fluoro-5-(4-((8-((4-fluorophenyl)amino)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-N-methylpicolinamide 6-Fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (0.10 g, 0.42 mmol) was dissolved in dichloromethane (2 mL) and methanol (2 mL). Triethylamine (0.097 g, 0.96 mmol), 8-((4-fluorophenyl)amino)-2-methyl-3-oxo-3,4-dihydroquinoxalolin)-6-carboxyaldehyde (0.095 g, 0.32 mmol), acetic acid (0.0038 g, 0.064 mmol), and sodium borohydride cyanohydride (0.060 g, 0.96 mmol) were added, and the mixture was reacted at room temperature for 5 hours. The solution was concentrated under reduced pressure, and the residue was separated by thin-layer silica gel chromatography (DCM / MeOH(v / v) = 20 / 1) to obtain a yellow solid (0.02 g, 12%). MS (ESI, pos. ion) m / z: 520.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 8.40 (d, J = 4.7 Hz, 1H), 8.19 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.60 - 7.52 (m, 1H), 7.34 (dd, J = 8.8, 4.9 Hz, 2H), 7.17 (t, J = 8.8 Hz, 2H), 6.90 (s, 1H), 6.63 (s, 1H), 3.60 (s, 2H), 3.15 (s, 4H), 2.76 (d, J = 4.7 Hz, 3H), 2.52 (s, 4H), 2.43 (s, 3H).

[0518] (Example 34) 6-Fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-((1,1,1-trifluoropropane-2-yl)oxy)-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)picolinamide

[0519] [ka]

[0520] Step 1) Synthesis of 7-bromo-3-methyl-5-((1,1,1-trifluoropropane-2-yl)oxy)quinoxaline-2(1H)-one Under a nitrogen atmosphere at 0°C, 1,1,1-trifluoropropa-2-ol (2.66 g, 23.3 mmol) was added to a solution of N,N-dimethylformamide (10 ml). Sodium hydride (0.93 g, 23.3 mmol) was added gradually, and the mixture was stirred for 20 minutes. The mixture was then brought to room temperature and reacted for a further 30 minutes. Finally, 7-bromo-5-fluoro-3-methyl-1,2-dihydroquinoxalin-2-one (600 mg, 2.33 mmol) was added, and the temperature was raised to 100°C for 6 hours. The reaction solution was quenched with H2O (50 mL), and aqueous HCl (1 mol / L) was added dropwise until neutral. The mixture was stirred for 1 hour, filtered, and the filtered cake was dried under vacuum at 50°C to obtain a gray solid product (800 mg, 97.62%). MS (ESI, pos. ion) m / z: 351.0 [M+H] + .

[0521] Step 2) Synthesis of 7-(hydroxymethyl)-3-methyl-5-((1,1,1-trifluoropropane-2-yl)oxy)quinoxaline-2(1H)-one At room temperature, 7-bromo-3-methyl-5-((1,1,1-trifluoropropa-2-yl)oxy)quinoxaline-2(1H)-one (800 mg, 2.28 mmol), (tributyltin)methanol (1127.41 mg, 3.51 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (269.09 mg, 0.34 mmol) catalyst were added to 1,4-dioxane (15 ml), and the reaction was carried out at 80°C for 3 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (dichloromethane / ethyl acetate (V / V) = 1 / 1) to obtain a white solid product (485 mg, 70.43%). MS (ESI, pos. ion) m / z: 303.2 [M+H] + .

[0522] Step 3) Synthesis of 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-((1,1,1-trifluoropropan-2-yl)oxy)-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)picolinamide At 0°C, tetrabromomethane (617.64 mg, 2.35 mmol) was added to a 10 mL solution of 7-(hydroxymethyl)-3-methyl-5-((1,1,1-trifluoropropa-2-yl)oxy)quinoxaline-2(1H)-one (350 mg, 1.16 mmol) in acetonitrile, and the mixture was stirred for 20 minutes. After stirring, the mixture was allowed to cool to room temperature for 1 hour. Next, ethyldiisopropylamine (1357.02 mg, 10.5 mmol) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (380 mg, 1.58 mmol) were added to the reaction solution, and the temperature was raised to 70°C. The reaction mixture was stirred for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to obtain a white solid product (510 mg, 92.52%). MS (ESI, pos. ion) m / z: 523.4 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 8.39 (d, J = 4.4 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 9.2 Hz, 1H), 6.98 (s, 2H), 5.32 (dt, J = 12.7, 6.3 Hz, 1H), 3.58 (s, 2H), 3.18 (s, 4H), 2.76 (d, J = 4.6 Hz, 3H), 2.56 (s, 4H), 2.40 (s, 3H), 1.52 (d, J = 6.1 Hz, 3H).

