Substituted nitrogen-containing bicyclic compounds and uses thereof

Abstract

The invention belongs to the field of medicines, and relates to a substituted nitrogen-containing bicyclic compound and application thereof. Specifically, the invention relates to a novel substituted nitrogen-containing bicyclic compound and a pharmaceutical composition containing the compound, the novel substituted nitrogen-containing bicyclic compound can be used for inhibiting PARP1, and the PARP1 selectivity of the novel substituted nitrogen-containing bicyclic compound is obviously higher than that of other PARP subtypes. The invention also relates to a method for preparing the compound and the pharmaceutical composition, and application of the compound and the pharmaceutical composition in preparation of drugs for treating PARP1-mediated diseases, especially cancers.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology and specifically relates to novel substituted nitrogen-containing bicyclic compounds and pharmaceutical compositions comprising these compounds, as well as methods and uses thereof. In particular, the novel substituted nitrogen-containing bicyclic compounds of the present invention can be used to inhibit PARP1 and prevent, treat, or alleviate diseases mediated by PARP1, particularly cancer. Background Art

[0002] Cancer refers to a malignant tumor originating from epithelial tissue and is the most common type of malignant tumor. Generally speaking, "cancer" refers to all malignant tumors. Cancer is a group of diseases characterized by abnormal cell differentiation and proliferation. In the late stage, it will spread to other areas of the body, including bones and vital organs. Cancer has biological characteristics such as abnormal cell differentiation and proliferation, uncontrolled growth, metastasis and invasion. Its occurrence is a complex process with multiple factors and steps, which can be divided into three processes: carcinogenesis, cancer promotion and evolution. The cause of malignant tumors is not yet fully understood, but it is closely related to infection, smoking, occupational exposure, environmental pollution, genetic factors and unreasonable diet.

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

[0004] Despite significant progress in the availability of multiple therapeutic options for treating cancer, currently available chemotherapy remains unsatisfactory, and the prognosis for most patients diagnosed with cancer remains dismal. Therefore, the development of new antitumor drugs (or anticancer drugs) is of great significance.

[0005] Poly(ADP)-ribose polymerases (PARPs) are a class of cellular enzymes that catalyze ADP-ribosylation and are widely present in eukaryotic cells. There are at least 18 isoforms, all of which contain the highly conserved PARP catalytic sequence. They can be divided into three categories based on the degree of modification in their catalytic ADP-ribosylation: the first category, including PARP1, PARP2, Tank1, and Tank2, catalyzes the formation of long and branched poly(ADP-ribose) chains (PARs); the second category, including PARP3, 4, 6-8, 10-12, and 14-16, catalyzes the formation of mono(ADP-ribosyl) transferases (MARs); and the third category, including PARP9 and PARP13, lacks enzymatic activity. Although these isoforms all have similar catalytic domains, only PARP1 and PARP2 contain DNA binding domains, enabling them to bind to damaged DNA and repair it through the base excision repair (BER) pathway. PARP1 was the first to be discovered and has the highest intracellular content, accounting for 85% to 90% of total intracellular PARP activity. It is primarily involved in DNA damage repair and is the most important PARP enzyme. It is also the most intensively studied and widely used isoform, implicated in the treatment of diseases such as cancer, stroke, inflammation, diabetes, myocardial ischemia, and neurodegenerative diseases.

[0006] PARP1 consists of 1014 amino acid residues with a relative molecular mass of 116 kDa. Its primary structure is highly conserved across eukaryotes (e.g., the human and mouse amino acid sequences share 92% identity) and comprises three domains: a C-terminal catalytic domain, an intermediate autoregulatory domain (AD), and an N-terminal decomposition domain (DBD). The C-terminal catalytic domain contains two active catalytic sites: a donor domain and a receptor domain; the intermediate autoregulatory domain includes two closely linked nuclear localization signal sequences and has Capase-3 cleavage function; and the N-terminal domain includes three zinc finger motifs.

[0007] PARP1 and PARP2 are very similar in structure and are important protein-modifying enzymes involved in DNA damage repair. They are highly expressed in many tumors. Among them, the PARP1 subtype plays a key role in the DNA damage repair pathway, undertaking more than 90% of the repair tasks. The DNA damage repair pathway is abnormally active in tumor cells. Therefore, inhibiting the activity of PARP1 can inhibit tumor growth. In recent years, several PARP1 inhibitors have been approved for marketing, and several PARP1 inhibitors have entered the clinical research stage. Therefore, PARP1 inhibitors have become one of the hot spots in the research and development of anti-tumor drugs.

[0008] The mechanisms of action of PARP1 inhibitors in tumors are complex and diverse, including the synthetic lethality hypothesis, the involvement of PARP1 in DNA damage repair in tumor cells, and the regulation of nuclear factor kappa B (NF-κB) and heat shock protein 70 (HSP70) in tumor cells. Although the mechanism of action of PARP1 inhibitors is not yet fully understood, their tumor-suppressing effects offer new hope for cancer treatment.

[0009] Since many chemotherapy drugs exert their anti-tumor effects by damaging the structure of tumor cell DNA, tumor cells can use PARP1 to repair damaged DNA, resist chemotherapy drugs, and thus develop drug resistance. Therefore, PARP1 inhibitors can be used as sensitizers in combination with other chemotherapy drugs to overcome drug resistance and improve efficacy. At the same time, studies have also found that the use of PARP1 inhibitors alone can also produce a good anti-tumor effect on tumor cells with BRCA1 / 2 (breast cancer 1 / 2) deletions or mutations.

[0010] Compared with other clinical PARP1 / 2 inhibitors, PARP inhibitors with enhanced selectivity for PARP1 offer the advantages of improved efficacy and reduced toxicity. Furthermore, strong and selective inhibition of PARP1 leads to PARP1 trapping on DNA, causing DNA double-strand breaks (DSBs) by collapsing replication forks during S phase. PARP1-DNA trapping is an effective mechanism for selectively killing tumor cells with homologous recombination deficiency (HRD).

[0011] Therefore, further research is still needed to find better, more effective and safer PARP inhibitors, especially PARP inhibitors that are selective for PARP1.

[0012] Through continuous research, the inventors have developed an unexpectedly novel class of highly selective PARP1 inhibitors. The substituted nitrogen-containing bicyclic compounds described herein exhibit potent PARP1 inhibitory activity and are therefore useful for treating PARP1-mediated diseases, particularly cancer. Furthermore, the substituted nitrogen-containing bicyclic compounds described herein exhibit significantly higher selectivity for PARP1 than for other PARP isoforms (such as PARP2). Summary of the Invention

[0013] The present invention provides a class of novel substituted nitrogen-containing bicyclic compounds that are highly selective PARP1 inhibitors. These compounds can be used to inhibit PARP1 and, therefore, can be used to treat diseases mediated by PARP1, particularly cancer. Furthermore, the substituted nitrogen-containing bicyclic compounds of the present invention have significantly higher selectivity for PARP1 than for other PARP isoforms (e.g., PARP2). Experiments have shown that the substituted nitrogen-containing bicyclic compounds of the present invention are stable, safe, and have good pharmacodynamic and pharmacokinetic properties, such as a good brain-to-plasma ratio, good bioavailability, or good metabolic stability. Therefore, they have promising prospects for clinical application.

[0014] The present invention also provides methods for preparing the compounds, pharmaceutical compositions containing the compounds, and uses of the compounds and pharmaceutical compositions containing the compounds in preparing drugs.

[0015] In one aspect, the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I).

[0016]

[0017] in:

[0018] X is CR x or N;

[0019] is a 3-12 membered heterocyclic group;

[0020] R 1 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, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl or 3-8 membered heterocyclyl;

[0021] Each R 2a and R 2bindependently 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 Aryl or 5-10 membered heteroaryl;

[0022] R 2 -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1-C6

[0023] alkyl), -C(=O)-(C1-C6 alkoxy), C1-C6 alkyl, C2-C6 alkenyl, C 2- 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 Aryl-L- or 5-10 membered heteroaryl-L-; wherein said R 2 Unsubstituted or substituted with 1, 2, 3, 4 or 5 R w replace;

[0024] Each -L- is independently a bond, -NR n -, -O-, -S-, -C(=O)-, -C(=O)O-, -C(=O)N(R n1 )-or-(CR a R b ) m -;

[0025] m is 1, 2, 3, 4, 5 or 6;

[0026] Each R n and R n1 are independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl;

[0027] Each R a and R bare 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;

[0028] Each R 3 、R 3a and R 3b 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;

[0029] 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 membered heterocyclyl, C6-C 10 Aryl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl are independently 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;

[0030] Each R x and R z are 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;

[0031] Each R windependently 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 Aryl or 5-10 membered heteroaryl;

[0032] n is 1, 2, 3, 4, 5 or 6;

[0033] Wherein, the compound represented by the formula (I) does not include the following compounds:

[0034]

[0035]

[0036] In another embodiment, for

[0037]

[0038] Among them, * represents the -CH2- connected to the left, and ** represents the pyridyl connected to the right.

[0039] In one embodiment, R 1 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-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;

[0040] Each R 3 、R 3a and R3b 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 or C1-C4 hydroxyalkyl;

[0041] Each R x and R z are 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.

[0042] 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, -CH2C F3, -CH2CF2CHF2, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl;

[0043] Each R 3 、R 3a and R 3bare 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;

[0044] Each R x and R z and independently represent 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.

[0045] In one embodiment, R 4 is 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 membered heterocyclyl, C6-C 10 Aryl or 5-6 membered heteroaryl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, C6-C 10 Aryl and 5-6 membered heteroaryl are independently optionally 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.

[0046] In another embodiment, R 4is H, 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, -OCH2CF2CHF 2. methylthio, ethylthio, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein the methyl, ethyl, n-propyl , isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl are independently optionally substituted by 1, 2, 3, 4 or 5 moieties 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 are substituted.

[0047] In one embodiment, each R 2a and R 2b 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 membered heterocyclyl, C6-C 10 aryl or 5-6 membered heteroaryl.

[0048] In one embodiment, each R n and Rn1 are independently H, D, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, C6-C 10 Aryl or 5-6 membered heteroaryl;

[0049] Each R a and R b are 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.

[0050] 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, C 2- 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 membered heterocyclyl-L-, C6-C 10 Aryl-L- or 5-6 membered heteroaryl-L-; wherein said R 2 Unsubstituted or substituted with 1, 2, 3, 4 or 5 R w replace;

[0051] Each R w 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 membered heterocyclyl, C6-C 10 Aryl or 5-6 membered heteroaryl;

[0052] Each L has the meaning as defined in the present invention.

[0053] In one embodiment, each R 2a and R 2bare 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, 2-Hydroxy-4-[4-[4-biphenyl]-1-ol], 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol

[0054] In one embodiment, each R n and R n1 is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl;

[0055] Each R a and R b and independently represent 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.

[0056] 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-hydroxy alkyl, ethyl, cyanomethyl, cyclopropyl-L-, cyclobutyl-L-, cyclopentyl-L-, cyclohexyl-L-, oxirane-L-, aziridine-L-, oxetanyl-L-, azetidinyl-L-, tetrahydrofuranyl-L-, pyrrolidinyl-L-, tetrahydropyranyl-L-, piperidinyl-L-, piperazinyl-L-, morpholinyl-L-, phenyl-L-, naphthyl-L-, pyrrolyl-L-, furanyl-L-, thienyl-L-, pyrazolyl-L-, imidazolyl-L-, thiazolyl-L-, oxazolyl-L-, triazolyl-L-, tetrazolyl-L-, pyridinyl-L-, pyrimidinyl-L-, pyrazinyl-L- or pyridazinyl-L-; wherein, R 2 Unsubstituted or substituted with 1, 2, 3, 4 or 5 R w replace;

[0057] Each R w 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, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; each L has the meaning as described in the present invention.

[0058] In some embodiments, the present invention relates to a compound, which is a compound represented by formula (II) or formula (III), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (II) or formula (III).

[0059]

[0060] Among them, each R 1 、R 2 、R 2a 、R 2b 、R 3 、R z 、R 4 and n have the meanings as defined in the present invention.

[0061] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound represented by formula (I), (II) or (III) disclosed in the present invention.

[0062] In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.

[0063] In another aspect, the present invention relates to the use of the compound represented by formula (I), (II) or (III) disclosed in the present invention or its pharmaceutical composition in the preparation of a drug for preventing, treating or alleviating diseases mediated by PARP1.

[0064] In one embodiment, the disease mediated by PARP1 is cancer, neurodegenerative disease, cardiovascular disease, ischemic disease, diabetic neuropathy, reperfusion injury, osteoarthritis, osteoporosis, inflammatory disease and metabolic disease.

[0065] 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, lymphatic system cancer, thyroid cancer, bladder cancer, ovarian cancer, cervical cancer, prostate cancer, genitourinary tract cancer, breast cancer, blood cancer, small cell lung cancer, lung adenocarcinoma, pancreatic cancer, colon cancer, glioblastoma and / or monocytic leukemia.

[0066] In another aspect, the present invention relates to the use of the compound represented by formula (I), (II) or (III) disclosed in the present invention or a pharmaceutical composition thereof in the preparation of a drug for inhibiting PARP1.

[0067] In another aspect, the present invention relates to methods for preparing, separating and purifying the compounds represented by formula (I), (II) or (III).

[0068] The results of biological tests show that the compounds of the present invention can inhibit PARP1, and their selectivity for PARP1 is significantly higher than that for other PARP isoforms (such as PARP2). Therefore, they can be used as highly selective PARP1 inhibitors.

[0069] Any embodiment of any aspect of the present invention can be combined with other embodiments, as long as they do not conflict. In addition, in any embodiment of any aspect of the present invention, any technical feature can be applied to the technical feature in other embodiments, as long as they do not conflict.

[0070] The foregoing description only summarizes certain aspects of the present invention, but is not intended to be limiting. These and other aspects will be described in more detail and fully below. All references in this specification are incorporated herein by reference in their entirety. In the event of a discrepancy between the disclosure of this specification and a reference, the disclosure of this specification shall prevail.

[0071] Detailed description of the present invention

[0072] Definitions and General Terms

[0073] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0074] It will be further appreciated that certain features of the invention, which, for clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which, for brevity, are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0075] Unless otherwise indicated, the following definitions used in the present invention shall apply. For purposes of the present invention, chemical elements are consistent with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0076] Unless otherwise specified or clearly contradicted by context, the articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more." Thus, as used herein, these articles refer to one or more than one (i.e., at least one) of the objects. For example, "a component" refers to one or more components, i.e., more than one component may be contemplated for use or use in implementing the described embodiment.

[0077] The term "stereoisomers" refers to compounds that have identical chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans isomers), atropisomers, and the like.

[0078] The term "chiral molecule" refers to a molecule that is non-superimposable on its mirror image; whereas "achiral molecule" refers to a molecule that is superimposable on its mirror image.

[0079] The term "enantiomers" refers to two non-superimposable isomers of a compound that are mirror images of each other.

[0080] The term "racemate" or "racemic mixture" refers to an equimolar mixture of two enantiomers, which mixture lacks optical activity.

[0081] The term "diastereoisomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0082] The stereochemical definitions and conventions used herein generally follow those of 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. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to designate the rotation of plane-polarized light caused by the compound, where (-) or l indicates that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0083] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of the (R)- or (S)-configuration.

[0084] Depending on the choice of starting materials and process, the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, such as a racemate or a mixture of diastereoisomers (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.

[0085] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, and diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0086] Any racemate of the resulting final product or intermediate can be separated into its optical antipodes by methods familiar to those skilled in the art using known methods, such as by separating the diastereomeric salts obtained. The racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed.Robert E.Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of NotreDame Press, Notre Dame, IN 1972); Chiral Separation Techniques: APractical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0087] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interconvertible across a low energy barrier. If tautomerism is possible (e.g., in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization.

[0088] "Pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response or other problems and complications commensurate with a reasonable benefit / risk ratio, and are effective for their intended use.

[0089] The term "optionally substituted with" can be used interchangeably with the term "unsubstituted or substituted with," meaning that the structure is unsubstituted or substituted with one or more substituents described herein, 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, and the like.

[0090] In general, the term "substituted" means that one or more hydrogen atoms in a given structure or group are replaced with a specified substituent. Unless otherwise indicated, a substituent may be substituted at every possible position in the group. When more than one position in a given structure can be substituted with one or more of the specified substituents, the substituents may be the same or different at every possible position in the structure.

[0091] In addition, it should be noted that, unless otherwise explicitly stated, the description methods used in the present invention such as "each...independently is" and "...each independently is" and "...independently is" can be interchanged and should be understood in a broad sense. They can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0092] As used herein, the term "subject" refers to an animal. Typically, the animal is a mammal. A subject also refers, for example, to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0093] The term "patient" used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

[0094] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0095] Throughout this specification, substituents of the compounds disclosed herein are disclosed by group class or range. It is specifically noted that the present invention includes each independent subcombination of the individual members of these group classes and ranges. For example, the term "C1-C6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl groups.

[0096] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0097] The term "D" refers to a single deuterium atom.

[0098] The terms "halogen" and "halo" are used interchangeably herein to refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0099] The term "heteroatom" refers to O, S, N, P and Si, including any oxidation state of N, S and P; primary, secondary, tertiary amines and quaternary ammonium salts; or the hydrogen on the nitrogen atom in the heterocyclic ring is substituted, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl) or NR' (such as NR' in N-substituted pyrrolidinyl, R' is a substituent described in the present invention).

[0100] As used herein, the term "alkyl" or "alkyl group" refers to a saturated, linear or branched, monovalent hydrocarbon radical containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with 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), and the like.

[0101] The term "alkylene" refers to a saturated divalent hydrocarbon radical derived by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon radical. Unless otherwise specified, an alkylene group contains 1-12 carbon atoms. In one embodiment, an alkylene group contains 1-6 carbon atoms; in another embodiment, an alkylene group contains 1-4 carbon atoms; in yet another embodiment, an alkylene group contains 1-3 carbon atoms; and in yet another embodiment, an alkylene group contains 1-2 carbon atoms. Examples include methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), and the like. The alkylene group is optionally substituted with one or more substituents described herein.

[0102] The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e., a carbon-carbon sp 2 Double bond, wherein the alkenyl group can be optionally substituted with one or more substituents described herein, including "cis" and "trans" orientations, or "E" and "Z" orientations. In one embodiment, the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2-4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), 1-propenyl (i.e., propenyl, -CH=CH-CH3), and the like.

[0103] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein at least one site of unsaturation, i.e., a carbon-carbon sp triple bond, is present, wherein the alkynyl group may be optionally substituted with one or more substituents as described herein. In one embodiment, the alkynyl group contains 2 to 8 carbon atoms; in another embodiment, the alkynyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 to 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), 1-propynyl (i.e., propynyl, -C≡C-CH3), and the like.

[0104] The term "alkoxy" refers to an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; and in yet another embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents as described herein.

[0105] 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), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), and the like.

[0106] The term "alkylthio" refers to an alkyl group attached to the remainder of the molecule through a sulfur atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkylthio group contains 1-12 carbon atoms. In one embodiment, the alkylthio group contains 1-6 carbon atoms; in another embodiment, the alkylthio group contains 1-4 carbon atoms; and in yet another embodiment, the alkylthio group contains 1-3 carbon atoms. The alkylthio group may be optionally substituted with one or more substituents as described herein.

[0107] Examples of alkylthio groups include, but are not limited to, methylthio (MeS, -SCH3), ethylthio (EtS, -SCH2CH3), 1-propylthio (n-PrS, n-propylthio, -SCH2CH2CH3), 2-propylthio (i-PrS, i-propylthio, -SCH(CH3)2), 1-butylthio (n-BuS, n-butylthio, -SCH2CH2CH2CH3), 2-methyl-1-propylthio (i-BuS, i-butylthio, -SCH2CH(CH3)2), 2-butylthio (s-BuS, s-butylthio, -SCH(CH3)CH2CH3), 2-methyl-2-propylthio (t-BuS, t-butylthio, -SC(CH3)3), and the like.

[0108] The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino group is independently substituted with one or two alkyl groups, wherein the alkyl group has the meaning as described herein. Suitable alkylamino groups can be monoalkylamino or dialkylamino, such as, but not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N,N-dimethylamino (dimethylamino), N,N-diethylamino (diethylamino), etc. The alkylamino group is optionally substituted with one or more substituents described herein.

[0109] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group has the meaning described herein; such examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-1-propyl, 3-hydroxy-1-propyl, 2,3-dihydroxypropyl, and the like.

[0110] The term "cyanoalkyl" refers to an alkyl group substituted with one or more cyano groups, wherein the alkyl group has the meaning described herein; such examples include, but are not limited to, cyanomethyl, 2-cyanoethyl, 2-cyano-1-propyl, 3-cyano-1-propyl, 2,3-dicyanopropyl, and the like.

[0111] The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups, wherein the alkyl group has the meaning described herein; such examples include, but are not limited to, aminomethyl, 2-aminoethyl, 2-amino-1-propyl, 3-amino-1-propyl, 2,3-diaminopropyl, and the like.

[0112] The term "haloalkyl" means an alkyl group substituted by one or more halogen atoms, wherein the alkyl group has the meaning as described herein, such examples include, but are not limited to, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CHFCH3, -CH2CH2F, -CF2CH3, -CH2CF2CHF2, etc. In one embodiment, C1-C6 haloalkyl comprises fluorine-substituted C1-C6 alkyl; in another embodiment, C1-C4 haloalkyl comprises fluorine-substituted C1-C4 alkyl; in yet another embodiment, C1-C2 haloalkyl comprises fluorine-substituted C1-C2 alkyl.

[0113] The term "haloalkoxy" means an alkoxy group substituted by one or more halogen atoms, wherein the alkoxy group has the meaning as described herein, such examples include, but are not limited to, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCHFCH3, -OCH2CH2F, -OCF2CH3, -OCH2CF2CHF2, etc. In one embodiment, C1-C6 haloalkoxy comprises fluorine-substituted C1-C6 alkoxy; in another embodiment, C1-C4 haloalkoxy comprises fluorine-substituted C1-C4 alkoxy; in yet another embodiment, C1-C2 haloalkoxy comprises fluorine-substituted C1-C2 alkoxy.

[0114] The term "jk atoms" or "jk-membered" means that the cyclic group is composed of jk ring atoms, and the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, and P; j and k are each independently any non-zero natural number, and k>j; "jk" includes j, k, and any natural number in between. For example, "3-8 atoms" or "3-8-membered", "3-6 atoms" or "3-6-membered", "5-10 atoms" or "5-10-membered", "5-6 atoms" or "5-6-membered" means that the cyclic group is composed 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, and the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, and P. For another example, piperidinyl is a 6-atom heterocyclic group or a 6-membered heterocyclic group, while pyridinyl is a 6-atom heteroaryl group or a 6-membered heteroaryl group.

[0115] The terms "(alkoxy)-alkylene", "(alkylamino)-alkylene", "(cycloalkyl)-alkylene", "(heterocyclyl)-alkylene", "(aryl)-alkylene", and "(heteroaryl)-alkylene" mean that the alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is independently connected to the rest of the molecule through an alkylene group, wherein the alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, and alkylene each have the meanings described herein. For example, examples of (cycloalkyl)-alkylene include, but are not limited to, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene, and the like. For another example, examples of (aryl)-alkylene include, but are not limited to, phenylmethylene, phenylethylene, phenylpropylene, and the like. The (alkoxy)-alkylene, (alkylamino)-alkylene, (cycloalkyl)-alkylene, (heterocyclyl)-alkylene, (aryl)-alkylene, and (heteroaryl)-alkylene groups are each independently optionally substituted with one or more substituents described herein.

[0116] The term "carbocyclyl" or "carbocycle" refers to a monovalent or polyvalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. Carbobicyclic groups include spirocarbobicyclic groups and fused carbobicyclic groups. Suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl groups. In one embodiment, the carbocyclyl group contains 3 to 10 carbon atoms, for example, C 3- C 10 In another embodiment, the carbocyclyl group contains 3-8 carbon atoms, such as C 3- C8 carbocyclyl; In another embodiment, the carbocyclyl contains 3-6 carbon atoms, such as C 3-In another embodiment, the monocyclic carbocyclyl contains 4-8 carbon atoms, such as C 4- C8 monocyclic carbocyclyl; In another embodiment, the monocyclic carbocyclyl contains 4-6 carbon atoms, such as C 4- C6 monocyclic carbocyclyl.The example of carbocyclyl group further comprises, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.Described carbocyclyl group is optionally substituted by one or more substituents described in the present invention.

[0117] The term "cycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. The bicyclic or tricyclic ring system may include fused rings, bridged rings and spiro rings. In one embodiment, the cycloalkyl group contains 3 to 10 carbon atoms, for example, C 3- C 10 In another embodiment, the cycloalkyl group contains 3 to 8 carbon atoms, such as C 3- C8 cycloalkyl; In another embodiment, the cycloalkyl group contains 3-6 carbon atoms, such as C 3- C6 cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. 3- C8 cycloalkyl includes C 3- C6 cycloalkyl; the C 3- C6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl group is optionally substituted with one or more substituents described herein.

[0118] The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms, wherein the bicyclic or tricyclic ring system may include fused, bridged and spiro rings, wherein one or more ring atoms are independently replaced by a heteroatom, wherein the heteroatom has the meaning as described herein. In one embodiment, the heterocyclyl group is a monocyclic heterocyclyl group consisting of 3-8 ring atoms (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, and S, wherein S or P is optionally substituted with one or more oxygen atoms to give groups such as SO, SO2, PO, and PO2); in another embodiment, the heterocyclyl group is a monocyclic heterocyclyl group consisting of 3-6 ring atoms (2-5 carbon atoms and 1-3 heteroatoms selected from N, O, P, and S, wherein S or P is optionally substituted with one or more oxygen atoms to give groups such as SO, SO2, PO, and PO2); in another embodiment, the heterocyclyl group is a bicyclic heterocyclyl group consisting of 7-12 ring atoms (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, and S, wherein S or P is optionally substituted with one or more oxygen atoms to give groups such as SO, SO2, PO, and PO2). The heterocyclyl group is optionally substituted with one or more substituents described herein.

[0119] The ring atoms of the heterocyclic group can be carbon groups or heteroatom groups. In this case, the -CH2- group of the ring is optionally replaced by -C(=O)-, the sulfur atom of the ring is optionally oxidized to S-oxide, and the nitrogen atom of the ring is optionally oxidized to N-oxygen compound. Examples of heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine Base, diazepine Base, thiazolin Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinyl, 3,5-dioxopiperidinyl, pyrimidinedione, and the like. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1,1-dioxide, and the like. The heterocyclic group is optionally substituted with one or more substituents described herein.

[0120] The term "aryl" refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic and each ring system comprises a ring composed of 3-7 atoms. Aryl groups are typically, but not necessarily, attached to the parent molecule via the aromatic ring of the aryl group. The term "aryl" can be used interchangeably with the term "aromatic ring" or "aromatic ring". Examples of aryl groups can include phenyl, indenyl, naphthyl, and anthracenyl. The aryl group is optionally substituted with one or more substituents as described herein.