[0523] (Example 35) N-Cyclopropyl-6-fluoro-5-(4-((2-methyl-3-oxo-8-(propa-1-in-1-yl)-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)picolinamide

[0524] [ka]

[0525] Step 1) Synthesis of 5-(4-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-N-cyclopropyl-6-fluoropicolinamide At room temperature, N-cyclopropyl-6-fluoro-5-(piperazin-1-yl)picolinamide (0.48 g, 1.83 mmol), DIPEA (1.07 g, 8.30 mmol), and potassium iodide (0.014 g, 0.083 mmol) were added to a solution of 5-bromo-7-(bromomethyl)-3-methylquinoxaline-2(1H)-one (0.55 g, 1.66 mmol) in ACN (20 mL), and the reaction mixture was heated at 80°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: CH2Cl2 / MeOH (v / v) = 20 / 1) to obtain a yellow solid product (0.45 g, 52.7%). MS (ESI, pos. ion) m / z: 515.0 [M+H] + ;

[0526] Step 2) Synthesis of N-cyclopropyl-6-fluoro-5-(4-((2-methyl-3-oxo-8-(propa-1-in-1-yl)-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)picolinamide At room temperature, tributyl(propa-1-in-1-yl)stanan (0.52 g, 1.57 mmol) and Xphos Pd G2 (0.10 g, 0.13 mmol) were added to 1,4-dioxane (20 mL) of 5-(4-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxolin-6-yl)methyl)piperazin-1-yl)-N-cyclopropyl-6-fluoropicolinamide (0.45 g, 0.87 mmol), replacing N2. The mixture was then heated to 90°C and stirred for 12 hours. After the reaction solution cooled to room temperature, it was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: DCM / MeOH(v / v) = 20 / 1) to obtain a yellow solid product (0.061 g, 14.72%). MS (ESI, pos. ion) m / z: 475.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 12.32 (s, 1H), 8.37 - 8.32 (m, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 9.3 Hz, 1H), 7.29 (s, 1H), 7.20 (s, 1H), 3.57 (s, 2H), 3.19 - 3.12 (m, 4H), 2.87 - 2.82 (m, 1H), 2.62 - 2.52 (m, 7H), 2.41 (s, 3H), 2.13 (s, 3H), 1.40 - 1.30 (m, 4H), 0.68 - 0.61 (m, 4H).

[0527] (Example 36) 5-(4-((2-methyl-3-oxo-8-(propa-1-in-1-yl)-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)picolinonitrile

[0528] [ka]

[0529] Step 1) Synthesis of methyl 8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate Under ice bath conditions, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.98 g, 17.55 mmol) was gradually added to a solution of methyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (3.5 g, 11.70 mmol) in dichloromethane (100 mL). The reaction mixture was then allowed to cool to room temperature and reacted for 10 hours. The reaction solution was concentrated under reduced pressure, and saturated sodium bicarbonate (100 mL) was added at 0°C. The mixture was then allowed to cool to room temperature and stirred for 1 hour. After filtration, the filter cake was washed with water (50 mL) to obtain an orange-yellow solid product (3.23 g, 92.91%). MS (ESI, pos. ion) m / z: 297.05 [M+H] + .

[0530] Step 2) Synthesis of 5-bromo-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one At 0°C and under N2, lithium aluminum hydride (0.83 g, 21.74 mmol) was gradually added to a solution of methyl 8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (3.23 g, 10.87 mmol) in tetrahydrofuran (100 mL), and the mixture was stirred at room temperature for 5 hours. After quenching the sample with water at 0°C, 1 M hydrochloric acid was added dropwise to a pH of 3-4. After adding saturated brine (30 mL), the sample was extracted with tetrahydrofuran (50 mL x 3). The sample was dehydrated with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 97 / 5) to obtain a brown solid product (1.77 g, 60.05%). MS (ESI, neg. ion) m / z: 267.0 [MH] - .

[0531] Step 3) Synthesis of 5-(piperazin-1-yl)pyridinium nitrile hydrochloride At room temperature, a 5 mL solution of 4 M dioxane hydrochloride was added to 20 mL of ethyl acetate containing 4-(6-cyanopyridine-3-yl)piperazine-1-carboxylate tert-butyl ester (0.95 g, 3.29 mmol), and the mixture was reacted for 2 hours. After the reaction was complete, the reaction solution was filtered directly to obtain a solid product, which was dried at room temperature to obtain a pale yellow solid (0.71 g, 96.75%). MS (ESI, pos. ion) m / z: 189.25 [M+H] + .

[0532] Step 4) Synthesis of 5-bromo-7-(bromomethyl)-3-methylquinoxaline-2(1H)-one At 0°C and under N2, phosphorus tribromide (0.24 mL, 2.60 mmol) was added dropwise to a solution of 5-bromo-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one (0.5 g, 1.86 mmol) in acetonitrile (20 mL), and the mixture was stirred for 5-10 minutes. The temperature was then raised to 35°C for 4 hours. TLC results showed a complete reaction, and the reaction proceeded directly to the next step without further treatment.

[0533] Step 5) Synthesis of 5-(4-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)pyridinenitrile In an ice bath, potassium iodide (15 mg, 0.091 mmol), 5-(piperazin-1-yl)pyridinenitrile (0.51 g, 1.71 mmol), and N,N-diisopropylethylamine (4.79 mL, 28.96 mmol) were added to a solution of 5-bromo-7-(bromomethyl)-3-methylquinoxaline-2(1H)-one (0.6 g, 1.81 mmol) in acetonitrile (20 mL), and the mixture was heated to room temperature for 2 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (30 mL), washed with water (20 mL x 2), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 97 / 4) to obtain an orange-yellow solid powder (0.35 g, 44.71%). MS (ESI, pos. ion) m / z: 439.10 [M+H] + ;

[0534] Step 6) Synthesis of 5-(4-((2-methyl-3-oxo-8-(propa-1-in-1-yl)-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)picolinonitrile At room temperature, tributyl(propa-1-in-1-yl)tin (0.19 mL, 0.61 mmol) was added to a solution of 5-(4-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinonitrile (0.15 g, 0.31 mmol) in 1,4-dioxane (15 mL), followed by the addition of XPhos Pd G2 (0.040 g, 0.051 mmol). The reaction mixture was then replaced with N2 and allowed to react overnight at 90°C. The reaction solution was filtered through diatomaceous earth, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 96 / 4) to obtain a white solid powder (51 mg, 37.49%). MS (ESI, pos. ion) m / z: 399.18 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 8.44-8.37 (m, 1H), 7.77-7.70 (m, 1H), 7.35 (dd, J = 8.9, 3.0 Hz, 1H), 7.30-7.19 (m, 2H), 3.56 (s, 2H), 3.43-3.39 (m, 4H), 2.55-2.49 (m, 10H), 2.41 (s, 3H), 2.13 (s, 3H).