[0121] The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5-7 atoms. The heteroaryl group is typically, but not necessarily, attached to the parent molecule through the aromatic ring of the heteroaryl group. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring," "heteroaromatic ring," or "heteroaromatic compound." The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the 5-10 atom heteroaryl group contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.

[0122] Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, 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, yl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 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, 1,3,5-triazinyl; also include the following bicyclic rings, but are by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (such as 1-isoquinolyl), [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

[0123] The term "protecting group" or "PG" refers to a substituent that is attached to an amino group to block or protect a specific functionality, typically when reacting with another functional group. For example, an "amino-protecting group" refers to a substituent attached to an amino group to block or protect the amino functionality in a compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz), and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent attached to a hydroxy group to block or protect the hydroxy functionality. Suitable protecting groups include trialkylsilyl, acetyl, benzoyl, and benzyl. "Carboxyl protecting group" refers to a substituent of the carboxyl group used to block or protect the functionality of the carboxyl group. Typical carboxyl protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups, reference may be made to: Greene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 and Kocienski et al., Protecting Groups, Thieme, Stuttgart, 2005.

[0124] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound represented by formula (I), (II) or (III) in vivo. Such conversion is affected by the prodrug being hydrolyzed in the blood or being converted to the parent structure by enzymes in the blood or tissues. The prodrug compound of the present invention may be an ester. In the prior art, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound of the present invention containing a hydroxyl group can be acylated to produce a prodrug form of the compound. Other prodrug forms include phosphate esters, such as these phosphate ester compounds, which are obtained by phosphorylating a hydroxyl group on the parent compound.

[0125] "Metabolite" refers to a product resulting from the in vivo metabolism of a specific compound or salt thereof. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized using assays such as those described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention encompasses metabolites of the compound, including metabolites produced by contacting a compound of the invention with a mammal for a sufficient period of time.

[0126] As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in S.M. Berge et al., "Describe Pharmaceutically Acceptable Salts in Detail in J. Pharmaceutical Sciences, 1977, 66: 1-19." Pharmaceutically acceptable salts formed from non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, and perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates, or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4The present invention also contemplates quaternary ammonium salts formed by compounds of any group containing N. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-balancing ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-C8 sulfonates and aromatic sulfonates. Although other salts can be used, for example, to separate or purify products, non-toxic physiologically acceptable salts are preferred.

[0127] The salts may be formed by conventional means, for example by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble or in a solvent such as one in which water is removed in vacuo, or by freeze-drying, or by exchanging the anion of an existing salt for another anion on a suitable ion exchange resin.

[0128] As used herein, a "solvate" refers to an association formed between one or more solvent molecules and a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association formed when the solvent molecule is water.

[0129] When the solvent is water, the term "hydrate" may be used. In one embodiment, one molecule of the compound of the present invention may be associated with one water molecule, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be associated with more than one water molecule, such as a dihydrate; and in yet another embodiment, one molecule of the compound of the present invention may be associated with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the non-hydrated form of the compound.

[0130] The term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing, arresting, or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating the disease or condition physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a physical parameter), or both. In yet other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

[0131] The terms "prevent" or "prevention" refer to a reduction in the risk of acquiring a disease or disorder (i.e., halting the development of at least one clinical symptom of a disease in a subject who may be at risk or predisposed to the disease but has not yet experienced or displayed symptoms of the disease).

[0132] Unless otherwise stated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are encompassed within the scope of the invention.

[0133] In structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers of the structure are contemplated and included as compounds disclosed herein. When stereochemistry is indicated by a solid wedge or dashed line representing a specific configuration, the stereoisomers of the structure are unambiguous and defined.

[0134] The "nitrogen oxides" of the compounds of the present invention are also included within the scope of the present invention. The nitrogen oxides of the compounds of the present invention can be prepared by oxidation of the corresponding nitrogen-containing basic substance using a conventional oxidizing agent (e.g., hydrogen peroxide) in the presence of an acid such as acetic acid at elevated temperatures, or by reaction with a peracid in a suitable solvent, such as peracetic acid in dichloromethane, ethyl acetate, or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

[0135] The compound shown in formula (I), (II) or (III) may exist in the form of a salt. 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 ingredients of the formulation and / or the mammal treated therewith. In another embodiment, the salt is not necessarily a pharmaceutically acceptable salt and can be an intermediate for preparing and / or purifying the compound shown in formula (I), (II) or (III) and / or for separating the enantiomers of the compound shown in formula (I), (II) or (III).

[0136] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, the basic or acidic moiety using conventional chemical methods. Generally speaking, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as a hydroxide, carbonate, bicarbonate, 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 generally carried out in water or an organic solvent or a mixture of the two. Generally, where appropriate, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is used. Additional lists of suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 20th edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0137] Any structural formula given herein is also intended to represent non-isotopically enriched as well as isotopically enriched forms of these compounds. Isotopically enriched compounds have structures depicted by the general formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into the compounds of the present invention include 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.

[0138] In another aspect, the present invention relates to intermediates for preparing compounds represented by formula (I), (II) or (III).

[0139] 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, excipient, adjuvant, solvent, or a combination thereof. In another embodiment, the pharmaceutical composition can be in liquid, solid, semisolid, gel, or spray form.

[0140] Description of the compounds of the present invention

[0141] 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 potential applications in treating PARP1-mediated diseases, particularly cancer. Furthermore, the substituted nitrogen-containing bicyclic compounds of the present invention exhibit significantly higher selectivity for PARP1 than for other PARP isoforms (e.g., PARP2). The present invention further describes methods for synthesizing the compounds. The compounds of the present invention exhibit excellent biological activity.

[0142] In one aspect, the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I).

[0143]

[0144] Among them, each R 1 、R 2 、R 2a 、R 2b 、R 3 、R 3a 、R 3b 、R 4 ,X, R z and n have the meanings as defined in the present invention.

[0145] In some embodiments, the compound represented by formula (I) of the present invention does not include the following compounds:

[0146]

[0147]

[0148]

[0149] In one embodiment, X is CR x or N.

[0150] In one embodiment, It is a 3-12 membered heterocyclic group.

[0151] In one embodiment, It is a 3-8 membered heterocyclic group.

[0152] In another embodiment, for

[0153] Among them, * represents the -CH2- connected to the left, and ** represents the pyridyl connected to the right.

[0154] In one embodiment, R 1 It 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, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl or 3-8 membered heterocyclyl.

[0155] In one embodiment, R 1 It 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-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.

[0156] In another 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, -CH2C F3, -CH2CF2CHF2, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl.

[0157] In one embodiment, each R 2a and R 2b 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 aryl or 5-10 membered heteroaryl.

[0158] In one embodiment, each R 2a and R 2b 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 membered heterocyclyl, C6-C 10 aryl or 5-6 membered heteroaryl.

[0159] In another embodiment, each R 2a and R 2b 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-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, 2-Hydroxy-4-[4-[4-biphenyl]-1-ol], 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol, 4-[4-biphenyl]-1-ol

[0160] 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, C 2- 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 Aryl-L- or 5-10 membered heteroaryl-L-; wherein said R 2 Unsubstituted or substituted with 1, 2, 3, 4 or 5 R w Substitute; wherein L and R w has the meaning as described in the present invention.

[0161] 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, C 2- 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 membered heterocyclyl-L-, C6-C 10 Aryl-L- or 5-6 membered heteroaryl-L-; wherein said R 2 Unsubstituted or substituted with 1, 2, 3, 4 or 5 R w Substitute; wherein L and R w has the meaning as described in the present invention.

[0162] 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, propargyl, propynyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxy alkyl, ethyl, cyanomethyl, cyclopropyl-L-, cyclobutyl-L-, cyclopentyl-L-, cyclohexyl-L-, oxirane-L-, aziridine-L-, oxetanyl-L-, azetidinyl-L-, tetrahydrofuranyl-L-, pyrrolidinyl-L-, tetrahydropyranyl-L-, piperidinyl-L-, piperazinyl-L-, morpholinyl-L-, phenyl-L-, naphthyl-L-, pyrrolyl-L-, furanyl-L-, thienyl-L-, pyrazolyl-L-, imidazolyl-L-, thiazolyl-L-, oxazolyl-L-, triazolyl-L-, tetrazolyl-L-, pyridinyl-L-, pyrimidinyl-L-, pyrazinyl-L- or pyridazinyl-L-; wherein, R 2 Unsubstituted or substituted with 1, 2, 3, 4 or 5 R w Substitute; wherein L and R w has the meaning as described in the present invention.

[0163] In one embodiment, each -L- is independently a bond, -NR n-, -O-, -S-, -C(=O)-, -C(=O)O-, -C(=O)N(R n1 )-or-(CR a R b ) m -; among them, each R n 、R n1 、R a 、R b and m have the meanings as defined in the present invention.

[0164] In one embodiment, each -L- is independently a bond, -NH-, -O-, -S-, -C(=O)-, -C(=O)O-, -C(=O)NH-, or -(CH2) m -; wherein, m has the meaning as described in the present invention.

[0165] In one embodiment, each R n and R n1 are independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl.

[0166] In one embodiment, each R n and R n1 are independently H, D, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, C6-C 10 aryl or 5-6 membered heteroaryl.

[0167] In another embodiment, each R n and R n1 and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 67, 68, 69, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 113, 114, 125, 136, 137, 148, 159, 100

[0168] In one embodiment, each R 3 、R 3a and R 3bindependently represents 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.

[0169] In one embodiment, each R 3 、R 3a and R 3b 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 or C1-C4 hydroxyalkyl.

[0170] In another embodiment, each R 3 、R 3a and R 3b and independently represent 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.

[0171] In one embodiment, each R a and R bare 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.

[0172] In one embodiment, each R a and R b are 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.

[0173] In another embodiment, each R a and R b and independently represent 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.

[0174] In one embodiment, 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 membered heterocyclyl, C6-C 10 Aryl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl are independently 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.

[0175] In one embodiment, R 4is 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 membered heterocyclyl, C6-C 10 Aryl or 5-6 membered heteroaryl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, C6-C 10 Aryl and 5-6 membered heteroaryl are independently optionally 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.

[0176] In another embodiment, R 4 is H, 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, -OCH2CF2CHF 2. methylthio, ethylthio, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein the methyl, ethyl, n-propyl , isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl are independently optionally substituted by 1, 2, 3, 4 or 5 moieties 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 are substituted.

[0177] In one embodiment, each R xand R z are 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.

[0178] In one embodiment, each R x and R z are 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.

[0179] In another embodiment, each R x and R z and independently represent 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.

[0180] In one embodiment, each R w 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 aryl or 5-10 membered heteroaryl.

[0181] In one embodiment, each R windependently 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 membered heterocyclyl, C6-C 10 aryl or 5-6 membered heteroaryl.

[0182] In another embodiment, each R w 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 alkyl, -octyl ...

[0183] In one embodiment, m is 1, 2, 3, 4, 5 or 6.

[0184] In one embodiment, n is 1, 2, 3, 4, 5 or 6.

[0185] In some embodiments, the present invention relates to a compound, which is a compound represented by formula (II), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (II).

[0186]

[0187] Among them, each R1 、R 2 、R 2a 、R 2b 、R 3 、R 4 、R z and n have the meanings as defined in the present invention.

[0188] In other embodiments, the present invention relates to a compound, which is a compound represented by formula (III), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (III).

[0189]

[0190] Among them, each R 1 、R 2 、R 2a 、R 2b 、R 3 、R 4 、R z and n have the meanings as defined in the present invention.

[0191] In one embodiment, the compound of the present invention is a compound having one of the following structures or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound having one of the following structures, but is in no way limited to:

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound represented by formula (I), (II) or (III) disclosed in the present invention.

[0205] In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.

[0206] In another aspect, the present invention relates to the use of the compound represented by formula (I), (II) or (III) disclosed in the present invention or its pharmaceutical composition in the preparation of a drug for preventing, treating or alleviating diseases mediated by PARP1.

[0207] In one embodiment, the disease mediated by PARP1 is cancer, neurodegenerative disease, cardiovascular disease, ischemic disease, diabetic neuropathy, reperfusion injury, osteoarthritis, osteoporosis, inflammatory disease and metabolic disease.

[0208] In one 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, lymphatic system cancer, thyroid cancer, bladder cancer, ovarian cancer, cervical cancer, prostate cancer, genitourinary tract cancer, breast cancer, blood cancer, small cell lung cancer, lung adenocarcinoma, pancreatic cancer, colon cancer, glioblastoma and / or monocytic leukemia.

[0209] In another embodiment, the disease mediated by PARP1 is cancer.

[0210] In another aspect, the present invention relates to the use of the compound represented by formula (I), (II) or (III) disclosed in the present invention or a pharmaceutical composition thereof in the preparation of a drug for inhibiting PARP1.

[0211] In another aspect, the present invention relates to methods for preparing, separating and purifying the compounds represented by formula (I), (II) or (III).

[0212] Pharmaceutical compositions, formulations and administration of the compounds of the present invention

[0213] The present invention provides a pharmaceutical composition comprising a compound represented by formula (I), (II) or (III) or a stereoisomer thereof, a racemic or non-racemic mixture of the isomers, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment of the present invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally, other therapeutic and / or preventive ingredients.

[0214] The dosage form in which the compounds used in the methods of the present invention are administered will be determined by the particular compound chosen, the type of pharmacokinetic profile desired for the route of administration, and the condition of the patient.

[0215] Preparations suitable for oral, sublingual, intranasal or injection administration are prepared according to methods well known in the pharmaceutical art and contain at least one active compound. See, for example, REMINGTON'S PHARMACEUTICAL SCIENCES (16th ed. 1980).

[0216] In general, the formulations of the present invention include the active ingredient (a compound of Formula (I), (II), or (III)), typically mixed with an excipient, diluted with an excipient, or encapsulated in a carrier that can be in the form of a capsule, sachet, paper, or other container. When the excipient acts as a diluent, it can be a solid, semisolid, or liquid material that acts as an excipient, carrier, or medium for the active ingredient. Thus, the formulation can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (either solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard capsules, gels, suppositories, sterile injectable solutions, and sterile encapsulated powders.

[0217] In the preparation of a formulation, it may be necessary to grind the active compound to provide an appropriate particle size prior to mixing with the 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, the particle size is adjusted by grinding to provide a uniform particle size distribution in the formulation, for example, about 40 mesh. In one embodiment of the invention, the particle size is approximately 0.1-100 μm.

[0218] Suitable carriers, adjuvants, and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel HC et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro AR et al., Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe RC, Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.

[0219] As used herein, a "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, mixture, or vehicle that contributes to the consistency of a dosage form or pharmaceutical composition. Each excipient, when combined, must be compatible with the other ingredients of the pharmaceutical composition to avoid interactions that could significantly reduce the efficacy of the disclosed compounds upon administration to a patient and / or result in an unpharmaceutically acceptable pharmaceutical composition. Furthermore, each excipient must be pharmaceutically acceptable, e.g., possess a sufficiently high degree of purity.

[0220] Suitable pharmaceutically acceptable excipients will vary depending on the specific dosage form selected. In addition, pharmaceutically acceptable excipients may be selected based on their specific function in the composition. For example, certain pharmaceutically acceptable excipients may be selected to facilitate the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected to facilitate the production of a stable dosage form. Certain pharmaceutically acceptable excipients may be selected to facilitate the carrying or transport of the compound of the invention from one organ or part of the body to another organ or part of the body when administered to a patient. Certain pharmaceutically acceptable excipients may be selected to enhance patient compliance.

[0221] Some suitable excipient examples include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup and methylcellulose. Suitable pharmaceutically acceptable excipients also include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants (such as talc, magnesium stearate and mineral oil), glidants, granulating agents, coating agents, wetting agents, solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, preservatives (such as methyl hydroxybenzoate and propyl hydroxybenzoate), stabilizers, surfactants and buffers. Those skilled in the art will recognize that certain pharmaceutically acceptable excipients can serve more than one function, and can provide alternative functions, depending on how much of the excipient is present in the formulation and which other excipients are present in the formulation. The compounds of the invention can be formulated using methods known in the art so as to provide quick, sustained, or delayed release of the active ingredient after administration to a patient.

[0222] The skilled artisan has the knowledge and skill to select a suitable pharmaceutically acceptable excipient in an appropriate amount for use in the present invention. In addition, there are a large number of resources available to the skilled artisan that describe pharmaceutically acceptable excipients and are useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0223] To prepare pharmaceutical compositions using the compounds described herein, pharmaceutically acceptable carriers can be solid or liquid carriers. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. Powders and tablets can contain from about 5% to about 95% active ingredient. Suitable solid carriers are known in the art and include, for example, magnesium carbonate, magnesium stearate, talc, sugar, or lactose. Tablets, powders, cachets, 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, 18 th ed., 1990, Mack Publishing Company Co., Easton, Pennsylvania.

[0224] In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, various carriers for configuring pharmaceutically acceptable compositions and known techniques for their preparation are disclosed, and the respective contents of these documents are incorporated herein by reference. Except for any conventional carriers that are incompatible with the compounds of the present invention, such as those that may produce any undesirable biological effects or that may interact in a harmful manner with any other ingredient in the pharmaceutically acceptable compositions, the use of the carriers falls within the scope of the present invention.

[0225] The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. A description of some common methods in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0226] Thus, in another aspect, the present invention relates to a process for preparing a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, adjuvant, solvent, or combination thereof, the process comprising mixing the ingredients. Pharmaceutical compositions comprising a compound disclosed herein can be prepared, for example, by mixing at ambient temperature and atmospheric pressure.

[0227] The compounds disclosed herein are generally formulated into dosage forms suitable for administration to a patient via a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

[0228] It should also be recognized that certain compounds of the present invention may be used therapeutically in free form or, if appropriate, in the form of pharmaceutically acceptable derivatives thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adducts or derivatives that, when administered to a patient in need thereof, directly or indirectly provide a compound of the present invention or a metabolite or residue thereof.

[0229] In one embodiment, the compounds disclosed herein can be formulated as oral dosage forms. In another embodiment, the compounds disclosed herein can be formulated as inhalation dosage forms. In another embodiment, the compounds disclosed herein can be formulated as nasal dosage forms. In yet another embodiment, the compounds disclosed herein can be formulated as transdermal dosage forms. In yet another embodiment, the compounds disclosed herein can be formulated as topical dosage forms.

[0230] The pharmaceutical compositions provided herein can be provided as compressed tablets, tablets, chewable lozenges, fast-dissolving tablets, composite compressed tablets, or enteric-coated, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the effects of gastric acid but dissolves or disintegrates in the intestines, thereby protecting the active ingredients from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which helps mask unpleasant tastes or odors and prevents tablet oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general properties as sugar coatings. Composite compressed tablets are compressed tablets produced through more than one compression cycle, including multilayer tablets and press-coated or dry-coated tablets.

[0231] Tablet dosage forms can be prepared from the active ingredient in powder, crystal or granular form alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and / or colorants. Flavoring agents and sweeteners are particularly useful in forming chewable tablets and lozenges.

[0232] The pharmaceutical composition provided by the present invention can be provided in soft capsules or hard capsules, which can be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsule, also known as dry-filled capsule (DFC), consists of two sections, one section inserted into the other, thus completely encapsulating the active ingredient. Soft elastic capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by adding glycerol, sorbitol or similar polyols. The soft gelatin shells can contain preservatives to prevent microbial growth. Suitable preservatives are those as described in the present invention, including methylparaben and propylparaben, and sorbic acid. The liquid, semisolid and solid dosage forms provided by the present invention can be encapsulated in capsules. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or sustain dissolution of the active ingredient.

[0233] The pharmaceutical compositions provided herein can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems in which one liquid is completely dispersed in another liquid in the form of small globules, which can be oil-in-water or water-in-oil. Emulsions can include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers, and preservatives. Suspensions can include pharmaceutically acceptable suspending agents and preservatives. Aqueous alcoholic solutions can include pharmaceutically acceptable acetals, such as di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweet-tasting hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and can also contain preservatives. For liquid dosage forms, for example, solutions in polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for accurate and convenient administration.

[0234] The pharmaceutical compositions provided by the present invention can be formulated into any dosage form suitable for inhalation administration to a patient, such as a dry powder, an aerosol, a suspension or a solution composition. In one embodiment, the pharmaceutical compositions disclosed herein can be formulated into a dosage form suitable for inhalation administration to a patient using a dry powder. In another embodiment, the pharmaceutical compositions disclosed herein can be formulated into a dosage form suitable for inhalation administration to a patient via a nebulizer. The dry powder composition delivered to the lungs by inhalation typically comprises a fine powder of the compound disclosed herein and one or more fine powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di- and polysaccharides. Fine powders can be prepared, for example, by micronization and grinding. In general, size-reduced (e.g., micronized) compounds can be prepared by a D 50 values ​​(e.g., measured by laser diffraction).

[0235] Pharmaceutical compositions suitable for transdermal administration can be prepared as discontinuous patches intended to remain in close contact with the patient's epidermis for an extended period of time. For example, the active ingredient can be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).

[0236] The pharmaceutical composition that is suitable for topical administration can be formulated into ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, aerosol or oil.For example, ointment, cream and gel can configure with water or oil base, and applicable thickener and / or gel and / or solvent.Such matrix can comprise, water, and / or oil such as liquid paraffin and vegetable oil (such as peanut oil or castor oil), or solvent such as polyethylene glycol.The thickener and gel that use according to matrix properties comprise soft paraffin, aluminum stearate, cetearyl alcohol, polyethylene glycol, lanolin, beeswax, carboxyvinyl polyol and cellulose derivative, and / or glyceryl monostearate and / or nonionic emulsifier.

[0237] The compounds of the present invention can also be combined with soluble polymers as targetable drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethylene glycol polylysine substituted with palmitoyl residues. In addition, the compounds disclosed in the present invention can be combined with a class of biodegradable polymers used in achieving controlled release of drugs, for example, cross-linked or amphiphilic block copolymers of polylactic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogels.

[0238] Pharmaceutical composition provided by the invention can be administered parenterally by injection, infusion or implantation, for local or systemic administration. Parenteral administration as used in the present invention includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

[0239] Pharmaceutical composition provided by the invention can be mixed with any dosage form suitable for parenteral administration, including solution, suspension, emulsion, micelle, liposome, microsphere, nanometer system and the solid form that is suitable for making solution or suspension in liquid before injection.Such dosage form can be prepared (referring to Remington:The Science and Practice of Pharmacy, the same) according to conventional method known to those skilled in the art of pharmaceutical science.

[0240] Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous carriers, water-miscible carriers, non-aqueous carriers, antimicrobial agents or preservatives against microbial growth, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, antifreezes, cryoprotectants, thickeners, pH adjusters, and inert gases.

[0241] The pharmaceutical composition provided herein can be administered via rectal suppository. The drug is mixed with a suitable non-irritating excipient (e.g., cocoa butter or a glyceride synthesized from polyethylene glycol), which is solid at room temperature and then liquefies or dissolves in the rectal cavity to release the drug. Due to individual differences, the severity of symptoms can vary significantly, and each drug has unique therapeutic properties. Therefore, the precise administration method, dosage form, and treatment regimen for each individual should be determined by a licensed physician.

[0242] The pharmaceutical compositions provided herein can be formulated as immediate or modified release dosage forms, including delayed, sustained-pulse-controlled, targeted and programmed release forms.

[0243] Although the compounds of the present invention can be administered directly without any formulation, they are generally administered in the form of pharmaceutical formulations containing pharmaceutically acceptable excipients and at least one active ingredient. These formulations can be administered by a variety of 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.

[0244] For transdermal administration, a transdermal delivery device ("patch") is needed. This 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 delivering drugs are well known in the art. For example, see US5,023,252. This patch can be made into a continuous, pulsatile or on-demand release drug.

[0245] The compound represented by Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is typically administered orally in the form of a pharmaceutical preparation comprising the active ingredient or a pharmaceutically acceptable salt or solvate thereof, or a solvate of a pharmaceutically acceptable salt, in a pharmaceutically acceptable dosage form. The pharmaceutical preparation administered depends on the disease to be treated and the patient, and the pharmaceutical composition can be administered at different doses.

[0246] The pharmaceutical preparations described above having a compound represented by formula (I), (II) or (III) can be prepared for oral administration, specifically in the form of tablets or capsules, and particularly relate to a technique aimed at providing colon-targeted drug release (Patel, MM Expert Opin. Drug Deliv. [Expert Opinion on Drug Delivery] 2011, 8(10), 1247-1258).

[0247] The pharmaceutical preparations of the compounds of formula (I), (II) or (III) described above are conveniently administered in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA. (1985). The term "unit dosage form" refers to physically discrete units suitable as unit dosages for human patients and other mammals, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutically acceptable excipient as described above.

[0248] Pharmaceutical preparations suitable for oral administration can include one or more physiologically compatible carriers and / or excipients and can be in the form of solid or liquid. Tablets and capsules can be prepared with fillers, binders, lubricants and / or surfactants (such as sodium lauryl sulfate). Liquid compositions can contain conventional additives such as emulsifiers, suspending agents and / or preservatives. Liquid compositions can be encapsulated in, for example, gelatin 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 can be prepared, for example, by filling a compound shown in formula (I), (II) or (III) into hydroxypropyl methylcellulose (HPMC) or a gelatin shell.

[0249] The dry shell formulation typically comprises gelatin at a concentration of about 40% to 60% w / w, water at a concentration of about 30% to 40%, and a plasticizer (such as glycerol, propylene glycol, or sorbitol) at a concentration of about 20% to 30%. Other materials such as dyes, flavorings, preservatives, and opacifiers may also be present. The liquid filler material comprises a solid drug that has been dissolved, solubilized, or dispersed (using a suspending agent such as polyethylene glycol 4000, hydrogenated castor oil, or beeswax) or a liquid drug in a combination of a vehicle or multiple vehicles such as glycols, polyols, vegetable oils, mineral oils, triglycerides, and surfactants.

[0250] As used herein, the term "therapeutically effective amount" refers to the total amount of each active ingredient sufficient to exhibit a beneficial therapeutic effect. For example, the amount administered or brought into equilibrium in the body is sufficient to treat, cure, or alleviate the symptoms of a disease. The effective amount 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 being used, the route of administration, the clearance rate of the specific drug, the duration of treatment, the use of concomitant medications, the age, weight, sex, diet, and the health of the patient. A description of other factors that need to be considered in the art regarding a "therapeutically effective amount" can be found in Gilman et al., eds., Goodman And Gilman's: The Pharmacological Bases of Therapeutics, 8 th ed., Pergamon Press, 1990; Remington's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, Pa., 1990.

[0251] Oral formulations are preferred, particularly tablets or capsules, which can be formulated by methods known to those skilled in the art to provide a dose in the range of 0.1 mg to 1000 mg of active compound.

[0252] When treating humans, a suitable daily dose of a compound shown in formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is about 0.0001 to 100 mg / kg body weight. However, it should be understood that the amount of compound actually administered will be determined by the attending physician based on relevant circumstances, including the disease being treated, the selected route of administration, the actual one or more compounds to be taken, the age, body weight and response of the specific patient, and the severity of the patient's symptoms. Therefore, the above dosage range should not limit the scope of the invention in any way. In some cases, a dosage level lower than the lower limit of the above dosage range may be more appropriate, while in other cases, a higher dosage that does not produce any side effects can be adopted, provided that this larger dose is first divided into several smaller doses for administration throughout the day.

[0253] The term "administration" refers to providing a therapeutically effective amount of a drug to an individual, and administration routes include oral, sublingual, intravenous, subcutaneous, transdermal, intramuscular, intradermal, intrathecal, epidural, intraocular, intracranial, inhalation, rectal, vaginal, and the like. Dosage forms include ointments, lotions, tablets, capsules, pills, dispersible powders, granules, suppositories, pills, lozenges, injections, sterile solutions or non-aqueous solutions, suspensions, emulsions, patches, and the like. The active ingredient is compounded with a non-toxic pharmaceutically acceptable carrier (e.g., glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, silica gel, potato starch, urea, dextran, and the like).

[0254] The preferred route of administration will vary depending on clinical circumstances, and dosage must be adjusted based on the patient being treated. The physician will determine the appropriate dosage for each individual patient. The therapeutically effective amount per unit dose depends on body weight, physiology, and the chosen vaccination regimen. The compound per unit dose refers to the weight of the compound per administration, excluding the weight of the vehicle (which is present in the drug).

[0255] The pharmaceutical compositions provided herein can be formulated for single or multiple dose administration. The single dose formulations are packaged in ampoules, vials, or syringes. The multiple dose parenteral formulations must contain an antimicrobial agent at a bacteriostatic or fungistatic concentration. All parenteral formulations must be sterile, as known and practiced in the art.

[0256] The pharmaceutical composition provided by the present invention can be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or co-formulated with substances that supplement the intended effect.

[0257] In one embodiment, the treatment methods of the present invention comprise administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention. Various embodiments of the present invention include treating the diseases mentioned herein by administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention.

[0258] In one embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention can be administered by any suitable route of administration, including systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, and rectal administration. Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion. Topical administration includes application to the skin, as well as intraocular, ear, vaginal, inhalation, and intranasal administration. In one embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention can be administered orally. In another embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention can be administered by inhalation. In another embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention can be administered intranasally.

[0259] In one embodiment, the compound of the present invention or a pharmaceutical composition comprising the compound of the present invention can be administered once or several times at different time intervals within a specified time period according to a dosing regimen. For example, the drug is administered once, twice, three times, or four times a day. In one embodiment, the drug is administered once a day. In another embodiment, the drug is administered twice a day. The drug can be administered until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. The appropriate dosing regimen for the compound of the present invention or a pharmaceutical composition comprising the compound of the present invention depends on the pharmacokinetic properties of the compound, such as absorption, distribution, and half-life, which can be determined by a skilled person. In addition, the appropriate dosing regimen for the compound of the present invention or a pharmaceutical composition comprising the compound of the present invention, including the duration of implementation of the regimen, depends on the disease being treated, the severity of the disease being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of the concurrent therapy, the desired therapeutic effect, and other factors within the knowledge and experience of the skilled person. Such skilled persons should also understand that the appropriate dosing regimen may be required to be adjusted for individual patients' responses to the dosing regimen or as individual patient needs change over time.

[0260] The compounds of the present invention can be administered simultaneously with, before, or after one or more other therapeutic agents. The compounds of the present invention can be administered separately with other therapeutic agents by the same or different routes of administration, or can be administered with them in the form of the same pharmaceutical composition. This is selected by those skilled in the art based on the actual physical conditions of the patient, such as health, age, weight, etc. If formulated as a fixed dose, such a combination product uses a compound of the present invention (within the dosage range described herein) and other pharmaceutically active agents (within their dosage range).

[0261] Accordingly, in one aspect, the present invention encompasses a combination comprising a quantity 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 additional therapeutic agents as described above.

[0262] In addition, the compounds of the present invention can be administered in the form of prodrugs. In the present invention, a "prodrug" of a compound of the present invention is a functional derivative that, when administered to a patient, ultimately releases the compound of the present invention in vivo. When administering the compound of the present invention in the form of a prodrug, one skilled in the art may implement one or more of the following methods: (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 the side effects or other difficulties faced by the compound. Typical functional derivatives used to prepare prodrugs include variants of the compound that are chemically or enzymatically cleaved in vivo. These variants, including those for preparing phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.

[0263] Uses of the compounds and pharmaceutical compositions of the present invention

[0264] The compounds and pharmaceutical compositions provided by the present invention can be used to prepare drugs for inhibiting PARP1 and / or PARP2, and can also be used to prepare drugs for preventing, treating or alleviating diseases mediated by PARP, especially cancer.

[0265] Specifically, the amount of the compound or compound in the pharmaceutical composition of the present invention is effective to detectably and selectively inhibit PARP1 and / or PARP2.

[0266] The compounds of the present invention can be applied to, but are in no way limited to, preventing, treating, or alleviating PARP-mediated diseases by administering an effective amount of the compounds or pharmaceutical compositions of the present invention to a patient. PARP-mediated diseases further include, but are not limited to, cancer, neurodegenerative diseases, cardiovascular diseases, ischemic diseases, diabetic neuropathy, reperfusion injury, osteoarthritis, osteoporosis, inflammatory diseases, and metabolic diseases.

[0267] The compounds of the present invention can be used for, but are not limited to, preventing, treating, or alleviating cancer by administering an effective amount of the compounds or pharmaceutical compositions of the present invention to a patient. Such 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 system cancer, thyroid cancer, bladder cancer, ovarian cancer, cervical cancer, prostate cancer, genitourinary tract cancer, breast cancer, blood cancer, small cell lung cancer, lung adenocarcinoma, pancreatic cancer, colon cancer, glioblastoma, and / or monocytic leukemia.

[0268] The compounds of the present invention can be used for, but are in no way limited to, preventing, treating, or alleviating neurodegenerative diseases by administering an effective amount of the compounds or pharmaceutical compositions of the present invention to a patient. The neurodegenerative diseases further 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 damage.

[0269] The compounds of the present invention can be used, but are in no way limited to, for preventing, treating, or alleviating cardiovascular diseases by administering an effective amount of the compounds or pharmaceutical compositions of the present invention to a patient. Cardiovascular diseases further include, but are not limited to, angina pectoris, myocardial infarction, cardiogenic shock, arteriosclerosis, coronary artery disease, cardiovascular tissue damage, and hyperlipidemia.

[0270] In addition to being beneficial for human treatment, the compounds and pharmaceutical compositions of the present invention may also be used in veterinary treatment of pets, imported species, and mammals in farm animals. Other examples of animals include horses, dogs, and cats. The compounds of the present invention include pharmaceutically acceptable derivatives thereof.

[0271] General synthetic steps

[0272] To illustrate the present invention, the following examples are listed. However, it should be understood that the present invention is not limited to these examples, which are only provided to provide methods for practicing the present invention.

[0273] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are as defined in formula (I), (II) or (III). The following reaction schemes and examples are provided to further illustrate the present invention.

[0274] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare many other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modifications such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also generally applicable to the preparation of other compounds of the present invention.

[0275] In the examples described below, all temperatures are set forth in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company and used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Plant, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant.

[0276] Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether were dried over sodium reflux. Anhydrous dichloromethane and chloroform were dried over calcium hydride reflux. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

[0277] The following reactions were generally carried out under a positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction flasks were plugged with suitable rubber stoppers, and substrates were introduced via syringe. All glassware was dried.

[0278] The chromatographic column used was a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0279] 1 H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz nuclear magnetic resonance spectrometer. 1H NMR spectra were obtained using CDC13, DMSO-d6, CD3OD, or acetone-d6 as solvents (in ppm) and referenced to TMS (0 ppm) or chloroform (7.26 ppm). When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), brs (broadened singlet), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), td (triplet of doublets), and tt (triplet of triplets). Coupling constants, J, are expressed in Hertz (Hz).

[0280] Low-resolution mass spectrometry (MS) data were obtained using an Agilent 6120 quadrupole HPLC-M column (Zorbax SB-C18 column, 2.1 x 30 mm, 3.5 μm, 6 min, flow rate 0.6 mL / min). Mobile phase: 5%-95% (CH 3 CN containing 0.1% formic acid) in (H 2 O containing 0.1% formic acid), electrospray ionization (ESI), UV detection at 210 nm / 254 nm.

[0281] Pure compounds were analyzed using Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50 / 80 mm DAC) with UV detection at 210 nm / 254 nm.

[0282] The following abbreviations are used throughout this invention:

[0283]

[0284]

[0285] The following synthetic schemes describe the steps for preparing the compounds disclosed herein, unless otherwise indicated, wherein each R 1 、R 2 、R 3 and R 4 Has the definition described in the present invention.

[0286] Synthesis Scheme 1

[0287]

[0288] M represents a leaving group, such as -I, -Br, -Cl, -OH, -OMs, -OTs, wait.

[0289] The compound represented by formula (8) can be prepared by synthetic scheme 1: the compound represented by formula (1) and the compound represented by formula (2) undergo coupling reaction to obtain the compound represented by formula ( 3 ) shown in the formula ( 3 ) is reacted with an oxidant to give the compound of formula ( 4 ); the ester group of the compound represented by formula (4) is reduced to obtain the compound represented by formula (5); the hydroxyl group of the compound represented by formula (5) undergoes bromination reaction to obtain the compound represented by formula (6); 6 ) and the compound represented by formula ( 7 ) undergoes a substitution reaction to obtain the compound of formula ( 8 ) shown in the compound.

[0290] Synthesis Scheme 2

[0291]

[0292] M represents a leaving group, such as -I, -Br, -Cl, -OH, -OMs, -OTs, wait.

[0293] The compound represented by formula (8) can be prepared by synthetic scheme 2: 1a ) and the compound represented by formula ( 2 ) undergoes a coupling reaction to obtain the compound shown in formula ( 3a ) shown in the formula ( 3a ) is reacted with an oxidant to give the compound of formula ( 4a ); the ester group of the compound represented by formula (4a) is reduced to obtain the compound represented by formula (5); the hydroxyl group of the compound represented by formula (5) undergoes bromination reaction to obtain the compound represented by formula (6); 6 ) and the compound represented by formula ( 7 ) undergoes a substitution reaction to obtain the compound of formula ( 8 ) shown in the compound.

[0294] Synthesis Scheme 3

[0295]

[0296] R 2n With R of the present invention 2The definition mentioned above includes C1-C6 alkyl, etc.

[0297] Mode( 8b The compound shown in ) can be prepared by synthesis scheme 3: Formula ( 1b ) and the compound represented by formula ( 2b ) undergoes a substitution reaction to obtain the compound of formula ( 3b ) shown in the formula ( 3b ) and the compound represented by formula ( 4b ) undergoes a coupling reaction to obtain the compound shown in formula ( 5b ) shown in the formula ( 5b ) undergoes bromination reaction to obtain a compound represented by formula (6b); 6b )

[0298] The compound shown and the formula ( 7 ) undergoes a substitution reaction to obtain the compound of formula ( 8b ) shown in the compound.

[0299] Synthesis Scheme 4

[0300]

[0301] Mode( 8c The compound shown in ) can be prepared by synthetic scheme 4: Formula ( 1c ) and the compound represented by formula ( 7c ) undergoes a substitution reaction to obtain the compound of formula ( 9c ) shown in the formula ( 9c ) and the compound represented by formula ( 10 ) undergoes a coupling reaction to obtain the compound shown in formula ( 8c ) shown in the compound.

[0302] Mode( 8d The compound shown in ) can be prepared by synthetic scheme 4: Formula ( 1c ) and the compound represented by formula ( 7 ) undergoes a substitution reaction to obtain the compound of formula ( 9 ) shown in the formula ( 9 ) and the compound represented by formula ( 10 ) undergoes a coupling reaction to obtain the compound shown in formula ( 8d ) shown in the compound.

[0303] The compounds, pharmaceutical compositions and applications of the present invention are further described below with reference to the examples.

[0304] Intermediate 1: 6-Fluoro-N-methyl-5-(piperazin-1-yl)picolinamide hydrochloride

[0305]

[0306] Prepared by referring to the synthesis method of intermediate 23 in Example 7 of patent application WO2021013735. Example

[0307] Example 1: Synthesis of 5-(4-((8-cyclopropyl-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0308]

[0309] Step 1) Synthesis of 8-cyclopropyl-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid ethyl ester

[0310] To the flask, 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid ethyl ester (0.80 g, 2.55 mmol) and potassium cyclopropyltrifluoroborate (0.75 g, 5.1 mmol) were added in sequence, stirred and dissolved in 1,4-dioxane (20 mL), and then an aqueous solution (4 mL) of potassium phosphate (1.62 g, 7.65 mmol) was added and stirred evenly. Finally, Pd(dppf)Cl2 (0.19 g, 0.26 mmol) was added, the atmosphere was replaced with nitrogen, and the reaction was heated to 105 °C for 12 h. The mixture was cooled to room temperature, quenched with water (15 mL), extracted with EtOAc (15 mL × 3), and the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 3 / 2) to give a light yellow oily product (0.655 g, 93.46%).

[0311] MS(ESI,pos.ion)m / z:275.20[M+H] + .

[0312] Step 2) Synthesis of 8-cyclopropyl-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylic acid ethyl ester

[0313] To a flask, add ethyl 8-cyclopropyl-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.45 g, 1.64 mmol) and dissolve in DCM (9 mL) with stirring. Cool the mixture and add DDQ (0.41 g, 1.80 mmol) in an ice bath. The mixture is brought to room temperature and allowed to react overnight. The solvent is removed by concentration under reduced pressure and quenched with saturated aqueous sodium bicarbonate (18 mL). A solid precipitates and is stirred for 30 minutes. The filter cake is collected by filtration, washed with saturated aqueous sodium bicarbonate, and dried under vacuum to yield an off-white solid (0.345 g, 77.24%).

[0314] MS(ESI,pos.ion)m / z:273.20[M+H] + .

[0315] Step 3) Synthesis of 5-cyclopropyl-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one

[0316] To a 100 mL vial, ethyl 8-cyclopropyl-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (0.341 g, 1.25 mmol) and THF (12.5 mL) were added sequentially. The mixture was cooled, and LAH (0.098 g, 2.5 mmol) was added portionwise in an ice bath. Stirring continued until heat dissipated, the mixture was brought to room temperature, and the reaction was continued for 4 h. The mixture was cooled, quenched with water (2.5 mL) in an ice bath, and the pH was adjusted to 3-4 by dropwise addition of dilute hydrochloric acid (1 M). The mixture was extracted with THF (10 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (V / V) = 9 / 1) to yield an off-white solid (0.18 g, 62.42%).

[0317] MS (ESI, pos.ion) m / z: 231.2 [M+H] + .

[0318] Step 4) Synthesis of 7-(bromomethyl)-5-cyclopropyl-3-methylquinoxalin-2(1H)-one

[0319] To a flask, add 5-cyclopropyl-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (0.179 g, 0.78 mmol) and DCM (10 mL). Cool the mixture and dropwise add phosphorus tribromide (0.1 mL, 1.06 mmol) in an ice bath. Stir until exotherm subsides, then bring the mixture to room temperature and continue the reaction for 4 hours. Concentrate the mixture under reduced pressure to remove the solvent, and wash the residue with MTBE (10 mL x 2) to obtain a yellow solid (0.22 g, 99%), which is directly used in the next step.

[0320] Step 5) 5-(4-((8-cyclopropyl-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazine-1-yl Synthesis of 6-fluoro-N-methylpicolinamide

[0321] To a flask, 7-(bromomethyl)-5-cyclopropyl-3-methylquinoxalin-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 and dissolved in ACN (5 mL) with stirring. The mixture was cooled, and DIPEA (0.91 mL, 5.25 mmol) was slowly added dropwise in an ice bath. The mixture was heated to 80°C for 2 h. After cooling to room temperature, a solid precipitated with continued stirring. The filter cake was collected by filtration, washed with MTBE (5 mL × 3) and water (5 mL × 3), and dried in vacuo to give a white solid (0.184 g, 54.42%).

[0322] MS (ESI, pos.ion) m / z: 451.3 [M+H] + ;

[0323] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.20 (br, 1H), 8.41 (s, 1H), 7.84 (d, J = 6.8Hz, 1H), 7.57 (t, J = 9.3Hz, 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=3.1Hz,3H),2.61–2.53(m,4H),2.43(s,3H),1.08–0.78(m,4H).

[0324] Example 2: Synthesis of 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-phenyl-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0325]

[0326] Step 1) Synthesis of ethyl 4-((1-methoxy-1-oxopropan-2-yl)amino)-3-nitrobenzoate

[0327] To a flask, add ethyl 4-fluoro-3-nitrobenzoate (3.0 g, 14.07 mmol) and DL-alanine methyl ester hydrochloride (2.36 g, 16.88 mmol), stir and dissolve in acetonitrile (30 mL). Cool, then add potassium carbonate (4.67 g, 33.77 mmol) in an ice bath. Heat to 70°C and react overnight. Cool to room temperature, quench with water (60 mL) while stirring, and a solid precipitates. The filter cake is collected by filtration and dried in vacuo to yield a bright yellow solid (3.86 g, 92.57%).

[0328] MS(ESI,pos.ion)m / z:297.20[M+H] + .

[0329] Step 2) Synthesis of ethyl 2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate

[0330] To a flask, add 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). Heat to 70°C for 1 h. Cool to room temperature, quench with 15 mL of water, and extract with EtOAc (20 mL x 2). The combined organic phases are washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid (1.58 g, 99.92%).

[0331] MS(ESI,pos.ion)m / z:235.20[M+H] + .

[0332] Step 3) Synthesis of 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid ethyl ester

[0333] To a flask, add ethyl 2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (1.46 g, 6.23 mmol) and dissolve in 1,4-dioxane (30 mL). Cool the mixture and add NBS (1.13 g, 6.35 mmol) in an ice bath. Gradually warm the mixture to room temperature and stir overnight. Quench with saturated sodium thiosulfate and extract with EtOAc (40 mL x 2). The combined organic phases are washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (PE / EtOAc (V / V) = 2 / 1) to yield an off-white solid (1.56 g, 79.93%).

[0334] 1 H NMR(599MHz,DMSO-d6)δ(ppm)10.59(s,1H),7.62(s,1H),7.35(s,1H),6.39(s,1H ),4.24(dd,J=13.7,6.7Hz,2H),4.06(dd,J=12.4,6.3Hz,1H),1.35–1.25(m,6H);

[0335] MS(ESI,pos.ion)m / z:313.20[M+H] + .

[0336] Step 4) Synthesis of ethyl 2-methyl-3-oxo-8-phenyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylate

[0337] To a flask, 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 added sequentially. The mixture was dissolved in 1,4-dioxane (12 mL) and water (3 mL) with stirring and heated to 105°C overnight. The mixture was cooled to room temperature, quenched with water (25 mL), and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 3 / 2) to give a brown solid (0.54 g, 90.81%).

[0338] MS(ESI,pos.ion)m / z:311.20[M+H] + .

[0339] Step 5) Synthesis of ethyl 2-methyl-3-oxo-8-phenyl-3,4-dihydroquinoxaline-6-carboxylate

[0340] To a flask, ethyl 2-methyl-3-oxo-8-phenyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.54 g, 1.74 mmol) was added sequentially and dissolved in DCM (19 mL) with stirring. The mixture was cooled, and DDQ (0.43 g, 1.91 mmol) was added under ice-cooling. The mixture was allowed to react at room temperature for 8 h. The mixture was quenched by the addition of saturated aqueous sodium bicarbonate (38 mL), stirred for 2 h, and extracted with DCM (25 mL x 3). The organic phases were combined, washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield an orange-yellow solid (0.517 g, 96.37%).

[0341] MS(ESI,pos.ion)m / z:309.20[M+H] + .

[0342] Step 6) Synthesis of 7-(hydroxymethyl)-3-methyl-5-phenylquinoxaline-2(1H)-one

[0343] To a flask, ethyl 2-methyl-3-oxo-8-phenyl-3,4-dihydroquinoxaline-6-carboxylate (0.51 g, 1.64 mmol) was added sequentially and dissolved in THF (16.4 mL) with stirring. The mixture was cooled, and LAH (0.196 g, 5.01 mmol) was added portionwise in an ice bath. Stirring continued until the exotherm subsided, the mixture was brought to room temperature, and the reaction was continued for 4 h. The mixture was cooled and quenched with water (5 mL) in an ice bath. Dilute hydrochloric acid (1 M) was then added dropwise to adjust the pH to 3-4. The mixture was extracted with THF (25 mL x 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (V / V) = 10 / 1) to yield a white solid (0.28 g, 63.57%).

[0344] MS(ESI,pos.ion)m / z:267.40[M+H] + .

[0345] Step 7) Synthesis of 7-(bromomethyl)-3-methyl-5-phenylquinoxalin-2(1H)-one

[0346] To a flask, add 7-(hydroxymethyl)-3-methyl-5-phenylquinoxalin-2(1H)-one (0.15 g, 0.56 mmol) and DCM (10 mL). Cool the mixture and dropwise add phosphorus tribromide (0.08 mL, 0.85 mmol) in an ice bath. Stir until exotherm subsides, then bring the mixture to room temperature and continue the reaction for 4 h. Concentrate the mixture under reduced pressure to remove the solvent, and wash the residue with MTBE (10 mL x 2) to yield 0.185 g of a yellow solid, which is directly carried to the next step.

[0347] Step 8) 6-Fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-phenyl-3,4-dihydroquinoxalin-6-yl)methyl Synthesis of 1-(2-methyl)piperazine-1-yl)picolinamide

[0348] To a flask, 7-(bromomethyl)-3-methyl-5-phenylquinoxalin-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 and dissolved in ACN (4 mL) with stirring. The mixture was cooled, and DIPEA (0.68 mL, 3.92 mmol) was added dropwise in an ice bath. The mixture was heated to 80°C and reacted for 2 h. After cooling to room temperature, a solid precipitated with continued stirring. The filter cake was collected by filtration and washed sequentially with MTBE (4 mL × 3) and water (4 mL × 3). It was then dried in vacuo to give a white solid (0.177 g, 64.73%).

[0349] MS(ESI,pos.ion)m / z:487.20[M+H] + ;

[0350] 1H NMR (400MHz, DMSO-d6) δ (ppm) 12.32 (br, 1H), 8.38 (d, J = 4.2Hz, 1H), 7.82 (d, J = 7.7Hz, 1H), 7.57–7.52 (m, 3H), 7.44 (t, J = 7.2Hz, 2H) ,7.41–7.35(m,1H),7.25(d,J=15.5Hz,2H),3.64(s,2H),3.22–3.14(m,4H),2.75(d,J=4.2Hz,3H),2.63–2.55(m,4H),2.32(s,3H).

[0351] Example 3: Synthesis of 6-fluoro-5-(4-((8-isopropoxy-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0352]

[0353] Step 1) Synthesis of methyl (4-bromo-2-fluoro-6-nitrophenyl)aminopropionate

[0354] 5-Bromo-1,2-difluoro-3-nitrobenzene (10 g, 42.02 mmol), DL-alanine methyl ester hydrochloride (6.16 g, 44.12 mmol), and DIPEA (16.29 g, 126.06 mmol) were added to MeCN (120 mL) and allowed to react at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, diluted with DCM (120 mL), washed with water (80 mL) and saturated NaCl solution (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield a yellow liquid (13 g, 96%).

[0355] MS (ESI, pos.ion) m / z: 321.1 [M+H] + .

[0356] Step 2) Synthesis of 7-bromo-5-fluoro-3-methyl-3,4-dihydroquinoxaline-2(1H)-one

[0357] Methyl (4-bromo-2-fluoro-6-nitrophenyl)aminopropanoate (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 h. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. Water (100 mL) was added, stirred for 1 h, and filtered. The resulting solid was dried at 50°C for 12 h to yield a pale yellow solid (10.49 g, 90%).

[0358] MS (ESI, pos.ion) m / z: 259.0 [M+H]+ .

[0359] Step 3) Synthesis of 7-bromo-5-fluoro-3-methylquinoxalin-2(1H)-one

[0360] DDQ (9.16 g, 40.34 mmol) was added to a solution of 7-bromo-5-fluoro-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (9.5 g, 36.67 mmol) in DCM (150 mL) and allowed to react at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, stirred with saturated NaHCO₃ solution (400 mL), and filtered to obtain a solid. The solid was dried under vacuum at 50°C for 12 h to yield a light yellow solid (9.0 g, 95%).

[0361] MS (ESI, pos.ion) m / z: 257.0 [M+H] + .

[0362] Step 4) Synthesis of 7-bromo-5-isopropoxy-3-methylquinoxalin-2(1H)-one

[0363] NaH (390 mg, 9.75 mmol, 60%) was added to a solution of 7-bromo-5-fluoro-3-methylquinoxalin-2(1H)-one (500 mg, 1.95 mmol) and isopropanol (586 mg, 9.75 mmol) in DMF (10 mL) at 0°C. The mixture was allowed to react at room temperature for 15 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / EtOAc (V / V) = 4 / 1) to give a light yellow solid (400 mg, 69%).

[0364] MS (ESI, pos.ion) m / z: 297.1 [M+H] + .

[0365] Step 5) Synthesis of 7-(hydroxymethyl)-5-isopropoxy-3-methylquinoxalin-2(1H)-one

[0366] 7-Bromo-5-isopropoxy-3-methylquinoxalin-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) under nitrogen atmosphere at 80°C for 14 h. 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 give a light yellow solid (910 mg, 90%).

[0367] MS (ESI, pos.ion) m / z: 249.2 [M+H] + .

[0368] Step 6) Synthesis of 7-(bromomethyl)-5-isopropoxy-3-methylquinoxalin-2(1H)-one

[0369] CBr4 (602 mg, 1.81 mmol) was added to 7-(hydroxymethyl)-5-isopropoxy-3-methylquinoxalin-2(1H)-one (300 mg, 1.21 mmol) and PPh3 (476 mg, 1.81 mmol) in DCM (8 mL) and allowed to react at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V) = 1 / 1) to yield a yellow solid (300 mg, 80%).

[0370] MS (ESI, pos.ion) m / z: 311.1 [M+H] + .

[0371] Step 7) 6-fluoro-5-(4-((8-isopropoxy-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl) Synthesis of (1-piperazin-1-yl)-N-methylpicolinamide

[0372] 7-(Bromomethyl)-5-isopropoxy-3-methylquinoxalin-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 added sequentially to MeCN (8 mL) and reacted at 70°C for 4 h. The reaction solution was concentrated under reduced pressure, diluted with DCM (50 mL), washed with water (30 mL) and saturated NaCl solution (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (V / V) = 20 / 1) to give a light yellow solid (130 mg, 29%).

[0373] MS (ESI, pos.ion) m / z: 469.3 [M+H] + ;

[0374] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.15 (s, 1H), 8.39 (d, J = 4.7Hz, 1H), 7.84 (d, J = 7.9Hz, 1H), 7.62–7.51 (m, 1H), 6.81 (s, 2H), 4.7 9–4.73(m,1H),3.57(s,2H),3.23–3.10(m,4H),2.76(d,J=4.6Hz,3H),2.61–2.53(m,4H),2.37(s,3H),1.34(d,J=6.0Hz,6H).