[0535] (Example 37) 7-((4-(6-(difluoromethoxy)pyridine-3-yl)piperazine-1-yl)methyl)-3-methyl-5-(propa-1-in-1-yl)quinoxaline-2(1H)-one

[0536] [ka]

[0537] Step 1) Synthesis of methyl 8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate Under ice bath conditions, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.69 g, 25.08 mmol) was gradually added to a 150 mL solution of methyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (5 g, 16.72 mmol) in dichloromethane. The reaction mixture was then allowed to cool to room temperature and reacted for 6 hours. The reaction solution was concentrated under reduced pressure, and saturated sodium bicarbonate aqueous solution (100 mL) was added at 0°C. The mixture was then heated to room temperature and stirred for 3 hours. After filtration, the filter cake was washed with water (50 mL x 3) to obtain an orange-yellow solid product (4.7 g, 94.64%). MS (ESI, pos. ion) m / z: 297.15 [M+H] + .

[0538] Step 2) Synthesis of 5-bromo-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one At 0°C and under N2, lithium aluminum hydride (1.12 g, 29.62 mmol) was gradually added to a solution of methyl 8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (4.4 g, 14.81 mmol) in tetrahydrofuran (100 mL), and the reaction mixture was stirred at room temperature for 8 hours. After quenching the reaction mixture with water at 0°C, 1 M hydrochloric acid was added dropwise to a pH of 3-4. Then, saturated brine was added, and the mixture was extracted with tetrahydrofuran (100 mL x 3). The extract was dehydrated with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 97 / 5) to obtain a brown solid product (3.36 g, 84.31%). MS (ESI, neg. ion) m / z: 267.00 [MH] - .

[0539] Step 3) Synthesis of 5-bromo-7-(bromomethyl)-3-methylquinoxaline-2(1H)-one Phosphorus tribromide (0.24 mL, 2.60 mmol) was added dropwise to 25 mL of acetonitrile solution of 5-bromo-7-(hydroxymethyl)-3-methylquinoxaline-2(1H)-one (0.5 g, 1.86 mmol), stirred for 5-10 minutes, then the temperature was raised to 35°C and the reaction was carried out for 4 hours. TLC results showed a complete reaction, and the reaction proceeded directly to the next step without further treatment.

[0540] Step 4) Synthesis of 5-bromo-2-(difluoromethoxy)pyridine At room temperature, sodium carbonate (6.70 g, 63.22 mmol) was added to a solution of 5-bromo-1,2-dihydropyridine-2-one (10 g, 57.47 mmol) in acetonitrile (120 mL). The mixture was heated to 60 °C and stirred for 1 hour. Then, (bromodifluoromethyl)trimethylsilane (14.01 g, 68.96 mmol) was slowly added, and the reaction was continued at 60 °C with stirring. After the reaction was complete, water (100 mL) was added to the reaction solution, and the mixture was extracted with DCM (150 mL x 3). The organic phases were combined, washed with saturated brine, dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dried to obtain a yellow solid product (11.5 g, 89.33%).

[0541] Step 5) Synthesis of 4-(6-(difluoromethoxy)pyridine-3-yl)piperazine-1-carboxylate tert-butyl ester At room temperature, Ruphos-Pd-G3 (0.52 g, 0.63 mmol) was added to a solution of 5-bromo-2-(difluoromethoxy)pyridine (2 g, 8.93 mmol), piperazine-1-carboxylate tert-butyl ester (1.75 g, 9.38 mmol), and cesium carbonate (5.82 g, 17.86 mmol) in 1,4-dioxane (60 mL). The solution was then replaced with N2, and the reaction was carried out overnight at 110 °C. The mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE:siRNA(v / v) = 6 / 1) to obtain a yellow solid product (2.6 g, 88.42%). MS (ESI, pos. ion) m / z: 330.20 [M+H] + .

[0542] Step 6) Synthesis of 1-(6-(difluoromethoxy)pyridine-3-yl)piperazine At room temperature, a 4M dioxane hydrochloride solution (30.4 mmol) was added to ethyl acetate (20 mL) containing 4-(6-(difluoromethoxy)pyridine-3-yl)piperazine-1-carboxylate tert-butyl ester (1 g, 3.04 mmol), and the reaction was allowed to proceed overnight. After the reaction was complete, the reaction solution was filtered directly to obtain a solid product, which was dried at room temperature to obtain a pale yellow solid (0.62 g, 89.08%). MS (ESI, pos. ion) m / z: 230.10 [M+H] + .