[0375] Example 4: Synthesis of 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-phenoxy-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0376]

[0377]

[0378] Step 1) Synthesis of 7-bromo-3-methyl-5-phenoxyquinoxaline-2(1H)-one

[0379] 7-Bromo-5-fluoro-3-methylquinoxalin-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 a DMF (12 mL) solution. The mixture was microwaved at 120°C for 18 h. The reaction mixture was diluted with water (50 mL) to precipitate a solid, which was filtered to obtain a solid. The solid was dissolved in MeOH (5 mL) and DCM (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / EtOAc (V / V) = 4 / 1) to obtain a light yellow solid (300 mg, 23%).

[0380] MS (ESI, pos.ion) m / z: 331.1 [M+H] + .

[0381] Step 2) Synthesis of 7-(hydroxymethyl)-3-methyl-5-phenoxyquinoxaline-2(1H)-one

[0382] 7-Bromo-3-methyl-5-phenoxyquinoxalin-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 atmosphere at 80°C for 16 h. 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 afford a light yellow solid (200 mg, 78%).

[0383] MS (ESI, pos.ion) m / z: 283.2 [M+H] + .

[0384] Step 3) Synthesis of 7-(bromomethyl)-3-methyl-5-phenoxyquinoxaline-2(1H)-one

[0385] CBr4 (114 mg, 0.35 mmol) was added to 7-(hydroxymethyl)-3-methyl-5-phenoxyquinoxalin-2(1H)-one (65 mg, 0.23 mmol) and PPh3 (90 mg, 0.35 mmol) in DCM (6 mL) and allowed to react at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to yield a yellow solid (75 mg, 94%).

[0386] MS (ESI, pos.ion) m / z: 345.1 [M+H] + .

[0387] Step 4) 6-Fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-phenoxy-3,4-dihydroquinoxalin-6-yl) Synthesis of (methyl)piperazin-1-yl)picolinamide

[0388] 7-(Bromomethyl)-3-methyl-5-phenoxyquinoxalin-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 added sequentially to MeCN (4 mL) and reacted at 70°C for 4 h. The reaction solution was concentrated under reduced pressure, diluted with DCM (50 mL), washed with water (30 mL) and saturated NaCl solution (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (V / V) = 20 / 1) to give a light yellow solid (25 mg, 34%).

[0389] MS (ESI, pos.ion) m / z: 503.3 [M+H] + .

[0390] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.37 (s, 1H), 8.40 (d, J = 4.7Hz, 1H), 7.84 (d, J = 7.9Hz, 1H), 7.56 (dd, J = 10.5, 8.2Hz, 1H), 7.40 (t, J = 7.9Hz, 2H), 7.1 5(dd,J=15.8,8.4Hz,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).

[0391] Example 5: Synthesis of 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-(phenylamino)-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0392]

[0393] Step 1) Synthesis of ethyl 4-((1-methoxy-1-oxopropyl-2-yl)amino)-3-nitrobenzoate

[0394] 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 ester hydrochloride (4.63 g, 33.13 mmol) were added. The mixture was heated to 100°C for 3 hours, the reaction was stopped, the reaction mixture was cooled to room temperature, water (500 mL) was added, and the mixture was extracted with ethyl acetate (400 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 4 / 1) to give a yellow solid (1.6 g, 17.9%).

[0395] MS (ESI, pos.ion) m / z: 297.4 [M+H] + .

[0396] Step 2) Synthesis of ethyl 2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate

[0397] 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 the reaction flask, heated to 80°C, reacted for 5 hours, and the reaction was shut down. The reaction was cooled to room temperature, water (500 mL) was added, and the mixture was extracted with dichloromethane (150 mL*2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a light yellow solid (1.10 g, 92.7%).

[0398] MS (ESI, pos.ion) m / z: 235.2 [M+H] + .

[0399] Step 3) Synthesis of 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid ethyl ester

[0400] 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 with stirring at room temperature. The mixture was reacted for 16 hours, and water (150 mL) was added. The mixture was extracted with dichloromethane (200 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow solid (0.52 g, 73.3%).

[0401] MS (ESI, pos.ion) m / z: 313.3 [M+H] + .

[0402] Step 4) Synthesis of 8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylic acid ethyl ester

[0403] 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). Active manganese dioxide (0.2 g, 1.96 mmol, 85%) was added with stirring at room temperature. The mixture was stirred at room temperature for 2.5 hours and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 4 / 1) to give a light yellow solid (0.078 g, 78.5%).

[0404] MS (ESI, pos.ion) m / z: 311.2 [M+H] + .

[0405] Step 5) Synthesis of ethyl 2-methyl-3-oxo-8-(phenylamino)-3,4-dihydroquinoxaline-6-carboxylate

[0406] 8-Bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylic acid ethyl ester (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'-triisopropyl-1,1'-biphenyl) -Triisopropylbiphenyl (0.026 g, 0.054 mmol), sodium tert-butoxide (0.052 g, 0.54 mmol), and toluene (5 mL) were added to the reaction flask, the nitrogen was replaced, and the temperature was raised to 100 ° C under nitrogen protection. The reaction was reacted for 18 hours, the reaction was closed, the temperature was lowered to room temperature, and the product was concentrated under reduced pressure. The residue was separated and 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%).

[0407] MS (ESI, pos.ion) m / z: 324.2 [M+H] + .

[0408] Step 6) Synthesis of 7-(hydroxymethyl)-3-methyl-5-(phenylamino)quinoxalin-2(1H)-one

[0409] 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 continued at this temperature for 22 h. The temperature was raised to 65°C and the reaction was continued for 4.5 h. The reaction was stopped and cooled to room temperature. Water (0.5 mL) was added dropwise to quench the reaction. The product was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give a yellow solid (0.05 g, 35.92%).

[0410] MS (ESI, pos.ion) m / z: 282.2 [M+H] + .

[0411] Step 7) Synthesis of 2-methyl-3-oxo-8-(phenylamino)-3,4-dihydroquinoxaline-6-carbaldehyde

[0412] 7-(Hydroxymethyl)-3-methyl-5-(phenylamino)quinoxaline-2(1H)-one (0.04 g, 0.14 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 mL) and dichloromethane (2 mL). Dess-Martin reagent (0.12 g, 0.28 mmol) was added at 0°C, and then the mixture was returned to room temperature for 16 hours. The reaction was stopped and filtered. The filter cake was rinsed with dichloromethane (10 mL). The filtrate was concentrated to obtain a yellow oil (0.038 g, 95.6%).

[0413] MS (ESI, pos.ion) m / z: 280.2 [M+H] + .

[0414] Step 8) 6-Fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-(phenylamino)-3,4-dihydroquinoxaline-6- Synthesis of 1-(2-methyl)piperazin-1-yl)pyridinecarboxamide

[0415] 6-Fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (0.05 g, 0.21 mmol) was dissolved in a mixed solution of dichloromethane (2 mL) and methanol (2 mL), and triethylamine (0.028 g, 0.28 mmol), 2-methyl-3-oxo-8-(phenylamino)-3,4-dihydroquinoxaline-6-carbaldehyde (0.038 g, 0.14 mmol), acetic acid (0.0017 g, 0.028 mmol), and sodium cyanoborohydride (0.026 g, 0.42 mmol) were added. The reaction was carried out at room temperature for 20 hours, and the mixture was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 15 / 1) to give a yellow solid (0.014 g, 20.5%).

[0416] MS (ESI, pos.ion) m / z: 502.3 [M+H] + ;

[0417] HRMS:calcd.for C 27 H 28 FN7O2[M+H] + :502.2361,found:502.2368;

[0418] 1H NMR(400MHz, DMSO-d6)δ(ppm)12.19(s,1H),8.40(d,J=4.9Hz,1H),8.21(s,1H),7.84(d,J=7.8Hz,1H),7.68–7.51(m,1H),7.34(d,J=4.2Hz ,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=4.7Hz,3H),2.59–2.52(m,4H),2.44(s,3H).

[0419] Example 6: Synthesis of 6-fluoro-5-(4-((8-(4-fluorophenoxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0420]

[0421]

[0422] Step 1) Synthesis of 7-bromo-5-(4-fluorophenoxy)-3-methylquinoxalin-2(1H)-one

[0423] 7-Bromo-5-fluoro-3-methylquinoxalin-2(1H)-one (0.8 g, 3.11 mmol, Reference Example 3, Step 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. The mixture was microwaved at 130°C for 16 h. The reaction solution was diluted with water (60 mL) to precipitate a solid, which was filtered to obtain a solid. The solid was dissolved in methanol (5 mL) and dichloromethane (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a light yellow solid (0.6 g, 55%).

[0424] MS (ESI, pos.ion) m / z: 349.2 [M+H] + .

[0425] Step 2) Synthesis of 5-(4-fluorophenoxy)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one

[0426] 7-Bromo-5-(4-fluorophenoxy)-3-methylquinoxalin-2(1H)-one (600 mg, 1.72 mmol), (tributyltinyl)methanol (607 mg, 1.89 mmol), and Xphos-Pd-G2 (135 mg, 0.17 mmol) were added to 1,4-dioxane (16 mL) under nitrogen atmosphere and reacted at 80°C for 16 h. 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 give a light yellow solid (350 mg, 68%).

[0427] MS (ESI, pos.ion) m / z: 301.2 [M+H] + .

[0428] Step 3) Synthesis of 7-(bromomethyl)-5-(4-fluorophenoxy)-3-methylquinoxalin-2(1H)-one

[0429] CBr4 (776 mg, 2.34 mmol) was added to 5-(4-fluorophenoxy)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (350 mg, 1.17 mmol) and PPh3 (613 mg, 2.34 mmol) in dichloromethane (20 mL) at 0°C for 1 hour. The mixture was then allowed to react 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 give a yellow solid (300 mg, 71%).

[0430] MS (ESI, pos.ion) m / z: 363.1 [M+H] + .

[0431] Step 4) 6-fluoro-5-(4-((8-(4-fluorophenoxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl Synthesis of 1-methylpiperazine-1-yl)-N-methylpicolinamide

[0432] 7-(Bromomethyl)-5-(4-fluorophenoxy)-3-methylquinoxalin-2(1H)-one (300 mg, 0.83 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (198 mg, 0.83 mmol), and N,N-diisopropylethylamine (429 mg, 3.32 mmol) were added sequentially to acetonitrile (8 mL) and reacted at 70°C for 3 h. The reaction solution was concentrated under reduced pressure, diluted with dichloromethane (50 mL), washed with water (30 mL) and saturated NaCl solution (30 mL), dried over 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 give a light yellow solid (260 mg, 60%).

[0433] MS (ESI, pos.ion) m / z: 521.3 [M+H] + ;

[0434] HRMS:calcd.for C 27 H 26 F2N6O3[M+H] + :521.2034,found:521.2111;

[0435] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.34 (s, 1H), 8.37 (d, J = 4.7Hz, 1H), 7.84 (d, J = 7.9Hz, 1H), 7.58–7.51 (m, 1H), 7.22 (t, J = 8.7Hz, 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=4.7Hz,3H),2.56–2.51(m,4H),2.36(s,3H).

[0436] Example 7: Synthesis of 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-(prop-1-yn-1-yl)-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0437]

[0438] Step 1) Synthesis of methyl 8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate

[0439] To a 100 mL reaction flask, add methyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.31 g, 1.04 mmol, see Example 8, Step 3), stir and dissolve in dichloromethane (12 mL). Cool and then add 2,3-dichloro-5,6-dicyanobenzoquinone (0.26 g, 1.14 mmol) in portions under an ice bath. Stir and allow to react at room temperature for 4 h. Concentrate under reduced pressure to remove the solvent, cool, and quench with saturated aqueous sodium bicarbonate (24 mL) under an ice bath. Solid precipitates. Stir for 30 min, collect the filter cake by filtration, wash with saturated aqueous sodium bicarbonate, and dry in vacuo to obtain a brownish-red solid (0.18 g, 58.46%).

[0440] MS(ESI,pos.ion)m / z:297.10,299.05[M+H] + .

[0441] Step 2) Synthesis of 5-bromo-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one

[0442] To a 50 mL reaction flask, add methyl 8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (0.18 g, 0.61 mmol), stir and dissolve in tetrahydrofuran (9 mL), cool, and add lithium aluminum hydride (0.070 g, 1.79 mmol) in an ice bath. Continue the reaction at 0°C for 2 h. Quench the mixture with water (1.79 mL) in an ice bath, and adjust the pH to 3-4 with dropwise addition of 1 M dilute hydrochloric acid. Extract with tetrahydrofuran (10 mL x 2). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 95 / 5) to afford a brick-red solid (0.112 g, 68.70%).

[0443] MS(ESI,pos.ion)m / z:269.20,271.15[M+H] + .

[0444] Step 3) Synthesis of 5-bromo-7-(bromomethyl)-3-methylquinoxalin-2(1H)-one

[0445] To a 100 mL reaction flask, add 5-bromo-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (0.11 g, 0.41 mmol) and dichloromethane (10 mL). Cool the mixture and, under ice, add phosphorus tribromide (0.060 mL, 0.64 mmol) dropwise. Stir until exotherm subsides and allow to react at room temperature overnight. Concentrate under reduced pressure to remove the solvent to afford a yellow solid product (0.135 g, 99.5%), which is directly carried to the next step.

[0446] Step 4) 5-(4-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)- Synthesis of 6-Fluoro-N-Methylpicolinamide

[0447] To a 100 mL reaction flask, add 5-bromo-7-(bromomethyl)-3-methylquinoxalin-2(1H)-one (0.135 g, 0.41 mmol), 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). Stir and dissolve in acetonitrile (2.5 mL). Cool the mixture, then slowly add N,N-diisopropylethylamine (0.50 mL, 2.87 mmol) dropwise in an ice bath. Stir thoroughly and heat to 80°C for 2 h. Cool to room temperature, whereupon a solid precipitated. The filter cake was collected by filtration, washed with methyl tert-butyl ether (2.5 mL x 2), then with water (2.5 mL x 2), and dried in vacuo to afford an off-white solid (145 mg, 72.87%).

[0448] MS(ESI,pos.ion)m / z:489.15,490.10[M+H] + .

[0449] Step 5) 6-Fluoro-N-methyl-5-(4-(2-methyl-3-oxo-8-(prop-1-yn-1-yl)-3,4-dihydroquinoxaline Synthesis of (6-(1-(2-((1-((2-((-piperazin-6-yl)methyl)piperazin-1-yl)pyridinecarboxamide))

[0450] To a 100 mL reaction flask, 5-(4-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (0.10 g, 0.20 mmol) and tributylstannane (0.12 g, 0.36 mmol) were added sequentially. The mixture was stirred and dissolved in 1,4-dioxane (8 mL). Xphos-Pd-G2 (0.024 g, 0.031 mmol) was then added. The atmosphere was replaced with nitrogen and the reaction was heated to 90°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 97 / 3) to give a white solid (0.030 g, 32.73%).

[0451] MS(ESI,pos.ion)m / z:449.40[M+H] + ;

[0452] HRMS:calcd.for C 24 H 25 FN6O2[M+H] + :449.2096,found:449.2128;

[0453] 1 H NMR(400MHz,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).

[0454] Example 8: Synthesis of 6-fluoro-5-(4-((8-(2-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0455]

[0456] Step 1) Synthesis of methyl 4-((1-methoxy-1-oxopropyl-2-yl)amino)-3-nitrobenzoate

[0457] To a solution of methyl 4-fluoro-3-nitrobenzoate (10 g, 50.22 mmol) in acetonitrile (100 mL) at room temperature were added DL-alanine methyl ester hydrochloride (9.81 g, 70.31 mmol) and K2CO3 (17.35 g, 125.55 mmol). The mixture was then heated to 70°C for 12 h. After cooling, the reaction solution was filtered through celite, 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 the product as a yellow solid (14 g, 98.78%).

[0458] MS (ESI, pos.ion) m / z: 283.1 [M+H] + .

[0459] Step 2) Synthesis of methyl 2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate

[0460] To a solution of methyl 4-((1-methoxy-1-oxopropyl-2-yl)amino)-3-nitrobenzoate (14 g, 49.60 mmol) in acetic acid (200 mL) was added iron powder (13.85 g, 248 mmol) at room temperature. The mixture was heated to 80°C and stirred for 5 h. After the reaction mixture cooled, 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%).

[0461] MS (ESI, pos.ion) m / z: 221.3 [M+H] + .

[0462] Step 3) Synthesis of 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid methyl ester

[0463] 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) was added NBS (4.00 g, 22.47 mmol) at room temperature, and the reaction was stirred at room temperature for 8 hours. Water (150 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (150 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was 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 the product as a yellow solid (4.5 g, 73.62%).

[0464] MS(ESI,pos.ion)m / z:299.1,301.1[M+H] + .

[0465] Step 4) Synthesis of methyl 8-(2-fluorophenyl)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate

[0466] To a solution of methyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.6 g, 2.01 mmol) in 1,4-dioxane (12 mL) and water (3 mL) were added 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) at room temperature. The atmosphere was replaced with N2 and the mixture was heated to 105°C for 12 h. The reaction solution was cooled to room temperature, quenched by adding water (25 mL), extracted with ethyl acetate (50 mL*3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 3 / 1) to give a yellow solid product (0.4 g, 63.44%).

[0467] MS (ESI, pos.ion) m / z: 315.2 [M+H] + .

[0468] Step 5) Synthesis of methyl 8-(2-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate

[0469] 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) was added 2,3-dichloro-5,6-dicyanobenzoquinone (0.32 g, 1.40 mmol) under ice. The mixture was then slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (38 mL) and stirred for 2 hours. The mixture was then extracted with dichloromethane (25 mL x 3). The combined organic phases were washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the product as an orange-yellow solid (0.21 g, 52.84%).

[0470] MS (ESI, pos.ion) m / z: 313.1 [M+H] + .

[0471] Step 6) Synthesis of 5-(2-fluorophenyl)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one

[0472] 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) was added lithium aluminum hydride (0.080 g, 2.04 mmol) in an ice bath. The mixture was stirred until heat dissipated and allowed to react at room temperature for 4 h. The mixture was cooled and quenched with water (5 mL) in an ice bath. 1 M dilute hydrochloric acid was then added dropwise to adjust the pH to 3-4. The product was extracted with tetrahydrofuran (25 mL x 2). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. 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 give a white solid (0.11 g, 57.54%).

[0473] MS (ESI, pos.ion) m / z: 285.2 [M+H] + .

[0474] Step 7) Synthesis of 7-(bromomethyl)-5-(2-fluorophenyl)-3-methylquinoxalin-2(1H)-one

[0475] Under ice, 5-(2-fluorophenyl)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (0.16 g, 0.56 mmol) and dichloromethane (10 mL) were then dropwise added with phosphorus tribromide (0.056 mL, 0.59 mmol). The reaction was stirred for 5 minutes, then brought to room temperature and allowed to react for 2 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was washed with methyl tert-butyl ether (10 mL x 2) and dried to obtain a crude yellow solid (0.13 g, 96.77%), which was directly used in the next step.

[0476] MS(ESI,pos.ion)m / z:347.1,349.1[M+H] + .

[0477] Step 8) 6-Fluoro-5-(4-((8-(2-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methane Synthesis of 1-methylpiperazine-1-yl)-N-methylpicolinamide

[0478] To a solution of 7-(bromomethyl)-5-(2-fluorophenyl)-3-methylquinoxalin-2(1H)-one (0.19 g, 0.55 mmol) in acetonitrile (20 mL) were added 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (0.13 g, 0.55 mmol) and N,N-diisopropylethylamine (0.36 g, 2.75 mmol) at room temperature, followed by heating to 70°C with stirring for 3 h. 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 give the product as a yellow solid (0.029 g, 10.50%).

[0479] MS (ESI, pos.ion) m / z: 505.4 [M+H] + ;

[0480] HRMS:calcd.for C 27 H 26 F2N6O2[M+H] + :505.2085,found:505.2186;

[0481] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.34 (s, 1H), 8.36 (d, J = 5.7Hz, 1H), 7.84 (d, J = 8.0Hz, 1H), 7.56 (t, J = 9.3Hz, 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=4.7Hz,3H),2.63–2.58(m,4H),2.29(s,3H).

[0482] Example 9: Synthesis of 6-fluoro-5-(4-(((8-(3-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0483]

[0484] Step 1) Synthesis of 8-(3-fluorophenyl)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid methyl ester

[0485] 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) at room temperature were added (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). The atmosphere was then replaced with nitrogen and the temperature was raised to 105°C for 10 h. The reaction solution was diluted with dichloromethane and filtered through celite. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate (v / v) = 90 / 10) to afford the product as a yellow solid (0.65 g, 41.24%).

[0486] MS(ESI,pos.ion)m / z:315.1,316.2[M+H] + .

[0487] Step 2) 8-(3-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylic acid methyl ester

[0488] 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) was added 2,3-dichloro-5,6-dicyanobenzoquinone (0.56 g, 2.48 mmol). The reaction was allowed to proceed for 5 h at room temperature and monitored by TLC. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (10 mL), extracted with dichloromethane (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the organic phase concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate (v / v) = 9 / 1) to give the product as a white solid (0.55 g, 85.16%).

[0489] MS(ESI,pos.ion)m / z:313.15[M+H] + .

[0490] Step 3) Synthesis of 5-(3-fluorophenyl)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one

[0491] 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) at 0°C under N₂ was slowly added lithium aluminum hydride (0.2 g, 5.28 mmol). The mixture was stirred at 0°C for 5 minutes, then allowed to warm to room temperature and allowed to react 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 stirred for 10 minutes. The mixture was filtered through celite, and the filter cake was added with water. Dilute hydrochloric acid (14 mL, 1 M) was added to dissolve the solid, and the mixture was extracted with dichloromethane (50 mL x 3). The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 97 / 3) to give a gray solid product (0.3 g, 59.92%).

[0492] MS (ESI, pos.ion) m / z: 285.2 [M+H] + .

[0493] Step 4) Synthesis of 7-(bromomethyl)-5-(3-fluorophenyl)-3-methylquinoxalin-2(1H)-one

[0494] To a solution of 5-(3-fluorophenyl)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (0.3 g, 1.06 mmol) in dichloromethane (8 mL) was added dropwise phosphorus tribromide (0.15 mL, 1.59 mmol) under ice-cooling. The mixture was stirred for 5-10 minutes and then allowed to warm to 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 give a white solid powder (0.27 g, 73.70%).

[0495] MS(ESI,pos.ion)m / z:347.15,349.15[M+H] + .

[0496] Step 5) 6-fluoro-5-(4-((8-(3-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl Synthesis of 1-methylpiperazine-1-yl)-N-methylpicolinamide

[0497] To a solution of 7-(bromomethyl)-5-(3-fluorophenyl)-3-methylquinoxalin-2(1H)-one (0.27 g, 0.78 mmol) in acetonitrile (15 mL) was added 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) at room temperature. The mixture was stirred for 5-10 minutes and then allowed to warm to 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 give a white solid powder (0.15 g, 38.23%).

[0498] MS(ESI,pos.ion)m / z:505.25[M+H] + ;

[0499] HRMS:calcd.for C 27 H 26 F2N6O2[M+H] + :505.2158,found:505.2191;

[0500] 1H NMR(400MHz, 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=4.8Hz,3H),2.64–2.56(m,4H),2.34(s,3H).

[0501] Example 10: Synthesis of 6-fluoro-5-(4-((8-(4-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0502]

[0503] Step 1) Synthesis of methyl 8-(4-fluorophenyl)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate

[0504] In a 100 mL reaction flask, 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid methyl ester (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 in sequence, stirred and dissolved in 1,4-dioxane (12 mL) and water (3 mL), replaced with nitrogen, and heated to 105 ° C for reaction overnight. The mixture was cooled to room temperature and filtered to remove insoluble matter. The organic phase was collected and layered with water. The mixture was extracted with ethyl acetate (25 mL*2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 97 / 3) to give a white solid (0.383 g, 60.75%).

[0505] MS(ESI,pos.ion)m / z:315.15[M+H] + .

[0506] Step 2) Synthesis of methyl 8-(4-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate

[0507] To a 100 mL reaction flask, add methyl 8-(4-fluorophenyl)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.38 g, 1.22 mmol), stir and dissolve in dichloromethane (12 mL). Cool the mixture, then add 2,3-dichloro-5,6-dicyanobenzoquinone (0.30 g, 1.33 mmol) in an ice bath. The mixture is allowed to react at room temperature for 6 h. The solvent is removed by concentration under reduced pressure, and the mixture is quenched by addition of saturated aqueous sodium bicarbonate (24 mL). Stir for 30 min, and a solid precipitates. The filter cake is collected by filtration, washed with saturated aqueous sodium bicarbonate, and dried in vacuo to afford a tan solid (0.30 g, 79.46%).

[0508] MS(ESI,pos.ion)m / z:313.20[M+H] + .

[0509] Step 3) Synthesis of 5-(4-fluorophenyl)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one

[0510] To a 100 mL reaction flask, add methyl 8-(4-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (0.30 g, 0.96 mmol), stir and dissolve in tetrahydrofuran (11 mL). Cool, then add lithium aluminum hydride (0.106 g, 2.71 mmol) in an ice bath. Gradually warm to room temperature and react overnight. Cool, quench with water (2.7 mL) in an ice bath, and adjust the pH to 3-4 with the dropwise addition of 1 M dilute hydrochloric acid. Extract with tetrahydrofuran (10 mL x 2). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 95 / 5) to afford an off-white solid (0.186 g, 68.11%).

[0511] MS(ESI,pos.ion)m / z:285.20[M+H] + .

[0512] Step 4) Synthesis of 7-(bromomethyl)-8-fluoro-5-(4-fluorophenyl)-3-methylquinoxalin-2(1H)-one

[0513] To a 100 mL reaction flask, add 8-fluoro-5-(4-fluorophenyl)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (0.186 g, 0.65 mmol) and dichloromethane (8.5 mL). Cool the mixture and, under ice, add phosphorus tribromide (0.079 mL, 0.85 mmol) dropwise. Stir until exotherm subsides and allow the reaction to proceed to room temperature for 4 h. Concentrate under reduced pressure to remove the solvent to obtain a crude yellow solid, which is then directly used in the next step.

[0514] Step 5) 6-fluoro-5-(4-((8-(4-fluorophenyl)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl Synthesis of 1-methylpiperazine-1-yl)-N-methylpicolinamide

[0515] To a 100 mL reaction flask, add 7-(bromomethyl)-8-fluoro-5-(4-fluorophenyl)-3-methylquinoxalin-2(1H)-one (0.22 g, 0.63 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide hydrochloride (0.19 g, 0.69 mmol), and potassium iodide (0.021 g, 0.13 mmol). The mixture was stirred and dissolved in acetonitrile (4 mL). The mixture was cooled, and N,N-diisopropylethylamine (0.77 mL, 4.41 mmol) was added dropwise in an ice bath. The mixture was heated to 80°C and reacted for 2 h. After cooling to room temperature, a solid precipitated. The filter cake was collected by filtration, washed with methyl tert-butyl ether (4 mL x 3) and water (4 mL x 3), and dried in vacuo to give a white solid (0.19 g, 59.43%).

[0516] MS(ESI,pos.ion)m / z:505.30[M+H] + ;

[0517] HRMS:calcd.for C 27 H 26 F2N6O2[M+H] + :505.2158,found:505.2160;

[0518] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.36 (s, 1H), 8.40 (d, J = 4.8Hz, 1H), 7.84 (d, J = 7.9Hz, 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=4.6Hz,3H),2.63–2.55(m,4H),2.34(s,3H).

[0519] Example 11: Synthesis of 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-(pyridin-3-yl)-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0520]

[0521] Step 1) Synthesis of methyl 2-methyl-3-oxo-8-(pyridin-3-yl)-1,2,3,4-tetrahydroquinoxaline-6-carboxylate

[0522] To a solution of methyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (1 g, 3.34 mmol) in 1,4-dioxane (20 mL) and water (5 mL) at room temperature were added 3-pyridinium boronic 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 atmosphere was then replaced with nitrogen and the temperature was raised to 110°C for 8 h. The reaction solution was diluted with dichloromethane and filtered through celite. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 97 / 3) to give the product as a light red solid (0.55 g, 55.33%).

[0523] MS(ESI,pos.ion)m / z:298.25[M+H] + .

[0524] Step 2) Synthesis of methyl 2-methyl-3-oxo-8-(pyridin-3-yl)-3,4-dihydroquinoxaline-6-carboxylate

[0525] To a solution of methyl 2-methyl-3-oxo-8-(pyridin-3-yl)-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.55 g, 1.85 mmol) in dichloromethane (30 mL) was added 2,3-dichloro-5,6-dicyanobenzoquinone (0.63 g, 2.78 mmol) at 0°C. The reaction was allowed to proceed for 5 h at room temperature and monitored by TLC. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (50 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate (v / v) = 9 / 1) to give the product as a white solid (0.44 g, 80.55%).

[0526] MS(ESI,pos.ion)m / z:296.15[M+H] + .

[0527] Step 3) Synthesis of 7-(hydroxymethyl)-3-methyl-5-(pyridin-3-yl)quinoxaline-2(1H)-one

[0528] To a solution of methyl 2-methyl-3-oxo-8-(pyridin-3-yl)-3,4-dihydroquinoxaline-6-carboxylate (0.44 g, 1.49 mmol) in tetrahydrofuran (20 mL) was slowly added lithium aluminum hydride (0.17 g, 4.47 mmol) at 0°C under N₂. The mixture was stirred at 0°C for 5 minutes, then allowed to warm to room temperature and allowed to react for 3 hours. After the reaction was complete, water (0.2 mL), 15% aqueous NaOH (0.2 mL), and water (0.6 mL) were added at 0°C and stirred for 10 minutes. The mixture was filtered through celite and washed with dichloromethane (50 mL) and tetrahydrofuran (50 mL). The mixture was dried over anhydrous sodium sulfate and dried by spin drying. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 97 / 3) to yield the product as a gray solid (0.19 g, 47.71%).

[0529] MS (ESI, negative ion) m / z: 266.15 [MH] - .

[0530] Step 4) Synthesis of 7-(bromomethyl)-3-methyl-5-(pyridin-3-yl)quinoxalin-2(1H)-one

[0531] To a solution of 7-(hydroxymethyl)-3-methyl-5-(pyridin-3-yl)quinoxalin-2(1H)-one (0.19 g, 0.71 mmol) in dichloromethane (20 mL) was added dropwise phosphorus tribromide (0.1 mL, 1.06 mmol) under ice-cooling. Stir for 5-10 min, then warm to room temperature and react for 3.5 h. Dried in vacuo and used directly in the next reaction.

[0532] Step 5) 6-Fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-(pyridin-3-yl)-3,4-dihydroquinoxaline- Synthesis of 6-(6-yl)methyl)piperazin-1-yl)pyridinecarboxamide

[0533] To a solution of 7-(bromomethyl)-3-methyl-5-(pyridin-3-yl)quinoxalin-2(1H)-one (0.19 g, 0.58 mmol) in acetonitrile (10 mL) was added 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) at room temperature. The mixture was stirred for 5-10 minutes and then allowed to warm to room temperature for 5 hours. The mixture was dried in vacuo and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 97 / 3) to give a white solid powder (0.034 g, 12.12%).

[0534] MS(ESI,pos.ion)m / z:488.20[M+H] + ;

[0535] HRMS:calcd.for C 26 H26 FN7O2[M+H] + :488.5469,found:488.2227;

[0536] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.36 (s, 1H), 8.77 (dd, J = 2.1, 1.0Hz, 1H), 8.57 (dd ,J=4.8,1.6Hz,1H),8.38(q,J=4.9Hz,1H),8.02–7.95(m,1H),7.85–7.80(m,1H),7 .56(dd,J=10.6,8.1Hz,1H),7.49(dd,J=7.9,4.8Hz,1H),7.36–7.28(m,2H),3.67 (s,2H),3.21–3.15(m,4H),2.75(d,J=4.8Hz,3H),2.63–2.56(m,4H),2.33(s,3H).

[0537] Example 12: Synthesis of 2-fluoro-N-methyl-1'-((2-methyl-3-oxo-8-(prop-1-yn-1-yl)-3,4-dihydroquinoxalin-6-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0538]

[0539]

[0540] Step 1) Synthesis of methyl 5-bromo-6-fluoropicolinate

[0541] Methyl 5-bromopyridine-2-carboxylate (2.00 g, 9.26 mmol), AgF2 (4.73 g, 32.41 mmol) and acetonitrile (30 mL) were added sequentially into a sealed tube, reacted at room temperature for 48 h, filtered, and the filter cake was rinsed with EA (20 mL). The product was concentrated under reduced pressure, and the concentrated residue was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 4 / 1) to give a white solid (0.57 g, 26%).

[0542] MS(ESI,pos.ion)m / z:234.0,236.0[M+H] + .

[0543] Step 2) 1'-tert-Butyl 6-methyl 2-fluoro-5',6'-dihydro-[3,4'-bipyridine]-1',6(2'H)-dicarboxylate Synthesis

[0544] Methyl 5-bromo-6-fluoropyridine-2-carboxylate (0.5 g, 2.14 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 added to 1,4-dioxane (20 mL) in sequence, protected by nitrogen, heated to 85°C, and reacted for 16 h. The reaction solution was concentrated under reduced pressure, and water (50 mL) and EA (80 mL) were added. The organic phase was extracted and separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 4 / 1) to give a light yellow solid (0.48 g, 66.8%).

[0545] MS (ESI, pos.ion) m / z: 337.4 [M+H] + .

[0546] Step 3) tert-Butyl 2-fluoro-6-(methylcarbamoyl)-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid Salt synthesis

[0547] Methyl 5-(1-(tert-Butyloxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-6-fluoropyridine-2-carboxylate (0.54 g, 1.61 mmol) and methanol (5 mL) were added to a 2M solution of methylamine in methanol (10 mL). The mixture was sealed and reacted at 50°C for 12 h. 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 give a colorless liquid (0.38 g, 70.6%).

[0548] MS (ESI, pos.ion) m / z: 336.2 [M+H] + .

[0549] Step 4) Synthesis of 2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0550] Tert-butyl 4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (0.35 g, 1.04 mmol) was added to EtOAc (10 mL), and a solution of HCl in ethyl acetate (1 mL, 4 M) was added dropwise. The mixture was allowed to react at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure to afford the product as a brown oil (0.21 g, 85.5%).

[0551] MS (ESI, pos.ion) m / z: 236.3 [M+H] + .

[0552] Step 5) 1'-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-2-fluoro-N-methyl- Synthesis of 1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0553] To a solution of 5-bromo-7-(bromomethyl)-3-methylquinoxalin-2(1H)-one (0.49 g, 1.48 mmol, from Example 7, Step 3) in acetonitrile (20 mL) were added 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) at room temperature. The reaction mixture was then heated to 80°C for 3 h. 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 afford the product as a yellow solid (0.32 g, 44.58%).

[0554] MS(ESI,pos.ion)m / z:486.30,488.3[M+H] + .

[0555] Step 6) 2-Fluoro-N-methyl-1'-((2-methyl-3-oxo-8-(prop-1-yn-1-yl)-3,4-dihydroquinoxaline- Synthesis of 6-(6-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0556] 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) at room temperature were added tributylstannane (0.18 g, 0.56 mmol) and Xphos-Pd-G2 (0.037 g, 0.046 mmol). After replacing the nitrogen atmosphere with nitrogen, the mixture was heated to 90°C and stirred for 12 hours. After cooling to room temperature, the reaction solution was filtered through celite, 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 give the product as a yellow solid (0.075 g, 54.58%).

[0557] MS (ESI, pos.ion) m / z: 446.5 [M+H] + ;

[0558] HRMS:calcd.for C 25 H 24 FN5O2[M+H] + :446.1914,found:446.2001;

[0559] 1H NMR (400MHz, DMSO-d6) δ (ppm) 12.31 (s, 1H), 8.67–8.61 (m, 1H), 8.09 (t, J = 8.7Hz, 1H), 7.93 (d, J = 7.7Hz, 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=4.8Hz,3H),2.70–2.66(m,2H),2.42(s,3H),2.14(s,3H).

[0560] Example 13: Synthesis of 5-(4-((8-(difluoromethoxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0561]

[0562] Step 1) Synthesis of 7-bromo-5-hydroxy-3-methylquinoxaline-2(1H)-one

[0563] 2,3-Diamino-5-bromophenol (100 mg, 0.49 mmol), methyl 2-oxopropanoate (75 mg, 0.73 mmol), and acetic acid (29 mg, 0.49 mmol) were added to an ethanol (6 mL) solution and reacted at 50°C for 8 h. 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 give a yellow solid (50 mg, 40%).

[0564] MS (ESI, pos.ion) m / z: 255.1 [M+H] + .

[0565] Step 2) Synthesis of 7-bromo-5-(difluoromethoxy)-3-methylquinoxalin-2(1H)-one

[0566] A solution of KOH (881 mg, 15.70 mmol) in water (6 mL) was added to a solution of 7-bromo-5-hydroxy-3-methylquinoxalin-2(1H)-one (400 mg, 1.57 mmol) in acetonitrile (16 mL) at 0°C, followed by diethyl (bromodifluoromethyl)phosphonate (2.10 g, 7.85 mmol). The mixture was allowed to react at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (30 mL) and water (20 mL), separated, and the upper organic phase was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 2 / 1) to yield a white solid (100 mg, 21%).

[0567] MS (ESI, pos.ion) m / z: 305.0 [M+H] + .

[0568] Step 3) Synthesis of 5-(difluoromethoxy)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one

[0569] 7-Bromo-5-(difluoromethoxy)-3-methylquinoxalin-2(1H)-one (100 mg, 0.33 mmol), (tributyltinyl)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 atmosphere at 80°C for 3 h. 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 give a light yellow solid (50 mg, 60%).

[0570] MS (ESI, pos.ion) m / z: 257.1 [M+H] + .

[0571] Step 4) Synthesis of 7-(bromomethyl)-5-(difluoromethoxy)-3-methylquinoxalin-2(1H)-one

[0572] CBr4 (133 mg, 0.40 mmol) was added to 5-(difluoromethoxy)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (50 mg, 0.20 mmol) and PPh3 (105 mg, 0.40 mmol) in dichloromethane (3 mL) at 0°C. The mixture was allowed to react at room temperature for 4 h. 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 give a white solid (40 mg, 64%).

[0573] MS (ESI, pos.ion) m / z: 319.1 [M+H] + .

[0574] Step 5) 5-(4-((8-(difluoromethoxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperidin Synthesis of (1-oxazine-1-yl)-6-fluoro-N-methylpicolinamide

[0575] 7-(Bromomethyl)-5-(difluoromethoxy)-3-methylquinoxalin-2(1H)-one (40 mg, 0.13 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (40 mg, 0.17 mmol), and N,N-diisopropylethylamine (67 mg, 0.52 mmol) were added sequentially to acetonitrile (3 mL) and reacted at 70°C for 3 h. The reaction solution was concentrated under reduced pressure, diluted with dichloromethane (50 mL), washed with water (30 mL) and saturated NaCl solution (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 20 / 1) to give a light yellow solid (40 mg, 67%).

[0576] MS (ESI, pos.ion) m / z: 477.4 [M+H] + ;

[0577] HRMS:calcd.for C 22 H 23 F3N6O3[M+H] + :477.1784,found:477.1880;

[0578] 1 H NMR(400MHz, DMSO-d6)δ(ppm)10.57(s,1H),8.00(d,J=8.2Hz,1H),7.50(d,J=4.4Hz,1H),7.34–7.28(m,1H),7.19(s,1H),7 .11(s,1H),6.99(t,J=74.7Hz,1H),3.65(s,2H),3.29–3.19(m,4H),3.00(d,J=4.9Hz,3H),2.72–2.64(m,4H),2.63(s,3H).

[0579] Example 14: 5-(4-((8-(difluoromethoxy)-5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0580]

[0581] Step 1) Synthesis of methyl 5-(difluoromethoxy)-2-fluoro-4-nitrobenzoate

[0582] 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 DMF (100 mL) solution and reacted at 80°C for 22 h. The reaction solution was diluted with EtOAc (400 mL), washed with water (200 mL × 3), then with saturated NaCl solution (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 6 / 1) to give a light yellow solid (4.0 g, 32%).

[0583] MS (ESI, pos.ion) m / z: 266.1 [M+H] + .

[0584] Step 2) Synthesis of methyl 4-amino-5-(difluoromethoxy)-2-fluorobenzoate

[0585] Pd / C (600 mg, 10% by weight) was added to a solution of methyl 5-(difluoromethoxy)-2-fluoro-4-nitrobenzoate (6.0 g, 22.63 mmol) in MeOH (40 mL). The H₂ atmosphere was replaced by H₂, and the mixture was allowed to react at room temperature for 22 h. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 4 / 1) to afford a light yellow solid (4.6 g, 86%).

[0586] MS (ESI, pos.ion) m / z: 236.1 [M+H] + .

[0587] Step 3) Synthesis of methyl 4-amino-5-(difluoromethoxy)-2-fluoro-3-nitrobenzoate

[0588] 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 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 3 / 1) to give a yellow solid (900 mg, 38%).

[0589] MS (ESI, pos.ion) m / z: 281.0 [M+H] + .

[0590] Step 4) Synthesis of methyl 4-((1-ethoxy-1-oxopropyl-2-yl)amino)-2-fluoro-3-nitro-5-(trifluoromethoxy)benzoate

[0591] 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 h. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 4 / 1) to give a yellow liquid (150 mg, 27%).

[0592] MS (ESI, pos.ion) m / z: 399.1 [M+H] + ;

[0593] Step 5) Synthesis of methyl 8-(difluoromethoxy)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate

[0594] Methyl 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 h. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. EtOAc (40 mL) and water (20 mL) were added for extraction. The organic phase was washed with saturated NaCl solution (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / EtOAc (v / v) = 4 / 1) to give a white solid (84 mg, 67%).

[0595] MS (ESI, pos.ion) m / z: 305.1 [M+H] + ;

[0596] Step 6) Synthesis of methyl 8-(difluoromethoxy)-5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate

[0597] 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). The mixture was allowed to react at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure, diluted with water (20 mL), and then saturated NaHCO₃ solution (20 mL) was added and filtered to afford a light yellow solid (100 mg, 77%).

[0598] MS (ESI, pos.ion) m / z: 303.1 [M+H] + ;

[0599] Step 7) Synthesis of 5-(difluoromethoxy)-8-fluoro-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one

[0600] 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) at 0°C. The mixture was allowed to react at room temperature for 3 h. The reaction mixture was quenched by the addition of MeOH (10 mL), diluted with DCM (50 mL), filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to give a white solid (40 mg, 44%).

[0601] MS (ESI, pos.ion) m / z: 275.1 [M+H] + ;

[0602] Step 8) Synthesis of 7-(bromomethyl)-5-(difluoromethoxy)-8-fluoro-3-methylquinoxalin-2(1H)-one

[0603] CBr4 (99 mg, 0.30 mmol) was added to 5-(difluoromethoxy)-8-fluoro-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (40 mg, 0.15 mmol) and PPh3 (79 mg, 0.30 mmol) in DCM (4 mL) at 0°C and allowed to react for 6 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 1 / 1) to give a white solid (30 mg, 61%).

[0604] MS (ESI, pos.ion) m / z: 337.0 [M+H] + ;

[0605] Step 9) Synthesis of 5-(4-((8-(difluoromethoxy)-5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0606] 7-(Bromomethyl)-5-(difluoromethoxy)-8-fluoro-3-methylquinoxalin-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 added sequentially to ACN (4 mL) and reacted at 70°C for 2 h. The reaction solution was concentrated under reduced pressure, diluted with DCM (50 mL), washed with water (30 mL) and saturated NaCl solution (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to give a pale white solid (35 mg, 80%).

[0607] MS (ESI, pos.ion) m / z: 495.2 [M+H] + ;

[0608] 1 H NMR (400MHz, DMSO-d6) δ12.63(s,1H),8.40(d,J=4.9Hz,1H),7.84(d,J=8.0Hz,1H),7.56(dd,J=10.4,8.3Hz,1H),7.2 9(t,J=74.4Hz,1H),7.13(d,J=5.4Hz,1H),3.70(s,2H),3.17(s,4H),2.76(d,J=4.7Hz,3H),2.60(s,4H),2.44(s,3H).

[0609] Example 15 1'-((8-(difluoromethoxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0610]

[0611] 7-(Bromomethyl)-5-(difluoromethoxy)-3-methylquinoxalin-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 added sequentially to MeCN (8 mL) and reacted at 70°C for 3 h. The reaction solution was concentrated under reduced pressure, diluted with DCM (60 mL), washed with water (30 mL) and saturated NaCl solution (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to give a light yellow solid (140 mg, 59%).

[0612] MS(ESI,pos.ion)m / z:474.1[M+H]+;

[0613] 1H NMR (400MHz, DMSO-d6) δ12.43(s,1H),8.66(dd,J=9.3,4.5Hz,1H),8.09(dd,J=9.8,7.8Hz,1H),7.92(dd,J=7.9,1.5Hz,1H),7.38(t,J=74.4Hz ,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=4.8Hz,3H),2.67(t,J=5.1Hz,2H),2.52(s,2H),2.41(s,3H).

[0614] Example 16 1'-((8-(difluoromethoxy)-5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0615]

[0616] Step 1) Synthesis of 1'-((8-(difluoromethoxy)-5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0617] 7-(Bromomethyl)-5-(difluoromethoxy)-8-fluoro-3-methylquinoxalin-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 added sequentially to ACN (8 mL) and reacted at 70°C for 3 h. The reaction solution was concentrated under reduced pressure, diluted with DCM (50 mL), washed with water (30 mL) and saturated NaCl solution (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to give a pale white solid (95 mg, 81%).

[0618] MS (ESI, pos.ion) m / z: 492.2 [M+H] + ;

[0619] 1 H NMR (400MHz, DMSO-d6) δ12.64(s,1H),8.64(q,J=4.7Hz,1H),8.09(dd,J=9.8,7.8Hz,1H),7.92(dd,J=7.7,1.3Hz,1H),7.31(d,J=74.4Hz,1H), 7.15(d,J=5.4Hz,1H),6.26(s,1H),3.76(s,2H),3.20(d,J=2.7Hz,2H), 2.80(d,J=4.8Hz,3H),2.71(t,J=5.5Hz,2H),2.53(s,2H),2.45(s,3H).

[0620] Example 17 6-Fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-(trifluoromethoxy)-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0621]

[0622] Step 1) Synthesis of methyl 4-amino-3-nitro-5-(trifluoromethoxy)benzoate

[0623] Methyl 4-amino-3-(trifluoromethyl)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 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 9 / 1) to give a yellow solid (3.5 g, 73%).

[0624] MS (ESI, pos.ion) m / z: 281.0 [M+H] + .

[0625] Step 2) Synthesis of methyl 4-((1-methoxy-1-oxopropyl-2-yl)amino)-3-nitro-5-(trifluoromethoxy)benzoate

[0626] 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 h. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 9 / 1) to give a yellow liquid (1.5 g, 33%).

[0627] MS (ESI, pos.ion) m / z: 367.1 [M+H] + ;

[0628] Step 3) Synthesis of methyl 2-methyl-3-oxo-8-(trifluoromethoxy)-1,2,3,4-tetrahydroquinoxaline-6-carboxylate

[0629] 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 h. The mixture was filtered through celite, concentrated under reduced pressure, and extracted with EtOAc (60 mL) and water (30 mL). The organic phase was washed with saturated NaCl solution (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / EtOAc (v / v) = 4 / 1) to give a white solid (580 mg, 70%).

[0630] MS (ESI, pos.ion) m / z: 305.1 [M+H] + ;

[0631] Step 4) Synthesis of methyl 2-methyl-3-oxo-8-(trifluoromethoxy)-3,4-dihydroquinoxaline-6-carboxylate

[0632] 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-carboxylate (580 mg, 1.91 mmol) in DCM (16 mL). The mixture was allowed to react at room temperature for 11 h. The reaction mixture was concentrated under reduced pressure, diluted with water (30 mL), and basified with saturated NaHCO₃ solution (30 mL) while stirring. The mixture was filtered to afford a light yellow solid (530 mg, 92%).

[0633] MS (ESI, pos.ion) m / z: 303.1 [M+H] + ;

[0634] Step 5) Synthesis of 7-(hydroxymethyl)-3-methyl-5-(trifluoromethoxy)quinoxalin-2(1H)-one

[0635] LiAlH4 (87 mg, 2.06 mmol) was added to a solution of methyl 2-methyl-3-oxo-8-(trifluoromethoxy)-3,4-dihydroquinoxaline-6-carboxylate (520 mg, 1.72 mmol) in THF (15 mL) at 0°C. The mixture was allowed to react at room temperature for 3 h. The reaction mixture was quenched by the addition of MeOH (2 mL) and concentrated under reduced pressure. The residue was diluted with DCM (100 mL) and MeOH (10 mL), filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to give a white solid (260 mg, 55%).

[0636] MS (ESI, pos.ion) m / z: 275.0 [M+H] + ;

[0637] Step 6) Synthesis of 7-(bromomethyl)-8-fluoro-3-methyl-5-(trifluoromethoxy)quinoxalin-2(1H)-one

[0638] CBr4 (630 mg, 1.90 mmol) was added to 7-(hydroxymethyl)-3-methyl-5-(trifluoromethoxy)quinoxalin-2(1H)-one (260 mg, 0.95 mmol) and PPh3 (498 mg, 1.90 mmol) in DCM (10 mL) at 0°C under nitrogen protection for 15 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 1 / 1) to give a white solid (280 mg, 88%).

[0639] MS (ESI, pos.ion) m / z: 337.0 [M+H] + ;

[0640] Step 7) Synthesis of 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-(trifluoromethoxy)-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0641] 7-(Bromomethyl)-8-fluoro-3-methyl-5-(trifluoromethoxy)quinoxalin-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 added sequentially to ACN (6 mL) and reacted at 70°C for 3 h. The reaction solution was concentrated under reduced pressure, diluted with DCM (50 mL), washed with water (30 mL) and saturated NaCl solution (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to give a pale white solid (100 mg, 76%).

[0642] MS (ESI, pos.ion) m / z: 495.2 [M+H] + ;

[0643] 1 H NMR (400MHz, DMSO-d6) δ12.51(s,1H),8.40(dd,J=9.1,4.3Hz,1H),7.84(d,J=8.0Hz,1H),7.57(dd,J=10.2,8. 5Hz,1H),7.28(s,1H),7.26(s,1H),3.66(s,2H),3.18(s,4H),2.76(d,J=4.7Hz,3H),2.58(s,4H),2.42(s,3H).

[0644] Example 18 5-(4-((8-(3,3-difluorocyclobutyloxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0645]

[0646]

[0647] Step 1) Synthesis of methyl 4-chloro-3-(3,3-difluorocyclobutyloxy)-5-nitrobenzoate

[0648] Methyl 4-chloro-3-hydroxy-5-nitrobenzoate (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) under nitrogen protection at 0°C. DEAD (2.26 g, 12.96 mmol) was added and the mixture was allowed to react at room temperature for 20 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 9 / 1) to give a white solid (1.8 g, 65%).

[0649] MS (ESI, pos.ion) m / z: 322.9 [M+H] + .

[0650] Step 2) Synthesis of methyl 3-(3,3-difluorocyclobutyloxy)-4-((1-methoxy-1-oxopropyl-2-yl)amino)-5-nitrobenzoate

[0651] Methyl 4-chloro-3-(3,3-difluorocyclobutyloxy)-5-nitrobenzoate (600 mg, 1.87 mmol), methyl DL-2-aminopropanoate hydrochloride (391 mg, 2.81 mmol), and DIPEA (725 mg, 5.61 mmol) were added to 1,4-dioxane (8 mL) and reacted at 100°C for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 3 / 2) to obtain a yellow oil (410 mg, 57%).

[0652] MS (ESI, pos.ion) m / z: 389.2 [M+H] + .

[0653] Step 3) Synthesis of 8-(3,3-difluorocyclobutyloxy)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid methyl ester

[0654] Iron powder (519 mg, 9.30 mmol), NH₄Cl (497 mg, 9.30 mmol), and methyl 3-(3,3-difluorocyclobutyloxy)-4-((1-methoxy-1-oxopropyl-2-yl)amino)-5-nitrobenzoate (600 mg, 1.55 mmol) were added to MeOH (8 mL) and water (4 mL) and reacted at 70°C for 8 h. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was added to water (30 mL) and extracted with EtOAc (60 mL × 3). The organic phase was washed with saturated aqueous NaCl (30 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 3 / 2) to obtain the product as a white solid (400 mg, 79%).

[0655] MS (ESI, pos.ion) m / z: 327.0 [M+H] + .

[0656] Step 4) Synthesis of 8-(3,3-difluorocyclobutyloxy)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylic acid methyl ester

[0657] DDQ (459 mg, 2.02 mmol) was added to a solution of methyl 8-(3,3-difluorocyclobutyloxy)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (600 mg, 1.84 mmol) in DCM (12 mL) and allowed to react at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the residue was added to a saturated NaHCO solution (40 mL) and stirred to neutralize the precipitated solid. The solid was filtered and dried in vacuo at 50°C for 12 h to give a yellow solid (400 mg, 67%).

[0658] MS (ESI, pos.ion) m / z: 325.1 [M+H] + .

[0659] Step 5) Synthesis of 5-(3,3-difluorocyclobutyloxy)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one

[0660] LiAlH4 (103 mg, 2.46 mmol) was added to a solution of methyl 8-(3,3-difluorocyclobutyloxy)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (400 mg, 1.23 mmol) in THF (8 mL) and allowed to react at room temperature for 6 h. The reaction mixture was quenched by the addition of MeOH (5 mL), diluted with DCM (20 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10 / 1) to afford a white solid (110 mg, 30%).

[0661] MS (ESI, pos.ion) m / z: 297.0 [M+H] + .