[0543] Step 7) Synthesis of 5-bromo-7-((4-(6-(difluoromethoxy)pyridine-3-yl)piperazine-1-yl)methyl)-3-methylquinoxaline-2(1H)-one At room temperature, potassium iodide (15 mg, 0.091 mmol), 1-(6-(difluoromethoxy)pyridine-3-yl)piperazine (0.62 g, 2.71 mmol), and N,N-diisopropylethylamine (4.79 mL, 28.96 mmol) were added to a solution of 5-bromo-7-(bromomethyl)-3-methylquinoxaline-2(1H)-one (0.6 g, 1.81 mmol) in acetonitrile (25 mL). The mixture was heated to room temperature and reacted for 2 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane, washed three times with water (20 mL x 3), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 97 / 4) to obtain an orange-yellow solid powder (0.42 g, 48.38%). MS (ESI, pos. ion) m / z: 479.95 [M+H] + ;

[0544] Step 8) Synthesis of 7-((4-(6-(difluoromethoxy)pyridine-3-yl)piperazine-1-yl)methyl)-3-methyl-5-(propa-1-in-1-yl)quinoxaline-2(1H)-one At room temperature, tributyl(propa-1-in-1-yl)tin (0.23 mL, 0.76 mmol) was added to a solution of 5-bromo-7-((4-(6-(difluoromethoxy)pyridine-3-yl)piperazin-1-yl)methyl)-3-methylquinoxaline-2(1H)-one (0.2 g, 0.42 mmol) in 1,4-dioxane (15 mL), followed by the addition of XPhos Pd G2 (0.050 g, 0.063 mmol). The mixture was then replaced with N2, the temperature was raised to 90°C, and the reaction was allowed to continue overnight. The reaction solution was filtered through diatomaceous earth, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 96 / 4) to obtain a white solid powder (22 mg, 12.02%). MS (ESI, pos. ion) m / z: 440.19 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.89 - 7.84 (m, 1H), 7.54(t, J = 73.6, 1H), 7.56 - 7.51 (m, 1H), 7.31 - 7.18 (m, 2H), 6.98 - 6.93 (m, 1H), 3.16 - 3.11 (m, 4H), 2.57 - 2.51 (m, 4H), 2.40 (s, 3H), 2.13 (s, 3H).

[0545] (Example 38) N,6-dimethyl-5-(4-((2-methyl-3-oxo-8-(propa-1-in-1-yl)-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)picolinamide

[0546] [ka]

[0547] Step 1) Synthesis of tert-butyl 4-(6-(methoxycarbonyl)-2-methylpyridine-3-yl)piperazine-1-carboxylate At room temperature, Ruphos Pd G3 (0.64 g, 0.76 mmol) was added to a solution of methyl 5-bromo-6-methylpyridine-2-carboxylic acid (5 g, 21.73 mmol), piperazine-1-carboxylic acid tert-butyl ester (4.25 g, 22.82 mmol), and Cs2CO3 (14.16 g, 43.46 mmol) in 1,4-dioxane (250 mL). The solution was then replaced with N2 and heated to 110 °C for 12 hours with stirring. After cooling, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE / siRNA (v / v) = 1 / 1) to obtain a yellow solid product (5.7 g, 78.20%). MS (ESI, pos. ion) m / z: 336.2 [M+H] + ;

[0548] Step 2) Synthesis of tert-butyl 4-(2-methyl-6-(methylcarbamoyl)pyridine-3-yl)piperazine-1-carboxylate Methylamine (15.83 g, 509.70 mmol) was added to a solution of tert-butyl 4-(6-methoxycarbonyl)-2-methylpyridine-3-yl)piperazine-1-carboxylate (5.7 g, 16.99 mmol) in MeOH (100 mL) at room temperature, and the mixture was stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: PE / Â(v / v) = 1 / 1) to obtain a yellow solid product (5.6 g, 98.54%). MS (ESI, pos. ion) m / z: 335.2 [M+H] + ;

[0549] Step 3) Synthesis of N,6-dimethyl-5-(piperazine-1-yl)picolinamide At room temperature, HCl-1,4-dioxane (3.05 g, 83.75 mmol, 4 M) was added to a solution of tert-butyl 4-(2-methyl-6-(methoxycarbonyl)pyridine-3-yl)piperazine-1-carboxylate (5.6 g, 16.75 mmol) in 1,4-dioxane (20 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was filtered, and the resulting solid was added to DCM (50 mL). The pH was adjusted to 9-10 with triethylamine, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CH2Cl2 / MeOH (v / v) = 10 / 1) to obtain a yellow solid product (3.63 g, yield 92.52%). MS (ESI, pos. ion) m / z: 235.2 [M+H] + ;

[0550] Step 4) Synthesis of 5-(4-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide At room temperature, N,6-dimethyl-5-(piperazin-1-yl)picolinamide (0.51 g, 2.17 mmol), DIPEA (1.17 g, 9.05 mmol), and KI (0.015 g, 0.091 mmol) were added to a solution of 5-bromo-7-(bromomethyl)-3-methylquinoxaline-2(1H)-one (0.6 g, 1.81 mmol) in ACN (20 mL), and the mixture was reacted at 80°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: CH2Cl2 / MeOH (v / v) = 20 / 1) to obtain a yellow solid product (0.21 g, 23.94%). MS (ESI, pos. ion) m / z: 485.2 [M+H] + ;