[0662] Step 6) Synthesis of 7-(bromomethyl)-5-(3,3-difluorocyclobutyloxy)-3-methylquinoxalin-2(1H)-one

[0663] To a solution of 5-(3,3-difluorocyclobutyloxy)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (110 mg, 0.37 mmol) and PPh (146 mg, 0.55 mmol) in DCM (6 mL) was added CBr (184 mg, 0.55 mmol) at 0°C. The mixture was allowed to react at room temperature for 10 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 1 / 1) to give a white solid (80 mg, 60%).

[0664] MS (ESI, pos.ion) m / z: 359.0 [M+H] + .

[0665] Step 7) Synthesis of 5-(4-((8-(3,3-difluorocyclobutyloxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0666] 7-(Bromomethyl)-5-(3,3-difluorocyclobutyloxy)-3-methylquinoxalin-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 added sequentially to MeCN (5 mL) and reacted at 70°C for 3 h. The reaction solution was concentrated under reduced pressure, diluted with DCM (50 mL), washed with water (30 mL) and saturated NaCl solution (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to give a white solid (60 mg, 52%).

[0667] MS (ESI, pos.ion) m / z: 517.1 [M+H] + ;

[0668] 1H NMR (400MHz, CDCl3) δ (ppm) 10.30 (s, 1H), 8.00 (d, J = 7.9Hz, 1H), 7.50 (d, J = 4.6Hz, 1H), 7.32 (dd, J = 9.9, 8.1Hz, 1H), 6.84 (s, 1 H),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).

[0669] Example 19 5-(4-((8-cyclopropyl-5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0670]

[0671] Step 1) Synthesis of methyl (6-bromo-3-fluoro-2-nitrophenyl)aminopropionate

[0672] To a 250 mL bottle, add 1-bromo-2,4-difluoro-3-nitrobenzene (6.05 g, 25.42 mmol) and methyl 2-aminopropanoate hydrochloride (3.58 g, 25.67 mmol). Stir and dissolve in DMF (30 mL). Cool, then add DIPEA (13.28 mL, 76.26 mmol) dropwise in an ice bath. Gradually increase the temperature and allow to react overnight. Quench with 30 mL of water and extract with EtOAc (30 mL x 3). The combined organic phases are washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (PE / EtOAc (v / v) = 4 / 1) to yield a yellow solid (2.78 g, 34.06%).

[0673] MS(ESI,pos.ion)m / z:321.10[M+H] + .

[0674] Step 2) Synthesis of 5-bromo-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxaline-2-one

[0675] To a 100mL vial, add methyl (6-bromo-3-fluoro-2-nitrophenyl)aminopropanoate (2.78g, 8.66mmol), dissolve in AcOH (19mL), and then add iron powder (1.93g, 34.64mmol). Heat to 70°C for 2h. Cool to room temperature and quench with 38mL of water. A solid precipitates, which is collected by filtration, dried in vacuo, and purified by silica gel column chromatography (PE / EtOAc (v / v) = 1 / 1) to afford a white solid (1.6g, 71.33% yield).

[0676] MS(ESI,pos.ion)m / z:259.10[M+H] + .

[0677] Step 3) Synthesis of 5-cyclopropyl-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxaline-2-one

[0678] In a 100 mL bottle, 5-bromo-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxaline-2-one (0.80 g, 3.09 mmol) and potassium cyclopropyltrifluoroborate (0.91 g, 6.18 mmol) were added in sequence and dissolved in 1,4-dioxane (25 mL). Then, an aqueous solution (4 mL) of potassium phosphate (1.97 g, 9.27 mmol) was added and stirred evenly. Finally, Pd(dppf)Cl2 (0.23 g, 0.31 mmol) was added, the atmosphere was replaced with nitrogen, and the reaction was heated to 105 °C overnight. The mixture was cooled to room temperature, quenched with 20 mL of water, extracted with EtOAc (30 ml × 2), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (DCM / MeOH (v / v) = 30 / 1) to give a light yellow solid (0.31 g, 45.58%).

[0679] MS(ESI,pos.ion)m / z:221.20[M+H] + .

[0680] Step 4) Synthesis of 7-bromo-5-cyclopropyl-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxaline-2-one

[0681] To a 100 mL vial, 5-cyclopropyl-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxalin-2-one (0.304 g, 1.38 mmol) was added and dissolved in 1,4-dioxane (14 mL) with stirring. The mixture was cooled, and NBS (0.279 g, 1.57 mmol) was added under ice-cooling. The mixture was stirred until uniform, brought to room temperature, and stirred overnight under nitrogen. The mixture was quenched with saturated sodium thiosulfate and extracted with EtOAc (15 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 30 / 1) to yield 0.20 g, 48.44%.

[0682] MS(ESI,pos.ion)m / z:299.20[M+H] + .

[0683] Step 5) Synthesis of 7-bromo-5-cyclopropyl-8-fluoro-3-methyl-1,2-dihydroquinoxaline-2-one

[0684] To a 100 mL vial, 7-bromo-5-cyclopropyl-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxalin-2-one (0.197 g, 0.66 mmol) was added and dissolved in DCM (6 mL) with stirring. The mixture was cooled, and DDQ (0.16 g, 0.73 mmol) was added portionwise on an ice bath. Stirring was continued until uniform, and the mixture was brought to room temperature and stirred for 5 h. The mixture was concentrated under reduced pressure, cooled, and quenched with saturated sodium bicarbonate (12 mL) on an ice bath. Solid precipitated and stirred for 1 h. The filter cake was collected by filtration, washed with saturated sodium bicarbonate, and dried in vacuo to afford a brown-pink solid (0.13 g, 66.44% yield).

[0685] MS(ESI,pos.ion)m / z:297.10[M+H] + ;

[0686] Step 6) Synthesis of 5-cyclopropyl-8-fluoro-7-(hydroxymethyl)-3-methyl-1,2-dihydroquinoxaline-2-one

[0687] To a 50 mL vial, 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, Purity 95%) were added sequentially. The mixture was stirred and dissolved in 1,4-dioxane (4 mL). Xphos Pd G2 (0.021 g, 0.027 mmol) was then added. The atmosphere was replaced with nitrogen and heated to 80°C for 7 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 30 / 1) to afford a white solid (0.060 g, 55.24% yield).

[0688] MS(ESI,pos.ion)m / z:249.20[M+H] + ;

[0689] Step 7) Synthesis of 7-(bromomethyl)-5-cyclopropyl-8-fluoro-3-methyl-1,2-dihydroquinoxaline-2-one

[0690] To a 100 mL vial was added 5-cyclopropyl-8-fluoro-7-(hydroxymethyl)-3-methyl-1,2-dihydroquinoxalin-2-one (0.20 g, 0.81 mmol) and DCM (10 mL). The mixture was cooled and then phosphorus tribromide (0.1 mL, 1.06 mmol) was added dropwise in an ice bath. The mixture was stirred until heat dissipated and then brought to room temperature for another 4 hours. The reaction was concentrated under reduced pressure, and the residue was washed with MTBE (5 mL x 2) and purified by silica gel column chromatography (DCM / MeOH (v / v) = 30 / 1) to yield a white solid (0.072 g, 28.72%).

[0691] Step 8) Synthesis of 5-(4-((8-cyclopropyl-5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0692] To a 50 mL vial, 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 and dissolved in ACN (2.5 mL) with stirring. The mixture was cooled, and DIPEA (0.18 mL, 1.03 mmol) was slowly added dropwise in an ice bath. The mixture was stirred thoroughly and heated to 80°C for 2 h. The mixture was cooled to room temperature, whereupon solid precipitated with stirring. The filter cake was collected by filtration and dried in vacuo to afford a white solid (0.058 g, 53.50% yield).

[0693] MS(ESI,pos.ion)m / z:469.26[M+H] + ;

[0694] 1H NMR (400MHz, DMSO-d6) δ12.26(s,1H),8.39(dd,J=9.6,4.9Hz,1H),7.83(d,J=7.9Hz,1H),7.57–7.52(m,1H),6.70(d,J=6.6Hz,1H),3.64 (s,2H),3.15(br,4H),2.90–2.82(m,1H),2.76(d,J=4.5Hz,3H),2.55(br,4H),2.45(s,3H),1.06(q,J=5.7Hz,2H),0.76(q,J=6.2Hz,2H).

[0695] 19 F NMR(376MHz,DMSO-d6)δ-72.55(s),-139.71(s).

[0696] Example 20 5-(4-((8-ethynyl-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0697]

[0698] To a 100 mL vial, 5-(4-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridine-2-carboxamide (0.127 g, 0.26 mmol) and (tributyltin)acetylene (0.15 g, 0.47 mmol) were added sequentially and dissolved in 1,4-dioxane (5 mL). Xphos Pd G2 (0.016 g, 0.021 mmol) was then added. The atmosphere was replaced with nitrogen and the reaction was heated to 90°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to give a yellow solid (0.014 g, 12.4% yield).

[0699] MS(ESI,pos.ion)m / z:435.30[M+H] + ;

[0700] Example 21 6-Fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-8-(prop-1-yn-1-yl)-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0701]

[0702]

[0703] Step 1) Synthesis of methyl 2-((6-bromo-3-fluoro-2-nitrophenyl)amino)propionate

[0704] To a 250 mL bottle, 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 and stirred in DMF (30 mL). The mixture was cooled and DIPEA (13.28 mL, 76.26 mmol) was added dropwise in an ice bath. The reaction mixture was gradually heated to a temperature of 14°C and allowed to react overnight. The mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL x 3). The organic phases were combined, washed with water (20 mL), then with saturated brine (20 mL), dried over 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 give a yellow solid (2.78 g, 34.06%).

[0705] MS(ESI,pos.ion)m / z:321.10[M+H] + .

[0706] Step 2) Synthesis of 7-bromo-8-fluoro-3-methyl-3,4-dihydroquinoxaline-2(1H)-one

[0707] To a 250 mL bottle, add methyl 2-((4-bromo-3-fluoro-2-nitrophenyl)amino)propanoate (1.5 g, 4.67 mmol), stir and dissolve in AcOH (18 mL), then add iron powder (1.04 g, 18.68 mmol), and heat to 70°C for 2 h. Cool to room temperature, add EtOAc (40 mL), stir for 15 min, filter, and collect the filtrate, wash sequentially with water and saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 1.25 g of a brownish-red solid, which was directly carried to the next step.

[0708] MS (ESI, pos.ion) m / z: 259.1 [M+H] + .

[0709] Step 3) Synthesis of 7-(((tert-butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxalin-2-one

[0710] To a 250 mL bottle, 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 added sequentially. The mixture was stirred and dissolved in 1,4-dioxane (30 mL). Xphos Pd G2 (0.30 g, 0.39 mmol) was then added. The atmosphere was replaced with nitrogen and the mixture was heated to 90°C and allowed to react overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 4 / 1) to give a light yellow solid (1.02 g, 65.16%).

[0711] MS(ESI,pos.ion)m / z:325.20[M+H] + .

[0712] Step 4) Synthesis of 5-bromo-7-(((tert-butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxalin-2-one

[0713] To a 250 mL bottle, 7-(((tert-Butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxalin-2-one (0.61 g, 1.88 mmol) and sodium bicarbonate (0.24 g, 2.82 mmol) were added and stirred in 1,4-dioxane (10 mL). The mixture was cooled and NBS (0.35 g, 1.97 mmol) was added under ice-cooling. The atmosphere was replaced with nitrogen and stirred at room temperature for 2 h. The mixture was quenched by the addition of saturated sodium thiosulfate (20 mL) and extracted with EtOAc (25 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to yield an off-white solid (0.66 g, 87.04%).

[0714] MS (ESI, pos.ion) m / z: 403.2 [M+H] + ;

[0715] Step 5) Synthesis of 7-(((tert-butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-5-(prop-1-yn-1-yl)-1,2,3,4-tetrahydroquinoxalin-2-one

[0716] To a 100 mL vial, 5-bromo-7-(((tert-butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxalin-2-one (0.65 g, 1.61 mmol) and tributyl(prop-1-yn-1-yl)tin (0.79 g, 2.42 mmol) were added sequentially. The mixture was stirred and dissolved in 1,4-dioxane (13 mL). Xphos Pd G2 (0.10 g, 0.13 mmol) was then added. The atmosphere was replaced with nitrogen and the mixture was heated to 90°C 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 give a beige solid (0.57 g, 97.04%).

[0717] MS(ESI,pos.ion)m / z:363.35[M+H] + ;

[0718] Step 6) Synthesis of 7-(((tert-butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-5-(prop-1-yn-1-yl)-1,2-dihydroquinoxalin-2-one

[0719] To a 100 mL vial was added 7-(((tert-butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-5-(prop-1-yn-1-yl)-1,2,3,4-tetrahydroquinoxalin-2-one (0.56 g, 1.54 mmol), stirred and dissolved in DCM (16 mL). The mixture was cooled, and DDQ (0.38 g, 1.69 mmol) was added under ice-cooling. The mixture was brought to room temperature and stirred for 4 h. The mixture was concentrated under reduced pressure, cooled, and quenched with saturated sodium bicarbonate (32 mL) under ice-cooling. The mixture was stirred for 30 min, resulting in the precipitation of a solid. The filter cake was collected by filtration, washed with saturated sodium bicarbonate, and dried under vacuum to afford 0.77 g of a tan solid, which was directly carried to the next step.

[0720] MS(ESI,pos.ion)m / z:361.05[M+H] + ;

[0721] Step 7) Synthesis of 8-fluoro-7-(hydroxymethyl)-3-methyl-5-(prop-1-yn-1-yl)-1,2-dihydroquinoxaline-2-one

[0722] To a 100 mL vial was added 7-(((tert-Butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-5-(prop-1-yn-1-yl)-1,2-dihydroquinoxalin-2-one (0.56 g, 1.55 mmol), stirred and dissolved in THF (12 mL). TBAF solution in tetrahydrofuran (3.88 mL, 3.88 mmol) was then added dropwise, and the mixture was stirred at room temperature for 6 h. The mixture was quenched by the addition of saturated brine (25 mL) and extracted with EtOAc (25 mL x 2). The combined organic phases were washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to afford a brown solid (0.204 g, 53.33%).

[0723] MS(ESI,pos.ion)m / z:247.00[M+H] + ;

[0724] Step 8) Synthesis of 7-(bromomethyl)-8-fluoro-3-methyl-5-(prop-1-yn-1-yl)-1,2-dihydroquinoxaline-2-one

[0725] To a 100 mL vial, 8-fluoro-7-(hydroxymethyl)-3-methyl-5-(prop-1-yn-1-yl)-1,2-dihydroquinoxalin-2-one (0.12 g, 0.49 mmol) and triphenylphosphine (0.19 g, 0.73 mmol) were added and dissolved in DCM (5 mL) with stirring. The mixture was cooled, and carbon tetrabromide (0.24 g, 0.73 mmol) was added under ice-cooling. The mixture was stirred at 0°C for 1 h. 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 give a white solid (0.052 g, 34.52%).

[0726] MS (ESI, pos.ion) m / z: 309.1 [M+H] + ;

[0727] Step 9) Synthesis of 6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-8-(prop-1-yn-1-yl)-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0728] To a 50 mL vial, 7-(bromomethyl)-8-fluoro-3-methyl-5-(prop-1-yn-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 and dissolved in ACN (1.5 mL) with stirring. The mixture was cooled, and DIPEA (0.11 mL, 0.64 mmol) was slowly added dropwise in an ice bath. The mixture was stirred until uniform, and heated to 80°C for 2 h. After cooling to room temperature, a solid precipitated with stirring. The filter cake was collected by filtration, washed with MTBE (1.5 mL × 3), then water (1.5 mL × 3), and dried in vacuo to give a white solid (0.031 g, 40.28%).

[0729] MS(ESI,pos.ion)m / z:467.05[M+H] + ;

[0730] 1 H NMR (599MHz, DMSO-d6) δ12.51(s,1H),8.42–8.37(m,1H),7.83(d,J=7.8Hz,1H),7.55(dd,J=10.6,8.0Hz,1H),7.33( d,J=6.7Hz,1H),3.66(s,2H),3.18–3.14(m,4H),2.76(d,J=4.8Hz,3H),2.60–2.55(m,4H),2.43(s,3H),2.11(s,3H).

[0731] Example 22 5-(4-((8-(cyclopropylethynyl)-5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0732]

[0733] Step 1) Synthesis of 7-(((tert-butyldimethylsilyl)oxy)methyl)-5-(2-cyclopropylethynyl)-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxalin-2-one

[0734] To a 100 mL vial, 5-bromo-7-(((tert-butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-1,2,3,4-tetrahydroquinoxalin-2-one (1.0 g, 2.48 mmol) and tributyl(2-cyclopropylethynyl)tin (1.15 g, 3.22 mmol) were added sequentially and dissolved in 1,4-dioxane (15 mL). Xphos Pd G2 (0.16 g, 0.20 mmol) was then added. The atmosphere was replaced with nitrogen and heated to 90°C for 6 h. 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 give a yellow solid (0.895 g, 92.91%).

[0735] MS(ESI,pos.ion)m / z:389.10[M+H] + .

[0736] Step 2) Synthesis of 7-(((tert-butyldimethylsilyl)oxy)methyl)-5-(2-cyclopropylethynyl)-8-fluoro-3-methyl-1,2-dihydroquinoxalin-2-one

[0737] To a 250 mL bottle, 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 and dissolved in DCM (16 mL). The mixture was cooled, and DDQ (0.57 g, 2.52 mmol) was added under ice-cooling. The mixture was brought to room temperature and stirred overnight. The mixture was concentrated under reduced pressure, cooled, and quenched with saturated sodium bicarbonate (32 mL) under ice-cooling. The mixture was stirred for 30 min. A solid precipitated and was collected by filtration. The filter cake was washed with saturated sodium bicarbonate and dried under vacuum to give a brown solid (0.81 g, 91.48%).

[0738] MS(ESI,pos.ion)m / z:387.10[M+H] + .

[0739] Step 3) Synthesis of 5-(2-cyclopropylethynyl)-8-fluoro-7-(hydroxymethyl)-3-methyl-1,2-dihydroquinoxalin-2-one

[0740] To a 100 mL vial was added 7-(((tert-Butyldimethylsilyl)oxy)methyl)-5-(2-cyclopropylethynyl)-8-fluoro-3-methyl-1,2-dihydroquinoxalin-2-one (0.80 g, 2.07 mmol), stirred and dissolved in THF (16 mL), followed by dropwise addition of a tetrahydrofuran solution of TBAF (4.14 mL, 4.14 mmol). The mixture was stirred overnight at room temperature. The mixture was quenched with saturated brine (30 mL) and extracted with EtOAc (25 mL x 2). The combined organic phases were washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to afford a tan solid (0.32 g, 56.79%).

[0741] MS(ESI,pos.ion)m / z:273.15[M+H] + .

[0742] Step 4) Synthesis of 7-(bromomethyl)-5-(2-cyclopropylethynyl)-8-fluoro-3-methyl-1,2-dihydroquinoxalin-2-one

[0743] To a 250 mL vial, 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 and dissolved in DCM (9 mL) with stirring. The mixture was cooled, and carbon tetrabromide (0.58 g, 1.75 mmol) was added portionwise in an ice bath. Stirring was continued at 0°C for 1 h. 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 give a yellow solid (0.396 g, 101.16%).

[0744] MS(ESI,pos.ion)m / z:335.05[M+H] + ;

[0745] Step 5) Synthesis of 5-(4-((8-(2-cyclopropylethynyl)-5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridine-2-carboxamide

[0746] To a 50 mL vial, 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 and dissolved in ACN (3 mL) with stirring. The mixture was cooled, and DIPEA (0.29 mL, 1.68 mmol) was slowly added dropwise in an ice bath. The mixture was stirred thoroughly and heated to 80°C for 2 h. After cooling to room temperature, a solid precipitated with stirring. The filter cake was collected by filtration, washed with MTBE (3 mL × 3) and water (3 mL × 3), dried in vacuo, and purified by slurrying with methanol (1.5 mL) to give a white solid (0.030 g, 14.58%).

[0747] MS(ESI,pos.ion)m / z:493.15[M+H] + ;

[0748] 1 H NMR (400MHz, DMSO-d6) δ8.40(q,J=4.8Hz,1H),7.84(d,J=7.9Hz,1H),7.56(dd,J=10.5,8.2Hz,1H),7.31(d,J=6.9Hz,1H),3.65(s,2H), 3.19–3.13(m,4H),2.76(d,J=4.8Hz,3H),2.61–2.54(m,4H),2.44(s,3H),0.97–0.90(m,2H),0.85(t,J=6.7Hz,1H),0.81–0.75(m,2H).

[0749] Example 23 2-Fluoro-1'-((5-fluoro-2-methyl-3-oxo-8-(prop-1-yn-1-yl)-3,4-dihydroquinoxalin-6-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0750]

[0751] To a 50 mL vial, 7-(bromomethyl)-8-fluoro-3-methyl-5-(prop-1-yn-1-yl)-1,2-dihydroquinoxalin-2-one (0.21 g, 0.68 mmol), 6-fluoro-N-methyl-5-(1,2,3,6-tetrahydropyridin-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. The mixture was cooled, and DIPEA (0.36 mL, 2.04 mmol) was slowly added dropwise in an ice bath. The mixture was stirred until uniform, and heated to 80°C for 2 h. After cooling to room temperature, a solid precipitated with stirring. The filter cake was collected by filtration, washed with MTBE (1.5 mL × 3) and water (1.5 mL × 3), and dried in vacuo to give a yellow solid (0.025 g, 7.94%).

[0752] MS(ESI,pos.ion)m / z:464.15[M+H] + .

[0753] Example 24 1'-((8-(cyclopropylethynyl)-5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0754]

[0755] To a 50 mL vial, 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-tetrahydropyridin-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. The mixture was cooled, and DIPEA (0.24 mL, 1.35 mmol) was slowly added dropwise in an ice bath. The mixture was stirred thoroughly and heated to 80°C for 2 h. The mixture was cooled to room temperature, diluted with DCM (20 mL), washed with water (15 mL x 2), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified on a thin-layer silica gel preparative plate to give a white solid (0.018 g, 8.22%).

[0756] MS(ESI,pos.ion)m / z:489.80[M+H] + .

[0757] Example 25 Synthesis of 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-vinyl-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0758]

[0759] To a solution of 5-(4-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (0.2 g, 0.41 mmol) in 1,4-dioxane (8 mL) and water (2 mL) at room temperature were added 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). After nitrogen was replaced, the mixture was heated to 110°C and stirred for 12 h. The reaction solution was cooled to room temperature and filtered through celite. 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 give the product as a yellow solid (0.1 g, 56.06%).

[0760] MS (ESI, pos.ion) m / z: 437.2 [M+H] + ;

[0761] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.26 (s, 1H), 8.44–8.35 (m, 1H), 7.84 (d, J= 8.0Hz,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=17.9Hz,1H),5.46(d,J=11.3Hz,1H),3.62(s,2H) ,3.22–3.15(m,4H),2.76(d,J=4.8Hz,3H),2.61–2.54(m,4H),2.42(s,3H).

[0762] Example 26 5-(4-((8-ethoxy-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0763]

[0764] Step 1) Synthesis of 7-bromo-5-ethoxy-3-methylquinoxalin-2(1H)-one

[0765] At 0°C under nitrogen, NaH (466 mg, 11.65 mmol, 60% by weight) was added to a solution of 7-bromo-5-fluoro-3-methylquinoxalin-2(1H)-one (600 mg, 2.33 mmol) and ethanol (537 mg, 11.65 mmol) in DMF (10 mL). The mixture was allowed to react at room temperature for 10 h. The reaction mixture was concentrated under reduced pressure, and saturated NaCl solution (50 mL) and DCM (100 mL) were added. The mixture was separated by extraction, and the organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford a light yellow solid (550 mg, 83%).

[0766] MS (ESI, pos.ion) m / z: 283.0 [M+H] + .

[0767] Step 2) Synthesis of 5-ethoxy-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one

[0768] 7-Bromo-5-ethoxy-3-methylquinoxalin-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 atmosphere at 80°C for 6 h. 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 give a light yellow solid (231 mg, 51%).

[0769] MS (ESI, pos.ion) m / z: 235.3 [M+H] + .

[0770] Step 3) Synthesis of 7-(bromomethyl)-5-ethoxy-3-methylquinoxalin-2(1H)-one

[0771] CBr4 (478 mg, 1.44 mmol) was added to 5-ethoxy-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (210 mg, 0.90 mmol) and PPh3 (378 mg, 1.44 mmol) in DCM (8 mL) and allowed to react at room temperature for 20 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 1 / 1) to give a white solid (130 mg, 49%).

[0772] MS (ESI, pos.ion) m / z: 297.1 [M+H] + ;

[0773] Step 4) Synthesis of 5-(4-((8-ethoxy-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0774] 7-(Bromomethyl)-5-ethoxy-3-methylquinoxalin-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 added sequentially to MeCN (8 mL) and reacted at 70°C for 2 h. The reaction solution was concentrated under reduced pressure, diluted with DCM (50 mL), washed with water (30 mL) and saturated NaCl solution (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to give a light yellow solid (100 mg, 61%).

[0775] MS (ESI, pos.ion) m / z: 455.4 [M+H] + ;

[0776] 1 H NMR(400MHz, DMSO-d6)δ(ppm)10.62(s,1H),7.99(d,J=7.9Hz,1H),7.50(d,J=4.6Hz,1H),7.33–7.28(m,1H),6.82(d,J=13.1Hz ,2H),4.30(q,J=6.9Hz,2H),3.62(s,2H),3.24(s,4H),2.99(d,J=5.0Hz,3H),2.66(s,4H),2.63(s,3H),1.57(t,J=7.0Hz,3H).

[0777] Example 27 6-Fluoro-5-(4-((8-(2-fluorophenoxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0778]

[0779] Step 1) Synthesis of 7-bromo-5-(2-fluorophenoxy)-3-methylquinoxalin-2(1H)-one

[0780] 7-Bromo-5-fluoro-3-methylquinoxalin-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 a DMSO (12 mL) solution. The mixture was reacted at 160°C for 24 h. The reaction solution was diluted with water (60 mL) to precipitate a solid, which was filtered to obtain a solid. The solid was dissolved in MeOH (5 mL) and DCM (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a yellow solid (500 mg, 61%).

[0781] MS (ESI, pos.ion) m / z: 349.1 [M+H] + .

[0782] Step 2) Synthesis of 5-(2-fluorophenoxy)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one

[0783] 7-Bromo-5-(2-fluorophenoxy)-3-methylquinoxalin-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 atmosphere at 80°C for 16 h. 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 give a light yellow solid (250 mg, 58%).

[0784] MS (ESI, pos.ion) m / z: 301.1 [M+H] + .

[0785] Step 3) Synthesis of 7-(bromomethyl)-5-(2-fluorophenoxy)-3-methylquinoxalin-2(1H)-one

[0786] CBr4 (444 mg, 1.34 mmol) was added to 5-(2-fluorophenoxy)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (200 mg, 0.67 mmol) and PPh3 (351 mg, 1.34 mmol) in DCM (15 mL) at 0°C. After 1 hour, the mixture was allowed to react 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 / EtOAc (v / v) = 1 / 1) to give a light yellow solid (150 mg, 62%).

[0787] MS (ESI, pos.ion) m / z: 363.1 [M+H] + ;

[0788] Step 4) Synthesis of 6-fluoro-5-(4-((8-(2-fluorophenoxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0789] 7-(Bromomethyl)-5-(2-fluorophenoxy)-3-methylquinoxalin-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 added sequentially to MeCN (8 mL) and reacted at 70°C for 3 h. The reaction solution was concentrated under reduced pressure, diluted with DCM (60 mL), washed with water (30 mL) and saturated NaCl solution (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to give a light yellow solid (120 mg, 56%).

[0790] MS (ESI, pos.ion) m / z: 521.3 [M+H] + ;

[0791] 1 H NMR(400MHz, DMSO-d6)δ(ppm)10.93(s,1H),7.99(d,J=7.9Hz,1H),7.50(dd,J=10.0,5.1Hz,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=5.0Hz,3H),2.66(s,3H),2.59(s,4H).

[0792] Example 28 6-Fluoro-5-(4-((8-(3-fluorophenoxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0793]

[0794] Step 1) Synthesis of 7-bromo-5-(3-fluorophenoxy)-3-methylquinoxalin-2(1H)one

[0795] 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 an N-methylpyrrolidone solution (20 mL) at room temperature, and the mixture was heated to 160°C and stirred for 12 h. The reaction solution was quenched with water (20 mL), and saturated NaCl solution (10 mL) was added, stirred for 1 h, and filtered. The filter cake was dissolved in a mixed solvent (dichloromethane / methanol (v / v) = 10 / 1, 20 mL) and concentrated under reduced pressure to obtain a black solid (620 mg, 76%).

[0796] MS (ESI, pos.ion) m / z: 349.1 [M+H] + .

[0797] Step 2) Synthesis of 5-(3-fluorophenoxy)-7-hydroxymethyl-3-methylquinoxalin-2(1H)one

[0798] 7-Bromo-5-(3-fluorophenoxy)-3-methyl-1,2-dihydroquinoxalin-2-one (500 mg, 1.43 mmol), (tributyltinyl)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) were added to 1,4-dioxane (15 mL) at room temperature under a nitrogen atmosphere at 80°C for 12 h. 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 afford the product as a yellow solid (220 mg, 51.16%).

[0799] MS (ESI, pos.ion) m / z: 301.2 [M+H] + .

[0800] Step 3) Synthesis of 7-(bromomethyl)-5-(3-fluorophenoxy)-3-methylquinoxalin-2(1H)-one

[0801] Tetrabromomethane (444.38 mg, 1.34 mmol) was added to a solution of 5-(3-fluorophenoxy)-7-hydroxymethyl-3-methylquinoxalin-2(1H)-one (200 mg, 0.67 mmol) and triphenylphosphine (351.47 mg, 1.34 mmol) in dichloromethane (12 ml) at 0°C. Once the reaction solution became clear, the mixture was transferred to room temperature and allowed to react for 22 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to afford the product as a gray solid (120 mg, 49.61%).

[0802] MS (ESI, pos.ion) m / z: 363.1 [M+H] + .

[0803] Step 4) Synthesis of 6-fluoro-5-(4-((8-(3-fluorophenoxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0804] Ethyldiisopropylamine was added to a solution of 7-(bromomethyl)-5-(3-fluorophenoxy)-3-methylquinoxalin-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) at room temperature. The mixture was then heated to 70°C and stirred for 2 hours. The reaction solution was cooled and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to afford the product as a white solid (134 mg, 77.91%).

[0805] MS (ESI, pos.ion) m / z: 521.3 [M+H] + ;

[0806] 1 H NMR (400MHz, DMSO-d6) δ8.39(d,J=4.8Hz,1H),7.83(d,J=7.9Hz,1H),7.59–7.50(m,1H),7.38(q,J=8.0Hz,1H),7.10(s,1H),6.9 3(t,J=8.5Hz,1H),6.85(d,J=10.1Hz,2H),6.81(d,J=8.3Hz,1H),3.14(s,4H),2.76(d,J=4.7Hz,3H),2.54(s,4H),2.32(s,3H).

[0807] 13C NMR (151MHz, DMSO-d6) δ163.82,163.56,162.20,159.14,159.06,158.49,155. 22,153.68,152.08,150.99,141.12,138.58,138.51,137.38,137.23,133.85,1 31.40,131.33,128.43,128.40,123.57,121.31,113.95,113.86,113.85,111.25,110.02,109.88,105.56,105.39,61.32,52.31,49.36,49.33,26.18,20.83.

[0808] Example 29 6-Fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-(pyridin-4-yloxy)-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0809]

[0810] Step 1) Synthesis of 7-bromo-3-methyl-5-(pyridin-4-yloxy)quinoxalin-2(1H)-one

[0811] 7-Bromo-5-fluoro-3-methylquinoxalin-2(1H)-one (1.00 g, 3.89 mmol), pyridin-4-ol (1.11 g, 11.67 mmol), and K2CO3 (1.61 g, 11.67 mmol) were added to a DMF (16 mL) solution. The mixture was microwaved at 120°C for 14 h. The reaction mixture was diluted with water (60 mL) and adjusted to pH 5 by adding HCl solution (4 M). A solid precipitated and was filtered to obtain the solid. The solid was then dried in vacuo at 50°C for 8 h to give a light yellow solid (900 mg, 70%).

[0812] MS (ESI, pos.ion) m / z: 332.0 [M+H] + .

[0813] Step 2) Synthesis of 7-(hydroxymethyl)-3-methyl-5-(pyridin-4-yloxy)quinoxalin-2(1H)-one

[0814] 7-Bromo-3-methyl-5-(pyridin-4-yloxy)quinoxalin-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 atmosphere at 80°C for 24 h. 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 give a light yellow solid (140 mg, 33%).

[0815] MS (ESI, pos.ion) m / z: 284.2 [M+H] + .

[0816] Step 3) Synthesis of 7-(bromomethyl)-3-methyl-5-(pyridin-4-yloxy)quinoxalin-2(1H)-one

[0817] CBr4 (325 mg, 0.98 mmol) was added to 7-(hydroxymethyl)-3-methyl-5-(pyridin-4-yloxy)quinoxalin-2(1H)-one (138 mg, 0.49 mmol) and PPh3 (257 mg, 0.98 mmol) in DCM (10 mL) at 0°C. After 1 hour, the mixture was allowed to react 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 give a yellow solid (100 mg, 59%).

[0818] MS (ESI, pos.ion) m / z: 346.1 [M+H] + ;

[0819] Step 4) Synthesis of 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-(pyridin-4-yloxy)-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0820] 7-(Bromomethyl)-3-methyl-5-(pyridin-4-yloxy)quinoxalin-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 added sequentially to MeCN (8 mL) and reacted at 70°C for 3 h. 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 give a light yellow solid (60 mg, 41%).

[0821] MS (ESI, pos.ion) m / z: 504.3 [M+H]+ ;

[0822] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.62 (s, 1H), 9.72 (s, 1H), 8.40 (d, J = 4.7Hz, 1H), 7.85 (t, J = 8.2Hz, 3H), 7.64–7.53 (m, 1H) ,7.41(s,1H),6.25(d,J=7.5Hz,2H),3.36(s,4H),3.22(s,2H),3.06(d,J=6.7Hz,4H),2.76(d,J=4.6Hz,3H),2.37(s,3H).

[0823] Example 30 5-(4-((8-(cyclopent-1-en-1-yl)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0824]

[0825] To a 100 mL bottle, 5-(4-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridine-2-carboxamide (0.060 g, 0.12 mmol) and 1-cyclopenteneboronic acid pinacol ester (0.054 g, 0.28 mmol) were added in sequence, stirred and dissolved in 1,4-dioxane (2.5 mL), and then potassium phosphate (0.054 g, 0.25 mmol) in water (0.5 mL) was added and stirred evenly. Finally, Pd(dppf)Cl2 (0.0092 g, 0.013 mmol) was added, the atmosphere was replaced with nitrogen, and the reaction was heated to 105 °C. The mixture was cooled to room temperature, diluted with EtOAc (15 mL), washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to give a white solid (0.032 g, yield 54.76%).

[0826] MS(ESI,pos.ion)m / z:477.40[M+H] + ;

[0827] 1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),8.39(s,1H),7.83(s,1H),7.56(s,1H),7.16(s,2H),6.62(s,1 H),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).

[0828] Example 31 5-(4-((8-cyclopentyl-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0829] Step 1) Synthesis of 8-(cyclopent-1-en-1-yl)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid methyl ester

[0830] To a 100 mL bottle, 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid methyl ester (0.60 g, 2.01 mmol) and 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.70 g, 3.62 mmol) were added in sequence, stirred and dissolved in 1,4-dioxane (12 mL), and then an aqueous solution of potassium phosphate (0.85 g, 4.02 mmol) was added and stirred evenly. Finally, Pd(dppf)Cl2 (0.15 g, 0.20 mmol) was added, the atmosphere was replaced with nitrogen, and the reaction was heated to 105 ° C overnight. The mixture was cooled to room temperature, quenched with 15 mL of water, extracted with EtOAc (15 mL × 3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE / EtOAc (v / v) = 3 / 1) to give a light yellow oil (0.253 g, 44.05%).

[0831] MS(ESI,pos.ion)m / z:287.30[M+H] + .

[0832] Step 2) Synthesis of 8-cyclopentyl-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid methyl ester

[0833] To a 100 mL vial, add methyl 8-(cyclopent-1-en-1-yl)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.253 g, 0.88 mmol), dissolve in methanol (4 mL) and tetrahydrofuran (4 mL), then add 10% palladium on carbon (0.051 g, 0.048 mmol). After replacing the hydrogen atmosphere, stir and react at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 0.26 g of a colorless oil, which was directly carried to the next step.

[0834] MS(ESI,pos.ion)m / z:289.30[M+H] + .

[0835] Step 3) Synthesis of 8-cyclopentyl-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylic acid methyl ester

[0836] To a 100 mL vial was added methyl 8-cyclopentyl-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (0.255 g, 0.88 mmol), dissolved in DCM (10 mL), cooled, and DDQ (0.22 g, 0.97 mmol) was added under ice-cooling. The mixture was brought to room temperature and stirred overnight. The mixture was concentrated under reduced pressure, cooled, and quenched with saturated sodium bicarbonate (20 mL) under ice-cooling. The mixture was stirred for 30 min, resulting in the precipitation of a solid. The filter cake was collected by filtration, washed with saturated sodium bicarbonate (30 mL), and dried under vacuum to afford a tan solid (0.212 g, 83.72%).

[0837] MS(ESI,pos.ion)m / z:287.30[M+H] + ;

[0838] Step 4) Synthesis of 5-cyclopentyl-7-(hydroxymethyl)-3-methyl-1,2-dihydroquinoxaline-2-one

[0839] To a 100 mL vial, methyl 8-cyclopentyl-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (0.212 g, 0.74 mmol) was added and dissolved in THF (8 mL) with stirring. The mixture was cooled, and LAH (0.077 g, 1.97 mmol, Purity 97%) was added under ice-cooling. The reaction was brought to room temperature and continued for 4 h. The mixture was cooled and quenched with water (2 mL) under ice-cooling. 1 M dilute hydrochloric acid was then added dropwise to adjust the pH to 3-4. The mixture was extracted with THF (8 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to afford a white solid (0.090 g, 47.06% yield).

[0840] MS(ESI,pos.ion)m / z:259.20[M+H] + ;

[0841] Step 5) Synthesis of 7-(bromomethyl)-5-cyclopentyl-3-methylquinoxalin-2(1H)-one

[0842] To a 100 mL vial, add 5-cyclopentyl-7-(hydroxymethyl)-3-methyl-1,2-dihydroquinoxalin-2-one (0.090 g, 0.35 mmol) and DCM (4.5 mL). Cool the mixture and, under ice, add phosphorus tribromide (0.043 mL, 0.45 mmol) dropwise. Stir until exotherm subsides, then bring the mixture to room temperature and continue the reaction for 4 h. Concentrate under reduced pressure, and wash the residue with MTBE (4.5 mL x 2) to obtain the crude product, which is then directly used in the next step.

[0843] Step 6) Synthesis of 5-(4-((8-cyclopentyl-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0844] To a 100 mL vial, 7-(bromomethyl)-5-cyclopentyl-3-methylquinoxalin-2(1H)-one (0.11 g, 0.34 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide dihydrochloride (0.12 g, 0.37 mmol), and potassium iodide (0.011 g, 0.068 mmol) were dissolved in acetonitrile (3.5 mL). The mixture was cooled, and DIPEA (0.41 mL, 2.38 mmol) was slowly added dropwise in an ice bath. The mixture was stirred thoroughly and heated to 80°C for 2 h. The mixture was cooled to room temperature, diluted with EtOAc (15 mL), washed with water (10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to give a white solid (0.075 g, 45.76% yield).

[0845] MS(ESI,pos.ion)m / z:479.30[M+H] + ;

[0846] 1H NMR(599MHz, DMSO-d6)δ12.20(s,1H),8.40(d,J=4.0Hz,1H),7.84(d,J=7.8Hz,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=4.2Hz,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).

[0847] Example 32 5-(4-((8-(4-cyanophenoxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0848]

[0849]

[0850] Step 1) Synthesis of 4-((7-bromo-3-methyl-2-oxo-1,2-dihydroquinoxalin-5-yl)oxy)benzonitrile

[0851] 7-Bromo-5-fluoro-3-methylquinoxalin-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 a DMSO (16 mL) solution. The mixture was microwaved at 130°C for 15 h. The reaction mixture was diluted with water (60 mL) and adjusted to pH 5 by adding HCl solution (4 M). A solid precipitated and was filtered to obtain the solid. The solid was then dried in vacuo at 50°C for 8 h to give a light yellow solid (600 mg, 54%).

[0852] MS (ESI, pos.ion) m / z: 356.2 [M+H] + .

[0853] Step 2) Synthesis of 4-((7-(hydroxymethyl)-3-methyl-2-oxo-1,2-dihydroquinoxalin-5-yl)oxy)benzonitrile

[0854] 4-((7-Bromo-3-methyl-2-oxo-1,2-dihydroquinoxalin-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) under nitrogen atmosphere at 80°C for 10 h. 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 afford a light yellow solid (150 mg, 58%).

[0855] MS (ESI, pos.ion) m / z: 308.2 [M+H] + .

[0856] Step 3) Synthesis of 4-((7-(bromomethyl)-3-methyl-2-oxo-1,2-dihydroquinoxalin-5-yl)oxy)benzonitrile

[0857] CBr4 (259 mg, 0.78 mmol) was added to 4-((7-(hydroxymethyl)-3-methyl-2-oxo-1,2-dihydroquinoxalin-5-yl)oxy)benzonitrile (120 mg, 0.39 mmol) and PPh3 (205 mg, 0.78 mmol) in DCM (8 mL) at 0°C. After 1 hour, the mixture was allowed to react at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 1 / 1) to give a yellow solid (50 mg, 35%).

[0858] MS (ESI, pos.ion) m / z: 370.1 [M+H] + ;

[0859] Step 4) Synthesis of 5-(4-((8-(4-cyanophenoxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide

[0860] 4-((7-(Bromomethyl)-3-methyl-2-oxo-1,2-dihydroquinoxalin-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 added sequentially to MeCN (4 mL) and reacted at 70°C for 3 h. 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), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to give a light yellow solid (40 mg, 56%).

[0861] MS (ESI, pos.ion) m / z: 528.2 [M+H] + ;

[0862] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.58 (s, 1H), 8.00 (d, J = 7.9Hz, 1H), 7.63 (d, J = 8.8Hz, 2H), 7.50 (dd, J = 10.1, 4.9Hz, 1H), 7.28 (dd, J = 9.2, 1.8Hz,1H),7.11(s,1H),7.06(d,J=8.8Hz,2H),6.99(s,1H),3.63(s,2H),3.22(s,4H),3.00(d,J=5.0Hz,3H),2.65(s,4H),2.53(s,3H).

[0863] Example 33 6-Fluoro-5-(4-((8-((4-fluorophenyl)amino)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0864]

[0865] Step 1) Synthesis of methyl 8-((4-fluorophenyl)amino)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate

[0866] 8-Bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylic acid methyl ester (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, protected by nitrogen, heated to 110°C, reacted for 8 hours, and the reaction was closed. Water (100 mL) was added and the mixture was extracted with EtOAc (300 mL). The organic phase was washed with water (100 mL) and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (DCM / EtOAc (v / v) = 2 / 1) to give a yellow solid product (0.58 g, 36%).

[0867] MS (ESI, pos.ion) m / z: 328.3 [M+H] + .

[0868] Step 2) Synthesis of 5-((4-fluorophenyl)amino)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one

[0869] 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 and stirred at 0°C. Lithium aluminum hydride (0.17 g, 4.52 mmol) was added. After the addition was complete, the reaction was returned to room temperature for 4.5 hours. Water (0.2 mL) was added dropwise to quench the reaction. 15% sodium hydroxide solution (0.2 mL) was added dropwise and concentrated under reduced pressure. The residue was separated and purified by column chromatography (DCM / MeOH (v / v) = 20 / 1) to give a yellow solid (85 mg, 16%).

[0870] MS (ESI, pos.ion) m / z: 300.2 [M+H] + .

[0871] Step 3) Synthesis of 8-((4-fluorophenyl)amino)-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carbaldehyde

[0872] 5-((4-Fluorophenyl)amino)-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (0.12 g, 0.40 mmol) was dissolved in a mixed solution 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 h. The reaction was shut down and water (140 mL) was added. The mixture was extracted with DCM (40 mL). The organic phase was washed with saturated sodium bicarbonate (60 mL) and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid (0.09 g, 75%).

[0873] MS (ESI, pos.ion) m / z: 298.3 [M+H] + .

[0874] Step 4) Synthesis of 6-fluoro-5-(4-((8-((4-fluorophenyl)amino)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0875] 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-dihydroquinoxaline-6-carbaldehyde (0.095 g, 0.32 mmol), acetic acid (0.0038 g, 0.064 mmol), and sodium cyanoborohydride (0.060 g, 0.96 mmol) were added and reacted at room temperature for 5 h. The mixture was concentrated under reduced pressure and separated on a thin layer silica gel plate (DCM / MeOH (v / v) = 20 / 1) to give a yellow solid (0.02 g, 12%).

[0876] MS (ESI, pos.ion) m / z: 520.2 [M+H] + ;

[0877] 1 H NMR (400MHz, DMSO-d6) δ12.06(s,1H),8.40(d,J=4.7Hz,1H),8.19(s,1H),7.84(d,J=7.8Hz,1H),7.60–7.52(m,1H),7.34(dd,J=8.8,4 .9Hz,2H),7.17(t,J=8.8Hz,2H),6.90(s,1H),6.63(s,1H),3.60(s,2H),3.15(s,4H),2.76(d,J=4.7Hz,3H),2.52(s,4H),2.43(s,3H).

[0878] Example 34 6-Fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-((1,1,1-trifluoropropan-2-yl)oxy)-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0879]

[0880] Step 1) Synthesis of 7-bromo-3-methyl-5-((1,1,1-trifluoroprop-2-yl)oxy)quinoxalin-2(1H)-one

[0881] At 0°C under a nitrogen atmosphere, 1,1,1-trifluoropropan-2-ol (2.66 g, 23.3 mmol) was added to an N,N-dimethylformamide solution (10 ml). Sodium hydride (0.93 g, 23.3 mmol) was added portionwise. After stirring for 20 minutes, the mixture was brought to room temperature and the reaction continued for 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 mixture 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 filter cake was dried under vacuum at 50°C to yield a gray solid product (800 mg, 97.62%).

[0882] MS (ESI, pos.ion) m / z: 351.0 [M+H] + .

[0883] Step 2) Synthesis of 7-(hydroxymethyl)-3-methyl-5-((1,1,1-trifluoroprop-2-yl)oxy)quinoxalin-2(1H)-one

[0884] 7-Bromo-3-methyl-5-((1,1,1-trifluoropropan-2-yl)oxy)quinoxalin-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) were added to 1,4-dioxane (15 ml) at room temperature under a nitrogen atmosphere at 80°C for 3 h. 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 give the product as a white solid (485 mg, 70.43%).

[0885] MS (ESI, pos.ion) m / z: 303.2 [M+H]+ .

[0886] Step 3) Synthesis of 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-8-((1,1,1-trifluoropropan-2-yl)oxy)-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0887] Tetrabromomethane (617.64 mg, 2.35 mmol) was added to a solution of 7-(hydroxymethyl)-3-methyl-5-((1,1,1-trifluoropropan-2-yl)oxy)quinoxalin-2(1H)-one (350 mg, 1.16 mmol) in acetonitrile (10 mL) at 0°C. The mixture was stirred for 20 minutes and then allowed to react at room temperature for 1 hour. 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 then added to the reaction mixture. The temperature was raised to 70°C and the reaction was stirred for 2 hours. After cooling, the reaction mixture 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 afford the product as a white solid (510 mg, 92.52%).

[0888] MS (ESI, pos.ion) m / z: 523.4 [M+H] + ;

[0889] 1 H NMR (400MHz, DMSO-d6) δ12.29(s,1H),8.39(d,J=4.4Hz,1H),7.84(d,J=7.8Hz,1H),7.57(t,J=9.2Hz,1H),6.98(s,2H),5.3 2(dt,J=12.7,6.3Hz,1H),3.58(s,2H),3.18(s,4H),2.76(d,J=4.6Hz,3H),2.56(s,4H),2.40(s,3H),1.52(d,J=6.1Hz,3H).

[0890] Example 35 N-cyclopropyl-6-fluoro-5-(4-((2-methyl-3-oxo-8-(prop-1-yn-1-yl)-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0891]

[0892] Step 1) Synthesis of 5-(4-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-cyclopropyl-6-fluoropicolinamide

[0893] To a solution of 5-bromo-7-(bromomethyl)-3-methylquinoxalin-2(1H)-one (0.55 g, 1.66 mmol) in ACN (20 mL) were added 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) at room temperature, followed by heating to 80°C for 3 h. 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 give the product as a yellow solid (0.45 g, 52.7%).

[0894] MS (ESI, pos.ion) m / z: 515.0 [M+H] + ;

[0895] Step 2) Synthesis of N-cyclopropyl-6-fluoro-5-(4-((2-methyl-3-oxo-8-(prop-1-yn-1-yl)-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0896] To a solution of 5-(4-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-cyclopropyl-6-fluoropicolinamide (0.45 g, 0.87 mmol) in 1,4-dioxane (20 mL) at room temperature were added tributyl(prop-1-yn-1-yl)stannane (0.52 g, 1.57 mmol) and Xphos Pd G2 (0.10 g, 0.13 mmol). After replacing the nitrogen atmosphere with nitrogen, the mixture was heated to 90°C and stirred for 12 hours. After cooling to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to afford the product as a yellow solid (0.061 g, 14.72%).

[0897] MS (ESI, pos.ion) m / z: 475.2 [M+H] + ;

[0898] 1H NMR (400MHz, DMSO-d6) δ (ppm) 12.32 (s, 1H), 8.37–8.32 (m, 1H), 7.84 (d, J = 8.0Hz, 1H), 7.56 (t, J = 9.3Hz, 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).

[0899] Example 36 5-(4-((2-methyl-3-oxo-8-(prop-1-yn-1-yl)-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)pyridinecarbonitrile

[0900] Step 1) Synthesis of methyl 8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate

[0901] Under an ice bath, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.98 g, 17.55 mmol) was added portionwise 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 mixture was then allowed to react at room temperature for 10 h. The reaction solution was concentrated under reduced pressure, saturated sodium bicarbonate (100 mL) was added at 0°C, and the mixture was stirred at room temperature for 1 h. The mixture was filtered, and the filter cake was washed with water (50 mL) to give the product as an orange-yellow solid (3.23 g, 92.91%).

[0902] MS(ESI,pos.ion)m / z:297.05[M+H] + .

[0903] Step 2) Synthesis of 5-bromo-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one

[0904] At 0°C, under N2, lithium aluminum hydride (0.83 g, 21.74 mmol) was added portionwise 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 allowed to warm to room temperature and stirred for 5 h. The mixture was quenched with water at 0°C, and 1 M hydrochloric acid was added dropwise at this temperature until the pH reached 3-4. Saturated brine (30 mL) was then added, and the mixture was extracted with tetrahydrofuran (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 97 / 5) to give a brown solid product (1.77 g, 60.05%).

[0905] MS (ESI, negative ion) m / z: 267.0 [MH] - .

[0906] Step 3) Synthesis of 5-(piperazin-1-yl)pyridinecarbonitrile hydrochloride

[0907] To a solution of tert-butyl 4-(6-cyanopyridin-3-yl)piperazine-1-carboxylate (0.95 g, 3.29 mmol) in ethyl acetate (20 mL) was added a 4M hydrochloric acid solution in dioxane (5 mL) at room temperature and allowed to react for 2 h. After completion, the reaction mixture was filtered to obtain a solid product, which was then dried at room temperature to yield a light yellow solid (0.71 g, 96.75%).

[0908] MS(ESI,pos.ion)m / z:189.25[M+H] + .

[0909] Step 4) Synthesis of 5-bromo-7-(bromomethyl)-3-methylquinoxalin-2(1H)-one

[0910] To a solution of 5-bromo-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (0.5 g, 1.86 mmol) in acetonitrile (20 mL) was added dropwise phosphorus tribromide (0.24 mL, 2.60 mmol) at 0°C under N2. The mixture was stirred for 5-10 min and then heated to 35°C for 4 h. TLC indicated completion, and the reaction was carried on to the next step without further workup.

[0911] Step 5) Synthesis of 5-(4-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)pyridinecarbonitrile

[0912] To a solution of 5-bromo-7-(bromomethyl)-3-methylquinoxalin-2(1H)-one (0.6 g, 1.81 mmol) in acetonitrile (20 mL) was added potassium iodide (15 mg, 0.091 mmol), 5-(piperazin-1-yl)pyridinecarbonitrile (0.51 g, 1.71 mmol), and N,N-diisopropylethylamine (4.79 mL, 28.96 mmol) under ice. The mixture was allowed to warm to room temperature and react for 2 h. After completion of the reaction, the solution was diluted with dichloromethane (30 mL), washed with water (20 mL x 2), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 97 / 4) to afford an orange-yellow solid powder (0.35 g, 44.71%).

[0913] MS(ESI,pos.ion)m / z:439.10[M+H] + ;

[0914] Step 6) Synthesis of 5-(4-((2-methyl-3-oxo-8-(prop-1-yn-1-yl)-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)pyridinecarbonitrile

[0915] To a solution of 5-(4-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)pyridinecarbonitrile (0.15 g, 0.31 mmol) in 1,4-dioxane (15 mL) at room temperature was added tributyl(prop-1-yn-1-yl)tin (0.19 mL, 0.61 mmol), followed by XPhos Pd G2 (0.040 g, 0.051 mmol). The atmosphere was then replaced with nitrogen and the temperature was raised to 90°C for overnight reaction. The reaction mixture was filtered through celite, 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 give a white solid powder (51 mg, 37.49%).