[0551] Step 5) Synthesis of N,6-dimethyl-5-(4-((2-methyl-3-oxo-8-(propa-1-in-1-yl)-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)picolinamide At room temperature, tributyl(propa-1-in-1-yl) stannan (0.24 g, 0.74 mmol) and Xphos Pd G2 (0.048 g, 0.061 mmol) were added to a solution of 5-(4-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (0.2 g, 0.41 mmol) in 1,4-dioxane (20 mL). After replacing with N2, the mixture was heated to 90°C and reacted for 12 hours. After cooling the reaction solution to room temperature, it was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to obtain a yellow solid product (0.02 g, 10.92%). MS (ESI, pos. ion) m / z: 445.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 12.35 (s, 1H), 8.42 (s, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.30 (s, 1H), 7.21 (s, 1H), 3.58 (s, 2H), 3.31 - 3.20 (m, 4H), 2.95 (s, 3H), 2.82 - 2.77 (m, 3H), 2.61 - 2.55 (m, 4H), 2.41 (s, 3H), 2.13 (s, 3H).

[0552] (Example 39) N-Cyclopropyl-2-fluoro-1'-((2-methyl-3-oxo-8-(propa-1-in-1-yl)-3,4-dihydroquinoxaline-6-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0553] [ka]

[0554] Step 1) Synthesis of 1'-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-yl)methyl)-N-cyclopropyl-2-fluoro-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide At room temperature, N-cyclopropyl-2-fluoro-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (0.71 g, 2.71 mmol), DIPEA (1.17 g, 9.05 mmol), and KI (0.015 g, 0.091 mmol) were added to a solution of 5-bromo-7-(bromomethyl)-3-methylquinoxaline-2(1H)-one (0.6 g, 1.81 mmol) in ACN (20 mL), and the mixture was reacted at 80°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: CH2Cl2 / MeOH (v / v) = 20 / 1) to obtain a yellow solid product (0.9 g, 97.19%). MS (ESI, pos. ion) m / z: 512.9 [M+H] + ;

[0555] Step 2) Synthesis of N-cyclopropyl-2-fluoro-1'-((2-methyl-3-oxo-8-(propa-1-in-1-yl)-3,4-dihydroquinoxaline-6-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide At room temperature, tributyl(propa-1-in-1-yl)tin (0.20 g, 0.59 mmol) and Xphos Pd G2 (0.039 g, 0.050 mmol) were added to a solution of 1'-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-N-cyclopropyl-2-fluoro-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (0.17 g, 0.33 mmol) in 1,4-dioxane (20 mL). The nitrogen was replaced, and the mixture was heated to 90°C and stirred for 12 hours. After the reaction solution cooled to room temperature, it was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: DCM / MeOH(v / v) = 20 / 1) to obtain a yellow solid product (0.08 g, 51.13%). MS (ESI, pos. ion) m / z: 472.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 12.32 (s, 1H), 8.61 (s, 1H), 8.10 - 8.06 (m, 1H), 7.95 - 7.88 (m, 1H), 7.30 (s, 1H), 7.23 (s, 1H), 6.27 - 6.22 (m, 1H), 3.63 (s, 2H), 3.15 - 3.11 (m, 2H), 2.90 - 2.87 (m, 1H), 2.72 - 2.63 (m, 4H), 2.41 (s, 3H), 2.13 (s, 3H), 0.70 - 0.65 (m, 4H).

[0556] (Example 40) 5-(4-((5-fluoro-2-methyl-3-oxo-8-(propa-1-in-1-yl)-3,4-dihydroquinoxaline-6-yl)methyl)piperazine-1-yl)-N-methylpicolinamide

[0557] [ka]

[0558] Step 1) Synthesis of methyl(4-bromo-3-fluoro-2-nitrophenyl)malonate Ethyl diisopropylamine (16.29 g, 126.06 mmol) was added dropwise to a solution of 1-bromo-2,4-difluoro-3-nitrobenzene (10 g, 42.02 mmol) and methyl 2-aminopropionate (4.42 g, 42.86 mmol), and the mixture was heated overnight at room temperature. The reaction was stopped, the reaction solution was diluted with DCM, washed three times with water (50 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / siRNA(v / v) = 6 / 1) to obtain a yellow solid product (6 g, 44.47%). ...