[0916] MS(ESI,pos.ion)m / z:399.18[M+H] +

[0917] 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). Example 37 7-((4-(6-(difluoromethoxy)pyridin-3-yl)piperazin-1-yl)methyl)-3-methyl-5-(prop-1-yn-1-yl)quinoxalin-2(1H)-one

[0918]

[0919]

[0920] Step 1) Synthesis of methyl 8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate

[0921] Under an ice bath, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.69 g, 25.08 mmol) was added portionwise to a solution of methyl 8-bromo-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (5 g, 16.72 mmol) in dichloromethane (150 mL). The mixture was then allowed to react at room temperature for 6 h. The reaction solution was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate (100 mL) was added at 0°C. The mixture was then stirred at room temperature for 3 h, filtered, and the filter cake was washed with water (50 mL x 3) to give an orange-yellow solid product (4.7 g, 94.64%).

[0922] MS(ESI,pos.ion)m / z:297.15[M+H] + .

[0923] Step 2) Synthesis of 5-bromo-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one

[0924] At 0°C, under N2, lithium aluminum hydride (1.12 g, 29.62 mmol) was added portionwise 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 mixture was allowed to warm to room temperature and stirred for 8 h. The mixture was quenched with water at 0°C, and 1 M hydrochloric acid was added dropwise at this temperature until the pH reached 3-4. Saturated brine was then added, and the mixture was extracted with tetrahydrofuran (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 97 / 5) to give the product as a brown solid (3.36 g, 84.31%).

[0925] MS (ESI, negative ion) m / z: 267.00 [MH] - .

[0926] Step 3) Synthesis of 5-bromo-7-(bromomethyl)-3-methylquinoxalin-2(1H)-one

[0927] To a solution of 5-bromo-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (0.5 g, 1.86 mmol) in acetonitrile (25 mL) was added phosphorus tribromide (0.24 mL, 2.60 mmol) dropwise at 0°C under N2. The mixture was stirred for 5-10 min and then heated to 35°C for 4 h. TLC indicated completion, and the reaction was carried on to the next step without further workup.

[0928] Step 4) Synthesis of 5-bromo-2-(difluoromethoxy)pyridine

[0929] To a solution of 5-bromo-1,2-dihydropyridin-2-one (10 g, 57.47 mmol) in acetonitrile (120 mL) was added sodium carbonate (6.70 g, 63.22 mmol) at room temperature. The mixture was heated to 60°C and stirred for 1 h. (Bromodifluoromethyl)trimethylsilane (14.01 g, 68.96 mmol) was then slowly added and the reaction continued at 60°C with stirring. After completion of the reaction, water (100 mL) was added to the reaction solution, which was then extracted with DCM (150 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product as a yellow solid (11.5 g, 89.33%).

[0930] Step 5) Synthesis of tert-butyl 4-(6-(difluoromethoxy)pyridin-3-yl)piperazine-1-carboxylate

[0931] To a solution of 5-bromo-2-(difluoromethoxy)pyridine (2 g, 8.93 mmol), tert-butyl piperazine-1-carboxylate (1.75 g, 9.38 mmol) and cesium carbonate (5.82 g, 17.86 mmol) in 1,4-dioxane (60 mL) was added Ruphos-Pd-G3 (0.52 g, 0.63 mmol) at room temperature. The mixture was then replaced with N2 and heated to 110°C for overnight reaction. The mixture was filtered through celite and concentrated under reduced pressure. The mixture was separated and purified by silica gel column chromatography (eluent: PE:EtOAc (v / v) = 6 / 1) to give a yellow solid product (2.6 g, 88.42%).

[0932] MS(ESI,pos.ion)m / z:330.20[M+H] + .

[0933] Step 6) Synthesis of 1-(6-(difluoromethoxy)pyridin-3-yl)piperazine

[0934] To a solution of tert-butyl 4-(6-(difluoromethoxy)pyridin-3-yl)piperazine-1-carboxylate (1 g, 3.04 mmol) in ethyl acetate (20 mL) was added a 4M hydrochloric acid solution in dioxane (30.4 mmol) at room temperature and allowed to react overnight. After completion of the reaction, the reaction mixture was directly filtered to obtain a solid product, which was then dried at room temperature to yield a light yellow solid (0.62 g, 89.08%).

[0935] MS(ESI,pos.ion)m / z:230.10[M+H] + .

[0936] Step 7) Synthesis of 5-bromo-7-((4-(6-(difluoromethoxy)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylquinoxalin-2(1H)-one

[0937] To a solution of 5-bromo-7-(bromomethyl)-3-methylquinoxalin-2(1H)-one (0.6 g, 1.81 mmol) in acetonitrile (25 mL) was added potassium iodide (15 mg, 0.091 mmol), 1-(6-(difluoromethoxy)pyridin-3-yl)piperazine (0.62 g, 2.71 mmol), and N,N-diisopropylethylamine (4.79 mL, 28.96 mmol) at room temperature. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, the reaction solution was diluted with dichloromethane, washed with water (20 mL x 3), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 97 / 4) to yield an orange-yellow solid powder (0.42 g, 48.38%).

[0938] MS(ESI,pos.ion)m / z:479.95[M+H] +;

[0939] Step 8) Synthesis of 7-((4-(6-(difluoromethoxy)pyridin-3-yl)piperazin-1-yl)methyl)-3-methyl-5-(prop-1-yn-1-yl)quinoxalin-2(1H)-one

[0940] To a solution of 5-bromo-7-((4-(6-(difluoromethoxy)pyridin-3-yl)piperazin-1-yl)methyl)-3-methylquinoxalin-2(1H)-one (0.2 g, 0.42 mmol) in 1,4-dioxane (15 mL) at room temperature was added tributyl(prop-1-yn-1-yl)tin (0.23 mL, 0.76 mmol), followed by XPhos Pd G2 (0.050 g, 0.063 mmol). The atmosphere was then replaced with nitrogen and the temperature was raised to 90°C for overnight reaction. The reaction mixture was filtered through celite, 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 give a white solid powder (22 mg, 12.02%).

[0941] MS(ESI,pos.ion)m / z:440.19[M+H] + .

[0942] 1 H NMR (400MHz, DMSO-d6) δ7.89-7.84(m,1H),7.54(t,J=73.6,1H),7.56-7.51(m,1H),7.31-7.1 8(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).

[0943] Example 38 N,6-dimethyl-5-(4-((2-methyl-3-oxo-8-(prop-1-en-1-yl)-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0944]

[0945]

[0946] Step 1) Synthesis of tert-butyl 4-(6-(methoxycarbonyl)-2-methylpyridin-3-yl)piperazine-1-carboxylate

[0947] To a solution of methyl 5-bromo-6-methylpyridine-2-carboxylate (5 g, 21.73 mmol), tert-butyl piperazine-1-carboxylate (4.25 g, 22.82 mmol), and Cs2CO3 (14.16 g, 43.46 mmol) in 1,4-dioxane (250 mL) was added Ruphos Pd G3 (0.64 g, 0.76 mmol) at room temperature. After displacing the nitrogen atmosphere, the mixture was heated to 110°C and stirred for 12 hours. The reaction mixture was cooled, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1 / 1) to give the product as a yellow solid (5.7 g, 78.20%).

[0948] MS (ESI, pos.ion) m / z: 336.2 [M+H] + ;

[0949] Step 2) Synthesis of tert-butyl 4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[0950] Methylamine (15.83 g, 509.70 mmol) was added to a solution of tert-butyl 4-(6-methoxycarbonyl)-2-methylpyridin-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 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1 / 1) to give the product as a yellow solid (5.6 g, 98.54%).

[0951] MS (ESI, pos.ion) m / z: 335.2 [M+H] + ;

[0952] Step 3) Synthesis of N,6-dimethyl-5-(piperazin-1-yl)picolinamide

[0953] To a solution of tert-butyl 4-(2-methyl-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (5.6 g, 16.75 mmol) in 1,4-dioxane (20 mL) was added HCl-1,4-dioxane (3.05 g, 83.75 mmol, 4 M) at room temperature, and the reaction was stirred at room temperature for 3 h. 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 afford the product as a yellow solid (3.63 g, 92.52% yield).

[0954] MS (ESI, pos.ion) m / z: 235.2 [M+H] + ;

[0955] Step 4) Synthesis of 5-(4-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide

[0956] To a solution of 5-bromo-7-(bromomethyl)-3-methylquinoxalin-2(1H)-one (0.6 g, 1.81 mmol) in ACN (20 mL) were added 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) at room temperature, followed by heating to 80°C for 3 h. 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 afford the product as a yellow solid (0.21 g, 23.94%).

[0957] MS (ESI, pos.ion) m / z: 485.2 [M+H] + ;

[0958] Step 5) Synthesis of N,6-dimethyl-5-(4-((2-methyl-3-oxo-8-(prop-1-en-1-yl)-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide

[0959] To a solution of 5-(4-((8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (0.2 g, 0.41 mmol) in 1,4-dioxane (20 mL) at room temperature were added tributylstannane (0.24 g, 0.74 mmol) and Xphos Pd G2 (0.048 g, 0.061 mmol). After replacing the nitrogen atmosphere with nitrogen, the mixture was heated to 90°C and stirred for 12 hours. After cooling to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to afford the product as a yellow solid (0.02 g, 10.92%).

[0960] MS (ESI, pos.ion) m / z: 445.3 [M+H] + ;

[0961] 1H NMR (400MHz, DMSO-d6) δ (ppm) 12.35 (s, 1H), 8.42 (s, 1H), 7.79 (d, J = 7.9Hz, 1H), 7.47 (d, J = 8.3Hz, 1H), 7.30 (s, 1H), 7.2 1(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).

[0962] Example 39 N-cyclopropyl-2-fluoro-1'-((2-methyl-3-oxo-8-(prop-1-yn-1-yl)-3,4-dihydroquinoxalin-6-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0963]

[0964] Step 1) Synthesis 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

[0965] To a solution of 5-bromo-7-(bromomethyl)-3-methylquinoxalin-2(1H)-one (0.6 g, 1.81 mmol) in ACN (20 mL) were added 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) at room temperature. The reaction mixture was then heated to 80°C for 3 h. 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 afford the product as a yellow solid (0.9 g, 97.19%).

[0966] MS (ESI, pos.ion) m / z: 512.9 [M+H] + ;

[0967] Step 2) Synthesis of N-cyclopropyl-2-fluoro-1'-((2-methyl-3-oxo-8-(prop-1-yn-1-yl)-3,4-dihydroquinoxalin-6-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0968] 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) was added tributyl(prop-1-yn-1-yl)tin (0.20 g, 0.59 mmol) and Xphos Pd G2 (0.039 g, 0.050 mmol) at room temperature. After replacing the nitrogen atmosphere with nitrogen, the mixture was heated to 90°C and stirred for 12 hours. After cooling to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to afford the product as a yellow solid (0.08 g, 51.13%).

[0969] MS (ESI, pos.ion) m / z: 472.0 [M+H] + ;

[0970] 1 H NMR(400MHz,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).

[0971] Example 40 5-(4-((5-fluoro-2-methyl-3-oxo-8-(prop-1-yn-1-yl)-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0972]

[0973] Step 1) Synthesis of methyl (4-bromo-3-fluoro-2-nitrophenyl)malonate

[0974] 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) was added ethyldiisopropylamine (16.29 g, 126.06 mmol) dropwise at 0°C, followed by warming to room temperature overnight. The reaction was terminated, diluted with DCM, washed three times with water (50 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 6 / 1) to afford the product as a yellow solid (6 g, 44.47%).

[0975] MS(ESI,pos.ion)m / z:321.00[M+H] + .

[0976] Step 2) Synthesis of 7-bromo-8-fluoro-3-methyl-3,4-dihydroquinoxaline-2(1H)-one

[0977] To a solution of methyl (4-bromo-3-fluoro-2-nitrophenyl)malonate (12 g, 37.37 mmol) in acetic acid (100 mL) was added iron powder (8.35 g, 149.48 mmol) with stirring at room temperature. The reaction was allowed to proceed at 70°C and monitored by TLC. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (300 mL). The insoluble material was filtered off, and the organic phase was washed with water (100 mL x 1) and saturated brine (100 mL x 3) to obtain a yellow solid product (9.2 g, 95.02%).

[0978] MS(ESI,pos.ion)m / z:259.00[M+H] + .

[0979] Step 3) Synthesis of 7-(((tert-butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-3,4-dihydroquinoxalin-2(1H)-one

[0980] To a solution of 7-bromo-8-fluoro-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (9.2 g, 35.51 mmol) and tert-butyldimethyl((tributyltinyl)methoxy)silane (20.10 g, 46.16 mmol) at room temperature was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (1.40 g, 1.78 mmol). The atmosphere was then replaced with nitrogen and the reaction was heated to 90°C overnight. The reaction was terminated, the reaction solution was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 4 / 1) to afford the product as a light yellow solid (8.1 g, 70.30%).

[0981] MS(ESI,pos.ion)m / z:325.20[M+H] + .

[0982] Step 4) Synthesis of 5-bromo-7-(((tert-butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-3,4-dihydroquinoxalin-2(1H)-one: To a solution of 7-(((tert-butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (8.1 g, 24.96 mmol) and sodium bicarbonate (3.15 g, 37.44 mmol) in 1,4-dioxane (100 mL) was added N-bromosuccinimide (4.66 g, 26.21 mmol) at 0°C under N2, and the mixture was then warmed to room temperature. TLC indicated that the reaction was complete. The reaction was stopped and quenched by adding saturated aqueous sodium thiosulfate solution (100 mL). The product was extracted with EtOAc (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 4 / 1) to give a yellow solid product (9.8 g, yield 97.32%).

[0983] MS(ESI,pos.ion)m / z:402.90[M+H] + .

[0984] Step 5) Synthesis of 7-(((tert-butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-5-(prop-1-yn-1-yl)-3,4-dihydroquinoxalin-2(1H)-one

[0985] To a solution of 5-bromo-7-(((tert-butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (2 g, 4.96 mmol) in tributyl(prop-1-ynyl)stannane (2.12 g, 6.45 mmol) was added XPhos-G2-Pd (0.20 g, 0.25 mmol) at room temperature, followed by heating to 90°C for 12 h. The reaction was terminated, diluted with DCM (100 mL), filtered through celite, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 9 / 1) to afford the product as a light yellow solid (1.6 g, 89.01%).

[0986] MS(ESI,pos.ion)m / z:363.20[M+H] + .

[0987] Step 6) Synthesis of 7-(((tert-butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-5-(prop-1-yn-1-yl)quinoxalin-2(1H)-one

[0988] A solution of 7-(((tert-butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-5-(prop-1-yn-1-yl)-3,4-dihydroquinoxaline-2(1H)-one (4 g, 11.03 mmol) in dichloromethane (120 mL) was cooled to 0°C, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.75 g, 12.13 mmol) was added, and the temperature was then raised to room temperature for overnight reaction to stop the reaction. The reaction solution was concentrated under reduced pressure, and saturated NaHCO3 was slowly added at room temperature until no bubbles were generated. The reaction solution was stirred at room temperature for 6 h, filtered, and the filter cake was washed with water until the filtrate was colorless. The obtained filter cake was dissolved in methanol (50 mL) and concentrated under reduced pressure to give a light yellow solid product (3.8 g, 95.53%).

[0989] MS(ESI,pos.ion)m / z:361.20[M+H] + .

[0990] Step 7) Synthesis of 8-fluoro-7-(hydroxymethyl)-3-methyl-5-(prop-1-yn-1-yl)quinoxaline-2(1H)-one

[0991] To a solution of 7-(((tert-butyldimethylsilyl)oxy)methyl)-8-fluoro-3-methyl-5-(prop-1-yn-1-yl)quinoxalin-2(1H)-one (3.8 g, 10.54 mmol) in tetrahydrofuran (20 mL) was added tetrabutylammonium fluoride (5.51 g, 21.08 mmol) dropwise at room temperature. The mixture was then allowed to react at room temperature for 7 h. The reaction was quenched by the addition of saturated brine, and ethyl acetate (200 mL) was added. The mixture was washed with water (30 mL x 3), and the organic phase was collected and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to afford the product as a light yellow solid (1 g, 38.53%).

[0992] MS (ESI, negative ion) m / z: 245.10 [MH] - .

[0993] Step 8) Synthesis of 7-(bromomethyl)-8-fluoro-3-methyl-5-(prop-1-yn-1-yl)quinoxalin-2(1H)-one

[0994] To a solution of 8-fluoro-7-(hydroxymethyl)-3-methyl-5-(prop-1-yn-1-yl)quinoxalin-2(1H)-one (0.5 g, 2.03 mmol) in dichloromethane (40 mL) was added triphenylphosphine (0.80 g, 3.04 mmol) followed by carbon tetrabromide (1.01 g, 3.04 mmol) in portions under ice-cooling. The reaction was allowed to react for 1 h under ice-cooling. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 3 / 2) to give the product as a white solid (0.4 g, 63.72%).

[0995] Step 9) 4) Synthesis of 5-(4-((5-fluoro-2-methyl-3-oxo-8-(prop-1-yn-1-yl)-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0996] To a solution of 7-(bromomethyl)-8-fluoro-3-methyl-5-(prop-1-yn-1-yl)-1,2-dihydroquinoxaline-2-one (0.08 g, 0.26 mmol) in acetonitrile (6 mL) were added potassium iodide (0.0022 g, 0.013 mmol), ethyldiisopropylamine (0.067 g, 0.52 mmol), and N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (0.086 g, 0.39 mmol) at room temperature, and the temperature was then raised to 80°C for reaction. The reaction was monitored by TLC. The reaction was stopped, cooled to room temperature, filtered, and the resulting solid was washed with acetonitrile (10 mL). The filter cake was purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to give an off-white solid product (20 mg, 17.23%).

[0997] MS(ESI,pos.ion)m / z:449.21[M+H] + .

[0998] 1 H NMR (400MHz, DMSO-d6) δ12.51(s,1H),8.43–8.37(m,1H),8.25(d,J=2.8Hz,1H),7.81(d,J=8.8Hz,1H),7.40–7. 32(m,2H),3.66(s,2H),3.31–3.24(m,4H),2.77(d,J=4.8Hz,3H),2.59–2.53(m,4H),2.43(s,3H),2.12(s,3H).

[0999] Example 41 N-cyclopropyl-2-fluoro-1'-((5-fluoro-2-methyl-3-oxo-8-(prop-1-yn-1-yl)-3,4-dihydroquinoxalin-6-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[1000]

[1001] To a 25 mL bottle, 7-(bromomethyl)-8-fluoro-3-methyl-5-(prop-1-yn-1-yl)-1,2-dihydroquinoxaline-2-one (0.095 g, 0.31 mmol), N-cyclopropyl-6-fluoro-5-(1,2,3,6-tetrahydropyridin-4-yl)pyridine-2-carboxamide hydrochloride (0.13 g, 0.43 mmol), and potassium iodide (0.010 g, 0.062 mmol) were added. The mixture was dissolved in ACN (4 mL) with stirring, cooled, and DIPEA (0.16 mL, 0.93 mmol) was slowly added dropwise in an ice bath. The mixture was stirred evenly and heated to 80°C for 2 h. After cooling to room temperature, solid precipitated under stirring. The filter cake was collected by filtration, washed with acetonitrile (1 mL×3), MTBE (4 mL×3), and water (4 mL×3), and dried in vacuo to give a white solid (0.117 g, yield 77.77%).

[1002] MS(ESI,pos.ion)m / z:490.00[M+H] + ;

[1003] 1 H NMR (400MHz, DMSO-d6) δ12.52(s,1H),8.62(s,1H),7.98(s,s,2H),7.36(s,1H),6.23(s,1H),3. 71(s,2H),3.16(s,2H),2.87(s,2H),2.68(s,3H),2.44–2.36(m,3H),2.11(s,3H),0.66(s,4H).

[1004] Example 42: N-cyclopropyl-1'-((8-(difluoromethoxy)-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-2-fluoro-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[1005]

[1006]

[1007] Step 1) Synthesis of methyl 4-chloro-3-(difluoromethoxy)-5-nitrobenzoate

[1008] To a 50 mL flask, methyl 4-chloro-3-hydroxy-5-nitrobenzoate (1 g, 4.32 mmol), sodium 2-chloro-2,2-difluoroacetate (0.86 g, 5.62 mmol), and potassium carbonate (0.66 g, 4.75 mmol) were added at room temperature. Dimethylformamide (15 mL) was then added, and the temperature was raised to 80°C for 2 h. The reaction was monitored for completion by TLC. EtOAc was added to dilute the reaction solution, followed by extraction with water (80 mL). The organic phase was washed with saturated sodium chloride solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1 / 10) to afford light green crystals (0.48 g, 39.48%).

[1009] MS(ESI,pos.ion)m / z:282.00[M+H] + .

[1010] Step 2) Synthesis of methyl 3-(difluoromethoxy)-4-((1-methoxy-1-oxopropyl-2-yl)amino)-5-nitrobenzoate

[1011] To a solution of methyl 4-chloro-3-(difluoromethoxy)-5-nitrobenzoate (3.33 g, 11.83 mmol) in 1,4-dioxane (60 mL) at room temperature were added DL-alanine methyl ester hydrochloride (3.30 g, 23.66 mmol) and ethyldiisopropylamine (6.12 g, 47.32 mmol). The mixture was then heated to 100°C and allowed to react overnight. The reaction was terminated, cooled to room temperature, and the reaction mixture was evaporated to dryness. The residue was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 10 / 1) to yield a yellow viscous liquid (2.7 g, 65.56%).

[1012] MS(ESI,pos.ion)m / z:349.00[M+H] + .

[1013] Step 3) Synthesis of methyl 8-(difluoromethoxy)-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate

[1014] To a solution of methyl 3-(difluoromethoxy)-4-((1-methoxy-1-oxopropan-2-yl)amino)-5-nitrobenzoate (2.78 g, 7.98 mmol) in water (15 mL) and methanol (30 mL) at room temperature were added iron powder (2.67 g, 47.88 mmol) and ammonium chloride (2.56 g, 47.88 mmol). The mixture was then heated to 70°C and allowed to react for 4.5 h. The reaction was terminated, and the solution was cooled to room temperature and diluted with dichloromethane / methanol (v / v) = 10 / 1, 100 mL. The solution was filtered through celite and extracted with saturated brine and dichloromethane / methanol (v / v) = 10 / 1, 100 mL x 3. The residue was purified by ...

Claims

1. A compound, which is a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I), in: X is CR x or N; is a 3-12 membered heterocyclic group; 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)-(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; Each R 2a and R 2b 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, C1-C6 cyanoalkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 10 Aryl or 5-10 membered heteroaryl; R 2 is -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, C 2- 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 Aryl-L- or 5-10 membered heteroaryl-L-; wherein said R 2 Unsubstituted or substituted with 1, 2, 3, 4 or 5 R w replace; Each -L- is independently a bond, -NR n -, -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; Each R n and R n1 are independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic, C6-C 10 Aryl or 5-10 membered heteroaryl; Each R a and R b are 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; Each R 3 , R 3a and R 3b 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; 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 membered heterocyclyl, C6-C 10 Aryl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic, C6-C 10 Aryl and 5-10 membered heteroaryl are independently 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; Each R x and R z are 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 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 Aryl or 5-10 membered heteroaryl; n is 1, 2, 3, 4, 5 or 6; Wherein, the compound represented by the formula (I) does not include the following compounds:

2. The compound according to claim 1, wherein for in, * indicates the -CH2- on the left, and ** indicates the pyridyl on the right.

3. The compound according to claim 1 or 2, wherein R 1 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-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; Each R 3 , R 3a and R 3b 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 or C1-C4 hydroxyalkyl; Each R x and R z are 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.

4. The compound according to any one of claims 1 to 3, wherein 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, -CH2C F3, -CH2CF2CHF2, methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl; Each R 3 , R 3a and R 3b 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)-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; Each R x and R z and independently represent 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.

5. The compound according to any one of claims 1 to 4, wherein R 4 is 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 membered heterocyclyl, C6-C 10 Aryl or 5-6 membered heteroaryl, wherein The C1-C4 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, C6-C 10 Aryl and 5-6 membered heteroaryl are independently optionally 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.

6. A compound according to any one of claims 1 to 5, wherein R 4 is H, 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, -OCH2 CF2CHF2, methylthio, ethylthio, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein The methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl are independently and optionally substituted by 1, 2, 3, 4 or 5 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 are substituted.

7. The compound according to any one of claims 1 to 6, wherein Each R 2a and R 2b 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, C1-C4 cyanoalkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C 10 Aryl or 5-6 membered heteroaryl; Each R n and R n1 are independently H, D, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic, C6-C 10 Aryl or 5-6 membered heteroaryl; Each R a and R b are 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.

8. The compound according to any one of claims 1 to 7, wherein 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, C 2- 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 membered heterocyclyl-L-, C6-C 10 Aryl-L- or 5-6 membered heteroaryl-L-; wherein said R 2 Unsubstituted or substituted with 1, 2, 3, 4 or 5 R w replace; Each R w 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 membered heterocyclyl, C6-C 10 Aryl or 5-6 membered heteroaryl.

9. The compound according to any one of claims 1 to 8, wherein Each R 2a and R 2b 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-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 , isopropyl, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyanomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; Each R n and R n1 is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; Each R a and R b and independently represent 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.

10. The compound according to any one of claims 1 to 9, wherein 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-, aziridine-L-, oxetanyl-L-, azetidinyl -L-, tetrahydrofuranyl-L-, pyrrolidinyl-L-, tetrahydropyranyl-L-, piperidinyl-L-, piperazinyl-L-, morpholinyl-L-, phenyl-L-, naphthyl-L-, pyrrolyl-L-, furanyl-L-, thienyl-L-, pyrazolyl-L-, imidazolyl-L-, thiazolyl-L-, oxazolyl-L-, triazolyl-L-, tetrazolyl-L-, pyridinyl-L-, pyrimidinyl-L-, pyrazinyl-L- or pyridazinyl-L-; wherein said R 2 Unsubstituted or substituted with 1, 2, 3, 4 or 5 R w replace; Each R w 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 , 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl.

11. A compound according to any one of claims 1 to 10, which is a compound represented by formula (II) or formula (III), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound represented by formula (II) or formula (III), in, Each R 1 , R 2 , R 2a , R 2b , R 3 , R z , R 4 and n have the meanings as defined in any one of claims 1-10.

12. A compound having one of the following structures or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound having one of the following structures:

13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12; and The pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.

14. Use of the compound according to any one of claims 1 to 12 or the pharmaceutical composition according to claim 13 in the preparation of a medicament for preventing, treating or alleviating a disease mediated by PARP1; in, The disease mediated by PARP1 is cancer, neurodegenerative disease, cardiovascular disease, ischemic disease, diabetic neuropathy, reperfusion injury, osteoarthritis, osteoporosis, inflammatory disease or metabolic disease.

15. The method of claim 14, wherein the cancer is laryngeal cancer, esophageal cancer, gastric cancer, intestinal cancer, liver cancer, kidney cancer, lung cancer, brain cancer, head and neck cancer, squamous cell carcinoma, lymphatic system cancer, thyroid cancer, bladder cancer, ovarian cancer, cervical cancer, prostate cancer, genitourinary tract cancer, breast cancer, blood cancer, small cell lung cancer, lung adenocarcinoma, pancreatic cancer, colon cancer, glioblastoma and / or monocytic leukemia.

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