Claims

1. Compounds of formula (I), or their stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs. 【Chemistry 1】 [In the formula, X is CR x or N; 【Chemistry 2】 It is a 3- to 12-membered heterocycline; R 1 is H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)-(C 1 ~C 6 alkyl), -C(=O)-(C 1 ~C 6 alkoxy), C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxy, C 1 ~C 6 haloalkoxy, C 1 ~C 6 alkylthio, C 1 ~C 6 alkylamino, C 1 ~C 6 hydroxyalkyl, C 3 ~C 8 is cycloalkyl or 3- to 8-membered heterocyclyl; R 2a and R 2b Each of these is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 -C(=O)NHCH 3 -C(=O)N(CH 3 ) 2 -C(=O)-(C 1 ~C 6 Alkyl), -C(=O)-(C 1 ~C 6 Alkoxy), C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy, C 1 ~C 6 Alkylthio, C 1 ~C 6 Alkylamino, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Cyanoalkyl, C 3 ~C 8 Cycloalkyl, 3-8 membered heterocyclyl, C 6 ~C 10 It is an aryl or a 5- to 10-membered heteroaryl; R 2 is -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -C(=O)-(C 1 ~C 6 alkyl), -C(=O)-(C 1 ~C 6 alkoxy), C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 alkoxy, C 1 ~C 6 haloalkoxy, C [[ID=4ano, C 1 ~C 6 alkylthio, C 1 ~C 6 alkylamino, C [[ID=5ammonio, C 1 ~C 6 hydroxyalkyl, C 1 ~C 6 cyanoalkyl, C 3 ~C 8 cycloalkyl-L-, 3- to 8-membered heterocyclyl-L-, C 6 ~C 10 aryl-L- or a 5- to 10-membered heteroaryl-L-, and is unsubstituted or substituted by 1, 2, 3, 4 or 5 R w ; Each -L- is independent, combined, -NR n -, -O-, -S-, -C(=O)-, -C(=O)O-, -C(=O)N(R n1 )- or -(CR a R b ) m -and; m is 1, 2, 3, 4, 5, or 6; R n and R n1 Each of these is independently H, D, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 3 ~C 8 Cycloalkyl, 3-8 membered heterocyclyl, C 6 ~C 10 It is an aryl or a 5- to 10-membered heteroaryl; R a and R b Each of these is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 -OH, -SH, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy, C 1 ~C 6 Alkylthio, C 1 ~C 6 Alkylamino or C 1 ~C 6 It is a hydroxyalkyl group; R 3 , R 3a and R 3b Each of these is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 -C(=O)NHCH 3 -C(=O)N(CH 3 ) 2 -C(=O)-(C 1 ~C 6 Alkyl), -C(=O)-(C 1 ~C 6 Alkoxy), C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy, C 1 ~C 6 Alkylthio, C 1 ~C 6 Alkylamino or C 1 ~C 6 It is a hydroxyalkyl group; R 4 H, D, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy, C 1 ~C 6 Alkylthio, C 1 ~C 6 Alkylamino, C 3 ~C 8 Cycloalkyl, 3-8 membered heterocyclyl, C 6 ~C 10 It is an aryl or 5-10 membered heteroaryl, C 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, 3-8 membered heterocyclyl, C 6 ~C 10 Each of the aryl and 5- to 10-membered heteroaryls can be independently and arbitrarily selected from D, F, Cl, Br, I, -OH, and -NH. 2 , -NO 2 ,-CN,C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy and C 1 ~C 6 Substituted with 1, 2, 3, 4, or 5 groups selected from haloalkoxys; R x and R z Each of these is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 -OH, -COOH, -C(=O)NH 2 , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy or C 1 ~C 6 It is a hydroxyalkyl group; Each R w These are independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 -C(=O)NHCH 3 -C(=O)N(CH 3 ) 2 -C(=O)-(C 1 ~C 6 Alkyl), -C(=O)-(C 1 ~C 6 Alkoxy), C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenil, C 2 ~C 6 Alkinyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy, C 1 ~C 6 Alkylthio, C 1 ~C 6 Alkylamino, C 1 ~C 6 Hydroxyalkyl, C 3 ~C 8 Cycloalkyl, 3-8 membered heterocyclyl, C 6 ~C 10 It is an aryl or a 5- to 10-membered heteroaryl; n is 1, 2, 3, 4, 5, or 6. The compounds represented by formula (I) are the following compounds: 【Chemistry 3A】 【Chemistry 3B】 【Chemicals 3C】 A compound that does not contain any of the above. 【Request Item 2】 【Chemistry 4】 but 【Transformation 5】 And * is the left -CH 2 The compound according to claim 1, wherein - indicates a connection and ** indicates a pyridinyl connection on the right.

3. Each R 1 , H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 -C(=O)NHCH 3 -C(=O)N(CH 3 ) 2 -C(=O)-(C 1 ~C 4 Alkyl), -C(=O)-(C 1 ~C 4 Alkoxy), C 1 ~C 4 Alkyl, C 2 ~C 4 Alkenil, C 2 ~C 4 Alkinyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Alkoxy, C 1 ~C 4 Haloalkoxy, C 1 ~C 4 Alkylthio, C 1 ~C 4 Alkylamino, C 1 ~C 4 Hydroxyalkyl, C 3 ~C 6 They are cycloalkyl or 3- to 6-membered heterocyclines; R 3 , R 3a and R 3b Each of these is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 -C(=O)NHCH 3 -C(=O)N(CH 3 ) 2 -C(=O)-(C 1 ~C 4 Alkyl), -C(=O)-(C 1 ~C 4 Alkoxy), C 1 ~C 4 Alkyl, C 2 ~C 4 Alkenil, C 2 ~C 4 Alkinyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Alkoxy, C 1 ~C 4 Haloalkoxy, C 1 ~C 4 Alkylthio, C 1 ~C 4 Alkylamino or C 1 ~C 4 It is a hydroxyalkyl group; R x and R z Each of these independently comprises H, D, F, Cl, Br, I, -CN, and -NO. 2 , -NH 2 -OH, -COOH, -C(=O)NH 2 , C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Alkoxy, C 1 ~C 4 Haloalkoxy or C 1 ~C 4 It is a hydroxyalkyl group. The compound according to claim 1 or 2.

4. R 1 , H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 -C(=O)NHCH 3 -C(=O)N(CH 3 ) 2 -C(=O)-CH 3 -C(=O)-OCH 3 Methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 ,-CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 , -OCF 3 -OCHFCH 2 F, -OCF 2 CHF 2 ,-OCH 2 CF 3 ,-OCH 2 CF 2 CHF 2 methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidinyl, tetrahydrofuranil, piperidinyl, piperazinyl, or morpholinil; R 3 , R 3a and R 3b Each of these is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 -C(=O)NHCH 3 -C(=O)N(CH 3 ) 2 -C(=O)-CH 3 -C(=O)-OCH 3 Methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 ,-CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 , -OCF 3 -OCHFCH 2 F, -OCF 2 CHF 2 ,-OCH 2 CF 3 ,-OCH 2 CF 2 CHF 2 , methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, or 2-hydroxyethyl; R x and R z Each of these independently comprises H, D, F, Cl, Br, I, -CN, and -NO. 2 , -NH 2 -OH, -COOH, -C(=O)NH 2 Methyl, ethyl, n-propyl, isopropyl, -CHF 2 ,-CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 , -OCF 3 -OCHFCH 2 F, -OCF 2 CHF 2 ,-OCH 2 CF 3 ,-OCH 2 CF 2 CHF 2 , hydroxymethyl or 2-hydroxyethyl, The compound according to any one of claims 1 to 3.

5. R 4 However, H, D, C 1 ~C 4 Alkyl, C 2 ~C 4 Alkenil, C 2 ~C 4 Alkinyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Alkoxy, C 1 ~C 4 Haloalkoxy, C 1 ~C 4 Alkylthio, C 1 ~C 4 Alkylamino, C 3 ~C 6 Cycloalkyl, 3-6 membered heterocyclyl, C 6 ~C 10 It is an aryl or 5-6 member heteroaryl, C 1 ~C 4 Alkyl, C 3 ~C 6 Cycloalkyl, 3-6 membered heterocyclyl, C 6 ~C 10 Each of the aryl and 5-6 membered heteroaryl groups can be independently and arbitrarily selected as D, F, Cl, Br, I, -OH, -NH 2 , -NO 2 ,-CN,C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Alkoxy and C 1 ~C 4 The compound according to any one of claims 1 to 4, which is substituted with 1, 2, 3, 4, or 5 groups selected from haloalkoxys.

6. R 4 However, H, D, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 ,-CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 , -OCF 3 -OCHFCH 2 F, -OCF 2 CHF 2 ,-OCH 2 CF 3 ,-OCH 2 CF 2 CHF 2 methylthio, ethylthio, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, phenyl, indanyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, and methyl, ethyl, n-propyl Ropyr, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azacyclobutyl, oxacyclobutyl, pyrrolyl, tetrahydrofuranil, tetrahydropyranil, piperidinil, piperazine, morpholinil, phenyl, indole, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanil, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are each independently and arbitrarily selected as D, F, Cl, Br, I, -OH, -NH 2 , -NO 2 -CN, methyl, ethyl, n-propyl, isopropyl, -CHF 2 ,-CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 , -OCF 3 -OCHFCH 2 F, -OCF 2 CHF 2 ,-OCH 2 CF 3 and -OCH 2 CF 2 CHF 2 The compound according to any one of claims 1 to 5, which is substituted with 1, 2, 3, 4, or 5 groups selected from.

7. R 2a and R 2b Each of these independently comprises H, D, F, Cl, Br, I, -CN, and -NO. 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 -C(=O)NHCH 3 -C(=O)N(CH 3 ) 2 -C(=O)-(C 1 ~C 4 Alkyl), -C(=O)-(C 1 ~C 4 Alkoxy), C 1 ~C 4 Alkyl, C 2 ~C 4 Alkenil, C 2 ~C 4 Alkinyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Alkoxy, C 1 ~C 4 Haloalkoxy, C 1 ~C 4 Alkylthio, C 1 ~C 4 Alkylamino, C 1 ~C 4 Hydroxyalkyl, C 1 ~C 4 Cyanoalkyl, C 3 ~C 6 Cycloalkyl, 3-6 membered heterocyclyl, C 6 ~C 10 It is an aryl or a 5-6 member heteroaryl; R n and R n1 Each of these independently represents H, D, and C. 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 3 ~C 6 Cycloalkyl, 3-6 membered heterocyclyl, C 6 ~C 10 It is an aryl or a 5-6 member heteroaryl; R a and R b Each of these is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 -OH, -SH, C 1 ~C 4 Alkyl, C 2 ~C 4 Alkenil, C 2 ~C 4 Alkinyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Alkoxy, C 1 ~C 4 Haloalkoxy, C 1 ~C 4 Alkylthio, C 1 ~C 4 Alkylamino or C 1 ~C 4 It is a hydroxyalkyl group. The compound according to any one of claims 1 to 6.

8. R 2 However, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 -C(=O)NHCH 3 -C(=O)N(CH 3 ) 2 -C(=O)-(C 1 ~C 4 Alkyl), -C(=O)-(C 1 ~C 4 Alkoxy), C 1 ~C 4 Alkyl, C 2 ~C 4 Alkenil, C 2 ~C 4 Alkinyl, C 1 ~C 4 Alkoxy, C 1 ~C 4 Haloalkoxy, C 1 ~C 4 Alkylthio, C 1 ~C 4 Alkylamino, C 1 ~C 4 Hydroxyalkyl, C 1 ~C 4 Cyanoalkyl, C 3 ~C 6 Cycloalkyl-L-, 3-6 member heterocyclyl-L-, C 6 ~C 10 It is an aryl-L- or a 5- to 6-membered heteroaryl-L-, and is either unsubstituted or has 1, 2, 3, 4, or 5 R members. w It is replaced by; Each R w However, independently, H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 -C(=O)NHCH 3 -C(=O)N(CH 3 ) 2 -C(=O)-(C 1 ~C 4 Alkyl), -C(=O)-(C 1 ~C 4 Alkoxy), C 1 ~C 4 Alkyl, C 2 ~C 4 Alkenil, C 2 ~C 4 Alkinyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Alkoxy, C 1 ~C 4 Haloalkoxy, C 1 ~C 4 Alkylthio, C 1 ~C 4 Alkylamino, C 1 ~C 4 Hydroxyalkyl, C 3 ~C 6 Cycloalkyl, 3-6 membered heterocyclyl, C 6 ~C 10 It is an aryl or a 5-6 member heteroaryl. The compound according to any one of claims 1 to 7.

9. R 2a and R 2b Each of these independently comprises H, D, F, Cl, Br, I, -CN, and -NO. 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 -C(=O)NHCH 3 -C(=O)N(CH 3 ) 2 -C(=O)-(C 1 ~C 2 Alkyl), -C(=O)-(C 1 ~C 2 Alkoxy), methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 ,-CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 , -OCF 3 -OCHFCH 2 F, -OCF 2 CHF 2 ,-OCH 2 CF 3 ,-OCH 2 CF 2 CHF 2 methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyanomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazine, morpholinyl, phenyl, indole, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; R n and R n1 Each of these is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CHF 2 ,-CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazine, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; R a and R b Each of these is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 -OH, -SH, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 ,-CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 , -OCF 3 -OCHFCH 2 F, -OCF 2 CHF 2 ,-OCH 2 CF 3 ,-OCH 2 CF 2 CHF 2 , methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl or 2-hydroxyethyl, The compound according to any one of claims 1 to 8.

10. R 2 However, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 -C(=O)NHCH 3 -C(=O)N(CH 3 ) 2 -C(=O)-CH 3 -C(=O)-OCH 3 Methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, allyl, propenyl, propargyl, propynyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 , -OCF 3 -OCHFCH 2 F, -OCF 2 CHF 2 ,-OCH 2 CF 3 ,-OCH 2 CF 2 CHF 2 Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyanomethyl, cyclopropyl-L-, cyclobutyl-L-, cyclopentyl-L-, cyclohexyl-L-, oxetylpropyl-L-, aziridinylpropyl-L-, oxetylbutyl-L-, aziridinyl-L-, tetrahydrofuranyl-L-, pyrrolidinyl-L-, tetrahydropyranyl-L-, piperi Dinyl-L-, piperazinyl-L-, morpholinyl-L-, phenyl-L-, naphthyl-L-, pyrrolidinyl-L-, furanyl-L-, thiophenyl-L-, pyrazolyl-L-, imidazolyl-L-, thiazolyl-L-, oxazolyl-L-, triazolyl-L-, tetrazolyl-L-, pyridinyl-L-, pyrimidinyl-L-, pyrazinyl-L-, or pyridazinyl-L-, and either unsubstituted or with 1, 2, 3, 4, or 5 Rs. w It is replaced by; Each R w However, independently, H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -C(=O)NH 2 -C(=O)NHCH 3 -C(=O)N(CH 3 ) 2 -C(=O)-(C 1 ~C 3 Alkyl), -C(=O)-(C 1 ~C 3 Alkoxy), methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, allyl, propenyl, propargyl, propynyl, -CHF 2 ,-CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 , -OCF 3 -OCHFCH 2 F, -OCF 2 CHF 2 ,-OCH 2 CF 3 ,-OCH 2 CF 2 CHF 2 methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazine, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. The compound according to any one of claims 1 to 9.

11. Compounds represented by formula (II) or formula (III), or their stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs. 【Transformation 6】 [In the formula, R 1 , R 2 , R 2a , R 2b , R 3 , R z , R 4 Each of n has the meaning described in any one of claims 1 to 10. The compound according to any one of claims 1 to 10.

12. Compounds having one of the following structures, or their stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs. 【Chemical 7A】 【Chemistry 7B】 【Chem.7C】 【7D Transformation】 [Transformation 7E] 【Chemical 7F】 【7G】 【Chemical Formula 7H】 【Chemical Formula 7I】 【Chemical 7J】 [7K] [7L]

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, A pharmaceutical composition further comprising, optionally, pharmaceutically acceptable additives, carriers, adjuvants, or any combination thereof.

14. The use of a compound according to any one of claims 1 to 12 or a pharmaceutical composition according to claim 13 in the manufacture of a pharmaceutical for the prevention, treatment or mitigation of PARP1-mediated diseases, PARP1-mediated diseases include cancer, neurodegenerative diseases, cardiovascular diseases, ischemic diseases, diabetic neuropathy, reperfusion injury, osteoarthritis, osteoporosis, inflammatory diseases, or metabolic diseases. use.

15. The use according to claim 14, wherein the cancer is laryngeal cancer, esophageal cancer, stomach cancer, intestinal cancer, liver cancer, kidney cancer, lung cancer, brain cancer, head and neck cancer, squamous cell carcinoma, lymphoid cancer, thyroid cancer, bladder cancer, ovarian cancer, cervical cancer, prostate cancer, genitourinary cancer, breast cancer, hematological malignancy, small cell lung cancer, lung adenocarcinoma, pancreatic cancer, colon cancer, glioblastoma, and / or monocytic leukemia.

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